Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.NO.[N:27]1C=CC=CC=1.C(OCC)(=O)C>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:27])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (8.0 g), hydroxylamine hydrochloride (3.45 g) and pyridine (28 ml) are dissolved in ethanol (140 ml), and the mixture is stirred at 80° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a 1N-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100 ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and at 50° C. overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50 g). MS (m/z): 324 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[N:18]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH:9]=3)=[O:14])[CH2:31][CH2:32]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: COc1cccc2oc(C(=O)O)cc12
Agent: Cl
Product: COc1cccc2oc(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Methoxy-benzofuran-2-carboxylic acid and amine 5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>O1CCCC1>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCOc1ncncc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of 4-ethoxypyrimidine-5-amine (1.00 g, 7.19 mmol) and pyridine (1.74 ml, 21.6 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.49 ml, 10.8 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (1.73 g, 76.5%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N12CCCN=C1CCCCC2>CS(C)=O>[Br:1][CH:2]=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CC(Br)(CBr)c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CC(=CBr)c1ccccc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
A solution of 1,2-dibromo-2-phenyl-3-phthalimidopropane (1.27 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.51 g) in dimethyl sulfoxide (DMSO, 50 ml) is heated at 90° for 16 hours. The solution is cooled, diluted with ice-water, and exhaustively extracted with ether. The orange oil (0.98 g) is chromatographed on silica gel (75 g) with 20% ethyl acetate in light petroleum as eluent to give a colorless mass which is crystallized from n-hexane/dichloromethane to give 1-bromo-2-phenyl-3-phthalimidopropene (0.66 g): colorless plates; m.p. 128°-129°;
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[CH2:19]([N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(C(F)(F)F)=Nc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(Cc2ccccc2)C(C(F)(F)F)=Nc2ccccc2N1Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a solution of 4-trifluoromethyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one(3.0 g, 13.1 mmol) in N,N-dimethylformamide(20 mL) was added sodium hydride (content 60%, 1.1 g, 27.5 mmol), and the mixture was stirred for 15 minutes. To the mixture was added benzyl bromide (4.7 g, 27.5 mmol), which was stirred for further 30 minutes. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The concentrate was crystallized from ethyl acetate-hexane to give 3.3 g of the titled compound. Yield 61%. m.p. 150°-151° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:4](=[O:28])[CH2:3]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Reactant: Brc1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
To a stirring solution of 26.6 g (69.7 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 46, in 1 L DMF is added 13.3 g (209 mmol, 3 equiv) of Cu powder, 13.7 g (139 mmol, 2 equiv) of potassium acetate and 13.4 mL (139 mmol, 2 equiv) of 3-bromopyridine. The reaction is heated to 120° C. After 5 h, an additional 13 g (133 mmol) of potassium acetate and 15 mL (156 mmol) of 3-bromopyridine were added, and the reaction is allowed to stir overnight. After ca. 18 h, an additional 15 g (236 mmol) Cu and 5 g (51 mmol) potassium acetate were added, and stirring is continued for an additional 24 h. The reaction is then allowed to cool, and is filtered through celite, rinsing with ethyl acetate. The organics were extracted with 10% NH4OH, the twice with water. The aqueous layer is extracted with EtOAc/ethyl ether. The combined organics were dried (MgSO4) filtered and concentrated in vacuo to afford an oil. This is purified by silica gel flash chromatography to afford 15.8 g of the title compound as a white powder as well as 1.5 g of recovered unreacted starting material: 1H NMR (CDCl3, 400 MHz) δ8.68 (s, br, 2H), 7.86 (d, 1H, J=7.8), 7.36 (d, 2H, J=7.6) 7.27-7.10 (m, 6H ) 6.95 (t, 2H, J=7.6) 6.84 (d, 1H, J=7.1) 4.95 (m, 1H), 4.23 (s, br, 2H) 3.82 (s, 3H) 3.53 (dd, 2H, J=12.2, 44) 1.04 (dd, 6H, J=2.4, 6.8); low resolution MS (FAB)m/e (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[CH:2].[C:12]([O:16][C:17](N1C2C(=CC=C(CCOC3C=C4C(=CC=3)NC=C4)N=2)CCC1)=[O:18])(C)(C)[CH3:13]>>[CH2:12]([O:16][C:17](=[O:18])[C:2]#[C:1][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[CH3:13]
Reactant: C#Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C#Cc1ccc2c(c1)OCO2
Yield: 54 %

Procedure:
The title compound was synthesized from 5-ethynyl-benzo[1,3]dioxole and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 23, step (c), in 54% yield. 1H NMR (CDCl3) δ7.16 (dd, 1H, J=1.6, 8.1 Hz), 7.00 (d, 1H, J=1.6 Hz,), 6.80 (d, 1H, J=8.1. Hz,), 6.02 (s, 2H), 4.29 (q, 2H, J=7.2 Hz,), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][CH:18]=[C:5]12.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24]Cl)[CH3:21]>CN(C)C=O>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]2=[CH:18][S:17][CH:16]=[C:6]2[C:7]1=[O:15]
Reactant: CN(C)CCCCl
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.3 g. of 55% sodium hydride-mineral oil dispersion and 0.35 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.45 g. of dimethylaminopropyl chloride and stirring at room temperature is continued for 18 hours. The reaction mixture is cooled, quenched with water, acidified, decolorized and filtered. The filtrate is made alkaline and extracted with chloroform. The dried chloroform extracts are concentrated under reduced pressure to give an oil which is crystallized by dissolving in boiling hexane and a minimal volume of ethyl acetate and cooling to give off-white crystals, m.p. 52°-56°C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.S(N=[N+]=[N-])(C(F)(F)F)(=O)=O.Cl.N[CH:32]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:33]([O:35][CH3:36])=[O:34]>O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH:32]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:33]([O:35][CH3:36])=[O:34])=[N+:2]=[N-:3]
Reactant: COC(=O)C(N)CCCCNC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CCCCNC(=O)OCc1ccccc1)N=[N+]=[N-]
Yield: 95.7 %

Procedure:
Following the method described by Aubé and coworkers, supra, a solution of NaN3 (0.88 g, 13.7 mmol) in H2O (2.5 mL) was cooled to 0° C. and CH2Cl2 (4 mL) was added. Whilst the mixture was stirring vigorously, Tf2O (0.47 mL, 2.26 mmol) was added dropwise. The resulting solution was stirred for an additional 2 h. The mixture was then placed in a separating funnel, and the organic layer was removed. The aqueous phase was extracted further with CH2Cl2 (2×3 mL). The organic layers were combined, washed with saturated Na2CO3, dried over Na2SO4(s), and filtered. The resulting solution of TfN3 was added dropwise to solution of methyl 2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoate hydrochloride salt (0.46 g, 1.40 mmol) and DMAP (0.75 g, 6.16 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred overnight under Ar(g). The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography, eluting with 20% EtOAc/hexanes, to give azide 2f as an oil (0.43 g, 1.34 mmol, 96% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:30](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:6])=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To a solution of trimethylsilylethyl acetoacetate (10.6 g, 50.0 mmol) and triethylamine (7.10 mL, 51.5 mmol) in acetonitrile (85 mL) was added in an ice-bath p-toluenesulfonyl azide (10.0 g, 50.7 mmol) and the reaction mixture stirred at room temperature for 20 h. After evaporation of the solvent in vacuo, the residue was extracted with Et2O (90 mL) and this extract was washed with a solution of KOH (3.0 g) in H2O (83 mL) and again a solution of KOH (0.9 g) in H2O (30 mL), then brine, and dried (Na2SO4). Evaporation of the solvent in vacuo gave 11.6 g of a crude oil which was purified by column chromatography (SiO2, 150 g) eluting with 20% EtOAc/Hexanes, to obtain 9.65 g (42.3 mmol, yield 84.5%) of the title compound as yellowish oil: Rf 0.44 (20% EtOAc/Hex); ir (neat)νmax : 2130 (C=N2), 1715 (ester), and 1660 (ketone) cm-1 ; uv (CH2Cl2)λmax : 257 nm (ε7200); 1Hmr (CDCl3)δ: 0.07 (9H, s, SiMe3), 1.03 (2H, `t` J=8 Hz, CH2Si), 2.47 (3H, s, COCH3), and 4.30 (2H, `t` J=8 Hz, CO2CH2 ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32](SC)=[N+:31]([CH3:36])[C:30]=2[CH:37]=1.C(N(CC)CC)C>CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:32][N:31]([CH3:36])[C:30]=2[CH:37]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CSc1sc2ccc(Cl)cc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1NN(c2ccccc2)C(=O)C1=S1CN(C)c2cc(Cl)ccc21
Reaction time: 1.5 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.51 g,)) was mixed with 3.5 g (0.0087 mol) 5-chloro-2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (0.89 g,) was added. The mixture was stirred for 1.5 hours, then filtered and washed with methanol. After drying the yield was 2.75 g (89%), mp 206° C., λmax=379 (ε=26,000).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.BrC1C=CC(Br)=CN=1.C[O-].[Na+].[C:21]([O-])(O)=[O:22].[Na+]>CO>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:21]=[O:22])[CH:7]=[N:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: COc1cncc(Br)c1
Agent: Brc1ccc(Br)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(C=O)c1
Yield: 61 %

Procedure:
5-Bromo-3-methoxypyridine. To a stirred solution of 2,5-dibromopyridine (2.188 g, 9.2 mmol) in anhydrous MeOH (10 mL) was added NaOMe (10 mL of 25% NaOMe in MeOH, 42 mmol). The mixture was refluxed for 3 days and then poured into a stirred cold aqueous 5% NaHCO3 (75 mL). The mixture was extracted with ether (4×10 mL) and the extracts were washed with brine (3×10 mL). The organic layer was dried (Na2SO4, anhydrous) and evaporated. The crude was purified by chromatography on silica gel with hexane: EtOAc (4:1˜2:1) as eluant, yielding 1.02 g of (61%) the title compound. 1H NMR (CD3OD): 8.17 (s, 1H), 8.12 (s, 1H), 7.24 (s, 1H), 3.74 (s, 3H).
Reaction SMILES: N#N.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=1)(=[O:5])[CH3:4].[CH:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](OC2C=CC=CC=2)=[N:22][C:23]#[N:24])=[CH:16][CH:15]=1>COC(OC)C.CCOCC>[C:23]([N:22]=[C:21]([O:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[NH:13][C:10]1[CH:9]=[N:8][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:12][CH:11]=1)#[N:24]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: COC(C)OC
Agent: N#N
Solvent: CCOCC
Product: CC(=O)Nc1ccc(NC(=NC#N)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a N2 covered suspension of 0.909 g (6.0 mmol) of the product from Step 2 in 12 ml of dimethyoxyethane was added 1.43 g of diphenylcyanocarbonimidate. After stirring 16.5 hours at room temperature, the reaction mixture was diluted to a volume of 75 ml with Et2O. A suspended solid was collected on a filter and washed well with Et2O to yield after drying 1.62 g, m.p. 210.5°-211° C. (91.2%) of the titled product. Procedure C was then followed with the above intermediate to prepare Compound 30, m.p. 193.5°-194.5° C.
Reaction SMILES: [I-].C(OC([NH:9][C@@H:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])=[C:14]([CH2:17][N+:18]3[N:19]([CH2:26][CH2:27][O:28][CH:29]=[O:30])[C:20]([NH:23][CH:24]=[O:25])=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH2:9][C@@H:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O-:33])=[O:32])=[C:14]([CH2:17][N+:18]3[N:19]([CH2:26][CH2:27][O:28][CH:29]=[O:30])[C:20]([NH:23][CH:24]=[O:25])=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCOC=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 153.7 %

Procedure:
To a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate iodide (29.5 g) and anisole (30 ml) in methylene chloride (90 ml) was added dropwise trifluoroacetic acid (60 ml) under ice-cooling. After being stirred for 1 hour at ambient temperature, the mixture was poured into a mixture of diisopropyl ether (600 ml) and ethyl acetate (600 ml). The resultant precipitate was collected by filtration to give di(trifluoroacetic acid) salt of 7β-amino-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (22.7 g).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[N:11]2)=[CH:6][CH:5]=1.CO.O>C1COCC1>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 80 °C

Procedure:
To a solution of ethyl 1-(4-(difluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate (350 mg, 1.24 mmol) in a mixture of THF (3.1 ml), methanol (1.6 ml), Water (1.6 ml) lithium hydroxide hydrate (89 mg, 3.72 mmol) was added. The solution was heated to 80° C. for 2 h. Most of the organic solvent was removed under reduced pressure. Sodium bicarbonate solution and ethyl acetate were added and the organic layer was separated. The aqueous layer was made acid by addition of 25% aqueous hydrochloric acid and the mixture was extracted 2 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated. The product was dried in vacuo and was directly used for the next step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[CH3:34][CH2:35][O:36][C:37]([CH3:39])=[O:38]>N1C=CC=CC=1>[CH2:35]([O:36][C:37]([C@@H:39]1[CH2:32][C@H:3]([C:2]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]4([CH3:31])[C@@H:16]3[CH2:15][CH2:14][C@H:13]3[C@@:8]4([CH3:30])[CH2:9][CH2:10][C@@:11]4([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]43)[C:3]2([CH3:33])[CH3:32])=[O:1])[C:4]1([CH3:17])[CH3:5])=[O:38])[C:34]1[CH:9]=[CH:8][CH:7]=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@H]6C[C@@H](C(=O)OCc7ccccc7)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (1.3 g) in pyridine (10 ml) DMAP (0.57 g) was added followed by the crude reaction mixture (anhydride formation). The reaction mixture was stirred at reflux temperature for about 12 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, washed with dil HCl, water, followed by brine and dried over Na2SO4, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography using hexane and ethyl acetate mixtures as an eluent to afford the title compound (300 mg, 15% yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (5H, m), 5.16 (2H, m), 4.73 (1H, s), 4.61 (1H, s), 4.45-4.36 (1H, m), 3.65-3.6 (1H, m), 3.1-2.90 (1H, m), 2.85-2.6 (3H, m), 2.4 (1H, m), 2.3-1.9 (5H, m), 1.8-1.3 (17H, m), 1.26 (4H, m), 1.24 (3H, s), 1.22 (2H, m), 1.16 (3H, s), 1.14 (3H, s), 1.00 (2H, m), 0.8 (6H, s); Mass: [M+Na]+ 723 (15%); IR (KBr, cm−1): 3427, 2953, 17330, 1730, 1459, 1376, 1277, 1236, 1187, 1107, 1034, 940, 882.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:20]>C(OCC)(=O)C.CO>[ClH:20].[ClH:20].[F:19][C:2]([F:1])([F:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(F)(F)F)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)CCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(3,3,3-trifluoropropyl)-1-piperazinecarboxylate (5.77 g) in ethyl acetate (13 ml) and methanol (10 ml) was added dropwise 4N hydrogen chloride in ethyl acetate (29 ml) at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to give the title compound (4.70 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:11][CH:10]([C:21](O)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].C[Si](N[Si](C)(C)C)(C)C.[C:34]([O:37][CH2:38][CH3:39])(=[O:36])[CH3:35]>C1COCC1>[CH2:38]([O:37][C:34](=[O:36])[CH2:35][C:21]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:11]1)=[O:22])[CH3:39]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)C1CCC(C(=O)O)CN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,6-bis(tert-butoxycarbonyl)piperidine-3-carboxylic acid (41.4 mmol, 13.6 g) and N,N′-carbonyldiimidazole (CDI) (51.75 mmol, 8.4 g) in anhydrous THF (140 mL) were stirred 16 h at room temperature under argon. In a separate, sealed and argon-flushed flask, lithium HMDS (1.0 M in THF, 86.9 mmol) is added to 80 mL anhydrous THF stirring at −78° C. To this solution is added dropwise anhydrous ethyl acetate (89 mmol, 8.69 mL). This solution is allowed to stir at −78° C. for 1 hour prior to the dropwise addition of the original CDI/acid solution that had been stirred overnight. The reaction mixture is allowed to stir and warm to room temperature overnight. The reaction is then quenched with saturated NH4Cl(aq) (250 mL) and extracted with Et2O (100×2). The combined organics are then washed with water, saturated brine, and dried over Na2SO4. The solvent is removed in vacuo and the residue (12.6 g) was used in the next step without further purification.