Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)C.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:17][CH:18]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CN(CC(=O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CC(O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
tert-Butyl 2-oxo-2-(4-morpholin-4-ylphenyl)ethyl(methyl)carbamate (1.41 g, 4.22 mmol) was stirred under N2 in dry THF (25 ml) and absolute ethanol (2 ml). Sodium borohydride (0.16 g, 4.23 mmol) was added and the reaction stirred for 18 hr then the solvents evaporated. The residue was chromatographed over silica gel (90 g) eluting with 50% ethyl acetate-hexane. The product was obtained (1.0 g, 71%) as a clear gum which slowly crystallized to give a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[OH:18][CH:17]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)nc2)CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of 5-bromo-2-(trifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2° C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2° C. as a solid. The reaction mixture was warmed to 10° C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to afford the title compound which was used without further purification in the next step.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]([O-:30])=[O:29])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]([OH:30])=[O:29])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CCCC3C(=O)[O-])cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC[C@@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylate was hydrolyzed to the acid by dissolving in 5 ml methanol and potassium carbonate (0.100 g in 4 ml water) was added. The mixture was stirred for 2 days. The mixture was cooled to room temperature and methanol was removed in vacuo. The mixture was acidified to form a white precipitate. The solid was filtered to give (1R,2R)-2-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)methyl]cyclopentanecarboxylic acid (0.012 g, 10%)
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]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[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:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Morpholine (190 μl, 2.17 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (209 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=3/1). Thus, 4-[2-nitro-4-(trifluoromethyl)phenyl]morpholine (270 mg, 97.7%) was yielded as an orange-colored oily material.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[NH:30])[NH2:29])[CH2:23]1.CC(C)([O-])C.[K+]>C(O)C.O>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:3][N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:30]=1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccncc1
Reactant: CC1CCCN(C(=N)N)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1occc1-c1nc(N2CCCC(C)C2)ncc1-c1ccncc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(4-pyridinyl)-2-propen-1-one (256 mg, 1 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (267 mg, 1.500 mmol) in ethanol (5 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2.000 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25-50% ethyl acetate and isohexane to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(4-pyridinyl)pyrimidine (195 mg, 58%). A solution of 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(4-pyridinyl)pyrimidine (167 mg, 0.5 mmol) in dichloromethane (1 ml) was treated with hydrogen chloride (1M in diethyl ether, 0.6 ml). The solvent was evaporated and the residue co-evaporated with diethyl ether (×2). The residue was triturated with diethyl ether and the resulting solid was collected, washed with diethyl ether and dried to give the title compound as a yellow solid (121 mg, 65%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.76 (1H, d), 8.57 (1H, s), 7.80 (2H, d), 7.51 (1H, d), 6.00 (1H, d), 4.67-4.60 (2H, m), 3.06-2.99 (1H, m), 2.67-2.76 (1H, m), 2.37 (3H, s), 1.91-1.19 (5H, m), 0.93 (3H, d).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CN(C=O)C>[C:14]1([C:12](=[O:13])[CH2:11][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccnc1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COc1cccnc1)c1ccccc1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a suspension NaH (0.8 g, 60%, 20 mmol) in DMF (15 mL) was added a solution of 3-hydroxylpyridine (1.9 g, 20 mmol) in DMF (10 mL) at ° C. under nitrogen. After the mixture was stirred 15 min, a solution of 2-bromoacetophenone (3.98 g, 20 mmol) in DMF (10 mL) was added dropwise. The resulting mixture was stirred for 5 h until the starting material consumed. Water was added to quench the reaction and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography eluted by hexane:ethyl acetate (1:1) and the correct product was obtained as a white solid; mp 81-82° C.; yield 75% (3.19 g); H NMR (400 MHz, CDCl3): d 5.40 (s, 2H, OCH2), 7.28 (m, 2H, Ar), 7.59 (m, 2H, Ar), 7.67 (m, 1H, Ar), 8.03 (m, 2H, Ar), 8.32 (m, 1H, Ar), 8.43 (m, 1H, Ar); CNMR (100 MHz, CDCl3): δ 70.8, 121.7, 123.9, 128.1, 129.0, 134.2, 134.3, 138.2, 143.1, 154.4, 193.6; IR ν (cm−1) 3054, 3007, 2988, 2963, 2898, 1702, 1579, 1486, 1450, 1422, 1275, 1263, 1233, 1090, 974, 815, 765, 751.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[NH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ccsc1C(=O)OC
Temperature: 120 °C
Reaction time: 10 h
Yield: 47.8 %

Procedure:
34.1 ml (0.300 mol) of n-butyl iodide was added to a solution of 15.7 g (0.100 mol) of methyl 3-aminothiophene-2-carboxylate and 15.2 g (0.110 mol) of potassium carbonate in 200 ml of N,N-dimethylformamide at 25° C., and the mixture was stirred at 120° C. for 10 hours. After cooling, the solvent was evaporated under reduced pressure and 200 ml of ethyl acetate was added to the residue to remove inorganic salts by filtration. The filtrate was again concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=1/9 v/v) to give 10.2 g (yield: 48%) of methyl 3-(n-butyl)aminothiophene-2-carboxylate (Compound a-1)
Reaction SMILES: [Na].[S:2](=[CH:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH3:12])[N:7]=1)(=[O:4])=[O:3].[CH3:13]I>>[CH3:13][N:10]1[CH:9]=[C:8]([CH3:12])[N:7]=[C:6]([CH:5]=[S:2](=[O:3])=[O:4])[CH2:11]1
Reactant: CI
Reactant: Cc1cncc(C=S(=O)=O)n1
Agent: [Na]
Product: CC1=CN(C)CC(C=S(=O)=O)=N1

Procedure:
4.0 g of 2-sulfonylmethyl-6-methylpyrazine sodium salt (2900) was added to a solution of 15 ml methyl iodide/30 ml methanol and the mixture refluxed for 4 days. It was then cooled and filtered. The solid was chromatographed (Biogel P-2/water) and freeze-dried to give 3.4 g of product (3000). It was recrystallized from propanol/water, m.p.>280° (dec.). UV H2O max: 288 (3.92).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[NH4+:11]>CO>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [OH-]
Solvent: CO
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (8.54 g, 37.48 mmol) in methanol (12 mL) was added dropwise over 10 minutes to an ice-bath cooled solution of 7M ammonium hydroxide (60 mL, 420 mmol) in methanol (60 mL) and the resulting solution was stirred at room temperature for 24 hours. The mixture was concentrated and water was added. The solid was filtered and dried under reduced pressure to give the title compound (6.23 g, 73%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[K+].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1>C(#N)C>[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][N:46]([CH2:6][CH2:7][CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Reactant: COc1cncnc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Yield: 57.6 %

Procedure:
To a solution of crude 3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (18.3 mmol, 1.0 equiv.) in 225 mL of anhydrous acetonitrile was added 3.03 g (18.3 mmol, 1.0 equiv.) of potassium iodide, 3.81 mL (21.9 mmol, 1.2 equiv.) of N,N-diisopropylethylamine and 3.89 g (20.1 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 500 mL of chloroform. The organic layer was washed with 100 mL portions of 10% potassium carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide followed by chromatography on silica gel using 20% methanol in ethyl acetate to obtain 4.83 g (58%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from hot methanol gave 4.05 g (68%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine hydrochloride, m.p. 170° C. (d). Elemental analysis calculated for C22H30N6O3S/3 HCl: C, 46.52; H, 5.86; N, 14.80; found: C, 46.14; H, 6.22; N, 14.51.
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[C:8]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10](=[O:18])[NH:9]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6][CH:1]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:19])[NH:9][C:10]1=[O:18]
Reactant: COC(OC)OC
Reactant: O=C1Cc2ccccc2C(=O)N1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (5.648 mL, 51.56 mmol) is added to a solution of 4H-Isoquinoline-1,3-dione (4 g, 24.82 mmol) in acetic anhydride (41.6 mL) and N,N-dimethylformamide (10.4 mL). After it is heated at 125° C. for 50 min, it is cooled and filtered to collected 3.698 g (73%) of the title compound as a yellow solid. mp 260-261° C.; MS (ESI) m/z 204.04 (M+1). Found: C, 58.34; H, 3.63; N, 10.21.
Reaction SMILES: C1(C[O:8][C:9](=[O:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH3:33])[C:24]=3[O:34][CH3:35])=[C:12]([CH2:36][CH2:37][CH3:38])[C:11]=2[OH:39])C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:39][C:11]1[C:12]([CH2:36][CH2:37][CH3:38])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH3:33])[C:24]=2[O:34][CH3:35])[CH:14]=[CH:15][C:10]=1[C:9]([OH:40])=[O:8]
Reactant: [H][H]
Reactant: CCCc1c(OCCCCCCc2ccc(C(C)C)c(OC)c2OC)ccc(C(=O)OCc2ccccc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(C)C)c(OC)c2OC)ccc(C(=O)O)c1O

Procedure:
A solution of 6.96 g of 2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester in 150 mL of ethyl acetate and 1.4 g of 10% palladium on carbon was stirred in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to 5.45 g, mp 106°-108°, of 2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbenzoic acid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 50 using 20.0 g of (R)-2-pyrrolidinemethanol, 44.0 g of benzyl chloroformate and 200 ml of diethyl ether to give 56.4 g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenyl methyl ester. Forty-five g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester is reacted with 38.4 g of (1,1-dimethylethyl)dimethylsilylchloride, 58 ml of triethylamine, 1.3 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride to give 41.5 g of the desired product as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[NH:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=1)[CH3:10].[OH-].[Na+]>C(Cl)Cl>[Br:1][C:12]1[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1ccc(CC)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(CC)[nH]1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-Bromosuccinimide (5.86 g, 0.033 mol) was added to a solution of ethyl 5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 12, 5.0 g, 0.03 mol) in DCM (85 ml) at 0° C., and the reaction was stirred for 30 minutes then poured to a chilled beaker containing 2 N NaOH (50 ml). The layers were separated and the aqueous layer was extracted with DCM (×3). The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The resultant dark brown solid was purified by flash chromatography (hexanes/EtOAc, 10:1) to give the title product as a white solid (5.0 g, 68%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccns2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccns3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-isothiazol-5-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:31]([Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1c2c(c(O)c3ncccc3c2O)C(=O)N1Cc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O)(C(C)C)C(C)C

Procedure:
A solution of 7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 2 (1.039 g, 3.07 mmol) in 31 mL of DMF was stirred with imidazole (314 mg, 4.62 mmol) and triisopropylsilylchloride (TIPSCl, 0.723 mL, 3.38 mmol) under a N2 atmosphere for 1.5 days when most of the starting materials was converted to the regiospecific mono TIPS (triisopropylsilyl) protected compound. The solid bisphenol left in the reaction was filtered and recycled. The mother liquor was dried and the residue was suspended in EtOAc. The organic layer was washed with water and dried. The resulted solid 12 was carried to the next step. EI MS (m/z) 495.6 [MH+], 517.4 [M+Na].
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH2:4][CH2:3]1.[Cl:6][C:7]([Cl:12])(Cl)[C:8](Cl)=[O:9]>CCOCC.[Zn]>[Cl:6][C:7]1([Cl:12])[C:2]2([CH2:5][CH2:4][CH2:3]2)[CH2:1][C:8]1=[O:9]
Reactant: C=C1CCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CC2(CCC2)C1(Cl)Cl
Reaction time: 4 h

Procedure:
Methylenecyclobutane (5.00 g, 70.5 mmol) and zinc dust (13.8 g, 211 mmol) were suspended in dry Et2O (200 mL) in a 3 necked round bottomed flask having an addition funnel and reflux condenser and placed in a sonic bath at 25° C. The system was sonicated and 2,2,2-trichloroacetyl chloride (10.282 mL, 91.607 mmol) (as a solution in 50 mL dry Et2O) added drop-wise, during which time the reaction became warm and the Et2O began refluxing). The sonication was continued for 4 hours. The reaction mixture was filtered through a pad of Celite® and the organic layer was washed sequentially with NH4Cl, NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was in the next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=O)=[CH:7][CH:6]=1.C(OP([CH:23]1[C:28](=[O:29])[NH:27][C:26]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:25]=2[S:24]1)(OCC)=O)C>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][CH:13]=[C:23]2[C:28](=[O:29])[NH:27][C:26]3[CH:30]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:32]=[CH:33][C:25]=3[S:24]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(/C=C/C=O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)NC(=O)C(P(=O)(OCC)OCC)S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C(=CC=Cc1ccc(OC)cc1)S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, sodium hydride (4.65 g, content 60%) was added in small portions to a THF solution (300 ml) containing (2E)-3-(4-methoxyphenyl)acrylaldehyde (10 g) synthesized by the process described in Reference Example 1 and ethyl 2-(diethoxyphosphoryl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (21.7 g, synthesized according to the process disclosed in WO00/63197). The resulting mixture was slowly warmed up to room temperature and stirred overnight. The same aldehyde as above (1.5 g) was added thereto and stirred for another 2 hours. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (30 ml), hexane (100 ml), a 1N aqueous hydrochloric acid solution (50 ml) and water (600 ml) were added to the residue, followed by stirring at room temperature for 6 hours. The solid was collected by filtration and dried under reduced pressure. Ethyl 2-[3-(4-methoxyphenyl)prop-2-en-1-ylidene]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (22.43 g) was obtained as a yellow solid.