Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.O.S[C:4]1[N:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=1.[CH2:20](O)C>[Ni]>[C:13]1([CH:12]([N:5]2[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=[CH:4]2)[CH3:20])[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cnc(S)n1CCc1ccccc1
Reactant: CCO
Agent: [Ni]
Agent: N
Solvent: O
Product: CC(c1ccccc1)n1cncc1C(N)=O
Temperature: 25 °C

Procedure:
To 80 parts of ethanol, previously saturated with gaseous ammonia, are added 2.3 parts of (-)-2-mercapto-1-(2-phenylethyl)-1H-imidazole-5-carboxamide hydrate and 6 parts of Raney-nickel. The mixture is stirred and refluxed for 2 hours and thereafter allowed to cool to room temperature. The Raney-nickel is filtered off and the filter-cake is washed with ethanol. The filtrate is evaporated in vacuo and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide, essentially free of its (+)-isomer, as a residue.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc2ccccc2n1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1ccc2ccccc2n1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
155 mg (0.266 mmol) of (2R*,4S*)-2-benzyl-1-(2-quinolinylcarbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 40 mg (1.06 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR34## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS: M+ =486.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=O)=[O:7].[Na+].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6]([Cl:14])(=[O:9])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSCCCS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodium 3-(methylthio)propane-1-sulfonate (20 g) in dry DCM (200 mL), is added dropwise oxalyl chloride (80 mL) at 0° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure and ice (100 g) is added. The product is extracted with DCM (2×200 mL) and the organic phase is washed with brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 12 g of 3-(Methylthio)propane-1-sulfonyl chloride as colorless liquid. A solution of 3-(methylthio)propane-1-sulfonyl chloride (12 g) in dry THF (100 mL) is added dropwise to a solution of ammonia in dry THF (250 mL) at −78° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography using silica gel (60-120 mesh) and CHCl3/MeOH as eluent to afford 9 g (84%) of the title compound as pale a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 6.80 (br s, 2H), 3.02-3.06 (m, 2H), 2.55-2.59 (m, 2H), 2.03 (s, 3H), 1.89-1.92 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([NH2:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[O:6]=[C:1]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([NH2:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.9 %

Procedure:
Valeryl chloride (6.0 mL, 50 mmol) was added to a mixture of anthranilamide (6.8 g, 50 mmol) and triethylamine (7.0 mL, 50 mmol ) in tetrahydrofuran (100 mL) at 25° C. A rapid, exothermic reaction was observed, but no external cooling was required to prevent reflux. The mixture was stirred at ambient temperature for 19 hours, after which it was poured into excess aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried (magnesium sulfate), and concentrated in vacuo. The residue was triturated with hexane/ether to give the title compound as a tan solid (9.9 g, 90%); m.p. 119°-120° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:7]2[C:11]=1[CH2:10][N:9]([CH3:12])[C:8]2=[O:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[CH3:12][N:9]1[C:8](=[O:13])[C:7]2[C:11](=[C:3]([CH2:1][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:4]=[CH:5][C:6]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1
Reactant: C1CCNC1
Reactant: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of tert-Butyl (7-formyl-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)carbamate (Compound 109C, 23.0 mg, 0.0792 mmol) and sodium triacetoxyborohydride (101 mg, 0.475 mmol) in THF (0.5 mL) was stirred at room temperature for 20 minutes. Pyrrolidine (39.7 uL, 0.475 mmol) was added and the resulting mixture was stirred at room temperature overnight. The THF was removed in vacuo and the crude product was partitioned between EtOAc and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to deliver the desired product. MS (ES+): m/z 346.32 (100) [MH+]; HPLC: tR=0.76 min (UPLC, Analytical).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41]>ClCCl>[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:41]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(O)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In dichloromethane (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and dicyclohexylcarbodiimide (2.4 g), and a solution of 3-fluorobenzoic acid (1.6 g) dissolved in dichloromethane (10 ml) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([NH2:19])=[O:18])[CH2:15][CH:16]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22].CCOC(C)=O>[Pd].CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([NH2:19])=[O:18])[CH2:15][CH2:16]3)=[CH:9][O:10][C:4]=2[C:3]=1[O:20][C@@H:21]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[Cl:31])[CH3:22]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1c(N)ncc2c(C3CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-yl}-3,6-dihydro-2H-pyridine-1-carboxamide (17.0 mg, 0.037 mmol), palladium 10% wt on activated carbon (10 mg), EtOAc (4 mL) and MeOH (0.4 mL) was flushed with nitrogen, then a hydrogen (0.5 L) balloon was added, and the mixture was stirred at rt for 3 h. The suspension was filtered through a syringe filter pad, and the filtrate was concentrated in vacuo. The material was redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.55-1.69 (m, 2H), 1.87 (d, J=6.8 Hz, 3H), 1.98-2.06 (m, 2H), 2.89-3.03 (m, 3H), 4.11 (d, J=12.9 Hz, 2H), 6.53 (q, J=6.7 Hz, 1H), 7.18-7.25 (m, 1H), 7.37-7.43 (m, 2H), 8.02 (s, 1H). MS (ES+): m/z 467.01/469.00 (100/69) [MH+]. HPLC: tR=2.58 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:17][C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:8](=[O:18])[N:7]([CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:19])[C:12]=3[CH:13]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (1.08 g, 4.07 mmol), 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.12 g, 4.48 mmol) and Cs2CO3 (2.65 g, 8.12 mmol) in DMF (20 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.7 g, 41%). 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.4 Hz, 1H), 6.30 (m, 2H), 5.30 (q, J=7.2 Hz, 1H), 4.78 (m, 1H), 4.59 (d, J=15.2 Hz, 2H), 4.27 (m, 4H), 3.95 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:21]([C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[CH3:22]
Reactant: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g), bis(tricyclohexylphosphine)palladium (II) dichloride (332 mg), tripotassium phosphate (11 g) and vinylboronic acid pinacol ester (3 g) were added toluene (27 mL) and water (1.4 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in ethanol (20 mL), 5% palladium carbon-ethylenediamine complex (600 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 8 hr at room temperature. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg) was dissolved in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. 1N Aqueous sodium hydroxide solution (7 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (441 mg).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:7]=1)(=O)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31](/[CH:32]=[CH:43]/[P:52](=[O:59])([O:53][CH2:54][CH3:55])[O:56][CH2:57][CH3:58])=[CH:30][N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(O)c3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 15.2 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.025 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals from a fraction eluted with ethyl acetate-hexane (5:1, v/v). To a mixture of the obtained crystal, tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.050 g, yield 15%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=O)[CH2:15][CH3:16])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH:13][CH2:14][CH2:15][CH3:16])[CH:12]=1
Reactant: CCC(=O)Nc1cc(OC)cc2c1CC(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCNc1cc(OC)cc2c1CC(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 grams of N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)propanamide, prepared in the foregoing example, in 30 cc of anhydrous benzene is gradually added into a suspension of 1.1 grams of LiAlH4 in 30 cc of anhydrous ethyl ether at 0° C. and the resulting reaction mixture is heated to the reflux temperature for 6 hours. At the end of this time the temperature is decreased to 0° C. and the aluminum complex is decomposed by addition of 3.3 cc of water. After 30 minutes of stirring at room temperature, the inorganic salts are discarded by filtration and the filtrate, dried over Na2SO4, is concentrated to dryness. The under vacuum distillation of the obtained residue affords 2.8 grams (93 percent of theoretical) of the title compound. B.p./0.2 mmHg 140°-142° C. The corresponding hydrochloride prepared by treatment of the free base with HCl melts at 110°-111° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][CH:22]([F:28])[C:23](OCC)=[O:24]>O1CCCC1.C(OCC)(=O)C.C1CCCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:23](=[O:24])[CH:22]([F:28])[F:21])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C(c1cc(Br)ccc1F)C(F)F
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A solution of diisopropylamine (12.7 g, 17.9 ml, 126 mmol) in tetrahydrofuran (375 ml) was cooled to −78° C. and n-butyllithium (1.6 M in hexane) (78.6 ml, 126 mmol) was added dropwise. After stirring for 10 minutes commercially available 1-bromo-4-fluorobenzene {CAS[460-00-4]} (20 g, 12.4 ml, 114 mmol) was added dropwise at max. −60° C. Stirring was continued at −70° C. for 2.5 hours. Then ethyl difluoroacetate (17.0 g, 13.7 ml, 137 mmol) was added dropwise. The mixture was warmed to −10° C. and then quenched by pouring the mixture onto 1 M hydrochloric acid. The mixture was extracted twice with ethyl acetate, dried over sodium sulphate, filtered and evaporated to give a yellow liquid (34 g; 118%). The residue was purified by chromatography on 200 g silica gel with a 3:1-mixture of cyclohexane and ethyl acetate as the eluent to give 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (26.5 g, 91.6% yield) as a yellow liquid. MS (EI): m/z=252.0 [M]+ and 254.0 [M+2]+.
Reaction SMILES: [CH:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:29]>>[Cl:29][C:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(Cl)C1(Cl)CCCCC1

Procedure:
80 g (0.547 mol) of cyclohexanecarboxylic acid chloride, 30 ml of carbon tetrachloride, 63 ml (0.778 mol) of SO2Cl2 and 1.5 g of benzoyl peroxide are heated for 10 hours. The chlorinated acid chloride is then distilled from the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCOCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 92.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess tetrahydro-4H-pyran-4-one (1.16 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.51 g (93%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([O:19]C(C)C)=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[ClH:23]>>[ClH:23].[OH:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)OC(=O)c1cc(-c2ccc(C(C)(C)O)nc2)ccn1
Agent: Cl
Product: CC(C)(O)c1ccc(-c2ccnc(C(=O)O)c2)cn1
Yield: 87 %

Procedure:
A solution of isopropyl 6-(2-hydroxypropan-2-yl)-3,4′-bipyridine-2′-carboxylate (140 mg, 0.47 mmol) in 1 M hydrochloric acid (2 mL) was heated at 100° C. overnight. The solvent was removed under reduced pressure to give 6-(2-hydroxypropan-2-yl)-3,4′-bipyridine-2′-carboxylic acid hydrochloride salt as a white powder (106 mg, 87%). 259.1 (M+1).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]1([C:20]([O-])=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=1)[N+:7]([O-:9])=[O:8].[NH4+].O>S1(CCCC1)(=O)=O>[CH:10]1[C:6]([N+:7]([O-:9])=[O:8])=[C:20]([NH2:5])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 177 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Ammonium acetate (1.16 g, 15.0 mmol) and ammonium picrate (0.18 g, 0.75 mmol) are suspended in sulfolane (3 ml), stirred for 2 hr at 177° C., cooled to ambient temperature and mixed with water (30 ml). The product is collected, washed with water and dried to yield 0.061 g (32%) of picramide (Table 1, entry 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1.Cl.[Cl:30]CC[CH2:33][N:34](C)[CH3:35]>>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][N:34]([CH3:35])[CH3:33])[CH:10]=1
Reactant: CN(C)CCCCl
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1
Agent: Cl
Product: Cc1csc(Nc2ncc(SCCCN(C)C)cc2Sc2ccccc2Cl)n1

Procedure:
Prepared according to the method of Example 16 using methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s, 3H), 1.84 (m, 2H); Mass spectrum (esi) m/z 451.0 (M+H-2HCl).