Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.O>CS(C)=O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]([CH3:19])([CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccccc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.107 g, 0.378 mmol), potassium carbonate (0.183 g, 1.324 mmol), and 2-chlorobenzo[d]thiazole (0.077 g, 0.454 mmol) in DMSO (3 mL) was heated at 110° C. in 2 h. The reaction mixture was cooled, H2O was added, and extracted with DCM (3×). The organic extracts were dried over Na2SO4, filtered, concentrated, and purified by reverse phase HPLC. The pure fractions were concentrated to minimal H2O, neutralized with saturated aqueous NaHCO3. The white solid was collected, washed with H2O, and dried to afford the title compound (67 mg, 47%). MS (M+1): 380. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04-8.19 (2 H, m), 7.77 (1 H, d, J=7.4 Hz), 7.46 (1 H, d, J=8.0 Hz), 7.21-7.35 (1 H, m), 6.98-7.14 (1 H, m), 4.46-4.65 (1 H, m), 4.18 (2 H, d, J=13.1 Hz), 3.32-3.41 (2 H, m), 2.52-2.62 (2 H, m), 1.83 (2 H, d, J=10.8 Hz), 1.33 (6 H, s)
Reaction SMILES: Cl.[CH2:2]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24][CH3:25])=[C:19]([O:27]COC)[C:18]=3[F:31])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].O>C(O)C>[CH2:2]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24][CH3:25])=[C:19]([OH:27])[C:18]=3[F:31])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:3][CH3:4]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C(=O)CC)c(OCOC)c3F)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCC1CCC(c2ccc(-c3ccc(C(=O)CC)c(O)c3F)cc2)CC1
Temperature: 25 °C

Procedure:
17.7 mL of 1N hydrochloric acid was added to Compound (7) dissolved in 17.7 mL of ethanol, followed by refluxing under heating for 2 hours. After cooling the reaction solution to ambient temperature, water was added to the solution. The aqueous layer was extracted with toluene, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography and recrystallization to obtain 1.48 g of 1-(4-(4-(4-propylcyclohexyl)phenyl)-3-fluoro-2-hydroxyphenyl)-1-propanone (Compound (1-2-2-21)) as colorless crystals.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[NH2:20][CH2:21][CH2:22][SH:23].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:23]1[CH2:22][CH2:21][NH:20][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: NCCS
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1NCCS1
Yield: 73.8 %

Procedure:
In 20 ml of methanol was dissolved 2.0 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 800 mg of 2-aminoethanethiol, 1.0 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.8 g of the titled compound as a colorless crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CCOc1cc(Cl)nc(SC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassium carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2H), 6.68 (s, 1H), 4.46 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH3:22][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(N)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
0.6 g of 4-fluoronitrobenzene, 0.807 g of 4-aminoquinaldine, and 0.705 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 6 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.09 g of 2-methyl-N-(4-nitrophenyl)quinol-4-amine (13) was obtained after purification by chromatography on a column of silica (eluent: 50/50 dichloromethane/heptane).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(O[CH2:30][CH3:31])=O>O>[CH2:30]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:13][CH3:14])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]1)[CH3:31]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(OC)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC)c2c(OC)c(OC)ccc2c1=O
Temperature: 120 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of ethyl 7,8-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (40 g, 144 mmol) and potassium carbonate (29.9 g, 216 mmol) in triethyl phosphate (123 ml, 721 mmol) was stirred at 120° C. for 24 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to rt and diluted with water, extracted with DCM, dried over sodium sulfate and evaporated in vacuo. The crude material was recrystallized in EtOH, the precipitate was collected by filtration, washed by cold EtOH and dried in air to afford ethyl 1-ethyl-7,8-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (26 g, 85 mmol, 59.0% yield) as a yellow solid. LCMS: (M+H)+: 306.2.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)C>C(O)(=O)C>[C:1]1([CH2:7][C@H:8]([O:12][C:18](=[O:20])[CH3:19])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](Cc1ccccc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
Mix (S)-3-phenyllactic acid (11.17g, 67.2mmol) and sulfuric acid (0.3mL of a 10% solution in acetic acid). Add acetic anhydride (6.34mL, 67.2mmol) over 10 minutes. Warm to 90° C. with stirring for 45 minutes. Allow to cool, pour into diethyl ether and wash with water three times. Separate the organic phase, dry (MgSO4) and concentrate in vacuo to yield 13.16g (94%) (S)-3-phenyl-2-acetyloxypropionic acid as a white oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(Cl)Cl>O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 10.5 g. (0.054 mol.) of 2-phenylbenzofuran and 11.5 g (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for two hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(3,5-dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH:20]1([NH:23][S:2]([C:5]2[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CC1
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate, 1.2 mL of cyclopropylamine, and 20 mL of pyridine was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with 1.0 M hydrochloric acid and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.12 g of 2-(trimethylsilyl)ethyl 3-(cyclopropylsulfamoyl)benzoate as a pale yellow oily substance. EI: 341
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (2.27 g, 4.13 mmol) in CH2Cl2 (25 ml) was added TFA (41.3 mmol, 3.18 ml) and the reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was added to 10% aqueous NaHCO3 solution (pH>8) and the free base was extracted with EtOAc. Combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was re-crystallized twice by dissolving the material in EtOH (15 ml) at 50-60° C. and after saturation with H2O (6-8 ml) the clear solution was allowed to cool to ambient temperature overnight to provide after filtration and drying the title compound in >99% purity as white crystals: UPLC RtH5=0.905 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): 10.72 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 7.78 (d, 1H), 7.71 (m, 1H), 7.15 (t, 1H), 6.08 (br s, 2H), 3.91 (d, 1H), 3.78 (d, 1H), 2.52 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C=O)C>[C:20]([S:22][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1)(=[O:23])[CH3:21].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CC([O-])=S
Reactant: BrCc1ccc(-[c-]2cccc2)cc1
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Solvent: CN(C)C=O
Product: CC(=O)SCc1ccc(-[c-]2cccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general procedure (Zhang et al. (1999) Tetrahedron Lett., 40: 603–606), a solution of 19 (1.5 g, 4.2 mmol) in DMF (10 mL) was added to a solution of potassium thioacetate (0.60 g, 5.0 mmol) in DMF (10 mL) and the mixture was stirred overnight at rt. The mixture was filtered and water was added to the filtrate. The filtrate was extracted with ethyl ether (3×50 mL), and the combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:1) affording a yellow solid (1.3 g, 90%): mp 79–81° C.; 1H NMR δ 2.38 (s, 3H), 4.05 (s, 5H), 4.12 (s, 2H), 4.31 (A2B2,J=1.5 Hz, 2H), 4.62 (A2B2, J=1.5 Hz, 2H), 7.21, 7.41 (AA′BB′, J=8.5 Hz, 2×2H); 13C NMR δ 31.1, 34.0, 67.2, 69.6, 70.3, 85.7, 127.0, 129.5, 135.7, 139.1, 196.1; FAB-MS obsd 350.0431, calcd exact mass 350.0428; Anal. Calcd for C19H18FeOS: C, 65.15; H, 5.18; Found: C, 64.91; H, 5.15.
Reaction SMILES: [H-].[CH2:2]1[O:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[CH2:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:5]=2[O:6]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1ccc2c(c1)OCO2)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
In 1 L DMF, sodiul hydride (8.7 g, 0.36 mole, 1 eq.) was added under N2 at room temperature. Then sesamol (50 g, 0.36 mole) was added portionwise to the reaction mixture and stirred 20 minutes at room temperature. Ethyl 2-chloroacetoacetate (59.6 g, 1 eq.) was added slowly and the mixture was heated to 100° C. using an oil bath for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated. The residue was flash chromatographed using hexane ethyl acetate 10%, to give: 50 g (52% yield) of ethyl 2-(3,4-methylenedioxyphenoxy)acetoacetate.
Reaction SMILES: [C:1]([C:5]1[C:15]([F:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:33]([F:42])[CH:32]=1)[CH3:30]>C(N(CC)CC)C>[C:1]([C:5]1[C:6]([F:17])=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:33]([F:42])[CH:32]=2)[CH3:30])=[O:13])=[CH:14][C:15]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)c(F)c1
Yield: 36.9 %

Procedure:
(4-tert-Butyl-3,5-difluorophenoxy)acetic acid (166 mg, 0.68 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-fluorophenyl}methanesulfonamide hydrochloride (183 mg, 0.68 mmol) were mixed by the same procedure as described in Example 1(e) to give 115 mg (37%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:12]1[C:13]([NH:14][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=1
Reactant: Clc1ccc(I)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2ccc(Cl)cc2)cc1
Reaction time: 0.67 h
Yield: 35 %

Procedure:
p-Chloroiodobenzene (14 g), p-chloroaniline (11.23 g), potassium carbonate (12.15 g), and cuprous chloride (1.16 g) were suspended in dimethylsulfoxide (15 ml), and heated with stirring at 180°-190° C. for 3 hours and 40 minutes. After cooling the reaction mixture, ethyl acetate was added thereto, and washed with conc. aqueous ammonia 2 times, and with aqueous sodium chloride solution 3 times, and then, the mixture was concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/n-hexane [1:2 (v/v)] to give 4,4'-dichlorodiphenylamine (4.89 g).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:17]O>>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:17])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (3.0 g, 19.1 mmol) in methanol (50 mL). Sulfuric acid (3 mL) was carefully added and the resulting solution was stirred overnight at 80° C., then concentrated under reduced pressure. The pH of the solution was carefully adjusted to 7 with aqueous sodium bicarbonate (sat.), then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.3 g, 70%).
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.ClCl.S(Cl)(Cl)(=O)=[O:15]>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5](=[O:15])[NH:6]1
Reactant: CSc1ccccc1C=NO
Reactant: O=S(=O)(Cl)Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: O=c1[nH]sc2ccccc12
Yield: 91.1 %

Procedure:
From the monochlorobenzene layer obtained by the same procedures as in Example 1, 2-(methylthio)benzaldehyde oxime was isolated in the same manner as in Example 2. 39.7 g of the oxime isolated was dissolved in 150 g of monochlorobenzene. Then, the oxime was cyclized in the same manner as in Example 1 except that chlorine was changed to 35.3 g (0.26 mol) of sulfuryl chloride. As a result, 32.7 g of 1,2-benzisothiazol-3-one was obtained. The yield against 2-(methylthio)benzaldehyde oxime was 91%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.O1C=CC=C1.CN(OC)[C:15]([CH:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15]([C@H:17]1[CH2:18][N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:20](=[O:22])[CH2:21]1)=[O:16]
Reactant: Br[Mg]c1ccco1
Reactant: CON(C)C(=O)C1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccoc1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccco2)CC1=O
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In an atmosphere of nitrogen, 0.5 mol/l of 2-furylmagnesium bromide (180 ml) prepared from furan was added dropwise to a tetrahydrofuran solution (160 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide (8.30 g, 30.0 mmol), and the mixture was stirred for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml) under ice-cooling and extracted with ethyl acetate (200 ml×2), and then the organic layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with a n-hexane:ethyl acetate system of from (1:1) to (1:2), 3.94 g (46%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([O:25][C:44](=[O:46])[CH3:45])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc2c(C(O)CC(C)C)cn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1-c1cc2c(C(CC(C)C)OC(C)=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butan-1-ol (20 mg, 0.044 mmol) in DCM (2 mL), N,N-diisopropylethylamine (15 μL, 0.08 mmol), acetic anhydride (6.6 μL, 0.06 mmol), and DMAP (1 mg) were added. The mixture is stirred at room temperature for 4 h. All volatiles are removed under reduced pressure and the residue is purified by chromatography to afford acetic acid 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5]2[C:8]3[C:13]([CH:14]=[CH:15][C:4]=2[N:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:16]([O:18][P:19]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>>[CH3:7][N:6]1[C:5]2[C:8]3[C:13]([CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[NH:1][C:29]([C:28]1[CH:32]=[CH:33][C:25]([CH2:24][P:19](=[O:20])([O:18][CH2:16][CH3:17])[O:21][CH2:22][CH3:23])=[CH:26][CH:27]=1)=[O:30])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cn1c(N)nc2ccc3ccccc3c21
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccc4ccccc4c3n2C)cc1)OCC

Procedure:
Using 2-amino-1-methyl-1H-naphtho[1,2-d]imidazole (commercially available) and 4-[(diethoxyphosphoryl)methyl]benzoyl chloride, the procedure of Example 1 was otherwise repeated to provide the objective compound.