Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (81 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL) was treated with 0-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (112 mg, 0.29 mmol), N,N-diisopropylethylamine (0.14 mL. 0.80 mmol), and 2-aminothiazole (40 mg, 0.40 mmol). The reaction was stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (10 mL) and extracted with ethyl acetate 3×15 mL). The combined organic layers were washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate to 60/40 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (35 mg, 34%) as a light yellow oil: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+) 384.0466. found 384.0468.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[N:30]=[CH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[N:30]=[CH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cc2ccccc2cn1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc3ccccc3cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 3-bromoacetylisoquinoline hydrobromide*.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)C.N1CCCCC1>C(Cl)Cl.C(OCC)(=O)C.CC(C)=O.CCCCCC.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[CH:2][C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C=CC(=O)c2c(O)cc(C)oc2=O)c(OC)c1
Temperature: 25 °C

Procedure:
3-Acetyl-4-hydroxy-6-methyl-pyran-2-one (5.07 g, 30.15 mmol) and 2,4-dimethoxybenzaldehyde (5.03 g, 30.27 mmol) were combined in a 250 mL round bottom flask. Absolute ethanol (20 mL) and piperidine (0.10 eq, 0.30 mL, 3.0 mmol) were added and the mixture heated to between 80 and 85 ° C. The reaction was monitored by TLC (silica gel, hexane-ethyl acetate (1:1 v/v) and methylene chloride-ethyl acetate-acetone (5:5:1 v/v)) and analytical HPLC. After 20 hours (>95% completion) the reaction mixture was cooled to room temperature to provide 3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one as a bright orange crystalline precipitate. MS M+317. NMR (CDCl3-TMS): d 8.31 (m, 2H), 7.69 (d, 1H, J=9 Hz), 6.54 (d, 1H, J=9 Hz), 6.45 (s, 1H), 5.93 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.26 (s, 3H) NMR (DMSO-d6): d 8.11 (s, 2H), 7.62 (d, 1H, J=9 Hz), 6.63 (bs, 2H), 6.23 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH2:20])[CH2:19][O:18][CH2:17]1>CO>[NH2:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:19][O:18][CH2:17]1
Reactant: NCC1(N)COC1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CO
Product: Cc1ccc2nc(Cl)nc(NCC3(N)COC3)c2c1

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (645 mg, 3 mmol) and 3-(aminomethyl)oxetan-3-amine (340 mg, 3.3 mmol) in methanol (15 mL) was stirred at room temperature overnight. After the resulting mixture was concentrated in vacuo, the residue was purified by column chromatography (eluting with 10% methanol in dichloromethane) to afford the desired product.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: OC(=S)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.5 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 10.05 g. (0.035 mole) of α, 2'-dichloro-4-biphenylylacetic acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([CH3:43])[CH3:42])=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1>CCOC(C)=O.O>[CH:41]([O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]2[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[CH:5]3)=[CH:35][C:36]=1[C:44]([F:45])([F:46])[F:47])([CH3:43])[CH3:42]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Temperature: 50 °C
Yield: 80.5 %

Procedure:
Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391 mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL, 0.587 mmol) to give a suspension. The reaction was heated at 50° C. for 5 h. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography to give the title compound as an oil (0.154 g). LCMS m/z=490.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) α ppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H), 2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94 Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74 (dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd, J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.NN.[OH-].[K+]>C(O)COCCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)c2nccc3ccccc23)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCc1ccc(Cc2nccc3ccccc23)cc1
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 55.3 %

Procedure:
The compound of Example B3 (1.7 g, 6.0 mmol), hydrazine monohydrate (836 mg, 17 mmol), and potassium hydroxide (769 mg, 14 mmol) were added to diethylene glycol (8.5 ml), and this mixture was stirred at 80° C. for 1 hour, at 160° C. for 3.5 hours, then at 200° C. 1 hour. The mixture was cooled to room temperature, ice water was added, and this was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (914 mg).
Reaction SMILES: S(O)([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH3:37])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.[C:38](=O)([O-:40])[OH:39].[Na+:42]>>[C:38]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH3:37])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([O-:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:40])=[O:39].[Na+:42]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1

Procedure:
Sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared by reacting 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (50 mg) and sodium hydrogencarbonate (22 mg) and detected according to a similar manner to that of Example 17.
Reaction SMILES: C(S[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=1)C.C1C=C(Cl)C=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.C(Cl)Cl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:12]1[C:11]([C:6]2[N:5]=[CH:4][C:9]([NH2:10])=[CH:8][CH:7]=2)=[CH:15][N:14]([CH3:16])[N:13]=1
Reactant: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(N)cn2)c(-c2ccccc2F)n1
Reaction time: 0.17 h
Yield: 115.3 %

Procedure:
To a solution of 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine (1.00 g, 3.04 mmol, 1.0 eq.) in THF (100 mL) under nitrogen at 0° C. was added MCPBA (77%, 1.60 g, 9.27 mmol, 3.05 eq.). After 3 h 15 min, 5% aqueous sodium thiosulfate and saturated aqueous NaHCO3 were added, and the solution was stirred for 10 min. CH2Cl2 was then added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with EtOAc afforded 2-ethylsulfonyl)-6(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine as a light tan solid (0.94 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:29][N:28]=[CH:27]1.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: NCCCCCn1ccnc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A mixture of 0.90 g of 5-chloroindole-2-carboxylic acid and 0.74 g of 1,1'-carbonyldiimidazole in 25 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 0.70 g of 1H-imidazole-1-pentanamine in 25 ml of tetrahydrofuran was added and stirring was continued for 16 hours. The mixture was heated at reflux for 5 hours, 5 ml of water was added and heating was continued for one hour longer. The mixture was concentrated, then one ml of 5N sodium hydroxide and about 25 ml of dichloromethane was added with shaking. The organic layer was separated and filtered and gave 1.2 g of the compound of the Example as white crystals, mp 214°-216° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([NH:16][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: Clc1ncccn1
Reactant: NC1CCCCc2c1[nH]c1ccc(Br)cc21
Product: Brc1ccc2[nH]c3c(c2c1)CCCCC3Nc1ncccn1

Procedure:
2-Bromo-N-pyrimidin-2-yl-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-6-amine was prepared from 2-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-6-amine (150 mg, 0.54 mmol) and 2-chloropyrimidine (123 mg, 1.07 mmol) in a similar manner as described in Example 22 to give 18 mg (9%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.80 (s, 1H), 8.31 (d, 2H), 7.57 (s, 1H), 7.49 (d, 1H), 7.20 (d, 1H), 7.07-7.04 (m, 1H), 6.60 (t, 1H), 5.36-533 (m, 1H), 2.94-2.89 (m, 1H), 2.70-2.63 (m, 1H), 2.05-1.94 (m, 2H), 1.89-1.59 (m, 4H); MS m/z (M+1) 357, 359; (M−1) 355, 357.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazine-2-carbonitrile (45 mg, 0.108 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (24 mg). MS 432.3 (M+H); UV 209.6, 308.9 nm; t 0.422 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:16]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)N(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Yield: 98.7 %

Procedure:
A mixture of 1-benzyloxycarbonyl-2,3-dihydro-6-nitroindole (1.0 g, 3.36 mmol) and tin(II) chloride dihydrate (3.78 g, 16.75 mmol) in ethanol (70 mL) was heated at 70° C., under an atmosphere of nitrogen, for 3 hours. The solution was cooled and the solvent evaporated under reduced pressure to give an off-white solid. The solid was partitioned between water (50 mL) and ethyl actate (100 mL) and the aqueous layer basified (pH 11) with 1M sodium hydroxide solution. The mixture was filtered to remove tin salts and the ethyl acetate was separated, dried (MgSO4) and evaporated under reduced pressure to give the amine as a yellow oil (0.89 g, 99%).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([OH:25])(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(O)C1C=CC=CC=1>C1C=CC=CC=1>[C:13]([O:25][CH2:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCCCC(=O)O
Solvent: OCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)CCCCCCCC(=O)OCc1ccccc1

Procedure:
Toluene-4-sulfonic acid monohydrate (0.71 g, 3.72 mmol) is added to a suspension of azelaic acid (25.0 g, 132.82 mmol) in benzene (550 ml). The mixture is heated to 80° C., whereafter benzyl alcohol (14.36 g, 132.82 mmol) in benzene (50 ml) is added dropwise to the resulting solution. The reaction mixture is refluxed overnight and water is removed azeotropically with a Dean Stark trap. The reaction mixture is allowed to cool, the white precipitate which forms is removed by filtration and the filtrate is concentrated to a brownish oil under reduced pressure. The crude product (33.97 g) is dissolved in dichloromethane (50 ml) and purified by flash chromatography, on a 5.5×15 cm silica column with dichloromethane/methanol (20:1) as eluant. The product, a yellow oil, is dried under vacuum. The oil crystallizes after a few hours at room temperature. Yield: 12.8 g (35%). 13C NMR (75 MHz, CDCl3): δ 24.5, 24.8, 28.8, 34.0, 34.2, 66.1, 128.2, 128.5, 136.1, 173.6, 180.0.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1>O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
3.5 g (0.111 mol) of methylamine were passed over the course of 20 minutes into a stirred solution of 11 g (0.055 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for one hour and at 22° C. overnight. It was then concentrated under reduced pressure, stirred with water and dried. 10.8 g (93.1% of theory) of the title compound of melting point 155°-157° C. (decomposition) were obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([O:11][CH3:12])=[O:10].OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.P(Cl)(Cl)([Cl:36])=O.C(N(C(C)C)C(C)C)C.[OH-].[Na+]>ClCCl.ClCCCl>[Cl:36][C:7]1[N:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:8]=1
Reactant: COC(=O)c1cnccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Agent: NC(N)=O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h

Procedure:
9.6 g (0.047 mol) of methyl 4-trifluoromethylpyridin-3-ylcarboxylate, dissolved in 50 ml of dichloromethane, are treated with 30% hydrogen peroxide/urea adduct and 17 ml of trifluoroacetic anhydride. The reaction solution is stirred at temperature of 20° C. for 20 hours and then washed once each with dilute sodium hydroxide solution and half-saturated sodium chloride solution. The product obtained is 3-methoxycarbonyl4-trifluoromethyl-3-pyridine N-oxide; 1H NMR (CDCl3, ppm): 8.55, s, 1H; 8.31, d, 1H; 7.6, d, 1H; 3.98, s, 3H. 4.85 g (0.022 mol) of the above product are then added to a mixture of 5 ml of phosphorus oxychloride and 4.3 ml of ethyidiisopropylamine in 15 ml of 1,2dichloroethane, and the mixture is heated to a temperature of 60° C. After about 2 hours, another 2 ml of phosphorus oxychloride and 2.8 ml of ethyidiisopropylamine are added, and the mixture is stirred at this temperature for 20 hours. The reaction mixture is subsequently added to ice-water, adjusted to pH 3 using 30% NaOH and then extracted with dich ioromethane. Filtration through a little silica gel gives an approximately 5:1 product mixture of the two 6-chloro- and 2-chloro-4-trifluoromethylpyridin-3-yl methyl esters, which can be separated by HPLC into the pure components. Thus, pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the main product; 1H NMR (CDCl3, ppm): 8.91, s, 1H; 7.68, s, 1H; 3.98, s, 3H, and pure methyl 2-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the byproduct; 1H NMR (CDCl3, ppm): 8.64, d, 1H; 7.52, d, 1H; 4.01, s, 3H. In the presence of 0.073 g of potassium hydroxide, 0.22 g of pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate are hydrolysed at room temperature in a 1:1 mixture of 6 ml of dioxane/water. Recrystallization gives the pure 6-chloro-4-trifluoromethyinicotinic acid: m.p. 115-117° C.; 1H NMR (CDCl3, ppm): 9.12, s, 1H; 7.24, s, 1H.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O:11][C:12]([C:14]1[S:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:21][CH2:20]2)=[N:17][N:18]=1)=O)C>>[CH2:1]([NH:8][C:12]([C:14]1[S:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:23][CH2:24]2)=[N:17][N:18]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CCCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-heptylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.053 g, yield 90%). 1H NMR (300 MHz, CDCl3) δ 7.69-7.76 (m, 1H), 7.63-7.50 (m, 2H), 7.30-7.38 (m, 1H), 7.05 (br. t, 1H), 4.07-4.01 (m, 1H), 3.91-3.83 (m, 1H), 3.75-3.6 (m, 2H), 3.54-3.5 (m, 2H), 3.43-3.31 (m, 4H), 1.59-1.52 (m, 2H), 1.32-1.21 (m, 8H), 0.85 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.6, 31.6, 29.4, 28.8, 26.7, 22.5, 14.0. MS (ES+) m/z 484 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a stirred solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (10.0 g, 55.6 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 55.6 mmol, 1.0 equiv) in acetonitrile (300 mL) was added drop by drop N-ethyl diisopropylamine (48.5 mL, 36.6 g, 278 mmol, 5.0 equiv) keeping the temperature below 25° C. After stirring the reaction mixture at rt for 16 h, the heterogeneous mixture was poured onto ice water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 11.4 g (60%) of the title compound as a off-white foam. MS (ISP): 344.3 [M+H]+.