Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]C1C=C(SC(F)(F)F)C=CC=1O.CCN=C=NCCCN(C)C.[C:25]([OH:33])(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[C:25]([NH2:1])(=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccncc1
Temperature: 80 °C

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>CO.ClCCl>[CH2:23]([NH:27][C:3](=[O:22])[C@H:4]([CH:19]([CH3:20])[CH3:21])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CN
Reactant: COC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure H above and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-valine methyl ester (from Example 1 above) and isobutylamine (Aldrich), the title compound was prepared as a oil. The reaction was monitored by tic (Rf=0.3 in 10% methanol/dichloromethane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10](=[O:26])[NH:9]2)=[CH:4][CH:3]=1.Cl[S:28]([OH:31])(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:11][C:10](=[O:26])[NH:9]2)=[CH:6][C:7]=1[S:28]([OH:31])(=[O:30])=[O:29]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(O)cc2)N1
Solvent: ClC(Cl)Cl
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(O)c(S(=O)(=O)O)c2)N1
Temperature: 50 °C

Procedure:
To a solution of 4-(4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (68 mg, 0.2 mmol) in CHCl3 (1 mL) was added ClSO3H (35 mg, 0.3 mmol). The mixture was heated to 50° C. overnight. The residue was purified by prep-HPLC to give Compound 123 as a white power (6 mg, 7%). 1H NMR (MeOH-d4 500 MHz): δ 7.75 (d, J=7.5 Hz, 1H), 7.38 (d, J=7 Hz, 1H), 7.30 (m, 2H), 7.24 (t, J=1, 5 Hz, 3H), 7.01 (t, J=3.5, 5 Hz, 3H), 6.87 (m, 3H), 5.23 (s, 1H); MS (ESI): m/z 423.0 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:7]([Cl:25])=[N+:8]([O-:24])[C:9]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[CH:1]([O:4][CH2:5][C:6]1[C:7]([Cl:25])=[N+:8]([O-:24])[C:9]([CH2:20][CH:21]([CH3:22])[CH3:23])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=1)=[CH:2][CH3:3]
Reactant: C=CCOCc1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Product: CC=COCc1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1Cl
Yield: 130 %

Procedure:
To 200 mg of 3-allyloxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1-oxide were added 195 μl of diisopropylethylamine, 51 mg of a Wilkinson's catalyst ##STR69## and 4 ml of water (10% volume)-ethanol. The mixture was reacted for 3 hours at 85°-90° C. The catalyst was removed by filtration to obtain 260 mg of 3-(1-propenyl)oxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1-oxide (Compound B-6) [a cis/trans (about 4/3) mixture] as a colorless oily substance.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 54.4 %

Procedure:
Piperazine (0.06 g, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 24 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.13 g of the title compound as a solid, mp 166-167° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].C1C=C(C([O-])=[O:37])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[O:37][C:21]4([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[C:22]#[N:23])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2cccc(C=C(C#N)c3ccncc3)c2)c2ncccc2c1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(-c2cccc(C3OC3(C#N)c3ccncc3)c2)c2ncccc2c1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-acrylonitrile from Step 1 (75 mg, 0.3 mmol) in CH2Cl2/MeOH (1:1, 2 mL) was added MMPP (148 mg, 0.3 mmol). The resulting reaction mixture was stirred 18 h at 21° C., then diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with EtOH/ethyl acetate, 10:90) provided the title compounds.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:13]([N:20]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:10][CH:9]([OH:11])[CH2:8][O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Oc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Yield: 88.7 %

Procedure:
A mixture of phenylglycidyl ether (8.0 g), N-benzyltyramine hydrochloride (13.0 g) and triethylamine (7.5 ml) in isopropanol (200 ml) was heated to reflux for 3hours. The solvent was evaporated and toluene was added to the residue. Volatile material was evaporated. The residue was purified by chromatography on K60 silica (300 g) using a gradient mixture of methanol in dichloromethane (1 to 2% methanol). Thus was obtained 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenol (16.5 g) as an oil which slowly crystallised, m.p. 103°-5° C.: NMR: 2.55-2.85[m,6H, CHCH2NHCH2CH2 ]; 3.65-4.05 [m,5H, PhOCH2CHOH +PhCH2 ]; 6.65-7.4[m,14H, aromatic H].
Reaction SMILES: Cl[O-:2].[Na+].[C:4]1([S:10]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CN(C=O)C>[C:4]1([S:10]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:2])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 5 mL sodium hypochlorite and 4-benzenesulfinyl-benzoic acid (0.14 gm, 0.57 mmol) in DMF (5 mL) was stirred at room temperature overnight. A further 5 mL of sodium hypochlorite was then added and the mixture stirred at room temperature overnight. After acidification using 10% HCl, the resulting solid was filtered to afford 105 mg (70% yield) of 4-benzenesulfonyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH2:27])(=[O:23])=[O:22]>CO.C(O)C.[Pd]>[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH:27][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)CCCN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (280 mg) in methanol (10 mL) was added 3-amino-propane-1-sulfonic acid dimethylamide (284 mg) and the reaction stirred at room temperature for 16 h. The solvent was reduced in vacuo and the residue redissolved in ethanol (50 mL). Palladium on carbon (20 mg) was added and the reaction stirred at room temperature under a hydrogen balloon for 48 h. The reaction was then filtered through Celite and the filtrate reduced in vacuo to give 3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:25][C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1csc(N2CCOCC2)n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N4CCOCC4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (6.13 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile and 2.68 g (12.26 mmol) of 4-(4-(chloromethyl)-1,3-thiazol-2-yl]morpholine are dissolved in dry DMF (50 ml), and 1.83 ml (12.26 mmol) of DBU are added. After 3 hours of stirring at RT, the solvent is removed using a rotary evaporator and the residue is purified by preparative HPLC (column: Kromasil 100 C18 250×20 mm, 10 μm; acetonitrile/water gradient: 3 minutes of 10% acetonitrile which is then, over a period of 30 minutes, increased to 80% acetonitrile; flow rate: 25 ml/min). This gives 1.70 g (55% of theory) of product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1-c1ccccc1
Yield: 84 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.20 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 181-182° C.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[N:11]=[CH:12][CH:13]=[CH:14][C:5]1=2.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O>CN(C=O)C>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=[C:9]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[N:11][C:6]=2[NH:7][C:8]1=[O:10]
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1COc2cccnc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2OC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 0.01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled to room temperature, poured into crushed ice and left overnight at 4° C. The precipitated solid was filtered off, washed with water and dried. The dark solid was boiled with ethanol (150 ml) and filtered hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by silica gel chromatographed using (95:5) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=[CH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[BH3-]C#N.[Na+]>CO.CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCC(=O)O
Yield: 30.1 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol (6.5 mL) and AcOH (65 μL) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 mm of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0 AC and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 30%).
Reaction SMILES: [H-].[Na+].FC1C(F)=CC=CC=1[CH2:11][S:12]([C:15]1[N:20]=[C:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:18]=[C:17]([O:38][CH3:39])[N:16]=1)(=O)=O.[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]CS)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:21]([C:19]2[CH:18]=[C:17]([O:38][CH3:39])[N:16]=[C:15]([S:12][CH2:11][CH2:46][C:43]3[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=3)[N:20]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])=[CH:35][CH:34]=1
Reactant: SCCc1ccccc1
Reactant: COc1ccc(CN(c2cc(OC)nc(S(=O)(=O)Cc3cccc(F)c3F)n2)S(=O)(=O)N2CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(OC)nc(SCCc3ccccc3)n2)S(=O)(=O)N2CCC2)cc1

Procedure:
60% Sodium hydride (29 mg) was added to a solution of the product of step ii) (0.36 g) and 2-phenylethylthiol (0.1 g) in anhydrous DMF (4 ml) stirred under nitrogen. The reaction mixture was stirred for 18 h, diluted with EtOAc and washed with H2O. The separated organic solution was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using Et2O/isohexane (3:7) as eluent to give the product as a white solid. Yield: 0.17 g.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].Cl>ClC(Cl)C>[C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([C:26](=[O:28])[CH3:27])[CH:18]=2)[C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCC(=O)C1=C(O)C(c2ccc(O)c(C(C)=O)c2)CCC1=O
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
2-Butyryl-3-hydroxy-4-(4-methoxyphenyl)cyclohex-2-ene-1-one (7.1 g) in dichloroethane (35 ml) was added to a suspension of aluminium chloride (10.5 g) in dichloroethane (50 ml) at 0° C. After stirring for 1/2 hour, a solution of acetyl chloride (2.2 g) in dichloroethane (25 ml) was added dropwise. After stirring a further 1/2 hour at 0° C., the reaction mixture was allowed to come to room temperature and poured into cold 5N hydrochloric acid (50 ml). The aqueous solution was then extracted with dichloromethane. The extracts were dried over magnesium sulphate and evaporated in vacuo to give a red oil. Purification on a silica gel column using 5% (v/v) diethylether-dichloromethane as eluant gave the title compound (1.3 g) as a clear oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)n(-c2ccccc2)n1

Procedure:
134 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (75 mg, 0.310 mmol), 1-(2,4-dimethylphenyl)piperazine (59 mg, 0.310 mmol), DIPEA (0.081 mL, 0.465 mmol) and NaBH(OAc)3 (197 mg, 0.930 mmol).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]=[CH2:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:27])=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]=[CH2:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: C=Cc1cccc2c(Cl)c(C(=O)CCC)cnc12
Solvent: C1COCCO1
Product: C=Cc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)CCC)cnc12
Yield: 33.7 %

Procedure:
3-Butyryl-4-chloro-8-vinylquinoline (20.0 g, 77 mmol) and 4-amino-m-cresol (9.5 g, 77 mmol) were heated together under reflux in 1,4-dioxan (150 ml) for 2.5 hours. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, 2M hydrochloric acid, sodium hydrogen carbonate solution and brine. The solution was dried (anhyd. MgSO4), filtered and evaporated to an oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline as orange crystals (9.0 g, 32%) m.p. 150°-2°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[O:13])=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:28]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl)piperazine-1-carboxylate (0.048 g, 0.13 mmol) in methanol (2.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.025 g, 0.17 mmol). Then, the mixture was added with 7 drops of piperidine, and the mixture was stirred at 50° C. for 4 hours. The solid formed was removed by filtration, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl}piperazine-1-carboxylate (0.054 g, 85%).