Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]([OH:22])[CH2:20][OH:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:20][O:21][C:23]([CH3:28])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(O)CO)cnc21
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 930 %

Procedure:
A solution of 1-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-ethane-1,2-diol (3 g, 9.43 mmol), p-toluene sulfonic acid (160 mg, 0.84 mmol) and 2,2-dimethoxy-propane (10 mL) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (2.8 g, 83%) as a white solid: LC/MS m/e calcd for C18H19N2SO4 [M+H]+ 359.42, observed 359.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 3H), 1.56 (s, 3H), 3.73 (dd, J=7.5 Hz, 8.3 Hz, 1H), 4.35 (dd, J=6.4 Hz, 8.3 Hz, 1H), 5.16 (dd, J=6.4 Hz, 7.5 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.42 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(Cl)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 374. 1HNMR (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=1.52 Hz), 7.66 (d, 2H, J=8.55 Hz), 7.55-7.53 (m, 2H), 7.46 (d, 2H, J=8.55 Hz), 7.39 (d, 1H, J=8.56 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.13 (d, 2H, J=8.24 Hz), 6.53 (d, 1H, J=3.05 Hz), 5.39 (s, 2H), and 1.21 ppm (s, 9H). Elemental Analysis for C25H24ClN: Calculated: C, 78.05; H, 6.60; N, 3.64. Found: C, 78.02; H, 6.27; N, 3.53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1.C1(S(O)(=O)=O)C2C(=CC=CC=2)C=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: O=S(=O)(O)c1cccc2ccccc12
Solvent: c1ccccc1
Product: Clc1cc(Cl)c(OC2CCCCO2)cc1Cl
Temperature: 25 °C

Procedure:
2,4,5-trichlorophenol (9.85 g., 0.05 moles) and dihydropyran (9.1 ml., 0.10 moles) are mixed in 100 ml. of benzene as a solvent. Upon addition of 1.0 g. of naphthalene sulfonic acid, as catalyst, the reaction is exothermic and the solution turns a light purple color. The reaction mixture is cooled to room temperature and allowed to stand for about one-half hour. The reaction mixture is washed with dilute sodium carbonate solution and the color turns to a light orange. The solution is dried over magnesium sulfate and then the solvent is evaporated in vacuo to yield 14.5 g. of an orange oil, nD30 =1.5408.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2Cl)[CH:16]=1>O1CCCC1>[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2[NH:4][C:3]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])[CH:16]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(Br)sc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(Br)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (221.8 mg, 1.16 mmol) and 60% sodium hydride (46.2 mg, 1.16 mmol) in 6 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile (150 mg, 0.55 mmol) is added. The resulting reaction mixture is heated at reflux for 5 hours, cooled to room temperature, and then partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 40% ethyl acetate in hexane to provide 114.6 mg of 2-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 228-229° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.71 (s, 1H), 7.80 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H); MS 426.0, 428.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14](I)[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14]([CH3:17])[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1C1OOCC1I
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1C1OOCC1C
Temperature: 105 °C
Reaction time: 10 h

Procedure:
A suspension of 5-iodo-2,3-dioxolanebenzoic acid methyl ester (0.1 g, 0.32 mmol), potassium carbonate (0.048 g, 0.35 mmol), tetrakis(triphenylphosphine)palladium (1 mol %) and trimethylboraxine (0.089 ml, 0.64 mmol) in 1,4-dioxane (5 ml) is stirred under nitrogen at 105° C. for 10 hours. Solvent is removed and the residue is taken in ethyl acetate (50 ml). This mixture is washed with water (30 ml), dried with sodium sulphate and evaporated. Purification by chromatography (ethyl acetate/hexane 5:95) gives 5-methyl-2,3-dioxolanebenzoic acid methyl ester; GC/MS: 194 (M+1)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-].[K+].O>ClCCl>[CH3:12][O:13][CH:14]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(COCCOCCO)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
200 g of p-toluenesulfonyl chloride and 172.4 g of triethylene glycol monomethyl ether are dissolved in 1 liter of dichloromethane and cooled to 0° C. With vigorous stirring, 236.3 g of freshly powdered potassium hydroxide are metered in at a rate such that the temperature does not exceed 5° C. The mixture is maintained at 0° C. for 3 hours. 1 liter of dichloromethane and 1.2 liters of iced water are added. If more solids form, a further 0.5 liter of iced water are added. The organic phase is separated off and washed with 0.3 liter of saturated sodium chloride solution. It is dried over Na2SO4 and evaporated to dryness under reduced pressure.
Reaction SMILES: [K].[N+:2]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[N:7][C:6]=1[N+:13]([O-:15])=[O:14])([O-:4])=[O:3].[CH3:16]OS(OC)(=O)=O>O>[CH3:16][N:9]1[C:5]([N+:2]([O-:4])=[O:3])=[C:6]([N+:13]([O-:15])=[O:14])[N:7]=[C:8]1[N+:10]([O-:12])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1nc([N+](=O)[O-])c([N+](=O)[O-])[nH]1
Agent: [K]
Solvent: O
Product: Cn1c([N+](=O)[O-])nc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 71.9 %

Procedure:
A mixture of potassium salt of trinitroimidazole (100 mg, 0.41 mmol) and dimethylsulfate (1.0 g, excess) was heated in a preheated oil bath at 80° C. for about 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ether (3×25 mL). The combined organic layer was washed with water (3×25 mL), brine (1×25 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the pale yellow syrupy residue thus obtained was purified via Si-gel column chromatography (eluent: 10% ethyl acetate-hexane). The pure product (64 mg, 71%) was obtained as a pale yellow solid. m.p: 84-85° C.; DSC: 84.81° C. (5° C./min); 1H NMR (Acetone-d6): 4.37 ppm; 13C NMR (Acetone-d6): 37.64, 133.46 (t), 136.05 (br) and 139.97 (t).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(OC)(OC)OC.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=O.[BH4-].[Na+]>CO>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][NH:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1CN
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: Cn1ccnc1CNCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
The compound (201 mg) obtained in Example 14-7 was dissolved in methanol (4.0 ml) and added with trimethyl orthoformate (200 μl) and 2-imidazole carboxaldehyde (115 mg) and the whole was stirred at room temperature for 30 minutes. After having been cooled to 0° C., the solution was added with sodium borohydride (89.6 mg) and then the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (137 mg) as a pale-yellow oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:19])[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:18][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: c1cncc(-c2nc3nc(-c4ccncc4)c(-c4ccco4)nc3[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.5 %

Procedure:
A mixture of 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 87, 146 mg, 0.58 mmol) and nicotinoyl chloride hydrochloride (516 mg, 2.9 mmol) in pyridine (5 mL) was stirred and heated at reflux for 24 h. Then polyphosphoric acid was added and the stirring was continued at the same temperature for 24 h. The reaction was allowed to cool to room temperature and was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by silica gel chromatography (CH2Cl2/MeOH/NH3 50:8:1). The appropriate fractions were concentrated to leave a solid which upon washing with diethyl ether give the title compound as a light brown solid (82 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[C:24](O)=[O:25])=[CH:18][CH:17]=1>>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]2[C:24](=[O:25])[N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:7][C:2]([CH3:1])=[C:3]3[N:14]=2)=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccccc2)cnc1N
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Product: Cc1[nH]c(-c2ccccc2)cn2c(=O)c(Cc3ccc(O)cc3)nc1-2

Procedure:
Synthesized using method A with 3-methyl-5-phenylpyrazin-2-amine and 3-(4-hydroxyphenyl)-2-oxopropanoic acid as starting materials. 1H NMR (300 MHz, dmso) δ 8.84 (s, 1H), 8.00 (d, J=7.6, 2H), 7.47 (dd, J=8.6, 16.2, 3H), 7.17 (d, J=7.3, 2H), 6.69 (d, J=8.4, 2H), 6.26 (s, 4H), 4.17 (s, 2H), 2.86 (s, 3H), 2.48 (s, 1H).
Reaction SMILES: [CH:1]([C@:4]1([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2].C=O.[BH3-][C:36]#N.[Na+]>CO>[CH:1]([C@:4]1([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][N:24]=3)[CH2:21][CH2:22]2)=[O:16])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:36])[CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC2CCOC2)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N(C)C2CCOC2)C1

Procedure:
To a solution of N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydrofuran-3-amine (160 mg) in 5mL of methanol was added a solution of formaldehyde (10 equiv) followed by NaCNBH3 (3 equiv). Once the reaction was complete, the volatiles were removed and the residue taken in ethyl acetate. The ethyl acetate layer was washed with aqueous NaOH (2.5N). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography to give the title compound (126 mg). MS calculated for C24H35F3N4O2: (M+H) 469.2712; found 469.2817.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCC1Cc2ccccc2O1
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCC1Cc2ccccc2O1
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from (2,3-dihydro-1-benzofuran-2-yl)methylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.29 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.75 (br s, 1H), 7.48 (d, 1H, J=5.0 Hz), 7.15 (d, 1H, J=7.2 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.75 (t, 1H, J=7.4 Hz), 6.67 (d, 1H, J=7.9 Hz), 4.95-4.99 (m, 1H), 3.24-3.64 (m, 3H), 2.88-2.95 (m, 1H). [M+H] calc'd for C15H14N2O3, 271; found 271.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:20]1([C:2]2[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=3)[N:6]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1cccc(Cl)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(-n2cnc3ccccc32)nc1-c1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(3-chlorophenyl)-5-oxazolyl]propionate (2.31 g), 1H-benzoimidazole (1.82 g), potassium carbonate (3.19 g) and N,N-dimethylformamide (12 mL) was stirred at 120° C. for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-(1H-benzoimidazol-1-yl)-4-(3-chlorophenyl)-5-oxazolyl]propionate (1.85 g, 63%) was obtained as a solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:29])[NH:6][C:7]1[C:8]([CH3:28])=[C:9]([O:26][CH3:27])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[OH:35][CH2:34][CH2:33][NH:32][C:5]([NH:6][C:7]1[C:8]([CH3:28])=[C:9]([O:26][CH3:27])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:29]
Reactant: COc1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 140 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 127-129° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[C@H:22]([OH:23])[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC[C@@H]([C@@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (71 mg, 0.154 mmol) (Example 210, StepA) in THF (2 mL) was sparged with argon for 5 minutes. The mixture was cooled to 0° C. and methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol) was added at such a rate that the internal temperature did not get above 4° C. The mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (2×4 g stacked columns, eluent: 5 to 15% isopropanol/hexanes) to give the title compound as the more polar diastereomer.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14](C)[CH:13]=2)(C)C)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:20]([Cl:22])[Cl:21].C(Cl)(Cl)=O>[OH-].[K+]>[CH:5]1[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:20]([Cl:22])[Cl:21])=[CH:3][CH:2]=[C:7]([OH:8])[CH:6]=1
Reactant: ClCCl
Reactant: Cc1cc(C(C)(C)c2ccc(O)c(C)c2)ccc1O
Agent: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Product: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1

Procedure:
A solution prepared by dissolving 0.2 kg of 2.2-bis(3-methyl-4-hydroxyphenyl) propane in 1.2 kg of aqueous potassium hydroxide having a concentration of 16 mass % was mixed with 1.0 kg of methylene chloride. Then, while the solution was being stirred, phosgene gas was blown into the solution while cooling at 1 L/min until pH becomes 9 or less. Subsequently, the reaction solution was separated in a stand still manner, and a methylene chloride solution of an oligomer which has 2 to 6 polymerization degree and a chloroformate group at its molecular terminal was obtained as an organic layer (a solid content concentration of 0.30 kg/L). This oligomer is referred to as “PCO-C” hereinafter.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.O[C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C@H:29]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 13 %

Procedure:
A solution of 4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenol (1.3 g, 3.6 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.05 g, 5.4 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.36 g, 5.4 mmol) and triphenylphosphine (1.42 g, 5.4 mmol) in toluene (40 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give the object compound as an oily substance. 250 mg, (yield 13%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][N:21]=[CH:20]2)(=[O:31])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-1,3-propylenediamine (2.09 g, Tokyo Kasei Kogyo) and triethylamine (3.4 ml, Tokyo Kasei Kogyo) in dichloromethane (20 ml) was added with a solution of isoquinoline-5-sulfonyl chloride (2.73 g, prepared according to Japanese Patent Unexamined Publication (Kokai) No. 61-227581) in dichloromethane (15 ml) with stirring and ice cooling and stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. Then, the residue was purified by flash column chromatography (chloroform:methanol=50:1) to obtain the title compound (4 g).