Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[C:7]([O:10][C:11](=O)[CH3:12])(=[O:9])[CH3:8].C(C1OC=CC=1Br)(=O)C.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+](C)([O-])=O.C1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1([CH3:8])[O:10][CH2:11][CH2:12][O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccoc1
Agent: CC(=O)c1occc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: OCCO
Product: CC1(c2occc2Br)OCCO1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
At 0°, a solution of anhydrous ferric chloride (2.7 g, 17.0 mmol) in 50 ml of nitromethane is added portionwise with stirring over a period of 5 hours to a mixture of 3-bromofuran (25.0 g, 170.0 mmol) and acetic anhydride (20.4 g, 200.0 mmol) in 50 ml of nitromethane. After addition is completed, the resulting mixture is stirred at RT for 17 hours and is then evaporated in vacuo. The residue is taken up in 200 ml of diethyl ether, treated with 3.0 g of activated charcoal and filtered. The filtrate is washed with 5% sodium bicarbonate and dried and the solvent is removed by rotoevaporation to give, after purification, 2-acetyl-3-bromofuran. A well-stirred mixture of 2-acetyl-3-bromofuran (13.7 g, 72.0 mmol), ethylene glycol (5.9 g, 94.0 mmol), p-toluenesulfonic acid (p-TSOH; 20 mg) and benzene (50 ml) is refluxed for 9 hours, after which additional ethylene glycol (1.8 g, 29.0 mmol) and p-TSOH (5 mg) is added and the refluxing is continued a further 16 hours. The reaction mixture is then washed with sat. sodium bicarbonate and with water and is dried. The solvent is removed by rotoevaporation to give 2-(3-bromo-2-furyl)-2-methyl-1,3-dioxolane. To a solution of 1.6M butyllithium in hexane (38 ml) and dry diethylether (40 ml), under N2, is added dropwise with stirring a solution of the above dioxolane (11.18 g, 48.0 mmol) in 40 ml of ether, keeping the temperature below -68°. After addition is completed, the mixture is stirred for 30 min. at -70°, and then a slurry of CO2 (50.0 g) in 100 ml of dry diethyl ether is added. The mixture is kept at -65° for 15 min. and is then allowed to warm to 10°. Water is added, followed by 10% sodium carbonate. The phases are separated and the organic phase is extracted. The combined aqueous phases are acidified with conc. HCl and extracted with ether. The organic phases are combined and dried and the solvent is removed by rotoevaporation. The resulting product is suspended in 5% HCl (85 ml) and stirred at RT for 2 hours, then extracted with ether and the combined ether phases are dried and evaporated to dryness. The crude product is purified to give 2-acetyl-3-furancarboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N:12]=[N:13][CH:14]([C:24]([CH3:26])=[O:25])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])(=[O:29])[CH3:28]
Reactant: CC(=O)C(N=Nc1cc(S(=O)(=O)O)ccc1O)C(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-Hydroxy-5-sulfophenylazo)acetoacetanilide (40 g) was dissolved in boiling pyridine (750 ml) and acetic anhydride (100 ml) added. Some material precipitated while the reaction mixture was hot. After being cooled, the product was filtered off and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]([NH2:12])=[O:14])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](CC#N)Nc1ccc(Br)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](CC(N)=O)Nc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(3S)-3-[(4-bromophenyl)amino]butanenitrile (for a preparation see Intermediate 12) (17.3 g, 72.4 mmol) was taken up in Toluene (500 ml) and H2SO4 (19.28 ml, 362 mmol) added. The biphasic mixture was stirred at 60° C. After two hours, only a small amount of SM remained by LCMS so the reaction was diluted with water (500 ml) and the phases separated. The aqueous phase was basified with 10N NaOH and extracted with EtOAc (2×750 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.5 g). LCMS (Method B): Rt=0.77, MH+=257
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([OH:10])[CH:9]=1.Cl[CH:15]([CH3:18])[CH:16]=[CH2:17].[OH-].[Na+]>CS(C)=O>[CH3:17][CH:16]([O:10][C:8]1[CH:9]=[C:4]([CH3:3])[CH:5]=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12])[CH:15]=[CH2:18]
Reactant: C=CC(C)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CC(C)Oc1cc(C)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
24 g of sodium hydride was added in portions to a stirred mixture of 153 g of 5-methyl-2-nitrophenol and 500 ml of DMSO. Then 135.7 g of 3-chloro-1-butene was added drop-by-drop (over 5 minutes) to the stirred mixture, which then was stirred at reflux (79°-81° C.) for 24 hours. Then the mixture was made basic with 50% aqueous sodium hydroxide, poured over ice water and extracted with methylene chloride. The extract was washed with cold water, dried (MgSO4), filtered and stripped of solvent, to give 1-(1-methyl-2-propenyloxy)-5-methyl-2-nitrobenzene (1A), as a dark-colored syrup.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11]=O.[C:13]([BH3-])#[N:14].[Na+].[H-]>C(O)C.C(O)(=O)C>[CH3:11][N:14]([CH3:13])[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(N)cc1O
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(N(C)C)cc1O
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 5-amino-2-methoxyphenol (5.0 g, 36 mmol) in ethanol (250 mL), was added 33% formaldehyde (4×1.5 mL at times 0, 60 min, 140 min and 185 min) and sodium cyanoborohydride (4×0.8 g, at times 30 min, 120 min, 165 min and 210 min). After each addition of the hydride, pH was adjusted to ˜6 using acetic acid. The mixture was stirred for an additional 2 h and then concentrated in vacuo. The residue was partitioned between brine/diethyl ether and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel using hexane/EtOAc (7:3) as eluent to give 1.17 g (20%) of the title compound. MS m/z 168 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][N:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:42]([O:46][CH3:47])(=[O:45])[CH2:43][CH3:44]>CC#N.CCOC(C)=O>[C:11]([N:10]([CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28]/[CH:44]=[CH:43]/[C:42]([O:46][CH3:47])=[O:45])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)N(CCCc1ccccc1O)CCC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)OC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)/C=C/Oc1ccccc1CCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-(3,3-diphenylpropyl)-N-[3-(2-hydroxyphenyl)propyl]benzamide (100 mg) in MeCN (2 mL) was added NMM (2.3 mg) and methyl propionate (22.4 mg) at ambient temperature. The reaction mixture was stirred for 2 hours at the same temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-70:30) to give a methyl (2E)-3-(2-{3-[benzoyl(3,3-diphenylpropyl)amino]propyl}phenoxy)acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]([C:22]2[S:23][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][CH:21]=2)=[O:25])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)s1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg) and 5-(methylsulfonyl)thiophene-2-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)thiophene-2-carboxamide. MS (Q1) 393.0 (M)+.
Reaction SMILES: [Br:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[NH:23]1[CH2:27][CH2:26][NH:25][C:24]1=[S:28].C(O)C>C(O)(=O)C>[BrH:1].[CH2:16]([C:2]1[S:28][C:24]2=[N:23][CH2:27][CH2:26][N:25]2[C:3]=1[C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C1NCCN1
Reactant: O=C(C(Br)Cc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Clc1ccc(C2(C3=C(Cc4ccccc4)SC4=NCCN43)CCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of the crude 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one described above, imidazolidine-2-thione (1.02 g), ethanol (15 ml) and acetic acid (10 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was dried by azeotropic distillation with ethanol (50 ml) followed by ethyl acetate (50 ml). The solid remaining after removal of residual solvent in vacuo was crystallised from ethanol. The resulting product was collected by filtration, washed with ethanol (10 ml) and dried in vacuo at 60° C. to give 2-benzyl-3-[1-(4-chlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]-thiazole hydrobromide as white microneedles (2 g), m.p. 255-257° C.
Reaction SMILES: C(OC(N1C[C@@H](C)N2[C@H](CC3C2=NC(Br)=CC=3)C1)=O)(C)(C)C.C(OC([C:28]1[N:36]([C@H:37]([CH3:47])[CH2:38][NH:39][C:40](OC(C)(C)C)=[O:41])[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[CH:29]=1)=O)C>>[CH3:47][C@H:37]1[N:36]2[C:28](=[CH:29][C:30]3[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=3)[C:40](=[O:41])[NH:39][CH2:38]1
Reactant: CCOC(=O)c1cc2cccnc2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Product: C[C@@H]1CNC(=O)c2cc3cccnc3n21

Procedure:
This compound was prepared in analogy to Example 1 intermediate b), from (R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-pyrrolo [2,3-b]pyridine-2-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>ClCCl>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1NC(C)=O
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 3-amino-7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 3, 287 mg, 1.1 mmol) in dichloromethane (10 ml) was added pyridine (2 ml) and acetic anhydride (0.16 ml, 1.7 mmol) at room temperature. After stirring for 3 h, the mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with 2N aquous HCl (100 ml), water (100 ml), saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), and dried (MgSO4). After removal of solvent, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:101:1) to give 320 mg (98%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([NH2:20])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=[O:16])([O-:10])=[O:9].[C:21](Cl)(=O)[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][CH2:37][CH3:38].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:37]([C:38]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=2[N:20]=1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 51 %

Procedure:
Triethylamine (4.85 ml) was added to a suspension of 4-nitroanthranilic acid (3.00 g) in methylene chloride (30 ml) and then the mixture was cooled with ice. The reaction mixture, with stearoyl chloride (4.99 g) dropwise added thereto, was stirred for 3.25 hours at room temperature and then was cooled with ice. Then, triethylamine (2.55 ml) and ethyl chlorocarbonate (1.74 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 200 g, chloroform-hexane), thereby yielding 3.62 g of the aimed compound as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C(OC(Cl)=O)C(C)C.N>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH2:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
111.7 g of benzyloxycarbonyl-β-alanine were dissolved in 1 liter of dimethylformamide, cooled to -20° C, treated with 70 ml of triethylamine and 67 ml of chloroformic acid isobutyl ester and stirred at -20° C for 3 minutes. Dry ammonia gas was led into this mixture until the pH rose to 11, care being taken that the temperature did not exceed -10° C. The mixture was stirred for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The residue was recrystallised from water. Yield: 91 g; melting point 162°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(C2=CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a round bottom flask containing ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol), sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol (0.617 mL, 15.2 mmol). The mixture was stirred at room temperature overnight. Reaction was quenched via addition of 1N HCl in water (2 mL), then diluted with EtOAc and transferred to reparatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organics were washed with brine, dried over Na2SO4, and filtered, at adsorbed to Celite (10 mL). Column chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM afforded 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; 1H NMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d, J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd, J=5.4, 5.4, 2H), 3.32 (br s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18](=[O:34])[CH2:19][CH:20]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2)[C:21](O)=[O:22])([CH3:16])([CH3:15])[CH3:14].C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:21](=[O:22])[CH:20]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]=[CH:29]3)[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:34])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C)OC(=O)CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and 4-tert-butoxy-2-(5-isoquinolinyl)-4-oxobutanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 447 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 1.23 (s, 9H), 1.25 (s, 9H), 2.71 (dd, 1H), 3.02 (dd, 1H), 4.22 (m, 2H), 4.71 (m, 1H), 6.57 (s, 1H), 7.08 (d, J 8.5, 2H), 7.24 (d, J 8.5, 2H), 7.67 (m, 1H), 7.78 (m, 1H), 8.03 (d, J 7.8, 1H), 8.13 (d, J 7.1, 1H), 8.55 (d, J 6.8, 1H), 8.63 (m, 1H), 9.31 (s, 1H); Anal. Calcd for C28H34N2O3+1 CH3CN+0.8 H2O: C, 71,77; H, 7.75; N, 8.37. Found: C, 71.64; H, 7.38; N, 8.16.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-].[Ca+2].[OH-]>ClCCl>[ClH:1].[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:6])=[O:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2)=[O:16]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(S(=O)C2CCNCC2)ccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(S(=O)(=O)C2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 8.9 %

Procedure:
m-Chloroperoxybenzoic acid (0.30 g) was added to a solution of 2-chloro-5-(piperidin-4-ylsulfinyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g) in dichloromethane (10 ml). After 2 h calcium hydroxide (170 mg) was added and 30 min. later the salts removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 0-2% ethanol in dichloromethane). The residue was dissolved in methanol (5 ml) and hydrochloric acid (0.25 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the solution was concentrated under reduced pressure and triturated with diethyl ether to yield the title compound (0.03 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[CH2:30]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:32])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH3:31]
Reactant: Nc1cc(O)ccc1F
Reactant: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)SC(C)(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)Nc2cc(O)ccc2F)cc1

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-ethanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:11][C:10]=1[CH:21]=O>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:13][C:14]=1[CH2:15][NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1cc(-n2cncn2)cc(C=O)c1N
Reactant: CCOC(=O)CN
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNCc1cc(-n2cncn2)cc(C)c1N
Reaction time: 16 h
Yield: 51.7 %

Procedure:
A mixture of ethyl glycinate (0.38 g), 1-(4-amino-3-formyl-5-methylphenyl)-1,2,4-triazole (0.5 g) and 3Å molecular sieves (1.0 g; "Fluka" [Trade Mark] article No. 69828) was stirred and heated under reflux in chloroform (10 cm3) for 4 hours. The cooled mixture was filtered, evaporated in vacuo, and the residue taken into ethanol (30 cm3). The solution was then hydrogenated at 60 p.s.i. (4.13×105Pa) pressure and room temperature (20°) over 10% palladised charcoal (0.2 g) for 16 hours. The catalyst was then removed by filtration through "Solkafloc" (Trade Mark) and the solution was evaporated in vacuo to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of the appropriate fractions afforded the title compound as an oil (0.37 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([CH:14]=2)[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:24](=O)([O-])[O-:25].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:24]=[O:25])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3
Temperature: 60 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
3.35 g of 5,6,7,8-tetrahydro-2-phenylimidazo[2,1-b]benzothiazole was suspended in 20 ml of dimethylformamide. To the resultant mixture, 3 ml of phosphorus oxychloride was added dropwise at 0° C. over 10 minutes. The solution was gradually returned to room temperature, then heated and stirred at 60° C. for 3 hours, poured onto an aqueous sodium carbonate solution, then extracted with chloroform. The solvent was distilled off, the residue was then recrystallized from ethanol to obtain the desired substance in an amount of 2.31 g (yield of 82.0%) (melting point:150-150.5° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:42][CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CCCC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CNC3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopentylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (170 mg, 67%).