Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[C:22]1([CH:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C(=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: c1ccc(CC(c2ccccc2)C2CNCCO2)cc1
Temperature: 25 °C

Procedure:
To a methanolic solution of 4-Benzyl-2-(1,2-diphenyl-vinyl)-morpholine (4.9 g, 13.9 mmol) is added ammonium formate (14 g, 222.2 mmol) and 10% Pd—C (5 g). The reaction is stirred under nitrogen and heated at reflux for 30 min then cooled to room temperature and filtered through Celite®. The filtrate is concentrated under reduced pressure and the residue is taken up in methanol and purified by cationic ion exchange resin SCX-2® chromatography. The purified residue (2.9 g, 80%) comprises a 3:1 ratio of diastereoisomers.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCOCC3)s2)c(C)[nH]c1=O
Yield: 57.4 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with morpholine as described in Step 5, Example 24 to give the title compound as a solid (57.4% yield). LC/MS: RT 2.72 min; m/e 369 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, d); 7.3 (1H, d), 3.7 (4H, m), 2.95 (4H, s), 2.4 (2H, q), 2.36 (3H, s), 1.05 (3H, t).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:22])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[N:18][CH:17]=2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Reactant: O=C(O)CCI
Product: O=C(O)CCSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1

Procedure:
3-Cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 100 mg, 300 μmol) was reacted with 3-iodopropionic acid (60 mg, 300 mol), employing the procedure described in Step 1 of EXAMPLE 67, to furnish the title compound: RTA=3.61 min; m/z (ES+)=406.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9].Cl>C(O)C.[Fe]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]([CH3:13])[CH3:14])=[O:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl)C(C)C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(N)cc2)cc1Cl)C(C)C
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Iron powder (0.44 g, 7.8 mmol) was added to a solution of methyl N-[(3-chloro-4′-nitrobiphenyl-4-yl)carbonyl]-L-valinate (0.30 g, 0.78 mmol) in ethanol (10 mL). Concentrated HCl (0.39 mL, 0.78 mmol) was added, and the mixture was heated at reflux for 3 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.25 g (89%) of the title compound. LC/MS m/z/z 361.2 (MH+), retention time 2.36 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 3.80 (s, 3H), 4.71-4.78 (m, 1H), 6.82 (d, 3H), 7.40-7.74 (m, 5H).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:7]([OH:16])[CH:6]=1.Cl>CCO.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:7]([OH:16])[CH:6]=1
Reactant: COCCOc1ccc(C=NOC)cc1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCCOc1ccc(CN)cc1O
Reaction time: 4 h
Yield: 68.5 %

Procedure:
An amount of 3-hydroxy-4-(2-methoxyethoxy)benzaldehyde O-methyloxime (0.75 g, 3.33 mmol) in 10 mL of EtOH is added 1 mL of 12 N HCl and palladium on carbon. The reaction mixture is hydrogenated for 4 h. After removal of solid by filtration, solvent is evaporated to give yellow oil. Colorless solid is afforded after the oil is washed 5 times with EtOAc. Recrystallization from MeOH/EtOAc afforded 0.45 g (68.5% yield) of colorless solid: mp: 89-90° C.; MS (ESI) m/z 198.1 (M+H)+1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][CH:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:47][CH:44]3[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: CC1CCC(N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) into a 100 mL round-bottomed flask was added 4-methylcyclohexanamine (50 mg, 0.44 mmol), and The mixture was stirred at room temperature for 4 hours. LCMS showed the reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=437 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:37])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:37][C:8]1[CH:9]=[CH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)COc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([C@@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1OCC(=O)O
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A mixture of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid ethyl ester (146 mg, 0.26 mmol), potassium carbonate (71 mg, 0.52 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 130 mg (94%) of (S)-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC([S@]([NH2:21])=O)(C)C.[BH4-].[Na+].CO>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Cl:1][C:2]1[C:11]([CH2:12][NH2:21])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2cc(CN)c(Cl)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
2-Chloro-8-methylquinoline-3-carboxaldehyde (5 g, 24.6 mmol) in dry THF (75 mL) was treated with titanium(IV) isopropoxide (14.5 mL, 48 mmol). After 5 minutes, (R)-(−)-2-methyl-2-propanesulfinamide (2.95 g, 24 mmol) was added in one portion and the mixture was stirred for 60 h. The mixture was cooled to 0° C. in a water/ice bath and NaBH4 (1.9 g, 48 mmol) was added. The mixture was stirred for 3 h and cooled to 10° C. MeOH (20 mL) was added dropwise, followed by water (5 mL). The resulting slurry was filtered through Celite and washed thoroughly with EtOAc. The organic layer was washed with water and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in MeOH (20 mL) and HCl (4M in 1,4-dioxane; 30 mL). The mixture was stirred for 2 h and, after removing the solvent in vacuo, the residue was dissolved in DCM. The organic layer was washed with sat. NaHCO3 solution, water and brine, then dried (MgSO4), filtered and the solvent removed in vacuo. The residue was redissolved in MeOH and passed through an SCX cartridge, eluting with 0-0.1M MeOH/NH3 in MeOH. The solvent was removed in vacuo and the residue purified by column chromatography on silica, eluting with 0-5% MeOH in EtOAc, to afford the title compound (3 g, 60%). δH (DMSO-d6) 8.50 (1H, s), 7.89 (1H, d, J=8.1 Hz), 7.67 (1H, d, J=7.0 Hz), 7.57 (1H, t, J=7.6 Hz), 4.00 (2H, s), 2.70 (3H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:9](=[O:20])[CH:10]([CH3:19])[CH2:11][CH:12]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]1[CH:9]([OH:20])[CH:10]([CH3:19])[CH2:11][CH:12]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH:13]=1
Reactant: CC1=CC(CCC(C)C)CC(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1=CC(CCC(C)C)CC(C)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A suspension of lithium aluminum hydride (0.5 g, 0.013 mol) in anhydrous diethyl ether (100 mL) was stirred at 10° C. under nitrogen while 2,6-dimethyl-4-(3-methylbutyl)-2-cyclohexen-1-one (5.8 g, 0.03 mol) in anhydrous ether (10 mL) was added over a period of 30 minutes. The mixture was stirred at room temperature for 3 hours; then it was treated successively with water (0.5 mL), 15% NaOH solution (0.5 mL), and water (1.5 mL). The solution was filtered, dried and concentrated to give the crude alcohol. Short path distillation afforded 5.0 g of 2,6-dimethyl-4-(3-methylbutyl)-2-cyclohexen-1-ol, bp 90°-95° C. (1 mm), as a mixture of isomers by glc/ms (65.5%, 28%, and 5.5%). NMR (CDCl3) δ0.9-1.6 (19H, complex), 1.8 (3H, bs), 3.6 (1H, m), 5.4 (1H, m). IR (film) 3300, 1040, 1010 cm-1. MS (m/e) 196 (M+), 98, 82, 125, 107.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([O:32]C)=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:30]([OH:32])=[O:31])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Br:29])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 70 mg (2.92 mmol) LiOH in 5 mL water was added to a solution of 1.0 g (1.84 mmol) of (R)-2-(3-bromo-4-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the reaction mixture was stirred for 5 h at RT. The reaction solution was evaporated down i.vac., the residue was combined with DCM, the organic phase was washed with 1 M KHSO4 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH2:1]([C:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO>[CH2:1]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=Cc2ccc([C@H]3CC[C@]4(COC(=O)N4)C3)cc2CC1
Solvent: CO
Product: CCCCCCC1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Reaction time: 16.67 h
Yield: 83.7 %

Procedure:
A mixture of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2A, 760 mg, 2.15 mmol) and (−)-2,3-bis[(2R,5R)-2,5-dimethylphospholanyl]-N-[3,5-bis(trifluoromethyl)phenyl]maleicimide(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (273 mg, 0.43 mmol) in MeOH (27 mL) was hydrogenated at 850 PSI for 1000 minutes using a 100 mL HEL autoclave. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-100% EtOAc over 20 minutes) to afford 640 mg of (5R,7S)-7-(6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one in a 1:2 ratio of the two isomers. The desired major isomer was separated using a CHIRALPAK® AS-H column under SFC conditions (35% MeOH in CO2). Retention time=5.14 min. Recovered 400 mg of (5R,7S)-7-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one. 1H NMR (400 MHz, methanol-d4) δ 7.02-6.91 (m, 3H), 4.47-4.20 (m, 2H), 3.02 (tt, J=11.0, 7.2 Hz, 1H), 2.87-2.74 (m, 3H), 2.41-2.24 (m, 2H), 2.17-2.03 (m, 2H), 2.00-1.89 (m, 3H), 1.86-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.51-1.28 (m, 11H), 0.99-0.88 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][OH:28])=[CH:41][C:40]=1[NH:42][C:25]([C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=3)=[N:13][C:14]=12)=[O:26]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NC(C)(C)CO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 654.2 [(M−H)−]; mp 207° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[N:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[N:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (638 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (495 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 143–144° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[I:12]
Reactant: II
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Commercially available 4-methyl-2-nitro-phenylamine (20 g, 131.5 mmol) was dissolved in ethanol (300 mL), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with 100 mL of ethyl acetate, and concentrated. Water was added to the residue, which was then extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound (29 g, Yield 69%).
Reaction SMILES: C([N:8]([C@@H:16]([CH3:29])[C@@H:17]([F:28])[C:18]([O:20]CC1C=CC=CC=1)=[O:19])CC1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>CO.[OH-].[Pd+2].[OH-].O>[CH2:41]([O:40][C:38]([NH:8][C@@H:16]([CH3:29])[C@@H:17]([F:28])[C:18]([OH:20])=[O:19])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]([C@@H](F)C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)[C@@H](F)C(=O)O
Reaction time: 4.5 h
Yield: 74.5 %

Procedure:
Benzyl 3-(S)-N,N-dibenzylamino-2-(R)-fluorobutanoate (26.2 g, 66.8 mmol) in 370 mL of methanol containing 5.6 mL of concentrated hydrochloric acid is connected to a Parr hydrogenation apparatus with 2.62 g of palladium hydroxide as catalyst and hydrogenated in two lots at 50 psi. The lots are combined and filtered through a pad of celite. The celite is washed with water and methanol and the combined filtrates are concentrated in vacuo to give a yellow oil. The crude amino acid is taken up in 290 mL of water and treated with sodium carbonate (15.6 g, 140 mmol) and benzyl chloroformate (12.0 g, 70 mmol). After stirring for 4.5 hours, another 7.8 g of sodium carbonate is added and the reaction allowed to stir an additional 18 hours. The basic solution is washed with ether and then acidified with 500 mL of 1 hydrochloric acid. The resulting mixture is extracted with ether. Drying over magnesium sulfate followed by removal of the ether in vacuo affords 12.7 g of the desired N-benzyloxycarbonyl-3-(S)-amino-2-(R)-fluorobutanoic acid.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH:32](Br)[CH:33]=O)[CH:27]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]2=[O:44])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1[S:6][C:32]([C:31]2[CH2:30][S:29][CH:28]3[N:25]([C:26](=[O:44])[CH:27]3[NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24]=2[C:22]([O:21][CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:23])=[CH:33][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(N)=S
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
A solution of acetylthiourea (1.8 g) in dry tetrahydrofuran (20 cc) is added, in 5 minutes, to a solution, cooled to 3° C., of the mixture of the epimers of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(1-bromo-2-oxoethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.87 g) in dry tetrahydrofuran (58.7 cc). The reaction mixture is then stirred for 4 hours 30 minutes at 25° C. after which it is diluted with ethyl acetate (150 cc) and saturated sodium bicarbonate solution (150 cc). The organic layer is washed with distilled water (2×100 cc) and then with saturated sodium chloride solution (100 cc) and dried. After evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue is chromatographed on a column (height: 30 cm; diameter: 6 cm) of silica (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a 70:30 (by volume) mixture (1600 cc) of cyclohexane and ethyl acetate and then with a 30:70 (by volume) mixture (2000 cc) of cyclohexane and ethyl acetate, 100 cc fractions being collected. Fractions 27 to 33, containing the pure product, are combined and evaporated to dryness. 3-(2-Acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.54 g) is obtained in the form of a yellow froth.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([OH:20])[N:9]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]([O:20][C:26]([C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)=[O:27])[C:11]2=[O:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1N=C(c2ccccc2F)c2ccccc2N(C(=O)c2ccc(Cl)cc2)C1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A suspension of 1,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-1,4-benzodiazepin-2-one (610 mg, 2.25 mmole) in 25 ml of methylene chloride was treated with 4-chlorobenzoyl chloride (0.314 ml, 2.48 mmole) at room temperature. 4-Dimethylaminopyridine (303 mg, 2.48 mmole) was added and within minutes the reaction mixture became homogeneous. The reaction mixture was protected from moisture and stirred at room temperature overnight. An additional equivalent each of 4-chlorobenzoyl chloride and 4-dimethylaminopyridine were added and stirring was continued for 8 hours at 40°-45° C. The reaction mixture was diluted to 150 ml with methylene chloride and washed in succession with 10% citric acid solution (3×50 ml), saturated sodium bicarbonate solution (3×50 ml) and brine (50 ml). Rotoevaporation of the dried (MgSO4) organic phase gave a foam which on trituration with ether afforded a beige solid. Recrystallization from ethyl acetate afforded 612 mg of the title compound as a white powder in analytical purity: m.p. 198°-199° C.