Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C([O:34]C(N(C1CCNC1)C)=O)(C)(C)C.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[OH:34][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: CNC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1-chloro-4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 24) can be prepared by using 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 35-1, Step A instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, and then used in the method of Example 35-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(OC(F)(F)F)cc23)CC1

Procedure:
(9.3 mg, 32%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and benzoyl chloride (15.0 mg, 0.107 mmol), HRMS-FAB+ for C22H19N2O2F3, calculated MH+ : 401.14767; found: 401.14761.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH2:18].[O:19]1[CH2:23]CC[CH2:20]1>>[C:1]1([CH2:7][C:20]([O:19][CH3:23])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: Cc1ccccc1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COC(=O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of the above lactone in 45 ml. of toluene at -78° C. is added dropwise, while stirring, diisobutylaluminum hydride (3.9 ml.). Stirring is continued at -78° C. for 0.5 hr., whereupon a solution of 9 ml. of water in 17 ml. of tetrahydrofuran is added. After the mixture is stirred for an additional hour at about 25° C. it is filtered. The filtrate is washed with brine, dried, and concentrated to yield the formula-LXXII title compound, 4.39 g., on oil.
Reaction SMILES: C([O:8][NH:9][C:10]([C@@H:12]1[C@@H:17]([C:18](=[O:39])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[C:30]([CH3:38])[CH:29]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH:14]([CH2:40][C:41](O)=[O:42])[CH2:13]1)=[O:11])C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1.CN1CCOCC1>CN(C=O)C>[OH:8][NH:9][C:10]([C@H:12]1[CH2:13][CH:14]([CH2:40][C:41](=[O:42])[N:77]2[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]2)[CH2:15][CH2:16][C@@H:17]1[C:18]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[CH:22][CH:21]=1)=[O:39])=[O:11]
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 110.6 %

Procedure:
Part 10: 4-(2-Oxo-2-piperidin-1-yl-ethyl)-cyclohexan-1-(S)-,2-(S)-dicarboxylic acid 2-(S)-(benzyloxy-amide)1-(S)-{[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-amide. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: {3-(S)-benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid (20 mg, 0.034 mmol), anhydrous DMF (1 mL), PyBOP reagent (20 mg, 0.038 mmol), piperidine (0.010 mL, 0.101 mmol), and 4-methyl morpholine (0.01 mL, 0.092 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 10% methanol in methylene chloride over 30 min) to afford 21 mg (95%) of the desired amide. LCMS (ESI): 649 (M+1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[N:19]#[C:20]Br.[OH-].[K+].CC(C)=O>O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:20]2[NH2:19])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccccc2N)CC1
Reactant: N#CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCN(CCCn2c(N)nc3ccccc32)CC1
Yield: 32.5 %

Procedure:
To a stirred solution of N-[3-(4-methyl-1-piperazinyl)propyl]-o-phenylendiamine (334.8 g., 1.35 mole) in water (1400 ml.) under nitrogen, was added cyanogen bromide (200 g., 1.89 mole) at a rate sufficient to maintain the reaction temperature at 50°-65° C. The addition took place over a 2 hour period. The reaction mixture was then cooled and the pH adjusted to 10 by the dropwise addition of 50% KOH. The basic aqueous layer was extracted from chloroform (5 × 500 ml.). The organic layers were combined, dried (MgSO4), and evaporated in vacuo to give a dark brown semi-solid. Slurrying with acetone (300 ml.) gave on filtration and washing with acetone 120.1 g., (32.5% yield) of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-aminobenzimidazole as a pale yellow solid, m.p. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[C:4]([CH:18]=[CH:19][CH3:20])[C:3]=1[OH:21].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[Cl:8][C:7]1[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:5][C:4]2[CH2:18][CH:19]([CH2:20][OH:27])[O:21][C:3]=2[C:2]=1[Cl:1]
Reactant: CC=Cc1cc(C(=O)c2ccccc2F)c(Cl)c(Cl)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Reaction time: 96 h

Procedure:
A mixture of 2,3-dichloro-6-propenyl-4-(2-fluorobenzoyl)phenol (62.5 g., 0.192 mole) and m-chloroperoxybenzoic acid (47.6 g., 0.22 mole) in 550 ml. of methylene chloride was stirred at room temperature for 24 hours. The precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed successively with 5% aqueous sodium sulfite and 10% aqueous sodium bicarbonate. The methylene chloride was kept at room temperature for 4 days and then washed with 0.5N NaOH solution. After drying over MgSO4, the solvent was evaporated to give 45 g. of solid product, m.p. 148°-150° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:31](O)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].[PH2](O)=O>>[C:31]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)OCCCO
Agent: O=[PH2]O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A mixture of 1-hydroxy-3-(z-15-tetracosenoyloxy)propane, prepared according to Description 3, (0.045 mol, 19.0 g), z,z,z-6,9,12-octadecatrienoic acid (0.054 mol, 15.0 g) and hypophosphorous acid (0.4 g) was heated with stirring to 160° C. under nitrogen. After 5 h, TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) indicated that most of the mono-ester had reacted (Rf: 0.60). The mixture was cooled down to room temperature and petroleum ether (800 mL) was added. The resulting solution was washed with saturated sodium bicarbonate (3×80 mL) and saturated sodium chloride (3×80 mL). It was then dried over anhydrous sodium sulphate, concentrated and purified by flash chromatography on silica gel (19:1 petroleum ether-ethyl ether) to yield 1-(z,z,z-6,9,12-octadecatrienoyloxy)-3-(z-15-tetracosenoyloxy)propane as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:29].[Na+].OO>C1COCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[N:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:29])=[CH:8][CH:7]=2)=[CH:15][N:14]=1
Reactant: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of 5-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)pyrimidine (100 mg, 0.376 mmol) and 9-BBN (1.503 mL, 0.751 mmol) in THF (5 mL) under nitrogen, which was stirred overnight was added NaOH (0.501 mL, 1.503 mmol) and H2O2 (0.460 mL, 4.51 mmol). The mixture was heated at 60° C. for 1 h, and then quenched with NH4Cl sat. solution after cooling. The organic layer was separated and washed with Na2SO3 solution and brine. The organic layer was dried by Na2SO4. Concentration then afforded the title compound (80 mg, 0.281 mmol, 74.9% yield). LCMS: rt=2.82 min, [M+H]=285
Reaction SMILES: C(C1C=C(C(O)=O)C(O)=CC=1)=O.[CH2:13]([N:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[CH:22][C:21]=1[O:28]C)[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:31]([N:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[CH:22][C:21]=1[OH:28])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Agent: O=Cc1ccc(O)c(C(=O)O)c1
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1O

Procedure:
N,N-Di-n-pentyl-2-hydroxy-5-formylbenzamide was prepared from 5-formylsalicylic acid (250 mg, 1 eq) using the same procedure as for N,N-di-n-pentyl-2-methoxy-5-formylbenzamide. The product was obtained as pale brown oil (211 mg, 46%). 1H NMR (CDCl3) δ9.67 (s, 1H, O═C—H), 3.33 (m, 4H, NCH2).
Reaction SMILES: [OH-].[Na+].[O-:3][S:4]([C:7]([F:10])([F:9])[F:8])(=[O:6])=[O:5].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([S+:18]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.CS(C)=O.Cl[CH2:37][CH2:38][O:39][CH:40]=[CH2:41].[CH3:42][CH2:43][O:44][CH2:45][CH3:46]>O>[O-:6][S:4]([C:7]([F:10])([F:9])[F:8])(=[O:5])=[O:3].[CH:40]([O:39][CH2:38][CH2:37][O:11][C:12]1[CH:17]=[CH:16][C:15]([S+:18]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:46][CH2:45][O:44][CH:43]=[CH2:42])=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[CH2:41]
Reactant: Oc1ccc([S+](c2ccccc2)c2ccc(O)cc2)cc1
Reactant: CCOCC
Reactant: C=COCCCl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=COCCOc1ccc([S+](c2ccccc2)c2ccc(OCCOC=C)cc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 61.5 %

Procedure:
A 3-neck-round bottom flask was fitted with a condenser, an addition funnel, nitrogen source, and a magnetic bar. Sodium hydroxide (8.64 g, 0.216 mol), bis(4-hydroxyphenyl)phenylsulfonium triflate (16 g, 0.036 mol) and DMSO (90 ml) were added to a round bottom flask under N2. The mixture was heated to 60° C. for 1 hour. 2-chloroethyl vinylether (23 g, 0.216 mol) was added dropwise to the mixture via the addition funnel. The temperature was then increased to 80° C. and the reaction was held at that temperature for 5 hours. The reaction mixture was then allowed to cool down to room temperature. Thereafter, the reaction mixture was poured into diethyl ether to form three layers: aqueous, ether, and an oil. DI water was used to wash the ether solution 3 times. An oily layer was collected and concentrated to dryness. 12.9 g (61.5%) of bis(4-vinyloxyethyloxyphenyl)phenylsulfonium triflate was obtained. The structure was confirmed using 1H and 19F NMR.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:5]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.205 g, 5.13 mmol) was suspended in 5 mL dimethylformamide. The mixture was stirred for 10 min and then cooled at 0° C. with an ice bath. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 4.30 mmol) dissolved in 5 mL dimethylformamide was added dropwise and the mixture was stirred for 30 min. At the same temperature [2-(chloromethoxy)ethyl](trimethyl)silane (0.9 g, 5.4 mmol) dissolved in 5 mL dimethylformamide was added dropwise and stirred for 30 min at 0° C. The mixture was poured into water and extracted twice with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 1.18 g (76% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38].C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(C)(=O)=O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 425.9 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-chloro-5-hydroxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (62.5 mg, 0.0950 mmol) was dissolved in dichloromethane (2.4 mL), and the solution was treated with triethylamine (0.053 mL, 0.38 mmol) and methanesulfonyl chloride (0.015 mL, 0.019 mmol), followed by purification by slurry using hexane to obtain 4-chloro-5-methanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (50.1 mg, yield 72%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2cccc(O)c2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 7d (277 mg, 1.56 mmol) was reacted with the product from Example 25b (245 mg, 1.56 mmol) for 5 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (399 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.38 (s, 3 H) 2.75 (s, 3 H) 6.30 (d, J=6.99 Hz, 1 H) 6.53-6.58 (m, 2 H) 6.61 (d, J=8.09 Hz, 1 H) 6.90-7.08 (m, 1 H) 7.27-7.47 (m, 3 H) 7.77 (d, J=8.46 Hz, 1 H) 8.39 (d, J=6.99 Hz, 1 H) 8.94 (d, J=8.82 Hz, 1 H) 9.58 (s, 1 H) 10.96 (s, 1 H) 14.34 (s, 1 H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.CO.[NH2:29][CH:30]1[CH2:33][O:32][CH2:31]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN1CCCC1=O>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:29][CH:30]4[CH2:33][O:32][CH2:31]4)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NC1COC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4COC4)c(Cl)c32)c(F)cc1F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was dissolved in a mixed liquid of pyridine (0.5 ml) and N-methylpyrrolidone (0.5 ml). A methanol solution (45%; 1.5 ml) of 3-aminooxetane was added to the resultant solution. The mixture was stirred at 70° C. for 18 hours. The reaction mixture was acidified with a 3% aqueous solution (20 ml) of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol. Ether (5 ml) was added to the residue to conduct filtration, thereby obtaining the title compound (48 mg) as a pale yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]2[C:11]([CH:22]=[O:23])=[CH:12][C:13]([C:18]([F:21])([F:20])[F:19])=[C:14]([O:16][CH3:17])[CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:11]=2[CH2:22][OH:23])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
5′-Isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (692 mg) is dissolved in a mixed solvent of tetrahydrofuran (12 ml), ethanol (3.5 ml) and methylene chloride (1 ml), and thereto is added sodium borohydride (82 mg) and the mixture is stirred at room temperature for 40 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (566 mg). MS (m/z): 337 [M+H—H2O]+
Reaction SMILES: [CH3:1][I:2].[CH2:3]([S:9][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>>[I-:2].[CH2:3]([S:9][C:10]1[C:11]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCSc1nsnc1-c1cccnc1
Reactant: CI
Product: CCCCCCSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:24](=[O:25])[O:26][CH2:27][CH3:28])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
In 300 ml of tetrahydrofuran, was suspended 4.42 g of 2-amino-4-p-nitrophenylthiazole, followed by a further addition of 20 ml of triethylamine. The mixture was cooled to about 5° C., to which 10.5 ml of ethyl chloroformate was added dropwise. Then, the reaction mixture was stirred at room temperature for 3.5 days. Any insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated and then washed in ethyl acetate successively with water, dilute hydrochloric acid, and water. Then, the ethyl acetate solution was concentrated to about 50 ml and the resulting crystals were separated by filtration and then subjected to column chromatography on silica gel. The reaction product was eluted with a benzene/ethyl acetate mixed solvent. The resultant product was recrystallized from ethyl acetate to obtain 2.8 g of ethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:23]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:30]=1)[CH3:2].C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:33])[CH2:26][CH2:25]4)[CH:23]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:30]=1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCNCC3)c1)C2=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCN(C)CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
(S)-9-Ethylamino-5-[5-(piperazine-1-yl)pyridin-3-yl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (56.1 mg, 0.137 mmol) obtained in Step 2 was dissolved in 1,2-dichloroethane (4 mL), and the mixture was stirred at room temperature for 1 hour after adding 37% formalin solution (0.0310 mL, 0.411 mmol) and sodium triacetoxyborohydride (87.0 mg, 0.411 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (Compound 42) (43.0 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: NCCO
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1
Yield: 85.5 %

Procedure:
A mixture of p-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was stirred magnetically and heated in an oil bath at 90°-92° for 4 hours. Usual workup furnished the title compound as a pale yellow solid (2.74 g.), m.p. 250°-252° .