Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-cyclopropyl-4-methoxybenzoic acid (200 mg), toluene (2 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.10 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained resiue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S)N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223-224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14]2.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:15]=[CH:14]2
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(-c3cccnc3N)ccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (95 mg) was added to a suspension of 3-bromopyridin-2-amine (713.7 mg), 6-methoxynaphthalen-2-ylboronic acid (1000 mg) and sodium carbonate decahydrate (2361 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr and at 70° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the volatiles were removed in vacuo to give the title compound (1194 mg) as a crude orange solid. This product was subjected to the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]([N:17]1[CH2:22][C:21]([CH3:23])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:19]2[N:34]=[CH:35][C:36]([C:37]#[N:38])=[C:18]12)=[O:16]>CC(C)=O>[CH3:23][C:21]1[CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[C:18]2[N:19]([N:34]=[CH:35][C:36]=2[C:37]#[N:38])[C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CC(C)=O
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(c3ccccn3)CC2)C1
Yield: 100.2 %

Procedure:
A mixture of 2 g of 1-(2-pyridinyl)piperazine, 2 g of 4-(chloroacetyl)-4,5-dihydro-6-methyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 60 ml of acetone was refluxed on a steam bath for 8 hours and then evaporated. The residue was stirred in water and the solid collected. The solid was dissolved in dilute hydrochloric acid, filtered and the filtrate gasified with dilute ammonium hydroxide. The solid was collected, washed with water and dried in vacuo, giving 2.67 g of the desired product, mp 132°-134° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.[CH2:19]([S:21][C:22]1[C:30](O)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][NH:26]2)[CH3:20]>>[CH2:19]([S:21][C:22]1[C:30]([O:1][C@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:3]2)=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][NH:26]2)[CH3:20]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Reactant: CCSc1c(O)ccc2[nH]ncc12
Product: CCSc1c(O[C@H]2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12

Procedure:
The title compound was synthesized by carrying out reaction according to the method described in Example 610, except for using the cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 326, (d) and the 4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as starting materials.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:15]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (10.8 g, 1.2 eq, 58.0 mmol) and oxetan-3-one (3.5 g, 1.0 eq, 14 mmol) in 1,2-dichloroethane (100 mL) was stirred at room temperature. Sodium triacetoxyborohydride (16.4 g, 1.6 eq, 77.3 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (200 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate in 84% yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19](=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)C1=O)([CH3:3])[CH3:2].C(OC1C=CC=CC=1O)(C)C.C([O-])([O-])=O.[K+].[K+].BrCCC[N:47]1[C:55](=[O:56])C2[C:49](=[CH:50][CH:51]=[CH:52]C=2)[C:48]1=O>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:19][C:18]1[CH:17]=[C:16]([C:55]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:56])[CH:15]=[CH:14][CH:13]=1)([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)Oc1ccccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: CC(C)Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1OCCCNCc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
2-[3-(2-Isopropoxy-phenoxy)-propyl]-isoindole-1,3-dione. To a solution of 2-isopropoxy-phenol (0.50 g, 3.3 mmol) in DMF (5 mL) was added K2CO3 (2.3 g, 17 mmol), and the resulting suspension was stirred at 25° C. for 15 min. A solution of 2-(3-bromo-propyl)-isoindole-1,3-dione (0.97 g, 3.6 mmol) in DMF (2 mL) was added, and the reaction mixture was heated to 80° C. for 18 h. The mixture was filtered, and the filtrate was diluted with 1:1 Et2O/EtOAc (100 mL), washed with H2O (2×20 mL) then brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (5-20% EtOAc/hexanes) to provide the desired product (0.956 g, 87%). 1H NMR (400 MHz, CDCl3): 7.87-7.82 (m, 2H), 7.73-7.69 (m, 2H), 6.93-6.86 (m, 4H), 4.46 (hept, J=6.1 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.92 (t, J=7.1 Hz, 2H), 2.20 (quint, J=6.4 Hz, 2H), 1.33 (d, J=6.1 Hz, 6H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:20][CH:19]([CH2:21][OH:22])[CH2:18][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: OCC1CO1
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCC(O)CO)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 59.9 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (17.4 g, 68.7 mmol) in N,N-dimethylformamide (200 ml) was added glycidol (5.0 ml, 75 mmol) and cesium carbonate (1.55 g, 4.76 mmol). The suspension was heated to 70° C. for 17 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (13.48 g, 41.17 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 1.30 (m, 6H), 2.0-2.1 (m, 2H), 2.24 (m, 1H), 2.49-2.62 (m, 3H), 2.71 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.75 (s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 328 [M+H]+, 350 [M+Na]+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](O)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a suspension of 2-Morpholin-4-yl-5-nitro-benzoic acid (4.0 g, 16 mmol) in toluene were added 2 drops of DMF and thionylchloride (5.7 ml, 79.3 mmol). The mixture was heated to 80° C. for 50 minutes. The solvent was removed in vacuo, and the resulting solid was stirred in ether, filtered and dried to provide the title compound (4.0 g, 93%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3-Trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.86 min; [M+H]+=505.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.9 %

Procedure:
To a solution of 4-pyridin-4-yl-phenylamine (142 mg, 0.83 mmol) in tetrahydrofurane (5 mL) was added drop wise under benzoyl isothiocyanate (124 uL, 0.88 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (346 mg, 2.5 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (291 mg, 152%). MS ISP (m/e): 230.2 (56) [(M+H)+], 213.0 (100) [(M-NH3+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.86 (s, 1H, NH), 8.61 (d, 2H), 7.79 (d, 2H), 7.69 (d, 1H), 7.61 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH3:22]>C(OC(=O)C)(=O)C>[CH3:21][C:18]1[CH:19]=[CH:20][N:15]=[C:16](/[CH:22]=[CH:11]/[C:10]2[CH:13]=[CH:14][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH:17]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccnc(C)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Temperature: 150 °C
Yield: 45.3 %

Procedure:
A mixture of 4-phenyl benzaldehyde (6.45 g), 2,4-lutidine (7.59 g) and acetic anhydride (10 ml) was heated at a bath temperature of 150° C. for 12 hr, and refluxed under heating for 12 hr. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-5/1) to give the objective compound (4.35 g) as a yellow solid.
Reaction SMILES: N[C:2]1SC=C(/C(=N/OC)/C(O)=O)N=1.O.ON1C2C=CC=CC=2N=N1.C1(N=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)CCCCC1>CN(C)C=O>[CH3:2][N:33]([CH3:32])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 254 %

Procedure:
A mixture of 1.00 g (5.00 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid, 0.76 g (5.00 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.14 g (5.50 mmol) of dicyclohexylcarbodiimide and 20 ml of N,N-dimethylformamide was stirred at room temperature for 2 hours. The obtained white solid was filtered and the filtrate was cooled to 0° C. The filtrate was added to mixed solution of 2.5 g (5.00 mmol) of 7-amino-3-(2,3-cyclopenteno-4-carbamoyl-1-pyridinium)methyl-3-cephem-4-carboxylate hydroiodic acid obtained in Preparation Example 24, 10 ml of N,N-dimethylformamide and 1.6 ml (12.70 mmol) of N,N-dimethylaniline. The mixture was stored at room temperature overnight and the precipitate was removed therefrom. The residue was dropped into 500 ml of diethylether with stirring. The precipitate was filtered, triturated with 100 ml of acetone and filtered again. The crude product thus obtained was dissolved in 100 ml of water and insoluble material was discarded by filtration. The resultant was freeze-dried to obtain 1.0 g of the same compound as obtained in Method a (yield: 37%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[CH:16].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(O)(=O)C>ClCCCl>[CH2:25]([N:27]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[CH:16])=[CH:18][CH:19]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#Cc1ccc(CN(CC)CC)cc1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added to a solution of 4-ethynylbenzaldehyde (0.50 g, 3.84 mmol) in 1,2-dichloroethane (18.75 mL) at rt. Diethylamine (0.61 mL, 5.76 mmol) and acetic acid (0.12 mL, 1.92 mmol) were then added under N2 atmosphere to the mixture at rt and the reaction was stirred for 18 h. The reaction was quenched with sat. sodium bicarbonate solution (10 mL) and the mixture was stirred for 15 min. Dichloromethane (18.75 mL) was then added and the layers were separated. The aqueous layer was extracted using dichloromethane (10 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under vacuum at 40° C./200 mbar. The resultant oily residue was purified by silica gel column chromatography using dichloromethane: methanol (100 to 90:10) gradient to give the title compound as pale yellow thick oil (0.455 g, 63.2%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 3.78 (s, 2H), 3.08 (s, 1H), 2.72-2.66 (m, 4H), 1.13 (t, J=7.2 Hz, 6H); MS ESI 187.9 [M+H]+, calcd for [C13H7N+H]+ 187.14.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH2:8][CH2:7][C:6]1=[O:21])(=[O:4])[CH3:3].[O:22]1CCCC1>>[C:2]([NH:5][CH2:14][CH2:13][CH2:12][C:11]([C:10]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=1[CH2:8][CH2:7][C:6]([OH:21])=[O:22])=[O:15])(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 ml of 2N hydrochloric acid are added to a solution of 103 g (0.35 mol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 1 l of tetrahydrofuran and the mixture is stirred at room temperature overnight. The mixture is concentrated in a vacuum, treated with methylene chloride and extracted twice with 2N sodium hydroxide solution; the aqueous phase is then acidified with 6N hydrochloric acid and extracted with methylene chloride. Removal of the solvent by distillation in a vacuum and chromatography on silica gel with methylene chloride/methanol (20:1) yields 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid with melting point 90°-92°.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([OH:26])[C:23]([OH:25])=[O:24].[CH3:28][C:29]1[CH:33]=[CH:32][S:31][C:30]=1[C:34](Cl)=[O:35].Cl.C(Cl)Cl>N1C=CC=CC=1>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:34]([C:30]1[S:31][CH:32]=[CH:33][C:29]=1[CH3:28])=[O:35])[C:23]([OH:25])=[O:24]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Reactant: Cc1ccsc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccsc1C(=O)O[C@]1(C(=O)O)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(6S,9S,10S,11S,13S,16R,17R)-9,11-Epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (20 g) is dissolved in pyridine (50 mL) and cooled to 0° C. 3-Methylthiophene-2-carbonyl chloride (9.39 g) is added and the reaction is stirred at room temperature. After 2 hours, the reaction mixture is added dropwise to a vigorously stirred solution of 6M HCl. DCM is added, the phases are separated and the organic phase is washed with water and brine. After drying over magnesium sulphate, evaporation is followed by flash column chromatography on silica gel eluting with DCM-methanol (25:1) to afford 3-methylthiophene-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 0.90 (3H, d), 0.95 (3H, s), 1.40 (3H, s), 2.40 (3H, s).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>C(O)C.CCCCCCC>[OH:5][P:1]([O:4][P:1]([OH:4])([OH:3])=[O:2])(=[O:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: O=P(O)(O)O
Agent: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: CCCCCCC
Product: O=P(O)(O)OP(=O)(O)O
Temperature: 25 °C

Procedure:
A solution of phosphoric acid (13.2 mg) in ethanol (0.05 mL) was added to a mixed solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (50 mg) in heptane (0.6 mL)-ethanol (0.15 mL) at room temperature. The reaction solution was stirred at room temperature, and the precipitated solid was collected by filtration through a glass filter. The solid was washed with heptane-ethanol (3:1) and then dried under reduced pressure at room temperature to obtain 37.6 mg of the title compound as white solid crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[CH3:29]>CN(C=O)C.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:23][C:22]=1[CH3:29]
Reactant: Cc1cc(CCl)ccc1Br
Reactant: COC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To flask containing methyl 3-(3-hydroxyphenyl)propanoate (available from Aagile Labs Division of Tyger Scientific) (0.25 g, 1.387 mmol) and cesium carbonate (0.5876 g, 1.804 mmol) in DMF (8 mL), was added 1.2 (0.3654 g, 1.665 mmol). The resulting mixture was then stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/hexane) to provide 1.3 (0.4575 g, 90.78% yield). MS ESI (pos.) m/e: 382.0 (M+H2O)+.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Li+].[Li+].[Li+]>[N+]([O-])([O-])=O.[Co+2].[N+]([O-])([O-])=O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Agent: [Li+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Lithium citrate and cobalt nitrate were mixed at a mol ratio of 1:3 to obtain a mixture, citric acid was added to the mixture, and the resultant was dissolved in ion-exchanged water to obtain a solution. The solution was sprayed in an air stream of 200° C. to obtain a Li-Co oxide precursor fine powder.