Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[O:5][CH:4]=[C:3]1[O:9][CH2:10][C:11]([O:13]CC)=[O:12].Cl>[OH-].[Na+]>[O:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[O:5][CH:4]=[C:3]1[O:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)COc1coc(C)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(OCC(=O)O)co1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetate (8.3 g) in 1 N sodium hydroxide (40 ml) was stirred at room temperature for 30 minutes. To the mixture was added further 1 N sodium hydroxide (6 ml) and the resultant mixture was stirred for 30 minutes. To the reaction mixture was added dropwise conc. hydrochloric acid (4 ml) under ice-cooling, and resulting crystals were collected by filtration, washed with water, and dried to give crystals (6.8 g) of 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]>CCCCCC.CC(O)C>[NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C@:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1c(C)c2c(c(C)c1N)C[C@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2

Procedure:
1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinamine was subjected to preparative high-performance liquid chromatography (column: CHIRALCEL OD (20×250 mm, Daicel Chemical Industry, Ltd.), mobile phase: hexane-2-propanol=95:5); flow rate: 80 mL/min., column temperature: 30° C.) to provide the title compound. [α]D −21.4° (c 0.496, ethanol)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:2].Br[CH2:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:30][C:31]2[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:13][CH:12]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
N-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-N-(4-isopropylbenzyl)propanamide (0.18 g, 0.47 mmol) and methyl 2-(bromomethyl)benzoate (0.12 g, 0.52 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer-supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off, solvent was removed by evaporation, addition of EtOAc (10 ml) and the organic phase was washed with three portions of water. After drying the crude (MgSO4) and the solvent had been removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.16 gram of methyl 2-[(4-{3-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (yield 63.5%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.C(OC(C1C=NOC=1C1C=CC(Cl)=CC=1Cl)=O)C>C1(C)C=CC=CC=1>[C:11]1([C:10]2[O:9][N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cnoc1-c1ccccc1
Agent: CCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1cnoc1-c1ccccc1
Yield: 55 %

Procedure:
The procedure of Example 27 was employed utilizing ethyl-5-phenyl-4-isoxazolecarboxylate in lieu of ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate to yield upon recrystallization with toluene, 5-phenyl-4-isoxazolecarboxylic acid (7.5 g.; 55% yield) as a white solid having a melting point of 153°-154° C. and the following analysis:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:11].[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][NH2:12])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(=O)O)c(Cl)c1
Temperature: 0 °C

Procedure:
To a suspension of 4-amino-2-chlorobenzoic acid (3.00 g, 17.5 mmol) in hydrochloric acid (1.0 M, 30 mL) at 0° C. was added a solution of sodium nitrite (1.24 g, 18.0 mmol) in water (5.0 mL) over 5 min and the reaction mixture maintained at 0° C. for 5 hr. The resulting mixture was treated with tin(II) chloride (9.28 g, 49.0 mmol) in hydrochloric acid (1.0 M, 60 mL) and was warmed to RT for 64 hr. The resulting thick precipitate which formed was isolated by filtration, washed with ethanol (16 mL) and ether (15 mL) and was dried in vacuo to afford 2-chloro-4-hydrazinylbenzoic acid hydrochloride as a beige solid (3.54 g, 90% purity, 82%); Rt 0.22 min (Method 2); m/z 187 (M+H)+, (ES+). This material was used in the subsequent step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][CH:24]([NH2:28])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=[CH:12][CH:11]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CCN(C(C)C)C(C)C>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][CH:24]([NH:28][C:31](=[O:38])[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine trifluoroacetate salt (0.092 g, 0.21 mmol) in dichloromethane (5 mL) and Hunig's Base (0.20 mL) was added benzoyl chloride (50 μL, 0.43 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue partitioned between EtOAc and 1.0N NaOH. The organic layer was then separated, washed with brine (2×10 mL) and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC to give the desired product, N-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzamide as an off-white solid (0.046 g, 51%). Alternatively the crude product could be used in the next step without any further purification. M.p.>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.50 (d, J=7.6 Hz, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.87 (m, 2H), 7.48 (m, 3H), 7.17 (m, 2H), 6.85 (m, 2H), 5.53 (m, 2H), 4.30 (m, 1H), 3.70 (s, 3H), 3.24-3.13 (m, 3H), 2.95 (m, 1H), 2.16 (m, 1H), 1.99 (m, 1H); LCMS [M+H]: 413.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:18])[CH3:15])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCCO
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCCO
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 75 %

Procedure:
To a vigorously stirring solution of Boc-(Ala)2-OH (0.9 gm, 3.46 mmol) and NMM (0.57 mL, 5.2 mmol) in THF (20 mL) cooled to −15° C. was added under N2 atmosphere ethyl chloroformate (ECF) (372 μL, 3.56 mmol) and stirred for 2 min. A solution of H2N(CH2)4OH (462 mg, 5.19 mmol) in THF (5 mL) was added to the mixture followed by NMM (950 μL, 8.65 mmol) and the mixture was warmed to r.t. and stirred until silica gel TLC indicated complete consumption of the starting acid (eluting solvent—MeOH:DCM—1:10, Rf—0.45) (˜8 h). The solvent was evaporated, and the residue was diluted with EtOAc and washed with brine, water, saturated solutions of citric acid and NaHCO3, and the organic layer was dried using NaHSO4, and the solvent was removed under vacuum to yield a residue which was purified using silica gel flash column chromatography—Hexanes:EtOAc—1:3; to give the desired product in 75% yield (858 mg) as a solid—m.p.—102-104° C.
Reaction SMILES: C(O)C(O)C.[Na].[CH3:7][C@H:8]([C:21]([OH:23])=[O:22])[C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][C:17]=2[CH:18]=1.[O-]CC.[Na+:27].C(O)C>C(OCC)C>[CH3:7][C@H:8]([C:21]([O-:23])=[O:22])[C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][C:17]=2[CH:18]=1.[Na+:27]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(O)CO
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Reaction time: 0.02 h

Procedure:
A propylene glycol solvate of a sodium salt of naproxen was prepared. To a solution of naproxen (348 mg, 1.51 mmol) in diethyl ether (10 mL) was added propylene glycol (0.200 ml, 2.72 mmol). To the clear solution was added sodium ethoxide in ethanol (21%, 0.750 mL, 2.01 mmol). The solution became slightly yellow due to the sodium ethoxide. After 1 minute, crystals began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with diethyl ether (10 mL). The product was then air-dried and collected. The solvate was 2:1 naproxen Na:propylene glycol. The solid was characterized by TGA and PXRD.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH:12][C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[N:16]=[CH:15][N:14]=[C:13]2[NH:12][NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NNc2ncnc3c([N+](=O)[O-])cccc23)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NNc2ncnc3c(N)cccc23)cc1
Yield: 67.5 %

Procedure:
In a similar fashion using route 2 general procedure 4, 4-methyl-N′-(8-nitroquinazolin-4-yl)benzene-1-sulfonohydrazide 478 (100 mg, 0.27 mmol), SnCl2 (310 mg, 1.67 mmol), 6N HCl (1 drop) and EtOH (3 ml) at 80° C. for 3 h gave the title compound (60 mg, 65%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:25]2[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CNC2CCCC2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1

Procedure:
To a stirred solution of Ethyl1-[(cyclopentylamino)methyl]cyclopropane-1-carboxylate in acetone (700 mL) at room temperature was added potassium carbonate (29.0 g, 209.6 mmol) followed by the 2,4-dichloro-5-nitropyrimidine (Frontier Scientific; 29.81 g, 153.7 mmol).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl.[OH-].[NH4+:14]>CO>[NH2:14]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C/C(N)=C/C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 3-oxobutanoate (50 g, 0.32 mol) in MeOH (320 mL) and 30% ammonium hydroxide (280 mL) was stirred at ambient temperature overnight. The solution was neutralized carefully with conc. HCl (200 mL), partially concentrated at reduced pressure and extracted with EtOAc (2×300 mL). Combined organic phases were dried over Na2SO4, filtered and concentrated to afford 1,1-dimethylethyl (2Z)-3-amino-2-butenoate as an oil that crystallized on standing (54 g, 100% yield): 1H NMR (DMSO-d6) δ 7.63 (bs, 1H), 6.79 (bs, 1H), 4.18 (s, 1H), 1.74 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:11])[CH3:10])=[CH:4][N:3]=1.CC1(C)N([O])C(C)(C)CCC1.C(=O)(O)[O-].[Na+].ClCl>C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(O)c1cnc(Cl)nc1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClCl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-(2,4-dichloro-pyrimidin-5-yl)-ethanol (Example 20, 1.00 g, 5.2 mmol) in a mixture of methylene chloride (30 mL), THF (8 mL) and water (2 mL), tetrabutylammonium chloride (Aldrich, 50 mg, 0.15 mmol), TEMPO (Aldrich, 9 mg, 0.05 mmol) and sodium bicarbonate (208 mg, 2.48 mmol) were added and the mixture was cooled to 0° C. To the stirred mixture, colorex (Aldrich; active Cl2, 10-13%; 3.75 mL) was added and the mixture was stirred for 2 hours at 0° C. Water (10 mL) was added and the organic layer was separated and dried over sodium sulfate. Removal of solvent gave an oil which was purified by silica gel chromatography (1% MeOH/CH2Cl2) to yield a colorless oil. 232 mg, 23%. MS (M+H)+, 191.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](O)[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:34])=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([Cl:34])[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Temperature: 120 °C

Procedure:
To a suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (10.0 g) in phosphoryl chloride (25.7 mL) was added N,N-dimethylaniline (2.6 mL) and the mixture was heated at 120° C. for 6 hours. After cooling to room temperature the mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogencarbonate aqueous solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with diisopropylether to afford 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (8.0 g)
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]2=[O:31])[C@H:11]([CH:32]([CH3:34])[CH3:33])[CH2:10]1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]2=[O:31])[C@H:11]([CH:32]([CH3:34])[CH3:33])[CH2:10]1
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)[C@@H]1C[C@H](O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 72 h
Yield: 97.9 %

Procedure:
Benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.0 g) was dissolved in a 4/1/1 mixture of AcOH/THF/H2O (60 mL). After 72 h, additional 4/1/1 mixture of AcOH/THF/H2O (30 mL) was added. This solution was stirred an additional 24 h before it was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo to afford benzyl (S)-1-((1S,2S,4R)-4-hydroxy-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (750 mg). MS found: (M+H)+=375.3.
Reaction SMILES: [OH:1][C@@H:2]([C@H:10]([C:12]1C=CC=CC=1)C)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=S.C([OH:20])C>[Ni]>[OH:1][C@@H:2]([CH2:10][CH3:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:20]
Reactant: CCCCOC(=S)[C@@H](O)[C@@H](C)c1ccccc1
Reactant: CCO
Agent: [Ni]
Product: CCCCOC(=O)[C@@H](O)CC
Temperature: 80 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
n-Butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate (60 mg) was dissolved in ethanol (2.0 mL). Celite (240 mg) and an ethanol solution (3.0 mL) of Raney nickel (360 mg) were sequentially added at room temperature to the solution, and the mixture was stirred at 80° C. for 10 hours. The reaction mixture was filtered through Celite, and the filtrate was added to water (20 mL), followed by extraction with diethyl ether (20 mL×3). The organic layers were combined, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (methylene chloride), to thereby yield colorless oil (36 mg, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([O:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:34][CH:35]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: Oc1ccc(Cl)nc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc(Cl)nc2)cc1)c1ccccc1C(F)(F)F
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-chloro-5-hydroxy-pyridine, the title compound was isolated as a yellow solid in 73% yield (98% purity by HPLC).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=1.C([Mg]Br)C.[CH3:17][O:18][C:19]1[C:20]([N+:30]([O-:32])=[O:31])=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]2.[Cl-].[NH4+]>ClCCl>[OH:29][C:25]1([C:2]2[N:3]=[CH:4][N:5]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=2)[C:26]2[C:21](=[C:20]([N+:30]([O-:32])=[O:31])[C:19]([O:18][CH3:17])=[CH:28][CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: CN(C)S(=O)(=O)n1cnc(I)c1
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc2c(c1[N+](=O)[O-])CCCC2(O)c1cn(S(=O)(=O)N(C)C)cn1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (3.0 g, 10 mmol) (R. M. Turner, J. Org. Chem. (1991), 56, 5739-5740) in dichloromethane (40 mL) was treated with ethyl magnesium bromide (3.0M in diethyl ether, 3.3 mL) over 5 minutes, stirred for 30 minutes, treated with 6-methoxy-5-nitro-1-tetralone (2.6 g, 11.8 mmol), stirred for 16 hours, treated with ammonium chloride solution and extracted with dichloromethane. The extract was dried (MgSO4), filtered and concentrated to provide the desired compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.Cl[C:14]1[C:28]([F:29])=[CH:27][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([S:30][CH2:31][CH2:32][CH3:33])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC>[CH:21]1([NH:20][C:18]([C:17]2[CH:27]=[C:28]([F:29])[C:14]([N:2]3[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3]3)=[N:15][C:16]=2[S:30][CH2:31][CH2:32][CH3:33])=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Reactant: COC(=O)C[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)c(F)cc1C(=O)NC1CCCCC1
Temperature: 120 °C
Reaction time: 80 h

Procedure:
(S)-methyl 2-(piperidin-3-yl)acetate hydrochloride (263 mg, 1.36 mmol) was added to 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide (500 mg, 1.51 mmol) and potassium carbonate (418 μl, 3.02 mmol) in butyronitrile (20 ml) at room temperature and under air. The resulting suspension was stirred at 120° C. for 80 hours.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C1COCC1.O.[Cl-].[Na+].O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=1)=[O:22]
Reactant: COC(=O)c1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccc(C(=O)O)cc1
Yield: 70.6 %

Procedure:
4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester (127.7 mg, 0.36 mmol) in THF/H2O (3:1, 9 mL) was treated with LiOHH2O (30.2 mg, 0.72 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and added ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=4:1) to give 4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid as a white solid (86.4 mg, 70.6% 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]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21](O)=[O:22].C(OC(=O)[NH:30][CH2:31][CH2:32][NH2:33])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([NH:30][CH2:31][CH2:32][NH2:33])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)NCCN)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and N-(2-aminoethyl)carbamic acid tert-butyl ester.