Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].[C:38](Cl)(=[O:40])[CH3:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:38]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10])(=[O:40])[CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCOCC1(COC(=O)NCc2ccccn2)CCCO1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC1(COC(=O)N(Cc2ccccn2)C(C)=O)CCCO1

Procedure:
To 0.259 g (0.5 mmol) of the compound prepared in (b) above dissolved in 3 ml of chloroform was added, with stirring and under a nitrogen atmosphere, 0.393 g (5.0 mmol) of acetyl chloride. The resultant mixture was cooled in an ice bath and to the cooled mixture was added, dropwise, 0.51 g (5.0 mmol) of triethylamine. The resultant solution was then warmed to reflux and maintained at the reflux temperature for 2 hours. The volatiles were then removed under high vacuum and the resultant residue was dissolved in methylene chloride and washed rapidly with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resultant residue was then chromatographed on silica gel employing, successively as the eluents, a mixture of petroleum ether and ethyl acetate in a ratio of 4:1 by volume initially, with the product being eluted when the eluent was at a ratio of 7:3 by volume. The resultant solution was then concentrated to yield an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)=[CH:18][CH:17]=3)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1.[ClH:35].CCOCC>O1CCOCC1>[ClH:35].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][NH:24][CH2:23]4)=[CH:20][CH:21]=3)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn(-c4ccc(Br)cn4)nn3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cn(-c2ccc(Br)cn2)nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(5-bromopyridin-2-yl)-1H-1,2,3-triazole-4-carboxamido)phenyl)morpholine-4-carboxylate (63 mg, 0.12 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4 M, 0.36 ml, 1.44 mmol) was added. The reaction mixture was stirred for 2 hours at 60° C. After cooling, ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(5-bromopyridin-2-yl)-N-(4-(morpholin-2-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (48 mg, 87%) as a white solid. MS (ISP): 429.4 ({79Br} [M−H]+), 431.5 ({81Br} [M−H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:19])[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25].[OH-].[Na+:27].C>O>[CH3:1][C:2]1[C:7]([CH2:8][S+:9]([O-:19])[C:10]2[N-:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25].[Na+:27]
Reactant: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[n-]2)c1C
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Rabeprazole (10 g) was suspended in 20 ml water and sodium hydroxide solution (1.11 g sodium hydroxide dissolved in 10 ml water) was added at 25-30° C. Reaction mass was stirred for 30 minutes at 25-30° C. Added activated charcoal (1.0 g) and stirred for 30 minutes at 25-30° C. Filtered and washed charcoal bed with water (10 ml). Added 30 ml ethanol to filtrate and distilled out till get oily residue under reduced pressure at 30-35° C. Again added 30 ml ethanol to the oily residue and distilled out completely under reduced pressure at 35° C. To the residue added 100 ml diisopropyl ether and stirred at 25-30° C. for two hours. Filtered product under nitrogen atmosphere and washed with 20 ml diisopropyl ether. Dried under vacuum at 50° C. for 20-24 hours to obtain amorphous Rabeprazole sodium.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]2[CH:16]=[CH:17][CH:18]=[N:12][CH:13]=[CH:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CNCCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1C=CC=NC=C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromophenylsulphonyl chloride (1.50 g) in dicbloromethane (50 ml) was added slowly to a solution of homopiperazine (3.0 g) in dichloromethane (100 ml). The reaction was stirred at room temperature for 18 hours. The reaction mixture was washed with water (40 ml) and brine (150 ml), dried (MgSO4) and solvent removed in vacuo. The product was recrystallised from dichloromethane/hexane to give 1-(4-bromophenylsulphonyl) 1,4-diazepine a white solid (650 mg, mp 95-97° C.;
Reaction SMILES: C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.Cl.[CH2:32]([NH:39][C:40]([CH:42]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63](=[NH:65])[NH2:64])=[CH:59][CH:58]=1)[C:43]([NH:45][C@@H:46]([CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[C:47](O)=[O:48])=[O:44])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:66]([O:70][C:71]([N:73]1[CH2:78][CH2:77][N:76]([CH2:79][CH2:80][NH2:81])[CH2:75][CH2:74]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>CN(C)C=O>[C:66]([O:70][C:71]([N:73]1[CH2:74][CH2:75][N:76]([CH2:79][CH2:80][NH:81][C:47](=[O:48])[C@@H:46]([NH:45][C:43](=[O:44])[CH:42]([C:40](=[O:41])[NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:56][C:57]2[CH:58]=[CH:59][C:60]([C:63](=[NH:65])[NH2:64])=[CH:61][CH:62]=2)[CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:77][CH2:78]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]
Reactant: N=C(N)c1ccc(CC(C(=O)NCc2ccccc2)C(=O)N[C@H](C(=O)O)C2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCNC(=O)[C@@H](NC(=O)C(Cc2ccc(C(=N)N)cc2)C(=O)NCc2ccccc2)C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
N-ethyl-morpholine (28 μl, 0.22 mmol) and TOTU (78 mg, 0.24 mmol) was added to a solution of [2-benzylcarbamoyl-3-(4-carbamimidoyl-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid hydrochloric acid salt, (100 mg, 0.2 mmol, example 3 h, less polar diastereomer) in dimethylformamide (4 ml) at −15 to −20° C. After 30 min at that temperature 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (55 mg, 0.24 mmol, step a) in dimethylformamide (1 ml) was added and stirred for 2 more hours. The reaction mixture was warmed to room temperature and stand over night. The solvent was evaporated in vacuo, stirred for 2 days with diethyl ether, and the precipitate collected by suction to give the title compound in quantitative yield. mp.: 125-128° C., MS m/z: 676 ((M+H)+, 3%), 339.0 ((M+2H)2+, 100%).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:18])([F:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(C1C=CC(C)=CC=1)(OC)(=O)=O>CN(C)C=O>[CH3:1][O:16][C:9]([C:8]([F:17])([F:18])[F:7])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 20 °C
Yield: 60.1 %

Procedure:
Cesium carbonate (132.8 g) was added to a mixture of ethyl 4,4,4-trifluoroacetoacetate (75.0 g) and dimethylformamide (400 ml). The reaction mixture was heated to 20° C. for 30 minutes. A mixture of methyl tosylate (83.4 g) and dimethylformamide (150 ml) was added to the resulting reaction mixture within 40 minutes. The mixture was heated for 3 hours and cooled to room temperature. Upon dilution with water (800 ml) the reaction mixture was extracted with diethyl ether three times. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue distilled under reduced pressure to yield the product as a clear liquid (48.5 g, 60 %) with a boiling point of 62-70° C. at 12 mm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](Cl)=[O:8])[CH2:3][CH2:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.Cl>ClCCl.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])[CH:19]([C:23]([OH:25])=[O:24])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCOCC2)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tetrahydropyran-4-carbonyl chloride was added drop wise to a mixture of piperazine-1,3-dicarboxylicacid 1-tert-butyl ester (123 g, Reference Example 63) and triethylamine (150 g) in dichloromethane (2000 ml) over a period of 0.45 hours. After stirring at room temperature for 3 days the reaction mixture was treated with water (1500 ml) and then acidified to pH 2 by addition of hydrochloric acid (37%). The organic phase was separated, then washed with aqueous sodium chloride solution (1%) and then evaporated under reduced pressure to give a yellow foam (157 g) which was recrystallised from diethyl ether and then from ethyl acetate to give the title compound (67.9 g) as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:27])([CH3:26])[CH2:20][O:21][CH2:22][C:23]([OH:25])=[O:24])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29]C1C=CC(CN2C3C(=CC=CC=3)C(COC(C)(C)CO)=N2)=CC=1>>[CH3:28][O:29][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][O:18][C:19]([CH3:27])([CH3:26])[CH2:20][O:21][CH2:22][C:23]([OH:25])=[O:24])=[N:9]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cn2nc(COC(C)(C)CO)c3ccccc32)cc1
Reactant: CC(C)(COCC(=O)O)OCc1nn(Cc2ccccc2)c2ccccc12
Product: COc1ccc(Cn2nc(COC(C)(C)COCC(=O)O)c3ccccc32)cc1

Procedure:
The product was obtained with the method described for the preparation of compound 39b, using 2-{[1-(4-methoxybenzyl)-1H-indazol-3-yl]methoxy}-2-methylpropan-1-ol as starting material.
Reaction SMILES: CON(CC)[C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[Li].[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:19][C:14]1[C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4](=[O:21])[C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:10]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCN(OC)C(=O)CC1CCN(Cc2cccnc2OC)CC1
Reactant: [Li]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.50 g of N1-methoxy,N1-ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]acetamide obtained in Example 55 was dissolved in 3 ml of tetrahydrofuran and 1.8 ml of a 1.0M (2-thienyl)-lithium in tetrahydrofuran was added dropwise thereinto at −78° C. After completion of the dropwise addition, the mixture was further stirred at −78° C. for 1 hour. An aqueous saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 0.22 g of the title compound as a pale yellow oil. The NMR spectrum data of the title compound were agreed with those of Example 54.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:27]N1C(=O)CCC1=O>O1CCCC1>[Br:27][C:9]1[S:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][C:10]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(-c2cccnc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2cccnc2)sc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
A tetrahydrofuran (15 mL) solution of ethyl 2-(pyridin-3-yl)thiazole-4-carboxylate (1.17 g, 5.0 mmol) was added to −78° C. solution of potassium bis(trimethylsilyl)amide (12 mL, 6 mmol, 0.5 M in toluene) over 2 min. This reaction mixture was allowed to stir for 1.5 h and then was transferred via canula into a −78° C. solution of N-bromosuccinimide (1.35 g, 7.5 mmol) in tetrahydrofuran (5 mL). This mixture was stirred for 5 min and then the reaction vessel was removed from the cooling bath and allowed to warm to room temperature over 3 h. The reaction was quenched by pouring into a mixture of ether and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was subjected to silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a white solid (824 mg, 52%): 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=2.3 Hz, 1H), 8.71 (dd, J=4.9, 1.3 Hz, 1H), 8.25 (dt, J=8.2, 1.7 Hz, 1H), 7.41 (dd, J=7.9, 4.9 Hz, 1H), 4.48 (q, J=7.3 Hz, 2H), 1.46 (t, J=7.3 Hz, 3H); ESIMS m/z 315.0 (M+2).
Reaction SMILES: C(O)(C(F)(F)F)=O.Br[C:9]1[CH:10]=[N:11][N:12]([C:16]2[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:21])=[CH:18][N:17]=2)[C:13]=1[O:14]C.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[C:35]([CH3:42])[N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:36]=[C:35]([CH3:42])[N:34]=1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: Cc1cc(B(O)O)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)cc(C)n1

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 222 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and (2,6-dimethylpyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.27 (m, 2H) 1.57-1.67 (m, 2H) 1.77-1.86 (m, 1H) 2.57 (br. s., 6H) 3.17-3.24 (m, 2H) 3.24-3.32 (m, 2H) 3.79-3.92 (m, 2H) 8.06 (br. s., 2H) 8.42-8.60 (m, 2H) 8.72-8.86 (m, 2H) 8.86-8.97 (m, 1H) 14.03 (br. s., 1H). MS m/z [M+H]+ 408.5.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:25]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([C:7]2[C:8]3[N:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:25]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of compound 15b (500 mg, 0.960 mmol) in THF (20 mL) was added a solution of LiOH (100 mg, 4.18 mmol) in H2O (5 mL). The resulting solution was stirred at rt overnight, and then diluted with H2O (20 mL). The pH of the solution was adjusted to 3 with 2 N HCl solution. The resulting solids were collected by filtration and washed with Et2O to obtain compound 15c as a yellow solid (350 mg, 72% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O2: 482.2 (M+H). Found 482.0.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:27])/[CH:16]=[CH:17]/[C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[CH:9]=1>O1CCCC1>[O:22]1[C:21]2[CH:25]=[CH:26][C:18](/[CH:17]=[CH:16]/[C:15]([NH:14][C:10]3[CH:9]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:28])=[O:4])[CH:13]=[CH:12][CH:11]=3)=[O:27])=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: COC(=O)/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1

Procedure:
(Method G4) 1N NaOH solution (2.56 ml, 2.56 mmol) was added to a solution of 3-[3-[[(E)-3-(1,3-benzodioxol-5-yl)-1-oxo-2-propenyl]amino]phenyl]-(E)-2-propenoic acid methyl ester (3a) (0.30 g, 0.85 mmol) in tetrahydrofuran (4.0 ml), and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was washed with diethyl ether. The title compound was obtained as a white solid (0.24 g, 84%). 1H NMR (DMSO-d6, HMDSO), δ: 6.09 (2H, s); 6.43 (1H, d, J=16.0 Hz); 6.60 (1H, d, J=16.0 Hz); 6.89-7.76 (8H, m).; 7.92 (1H, br s); 10.16 (1H, br s); 12.38 ppm (1H, br s).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[NH:35][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(CCCCCCOC1CCCCO1)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CCCCCCO)c1ccc(C(F)(F)F)cc1
Yield: 99.2 %

Procedure:
To a magnetically stirred solution of 7-(tetrahydropyran-2-yloxy)-1-[4-(trifluoromethyl)phenyl]heptan-1-one (7.70 g, 0.0215 mol) in methanol (50 ml) was added para-toluenesulfonic acid hydrate (4.18 g, 0.022 mol). The resulting acidic mixture (pH˜2, pH paper) was reacted at room temperature for 20 hours. NaOH (1N) was added until the solution was neutral (pH˜7, pH paper) and the resulting mixture was concentrated in vacuo. NaOH (1N, 50 ml) was added and the mixture was extracted with dichloromethane (3×). The combined organic layers were successively washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude 7-hydroxy-1-[4-(trifluoromethyl)phenyl]heptan-1-one (5.85 g, 99% yield) as a white solid. This obtained solid was treated with pyridine (29.6 ml) and a solution of tosyl chloride (17.72 g, 0.093 mol) in pyridine (89 ml) was added at 0° C. The mixture was allowed to attain room temperature and reacted for 1 hour. The mixture was cooled at −10° C. and quenched with excess water. Extraction with diethyl ether (3×), followed by drying over Na2SO4, filtering and concentration in vacuo gave crude product which was purified by column chromatography (dichloromethane/heptane=2/1 (v/v)) to give pure toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl)phenyl]heptyl ester (7.91 g, 87% yield). 1H-NMR (400 MHz, CDCl3) δ 1.35-1.38 (m, 4H), 1.57-1.73 (m, 4H), 2.44 (s, 3H), 2.97 (t, J=7, 2H), 4.03 (t, J=7, 2H), 7.35 (d, J˜8, 2H), 7.73 (d, J˜8, 2H), 7.79 (d, J˜8, 2H), 8.04 (d, J˜8, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[Br:28][C:29]1[CH:42]=[CH:41][C:32]2[CH:33]=[C:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][O:36][C:31]=2[CH:30]=1>>[Br:28][C:29]1[CH:42]=[CH:41][C:32]2[CH:33]=[C:34]([S:37]([NH:8][C@H:9]3[CH2:13][CH2:12][N:11]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=5)[CH2:19][CH2:20]4)[C:10]3=[O:27])(=[O:38])=[O:39])[CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Reactant: O=S(=O)(Cl)C1=Cc2ccc(Br)cc2OC1
Product: O=C1[C@@H](NS(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 30.5 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 7-bromo-2H-benzopyran-3-sulfonyl chloride (161 mg), the title compound (87 mg) was obtained as a colorless amorphous material.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(O)/C=C/C1CCC(=O)C1CC/C=C\CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC(O)/C=C/C1CCC(O)C1CC/C=C\CCC(=O)O

Procedure:
150 mg of 7-[2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxocyclopentyl]-cis-4-heptenoic acid were dissolved in 20 ml of methanol and three times each time 150 mg of NaBH4 were added within the course 11/2 hours. The reaction solution was adjusted to pH 7 by means of glacial acetic acid, the solvent was removed by distillation under reduced pressure, the residue was acidified with 2N-HCl to pH 1 and extracted thrice with 150 ml of ether. After washing, the organic phase was concentrated.