Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C.CC([O-])(C)C.[K+].C(O)(C(F)(F)F)=O>C1COCC1.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[C:4]=1[OH:3])=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
A mixture of 4-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (964 mg, 2.00 mol) in THF (7.2 mL) was added drop wise a solution of 1 M KOtBu in THF (2.8 mL, 0.02 mmol) at −78° C. The red solution was stirred at −78° C. for 20 min, warmed to room temperature and stirred at that temperature for two hours before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil. It was dissolved in dichloromethane (4 mL) and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 h before it was concentrated in vacuo. It was redissolved in dichloromethane, triethylamine (1.4 mL) was added. The mixture was stirred under air overnight before it was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (59 mg): MS: (+) m/z 335.0 M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:24]=4[Cl:23])[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C(F)(F)F)c4Cl)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 2-chloro-3-(trifluoromethyl)benzoic acid (112 mg, 500 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (189 mg, 500 μmol) in pyridine (4 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→97/3), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (154 mg, 77%) as colorless crystals.
Reaction SMILES: FC1C=CC(C(S(C2C=CC(C)=CC=2)(=O)=O)NC(=O)C)=CC=1.N1C=CC(C=O)=NC=1.C(N(CC)CC)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH:54][C:55](=O)[CH3:56])[C:46](=O)[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)=[CH:41][CH:40]=1.C(O)(=O)C.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>[I-].OCCC1SC=[N+](C)C=1C>[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:54]=[C:55]([CH3:56])[N:62]([CH:63]3[CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67][CH2:68]3)[C:46]=2[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][N:48]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)NC(C(=O)c1ccncn1)c1ccc(F)cc1
Agent: CC(=O)NC(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: Cc1c(CCO)sc[n+]1C
Agent: O=Cc1ccncn1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
According to the method of J. A. Murry et al., J. Am. Chem. Soc. 2001, 123, 9696-9697, N-{(4-fluorophenyl)[(4-methylphenyl)sulfonyl]methyl}acetamide (C28) (250 mg, 0.778 mmol) and 5-(2-hydroxyethyl)-3,4-dimethyl-1,3-thiazol-3-ium iodide (44.5 mg, 0.156 mmol) were combined, and the reaction flask was evacuated and refilled with nitrogen gas twice. Dichloromethane (4 mL) was added, followed by pyrimidine-4-carbaldehyde (92.5 mg, 0.856 mmol), and the reaction mixture was heated to 35-40° C., then treated with triethylamine (1.63 mL, 11.7 mmol); the reaction was stirred at 35° C. for 1 hour, then cooled to room temperature. Aliquot: LCMS m/z 274.5 [(M+1) for N-[1-(4-fluorophenyl)-2-oxo-2-pyrimidin-4-ylethyl]acetamide (C29)]. After 2 hours at room temperature, the mixture was concentrated in vacuo, dissolved in ethanol (4 mL) and treated with acetic acid (0.22 mL, 3.8 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (358 mg, 1.79 mmol). The reaction was heated to reflux for 3 hours, then concentrated under reduced pressure and diluted with ethyl acetate and aqueous sodium bicarbonate solution until the mixture was basic. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Eluant: 5% methanol in ethyl acetate) provided the product. Yield: 60 mg, 0.14 mmol, 18%. LCMS m/z 438.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.95-2.00 (m, 2H), 2.12-2.23 (m, 2H), 2.61 (s, 3H), 2.68-2.77 (m, 2H), 4.21-4.33 (m, 2H), 4.65 (tt, J=12.4, 3.9 Hz, 1H), 6.97 (dd, J=8.7, 8.7 Hz, 2H), 7.12 (dd, J=5.2, 1.4 Hz, 1H), 7.29 (dd, J=8.8, 5.5 Hz, 2H), 8.54 (d, J=5.3 Hz, 1H), 9.27 (d, J=1.3 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][S:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][S:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCNC(=O)CSC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCNCCSC

Procedure:
5.18 g of S-methyl-thioglycolic acid-N-(2-methylthioethyl)-amide (Example 8a) is dissolved in 350 ml of tetrahydrofuran and added in drops to a suspension of 5.48 g of lithium aluminum hydride in 350 ml of tetrahydrofuran under a cover-gas atmosphere. Then, it is refluxed for 18 hours. While being cooled in an ice bath, the excess lithium aluminum hydride is carefully hydrolyzed by adding 100 ml of water in drops, it is stirred for 1 more hour, and then another 700 ml of water is added. The solution is extracted three times with methylene chloride/methanol 10/1, and the combined organic phases are washed with water one time. After concentration by evaporation, the residue is purified by chromatography with the mobile solvent system of methylene chloride/methanol: yield 1.5 g=32% of theory.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCOC(=O)c1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
This compound was prepared according to example 2 using ethyl bromopyruvate and N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) to yield ethyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-4-carboxylate as yellow solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([CH3:30])=[C:17]([CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:18][NH:19]C(=O)C(F)(F)F)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1>[NH2:19][CH2:18][C:17]1[C:16]([CH3:30])=[C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)[N:10]=2)[C:28]([CH3:29])=[CH:27][CH:26]=1
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(CN)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.7 %

Procedure:
To a solution of N-(3-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2,4-dimethylbenzyl)-2,2,2-trifluoro acetamide (Example-106, 0.800 g, 1.74 mmol) in THF (10 mL), aqueous solution of KOH was added and the reaction mass was stirred at RT for 3-4 h. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. MS (m/z): 362.86 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].Br[CH2:22][C:23]([N:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].[H-].[Na+]>CN(C=O)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:22][C:23]([N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C(CBr)N(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CNC1CCN(C(c2ccccc2)c2ccccc2)C1=O)N(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol in dry DMF (15 ml) was added 2-bromo-N,N-diphenyl acetamide (0.24 g, 0.82 mmol) and NaH (50 mg) under nitrogen. The reaction mixture was heated at 100 degrees overnight. After cooling, the solvent was evaporated and residue was taken up with ethyl acetate (50 ml) and washed with water (2×10 ml). The organic was dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give desired product in 73% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl>C(Cl)(Cl)Cl>[C:14]([S:21][CH2:11][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(Cc1ccc(Cl)cc1)C(=O)O
Reactant: OC(=S)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(SCC(Cc1ccc(Cl)cc1)C(=O)O)c1ccccc1

Procedure:
A solution of 2-(p-chlorobenzyl)acrylic acid (3.93 gm., 22 mmoles) and thiobenzoic acid (2.6 ml., 20 mmoles) in 40 ml. of methylene chloride was heated at reflux for 16 hours. The reaction mixture was evaporated to dryness and product crystallized from hexane (4.5 g.). Additional product was obtained by evaporation of the hexane mother liquor and chromatography of the residue (7.1 g.) on 200 g. of silica gel (230-400 mesh) with chloroform as eluant; 1.8 g., m.p. 111°-114° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](N1CCC(N(CC)C2C(N)=CC=C(F)N=2)CC1)[C:28]1C=CC=C[CH:29]=1.CC(C)=O.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.CO.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([NH:21][CH:28]([CH3:29])[CH3:27])=[CH:19][CH:18]=[C:17]([F:24])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1nc(F)ccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CCN(c1nc(F)ccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(c1nc(F)ccc1NC(C)C)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(6-fluoro-3-(nitro)-2-pyridinyl)amino]piperidine (EXAMPLE 195, 3.0 g, 8.37 mmol) is dissolved in ethanol (500 ml) and 0.75 g of platinum oxide is added. The reaction is placed on a Parr hydrogenator at 10 psi for 1 hr and then filtered through diatomaceous earth and concentrated under reduced pressure. The crude 1-benzyl-4-[N-ethyl-N-(6-fluoro-3-(amino)-2-pyridinyl)amino]piperidine (3.0 g, 9.13 mmol) is immediately dissolved in methanol (18 ml) and acetone (0.74 ml, 10.04 mmol) and acetic acid (13.1 ml, 228.3 mmol) are added. The reaction is stirred for 10 min, then cooled to 0° and sodium cyanoborohydride (0.61 g, 9.7 mmol) is added. The reaction is slowly warmed to 20°-25° and stirred for 18 hr. Then solid sodium bicarbonate is added with caution and the reaction is extracted with chloroform, washed with saline, dried over sodium sulfate and concentrated under reduced pressure. Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, NMR (300 MHz, CDCl3) 7.26-7.15, 6.88, 6.49, 4.28, 3.40, 3.44, 3.04, 2.93, 2.82, 1.93, 1.72-1.52, 1.13 and 0.81δ; CMR (CDCl3, 75 MHz) 155.9, 152.5, 146.1, 138.0, 129.1, 128.1, 126.9, 121.8, 104.3, 62.9, 57.5, 52.7, 44.4, 41.2, 29.7 and 22.8δ.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18]S(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:32])([F:31])[CH:25](O)[C:26]([F:29])([F:28])[F:27]>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:25]([C:26]([F:29])([F:28])[F:27])[C:24]([F:32])([F:31])[F:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C(OC1CN(C(c2ccccc2)c2ccccc2)C1)C(F)(F)F
Yield: 25 %

Procedure:
A solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (0.194 g, 0.61 mmol) in 2 mL of hexafluoroisopropanol in a sealed tube was stirred at 100° C. for 14 h, then concentrated. The residue was partitioned between 5 mL of ethyl acetate and 5 mL of a 10% NaOH solution. The organic layer was sequentially washed with 5 mL of water and 5 mL of a sat. aq. NaCl solution; dried over MgSO4, filtered and concentrated to an orange-yellow oil. Column chromatography (0-<20% EtOAc/hexanes) afforded 0.059 g (25%) of 1-benzhydryl-3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [K+].COC1C=C(C=CC=1S(O)(=O)=O)C([O-])=O.[Cl:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[O:30][CH3:31])(=[O:20])=[O:19].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>>[CH3:31][O:30][C:22]1[CH:23]=[C:24]([C:25]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:26])[CH:28]=[CH:29][C:21]=1[S:18]([Cl:17])(=[O:20])=[O:19]
Reactant: COc1cc(C(=O)Cl)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Agent: COc1cc(C(=O)[O-])ccc1S(=O)(=O)O
Agent: [K+]
Product: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)Cl
Yield: 92 %

Procedure:
Reacting the 3-methoxy-4-sulfobenzoic acid mono-potassium salt with an inorganic acid halogenide the 4-chlorosulfonyl-3-methoxybenzoyl chloride is obtained. To our surprise we have found that at lower temperature, in an appropriate solvent the t-butylamine reacts selectively with the aromatic acid chloride. Thus, the desired 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is obtained in 92% yield, with a purity of 96%, so it can be used without further purification for the synthesis of drug substances.
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:23][C@:22]3([CH3:36])[C@@H:24]([CH3:35])[CH2:25][CH2:26][C@H:27]4[C:28]([CH3:34])([CH3:33])[C@@H:29]([OH:32])[CH2:30][CH2:31][C@@:21]34[O:20][C:11]=2[C:12]2[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:10]2[CH2:23][C@:22]3([CH3:36])[C@@H:24]([CH3:35])[CH2:25][CH2:26][C@H:27]4[C:28]([CH3:34])([CH3:33])[C@@H:29]([OH:32])[CH2:30][CH2:31][C@@:21]34[O:20][C:11]=2[C:12]2[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=2[CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C)C4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2CN(C)C4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To Compound (27a) (54 mg, 0.11 mmol) dissolved in 6.0 ml of methanol was added 15 mg of 10% palladium-carbon, followed by stirring at room temperature for 2 hours under hydrogen atmosphere. The palladium-carbon was then filtered off, and the filtrate concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate) to give 44 mg (100%) of Compound (28a).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[OH:35])(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:37]1[C:46]2[C:41](=[C:42]([CH2:47][CH2:48]O)[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[O:35][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:41]=1[CH:40]=[CH:39][CH:38]=[N:37]2)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: OCCc1cccc2ncccc12
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of 0.22 g (0.41 mmol), (S)-3-[4-(4-dimethylamino-butanoylamino)-2-hydroxy-benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester, 0.079 g (0.41 mmol), 2-quinolin-5-yl-ethanol, 0.14 g (0.62 mmol) triphenylphosphine, and anhydrous methylene chloride (5 mL) was stirred at room temperature. Diethyl azodicarboxylate 0.1 mL (0.62 mmol) was added dropwise and the resulting orange solution was stirred at room temperature for 24 h. TLC analysis indicated complete reaction. The reaction mixture was concentrated in vacuo to give a deep yellow oil. The product was purified over silica eluting with 10% (8:1 EtOH/NH4OH): 90% methylene chloride to yield 0.115 g (0.17 mmol, 41%) of (S)-3-[4-(4-dimethylamino-butanoylamino)-2-(2-quinolin-5-yl-ethoxy) benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester as a yellow oil. MS (APCI) m/z 685.5 (M−1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14](Cl)=[O:15]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([O:10][CH3:9])[C:19]=1[O:20][CH3:21])[C:14]([NH:1][CH:2]1[CH2:6][N:5]([CH3:7])[N:4]([CH3:8])[CH2:3]1)=[O:15]
Reactant: CN1CC(N)CN1C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)NC2CN(C)N(C)C2)cc(OC)c1OC

Procedure:
To 10 g (0.09 mole) of 4-amino-1,2-dimethylpyrazolidine in chloroform was added with stirring 20.7 g. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride. After 30 minutes of stirring the solution was extracted with dilute sodium hydroxide. The chloroform solution was dried (sodium sulfate), filtered, and the filtrate concentrated. The resulting crystalline material was recrystallized from equal portions of ethyl acetate and isopropyl ether. The product (12.1 g.; 44%) melted at 163°-166° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C:49]1[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=1[NH:51][CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]([C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[O:48][CH3:47])[CH3:52])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNc1ccccc1OC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2ccccc2OC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-methoxy-n-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 784 [(M+H)+].