Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.[Pd].[Pd].CC(C)=O>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: O=C(c1ccc(Br)cc1)c1cccc(-c2ccccc2)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(N(c2ccccc2)c2ccccc2)cc1)c1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Biphenyl-3-yl(4-bromophenyl)methanone (5.0 g, 14.83 mmol) and diphenylamine (3.8 g, 22.2 mmol) were dissolved in toluene (150 mL) under a nitrogen atmosphere, and then tris(benzylidine acetone dipalladium) (0.3 g, 0.3 mmol) was added thereto under nitrogen. Also, P(t-Bu)3 (0.3 g, 1.5 mmol) was added to the reaction mixture solution, followed by addition of NaOBut (4.3 g, 44.5 mmol). The reaction mixture solution was refluxed and stirred for 24 hours. After the reaction was over, the reaction mixture solution was filtered through a thin silica pad at a high temperature to thereby remove palladium. The filtrate was concentrated, and was passed through a silica gel column by using hexane-dichloromethane 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain a white solid (5.1 g, yield: 81%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[N:13]=1)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][NH:15][C:14]([C:12]2[N:13]=[C:9]([CH2:8][NH2:7])[S:10][CH:11]=2)=[O:25])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reaction time: 12 h

Procedure:
To a solution of {4-[2-(3-Chlorophenyl)ethylcarbamoyl]thiazol-2-ylmethyl}carbamic acid tert-butyl ester (0.73 g, 1.8 mmol) in methanol (10 mL) was added HCl in dioxane (4M solution, 10 mL). The mixture stirred for 12 hours. The methanol and dioxane were removed in vacuo and the resulting solid was vigorously mixed with 0.1 N NaOH and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a solid. 1H NMR (400 MHz, d6-DMSO): 8.39 (br s, 1H), 8.08 (s, 1H) 7.25 (m, 4H), 4.00 (s, 2H), 3.48 (m, 2H), 2.84 (t, 2H), 2.41 (br s, 2H); MS (ESI-LCMS) for C13H14ClN3OS: 296 (MH+).
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:16][O:15][CH2:14]3)[NH:10][N:9]=2)C(C)=CC=1.CCO.NO.Cl.C([O-])(O)=O.[Na+]>O>[O:15]1[CH2:16][CH:13]([C:11]2[NH:10][N:9]=[C:8]([NH2:3])[CH:12]=2)[CH2:14]1
Reactant: Cc1ccc(C)n1-c1cc(C2COC2)[nH]n1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1cc(C2COC2)[nH]n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
Into a 250-mL 3-necked round-bottom was placed 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(oxetan-3-yl)-1H-pyrazole (4.0 g, 18.4 mmol, 1.0 equiv.), EtOH (100 mL), water (40 mL), and NH2OH.HCl (10.3 g, 148.2 mmol, 8.0 equiv.), followed by the addition of NaHCO3 (9.9 g, 117.8 mmol, 6.4 equiv.) portionwise. The resulting solution was stirred at 100° C. for 24 h, then cooled to 30° C. and concentrated in vacuo. The residue was diluted with 150 mL of THF. The solids were collected by filtration and dissolved in 200 mL of EtOH, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on neutral alumina eluting with a DCM/MeOH gradient (1 to 10% MeOH) to afford 0.5 g (19%) of 5-(oxetan-3-yl)-1H-pyrazol-3-amine (91) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][C:6]1([C:29](=[O:31])[CH3:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][C:6]1([CH:29]([OH:31])[CH3:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)=O)ccc1-c1cnc(C)o1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)O)ccc1-c1cnc(C)o1
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A suspension of 1-{8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}ethanone (85.0 mg) in THF (1 mL) was added to a suspension of lithium aluminum hydride (13.5 mg) in THF (1 mL) under ice-cooling. The reaction mixture was stirred for 10 min under ice-cooling, and sodium sulfate decahydrate (140 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (61.4 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:16]>C(OCC)(=O)C>[ClH:16].[NH:5]1[CH2:6][CH2:7][CH2:8][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC1CCCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-hydroxyazepane-1-carboxylate (1.00 g, 4.65 mmol) in ethyl acetate (23 ml) was added 4N hydrogen chloride in ethyl acetate (23 ml, 92.0 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo to afford azepan-4-ol hydrochloride as a pale yellow oil (710 mg, 4.65 mmol, >99%). This compound was used for the next reaction without further purification.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[Br:28][C:29]1[CH:33]=[N:32][N:31]([CH3:34])[C:30]=1[NH2:35]>C(OCC)C>[Br:28][C:29]1[CH:33]=[N:32][N:31]([CH3:34])[C:30]=1[NH:35][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: Cn1ncc(Br)c1N
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(Br)cnn3C)c2o1
Yield: 6.4 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 4-bromo-2-methyl-2H-pyrazol-3-ylamine (93 mg). Purification by column chromatography on silica eluting with 1-5% methanol in dichloromethane afforded, after trituration with diethyl ether, the title compound as a white solid (7 mg).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]#[N:12].[Br:13]N1C(=O)CCC1=O>C(Cl)Cl>[Br:13][C:3]1[C:2]([C:11]#[N:12])=[N:1][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(n1)NCCC2
Solvent: ClCCl
Product: N#Cc1nc2c(cc1Br)CCCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a vial is added 5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbonitrile (370 mg, 2.32 mmol) and N-bromosuccinimide (413 mg, 2.32 mmol) in 20 mL of CH2Cl2. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated. The residue is purified by flash column chromatography to give 550 mg of 3-bromo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](O)([C:24]([F:27])([F:26])[F:25])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([Cl:23])[CH:17]=2)=[O:15])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:24]([F:27])([F:25])[F:26])=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([Cl:23])[CH:17]=2)=[O:15])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(Br)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)C=C(c2cc(Br)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Temperature: 80 °C

Procedure:
To a solution of 4.28 g of 3-[3-bromo-5-(trifluoromethyl)phenyl]-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutane-1-one in 10 mL of toluene, 2.08 g of thionyl chloride and 1.38 g of pyridine were added while stirring the solution at 80° C. to continue the stirring of the resultant mixture at the same temperature for 2 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture while ice-cooling the reaction mixture and the stirring of the reaction mixture was continued until the temperature of the reaction mixture returned to room temperature. The organic phase was separated off and charged into a solution of 0.77 g of sodium hydroxide in 5 mL of water. The resultant mixture was stirred at room temperature for 30 minutes. The organic phase was separated off and then was dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order. The solvent was distilled off under reduced pressure to obtain 4.02 g of a crude objective substance as a yellow oily substance. This substance was used in the next process as it was without being further purified.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+].C(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[S:10][CH:12]=1)[CH3:19]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1ccccc1O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Yield: 92.6 %

Procedure:
A stirred solution of 2-hydroxybenzenecarbothioamide 3a (5.36 g, 35.0 mmol), ethyl 4-chloroacetoacetate (6.34 g, 38.5 mmol) in dry THF (70 mL) was heated to reflux under nitrogen for 2.5 days. At ambient temperature, the mixture was diluted with EtOAc (200 mL), then cautiously treated with saturated aq. NaHCO3 (40 mL), and followed by adding solid NaHCO3 in small portions until CO2 evolution ceased. The organic layer was separated, washed with brine (40 mL×2), dried over MgSO4, and filtered. After concentration in vacuo, the oily residue was chromatographed on silica gel (gradient EtOAc/CH2Cl2 : 0-4%) to provide 4a (8.53 g, 93%) as a white solid, which was recrystallized from toluene/hexane at -30° C. mp 35.5°-36.5° C.; IR (neat) 3120, 1740, 1480, 1225 cm-1 ; 1H NMR (DMSO-d6) δ1.15 (3H, t, J=7.1 Hz, CH3), 3.84 (2H, s, CH2), 4.07 (2H, q, J=7.1 Hz, CH2), 6.89 (1H, t, J=7.8 Hz, Ar), 6.97 (1H, d, J=7.8 Hz, Ar), 7.26 (1H, t, J=7.8 Hz, Ar), 7.48 (1H, s), 7.93 (1H, d, J=7.8 Hz, Ar), 11.29 (1H, s, OH); FABMS m/z 263 (M+), 264 (M+ +1); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.16; H, 4.97; N, 5.50.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([O-])=O.[Cl-].[Ca+2].[Cl-].O>C(O)C.[Zn]>[N:6]1[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1cnn2ccccc12
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cnn2ccccc12
Yield: 77.2 %

Procedure:
To a mixture of 3-nitropyrazolo[1,5-a]pyridine (2.35 g, 14.4 mmol) and zinc (28.2 g, 432 mmol) in 78% ethanol (75.0 mL) was added a solution of calcium chloride (0.8 g, 7.2 mmol) in a minimum amount of water. The resulting mixture was refluxed for 2 h and filtered in hot and washed with hot ethanol. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (EtOAc) to give an orangish solid as the desired product (1.48 g, 77%): 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=7.0 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.01–6.96 (m, 1H), 6.68–6.64 (m, 1H), 2.90 (br, 2H); MS (EI) m/z 134 (M++H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH2:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:13])[NH:8][C:9]=2[CH:10]=1
Reactant: O=C1Nc2cc(I)ccc2C1=O
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc(I)ccc2c(=O)o1
Temperature: 80 °C
Yield: 81.8 %

Procedure:
To a stirred warm (80° C.) solution of 6-iodo-1H-indole-2,3dione (3.0 g, 11 mM) in acetic acid (10 mL) and acetic anhydride (10 mL) was added in small portions chromium trioxide (1.83 g, 18.3 mM) while maintaining the temperature of the reaction mixture at 80°-90° C. The reaction mixture was then heated at 80° C. for 10 min, cooled and poured into water. The resulting mixture was filtered and the collected solids dried to provide the title compound as a yellow solid (2.6 g, 81.8%); MS(CI): 290 (M+H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([C:35]2([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>CS(C)=O>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:38]1[CH2:37][CH2:36][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:42])[F:43])[CH:30]=2)([OH:41])[CH2:40][CH2:39]1)[O:14]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)CO3
Temperature: 80 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and 4-[3-(trifluoromethyl)phenyl]-4-piperidinol (0.84 g, 3.43 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.33 g of the (S)-enantiomer of the title compound, m.p. 148-151° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C.O.C(OCC)(=O)C>[N+:23]([C:22]1[C:17]([S:10][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]([OH:9])=[O:8])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1Sc1ncccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 ml of ethanol and 11 ml of water is added portionwise 12.72 g of solid sodium bicarbonate. After the complete addition, the mixture is stirred for 15 minutes and 10.0 g of 2-chloro-3-nitropyridine added portionwise. The mixture is refluxed for 2 hours, cooled and then concentrated in vacuo. The residual aqueous solution is diluted with 15 ml of water, acidified with 2N HCl and extracted twice with 250 ml of ethyl acetate. The extract is concentrated under vacuum to give a yellow solid residue. The residue is dissolved in a minimum of ethyl acetate by heating on a steam bath. The solution is cooled overnight and filtered. (2.5 g of starting material). The filtrate is concentrated, chilled and filtered to give 12.5 g of 2-(3-nitro-2-pyridinylthio)benzoic acid as a yellow solid. The preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml of ethanol is shaken in a Parr hydrogenator under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatmoaceous earth and the filter cake washed with 200 ml of dichloromethane. The combined filtrate is evaporated in vacuo to give a solid. The solid is triturated with ethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g) is again hydrogenated with Pd/c (0.50 g) in 50 ml of ethanol and 30 ml of acetic acid under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with methanol. The combined filtrate is concentrated in vacuo to give 1.6 g of solid. This solid in 25 ml of N,N-dimethylformamide is again reduced with 0.80 g of Pd/C under 45 psi of hydrogen to give 0.57 g of solid. Recrystalization from ethyl acetate gives 0.28 g of 2-(3-amino-2-pyridinylthio)benzoic acid. The preceding compound (0.20 g) is heated in 2-hydroxypyridine at 170° C. to give 5,6-dihydropyrido[2,3-b][1,4]benzothiazepine as a yellow solid. The preceding compound is reacted with borane-dimethylsulfide as described for Reference Example 17 to give the product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:7][CH2:6]1.[OH-].[K+]>CO>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:10][CH2:9]1)[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=1
Reactant: COC(=O)CN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2N)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
In a round-bottomed flask were introduced {4-[1-(2-Amino-phenyl)-2-(3,5-bis-trifluoromethyl-benzyloxy)-ethyl]-piperazin-1-yl}-acetic acid methyl ester (compound 323; 1.3 g, 2.5 mmoles), KOH (0.35 g, 6.3 mmoles) and MeOH (20 ml). The reaction mixture was stirred at room temperature for 6 hours. MeOH was removed under reduce pressure and the residue was taken up in water. The pH was adjusted to 6 and the solution was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated. The residue (1.1 g, 88%) was recrystallized from diethylether to give {4-[1-(2-Amino-phenyl)-2-(3,5-bis-trifluoromethyl-benzyloxy)-ethyl]-piperazin-1-yl}-acetic acid (compound 324; 0.75 g, 60%) as white needles.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C1CCCCC1>[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:5]2[S:1][N:2]=[CH:3][CH:4]=2)[OH:17])=[CH:14][CH:13]=1
Reactant: c1cnsc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of isothiazole in 20 ml of tetrahydrofuran were added 8.1 ml of a 1.52M solution of n-butyllithium in hexane at -78° C. The mixture was allowed to stir for 15 minutes at which time 3.2 g of 4,4'-dichlorobenzophenone were added as a solution in 25 ml of tetrahydrofuran. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Twenty-five milliliters of a saturated ammonium chloride solution were added and the tetrahydrofuran was removed by evaporation. The resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with a saturated ammonium chloride solution, water, and a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed over silica gel. The appropriate fractions were combined and evaporated resulting in an oil. Cyclohexane was added and 1.21 g of the desired title product were recovered by filtration as white crystals, m.p. 118°-119.5° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)C.[Pt]=O>[NH2:14][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([CH:3]=[N:2][OH:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C=NO)cc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)c1cc(N)cc(C=NO)c1
Yield: 62.9 %

Procedure:
A mixture of methyl 3-[(N-hydroxylimino)methyl]-5-nitrobenzoate (2.0 g, 0.009 mol) in ethanol (150 mL) was hydrogenated in the presence of platinum oxide (0.25 g) at 30 psi for 0.5 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give 1.1 g (64%) of methyl 3-amino-5-[(N-hydroxylimino)methyl]benzoate as an off-white solid, mp 160°-162° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].Cl[CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19](=[O:25])[CH2:18][O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 6.28 g, 157 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 0° C. was added portion wise N-(2-hydroxyethyl)phthalimide (2, 20 g, 105 mmol). The reaction mixture was then allowed to warm to ambient temperature with stirring for 30 minutes. To a stirred suspension in a separate flask of sodium hydride (60% dispersion in mineral oil, 6.28 g, 157 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 0° C. was added portion wise methyl 4-chloroacetoacetate (1, 12.1 ml, 105 mmol). The reaction mixture was then allowed to warm to ambient temperature with stirring for 30 minutes. The two reaction mixtures were then combined portion wise and stirred at ambient temperature under nitrogen for 6 hours. After cooling to 0° C., a further portion of sodium hydride (2.0 g, 50.0 mmol) was added. The mixture was stirred for 10 minutes at 0° C., then a further portion of methyl 4-chloroacetoacetate (3.0 ml, 26.0 mmol) was added. The reaction mixture was then stirred at ambient temperature for 18 hours, then poured onto a mixture of ice and saturated ammonium chloride, and then neutralized with aqueous HCl (10 N). The precipitate which formed was filtered off and re-crystallized from ethyl acetate to give a first crop of 3 as a yellow solid. The combined filtrates were extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with saturated brine (2×300 mL) and water (300 mL), dried over MgSO4 and concentrated under reduced pressure to leave a residue which was purified by column chromatography over silica gel (50 g pre-packed Isolute® column) using ethyl acetate/hexane (1:1) as eluent to give a second crop of 3 as a yellow solid, which was combined with the first crop to give methyl 4-((2′-hydroxyethyl)phthalimide)acetoacetate (3) (10.8 g, 34% yield, 95% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 8.13 (m, 2H); 7.69 (m, 2H); 4.53 (s, 2H); 3.80 (m, 2H); 3.70 (m, 2H); 3.67 (s, 3H); 3.41 (s, 2H).