Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH3:38]>CC(C)=O>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:34]([CH2:35][CH2:36][O:37][CH3:38])[CH2:33][CH2:32][O:31][CH3:30])[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: COCCNCCOC
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCOS(C)(=O)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(CCOC)CCOC
Product: Cl

Procedure:
A solution of 4.36 g. of 5-chloro-2-{3-[(methylsulfonyl)oxy]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester in 40 ml. of acetone is treated with 10 ml. of bis-(2-methoxyethyl)amine and boiled at reflux for 17 hours. The mixture is then concentrated to dryness under reduced pressure and the residue taken up in ether. After acidification with ethereal hydrochloric acid, the crystallized hydrochloride is removed by filtration under vacuum, dried and recrystallized from methylene chloride/ether, and there is obtained 5-chloro-2-{3-[bis(methoxyethyl)amino]propyl}-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 120°-122° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2[nH]ncc2c1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1ncc2ccccc21

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and indazole (0.56 g, 4.74 mmol) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[NH2:27])[N:23]=[CH:22][NH:21][C:20]2=[O:28]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:16][C:17]3=[CH:18][C:19]4[C:20](=[O:28])[NH:21][CH:22]=[N:23][C:24]=4[CH:25]=[C:26]3[N:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cc2nc[nH]c(=O)c2cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3cc4nc[nH]c(=O)c4cc3[nH]2)cc1
Yield: 82 %

Procedure:
In a manner analogous to that described in Example 20, from 4-methoxy-benzaldehyde, sodium hydrogen sulphite and 6,7-diamino-3,4-dihydroquinazolin-4-one (see Example 2), after boiling with methanol, there was obtained the title compound in a yield of 82% of theory; m.p. >300° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3].[Br:11][CH2:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1>CC(C)=O>[Br-:11].[C:17]([C:16]1[CH:25]=[CH:26][C:13]([CH2:12][N+:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:14][CH:15]=1)(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: C=CC(=O)OCCN(C)C
Solvent: CC(C)=O
Product: C=CC(=O)OCC[N+](C)(C)Cc1ccc(C(=O)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.04 %

Procedure:
Dimethylaminoethyl acrylate (9.11 mls) was added to a stirred solution of 4-bromomethylbenzophenone (13.75g) in acetone (50 mls) at 55° C. and the mixture was stirred for two hours at 60°±2° C. After cooling to room temperature, the stirred mixture was further cooled in an ice bath for two hours prior to filtration. After washing the residue with acetone (X1) followed by isopropyl ether (X2) the solid was dried under vacuo at room temperature. The crude title compound was obtained as a white crystalline solid (14.48g; m.p. 121°-123° C.) which was recrystallised from acetone (150 mls). Filtration, followed by sequentially washing with acetone (X1) then isopropyl ether (X1) and drying under vacuo at room temperature gave the title compound (10.26g; yield =49.04%) as white fine granular crystals of melting point equal to 122°-124° C. Analysis:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].Cl>[Pd].O.CO>[CH:17]1[C:16]([NH2:19])=[CH:15][CH:14]=[C:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH:18]=1
Reactant: [H][H]
Reactant: Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Yield: 91.9 %

Procedure:
In a hydrogenation vessel 4-(4′-Nitro-benzenesulfonyl)-phenylamine (100 g), p-toluensulfonic acid (68.4 g), methanol (350 ml), water (150 ml) and 10% palladium on charcoal (7.6 g) are charge. The mixture is allowed to react with hydrogen at approximately 50° C. and 5 bar pressure. At reaction completion, hydrochloric acid is added, the catalyst is filtered and dried. 82 g of crude Dapsone are obtained (82% yield; >99.5% purity).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCCCCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C(CCCO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from EE/hexane yielded the title compound, white solid, m.p. 93° C. and MS: m/e=378.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:13]2[CH2:12]1)(C)(C)C.[Cl:45]CCl.[ClH:48]>CO>[ClH:45].[ClH:48].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([C:19]1[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[N:14]2[CH2:15][CH2:16][N:11]([C:10](=[O:33])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:12][C:13]=12)=[O:28]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 95.2 %

Procedure:
(R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.10 g, 0.16 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (pyridin-2-yl)amide dihydrochloride 31(80 mg, yield 95.2%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:30](=[O:33])[CH2:31][CH3:32])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(CN2CCCC(Nc3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(c1ccccc1)C1CCCN(Cc2ccccc2)C1
Reaction time: 2 h

Procedure:
To the crude (1-benzyl-piperidin-3-yl)-phenyl-amine (164) (1.11 g) in CH2Cl2 (5 ml) at 0° C. was added i-Pr2NEt (1.45 ml) and propionyl chloride (0.54 ml). The mixture was stirred for 2 hr. The mixture was diluted with CH2Cl2 (20 ml), washed with sat. NaHCO3 (2×10 ml), brine (10 ml) and water (10 ml) and dried with Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CH2Cl2) to give 165 as a colorless oil. LRMS (calculated for C21H26N2O) 322. found 322; IR (film) 3059, 2937, 2863, 2797, 1657, 1594, 1499, 1390, 1264, 1101, 1074, 739, 703 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][CH2:7][CH:8]=[CH2:9])[CH3:2].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)=O.Cl.[NH2:24][OH:25].C(OC)(OC)OC>C1COCC1.N1C=CC=CC=1>[OH:25][N:24]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])=[O:22])=[CH:16][CH:15]=1)[CH3:11]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: NO
Reactant: C=CCNCC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: c1ccncc1
Product: C=CCN(CC(=O)OCC)C(=O)Nc1ccc(C(C)=NO)cc1

Procedure:
A solution of 0.02 mol N-allylglycine ethyl ester, prepared as described byS. B. Hyeon, I. Nagai, H. Tesaka, T. Kajita, and M. Furushima in European Patent Application No. 181,494, in 40 mL of THF is added dropwise to a solution of 0.02 mol of 4-isocyanatoacetophenone, prepared as described byE. E. Kilbourn, D. L. Peardon, and J. E. Ware in U.S. Pat. No. 3,931,203, and 5 mL of pyridine in 40 mL of THF, and the reaction mixture is stirred for 3 hours. The solvent is then removed by rotary evaporator. The residueis dispersed in 50 mL of CH3OH, and 0.022 mol of hydroxylamine hydrochloride and 0.06 mol of trimethyl orthoformate are added. The reaction mixture is heated to reflux for 1 hour. The solvent is removed byrotary evaporator to give the product, N-[4-(1-hydroxyiminoethyl)phenyl]-N'-allyl-N'-ethoxycarbonylmethylurea.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.O>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and triethylamine hydrochloride (7.1 g) in N,N-dimethylformamide (30 ml) was refluxed for 14 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (3.4 g, 95% purity by HPLC). Recrystallization of the product using ethanol results in 3.05 g of irbesartan with 99.2% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.09%.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[C:5]1[C:6]([CH3:39])=[C:7]([CH:24]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:26]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:23])[NH:14][C:15]([CH3:22])=[C:16]([F:21])[C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:9])[CH3:3].C=[O:47].O.[C:49]([BH3-])#N.[Na+]>CO>[CH:44]([OH:43])=[O:47].[CH2:2]([N:4]([CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[C:5]1[C:6]([CH3:39])=[C:7]([CH:24]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:49])[CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:26]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:23])[NH:14][C:15]([CH3:22])=[C:16]([F:21])[C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:9])[CH3:3]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Product: O=CO
Reaction time: 0.33 h
Yield: 19 %

Procedure:
To a solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide hydrochloride (160 mg, 0.25 mmol) in methanol (2 mL) at 0° C. was added 35% solution of formaldehyde in water (0.196 mL, 2.495 mmol). After stirring for 20 min, sodium cyanoborohydride (31.4 mg, 0.499 mmol) was added. After 1.5 h at 0° C., the reaction was quenched with water (3 mL), cooling bath was removed, mixture was stirred for 10 min. Then DCM (10 mL) and saturated aq NaHCO3 (1 mL) were added. The organic layer was separated and the aqueous layer was extracted with DCM (2×15 mL) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by reverse phase HPLC/MS (ACN-H2O, 0.5% formic acid) to afford 3-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide formate (31 mg, 0.047 mmol, 19% yield) as a colorless glassy film.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32](O)[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32]([Cl:3])[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Thionyl chloride (0.26 ml, 3.54 mmol) and catalytically effective amount of DMF were added at room temperature to a solution of 9-benzenesulfonyl-2-(1-hydroxyethyl)carbazole (0.621 g, 1.77 mmol) in methylene chloride, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, the organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure to obtain 9-benzenesulfonyl-2-(1-chloroethyl)carbazole.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].C([O-])(O)=O.[Na+].CCOC(C)=O>CC#N>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf20 (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=1.[H-].[Na+].O>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([CH3:27])[CH:16]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Reactant: Cc1cc2c(c(Cl)n1)CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc2c(c(Cl)n1)CN(Cc1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1) to give 65 mg (34% yield) of the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH2:34]([CH:36]([CH2:42][CH3:43])[C:37]([O:39][CH2:40]I)=[O:38])[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:40][O:39][C:37](=[O:38])[CH:36]([CH2:42][CH3:43])[CH2:34][CH3:35])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(CC)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 2-ethylbutanoyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (55 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.C(OC(=O)[N:17]([C:21]1[CH:26]=[CH:25][C:24](Br)=[C:23]([O:28][CH3:29])[CH:22]=1)[CH2:18][CH2:19][F:20])(C)(C)C>>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH:17][CH2:18][CH2:19][F:20])=[CH:22][C:23]=3[O:28][CH3:29])[CH:3]=[CH:4][C:5]=12
Reactant: COc1cc(N(CCF)C(=O)OC(C)(C)C)ccc1Br
Reactant: Brc1ccc2nonc2c1
Product: COc1cc(NCCF)ccc1-c1ccc2nonc2c1

Procedure:
The starting compound is obtained according to the procedure described in Example 7 from 5-bromo-benzo[1,2,5]oxadiazole and (4-bromo-3-methoxy-phenyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester, as a yellow glass. MS(ES+): 410 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[C@H:17]([CH3:18])[CH2:16][O:15][C:14]2=[O:19])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]2[C@H:17]([CH3:18])[CH2:16][O:15][C:14]2=[O:19])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2C(=O)OC[C@H]2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.6 %

Procedure:
To a mixture of methyl 4-bromo-2-methoxybenzoate (5.8 mL), (R)-4-methyloxazolidin-2-one (2 g) described in Preparation Example 25, potassium carbonate (2.8 g) and copper (I) iodide (760 mg) were added toluene (10 mL) and N,N′-dimethylethylenediamine (880 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g). Methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), 1N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N hydrochloric acid (16 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (2.2 g) was obtained.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:72]1([CH3:82])[CH:77]=[CH:76][C:75]([S:78](Cl)(=[O:80])=[O:79])=[CH:74][CH:73]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[S:78]([C:75]1[CH:76]=[CH:77][C:72]([CH3:82])=[CH:73][CH:74]=1)([O:65][CH2:64][CH:22]1[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]1)(=[O:80])=[O:79]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 120 h
Yield: 96.1 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (68.5 g, 74.5 mmol) was dissolved in chloroform (700 ml), pyridine (26.9 ml, 0.33 mol), DMAP (903 mg, 7.39 mmol) and p-toluenesulfonyl chloride (44.9 g, 0.236 mol) were added, and the mixture was stirred for 5 days. The solvent was evaporated, and the residue was precipitated with acetonitrile (700 ml) and washed with acetonitrile (700 ml) to give 3,4,5-tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol, 96%).