Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([O:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[N:8]=2>CO>[CH3:1][O:2][C:5]1[N:6]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([O:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[N:8]=2
Reactant: C[O-]
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
A solution of sodium methoxide in methanol (0.5M, 20 ml, 10 mmol) was added to a solution of 8-bromo-2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.368 g, 5.95 mmol) in methanol (10 ml) and the mixture heated under reflux for 5 hours. More sodium methoxide in methanol (4 ml, 2 mmol) was added and the mixture refluxed for a further 2 hours and then cooled and evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.725 g).
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:37]=4[C:38]([F:41])([F:40])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C>[NH2:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:48](=[CH:49][CH:50]=1)[C:29]1=[N:30][O:31][C:32]([C:33]3[CH:34]=[N:35][N:36]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:37]=3[C:38]([F:39])([F:40])[F:41])=[C:28]1[CH2:27][CH2:26]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C)(N)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a stirred clear solution of ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50C, 120 mg, 0.174 mmol) in diethyl ether (3 mL) was added 4 N aqueous HCl (0.261 mL, 1.045 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. The ether layer was separated and the aqueous layer re-extracted with ether (2 mL). The aqueous solutions were basified with solid potassium carbonate and extracted with ethyl acetate (3×2 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure to give ethyl 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (86 mg, 0.164 mmol, 94% yield) as an yellow oil. The compound had an HPLC retention time=3.22 min (condition C); LC/MS M+1=525.5.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:29]([NH:31][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N+:8]([O-:10])=[O:9])(=[O:19])=[O:18])[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1cccc([C@@H](C)N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc([C@@H](C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
A 2.0 ml portion of triethylamine and 1.9 g of orthonitrobenzenesulfonyl chloride were added to a mixed solution of 1.0 g of (1R)-1-(3-methoxyphenyl)ethylamine and 10 ml of dichloromethane under ice-cooling and stirred for 5Hours. Thereafter, work-up and purification were carried out in the standard method to obtain 2.2 g of N-[(1R)-1-(3-methoxyphenyl)ethyl]-2-nitrobenzene sulfonamide as yellow crystals. EN: 335.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:18][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CO)ccc1Sc1ccc(O)cc1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To the product from Example 113B (500 mg, 1.82 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium aluminum hydride (1.0M in THF, 1.8 mL, 1.82 mmol) dropwise at room temperature followed by heating the mixture to 70° C. for 4 hours. Water (25 mL) was then carefully added to the solution and the organic layer separated, dried and concentrated under vacuum to provide the title compound (295 mg, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a solution of 0.220 g (0.940 mmol) of 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 5 mL of DMF was added 0.156 g (1.034 mmol) of t-butyldimethylsilyl chloride and 0.160 g (2.350 mmol) of imidazole and the reaction was stirred at room temperature for 14 h. The reaction mixture was diluted with water and extracted with ether. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.315 g of 4-tert-butyl(dimethyl)silyloxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]3[N:16]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[S:18][C:14]=3[CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]3[N:16]=[C:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[S:18][C:14]=3[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2c(s1)-c1nc(-c3cccnc3)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc3sc(-c4cccnc4)nc3c2s1
Temperature: 35 °C
Yield: 30.1 %

Procedure:
A suspension of N-ethyl-N′-[7-(3-pyridyl)-4,5-dihydro[1,3]thiazolo[4′,5′: 3,4]benzo[d]-[1,3]thiazol-2-yl]urea (10 mg, 0.028 mmol) and DDQ (13 mg, 0.056 mmol) in toluene (1 mL) was heated to about 35° C. for about 3 hrs. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. 3 mg (30%) pure product was isolated. LC/MS 356 (MH+); RP-HPLC 14.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21](I)=[CH:22][C:13]=12.[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:29]3[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)=[CH:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3sc(-c4ccc(C=O)cc4)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile (0.25 g, 0.52 mmol), 4-formylphenylboronic acid (0.16 mg, 1.05 mmol), and 30 mg of tetrakis(triphenylphosphine)palladium(0) in 45 mL of ethylene glycol dimethyl ether is prepared. To the mixture is added 20 mL of a saturated sodium carbonate solution and the reaction mixture is heated at reflux for 1 hour. The mixture is allowed to warm to room temperature and partitioned between water and dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is triturated with ethyl acetate and the resulting solid is filtered and washed with diethyl ether to provide 0.16 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp>240° C.; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.42 (s, 1H), 7.79 (s, 1H), 7.94 (d, J=8.3 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.47 (s, 1H), 9.92 (s, 1H), 10.06 (s, 1H); MS 452.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)(=[O:20])=[O:19])[C@H:13]([CH3:30])[CH2:12]1.O.NN>C(O)C.[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([S:18]([N:14]2[C@@H:15]([CH3:17])[CH2:16][N:11]([CH2:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[O:31])[CH2:12][C@H:13]2[CH3:30])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc([N+](=O)[O-])c2)[C@@H](C)C1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Reaction time: 1 h

Procedure:
To a stirred solution of the product of Example 56 (3.0 g) in ethanol (1500 ml) was added 5% palladium on charcoal (1.5 g) followed by dropwise addition of hydrazine hydrate (20 ml). The mixture was stirred for 1 hour, filtered through ‘hyflo’ and the filtrate was evaporated to dryness. The solid residue was crystallised from ethanol to give the title compound as a white solid. Yield 1.6 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[N:16]=1.Cl.C([N:40]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([NH2:40])=[O:21])=[CH:18][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)[N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.75 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.26 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.70 g, yield 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 158–159° C.
Reaction SMILES: C1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=S)CCCCC1.SCCC[Si](OCC)(OCC)[O:23]CC>C(Cl)(Cl)Cl>[C:8]1(=[O:23])[NH:7][C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]12
Reactant: O=C1c2ccccc2C(=S)N1C1CCCCC1
Reactant: CCO[Si](CCCS)(OCC)OCC
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)c2ccccc21
Reaction time: 8 h
Yield: 119.6 %

Procedure:
A 1-quart (0.946l) glass reactor was charged with 400 ml of chloroform, 55.4 g (0.21 mole) of N-cyclohexylthiophthalimide, and 47.6 g (0.20 mole) of 3-mercaptopropyltriethoxysilane dissolved in 400 ml of chloroform. The reaction was stirred and allowed to stand overnight to give white needles of phthalimide (35.2 g) which were separated by filtration and identified by mass spectrometry analysis. The solvent was distilled from the filtrate to give 56.9 g of an oil identified as cyclohexyl-3-dithiopropyltriethoxysilane by mass spectrometry analysis. This oil (53 g) was dissolved in 100 ml of acetone and homogeneously dispersed into N330 carbon black, with the acetone being stripped away.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13])=[O:4].N1(O)C2C=CC=CC=2N=N1.[N:31]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[C@@H:33](O)[CH2:32]2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[O:13]=[C:12]([O:14][C@@H:33]1[CH:34]2[CH2:37][CH2:38][N:31]([CH2:36][CH2:35]2)[CH2:32]1)[CH:11]([NH:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetic acid (I10) (700 mg, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (487 mg, 3.60 mmol), (R)-quinuclidin-3-ol (458 mg, 3.60 mmol), and DCC (744 mg, 3.60 mmol) in dry THF (20 ml) was stirred at room temperature overnight. THF was evaporated, the crude product was partitioned between DCM and 2M K2CO3. The organic phase was collected, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=95/5) to obtain methyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)thiophene-2-carboxylate (302 mg, 31.4% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8](O)=[O:9])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]([OH:11])[CH2:8][OH:9])=[CH:12][CH:13]=1
Reactant: O=C(O)C(O)c1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(O)c1ccc(C(F)(F)F)cc1
Yield: 85.5 %

Procedure:
To a stirred solution of 4-trifluoromethylmandelic acid (1.0 g, 4.54 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.36 g, 9.54 mmol). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was quenched with sat. ammonium chloride solution, filtered, concentrated to yield 0.8 g of 1-(4-trifluoromethylphenyl)ethane-1,2-diol.
Reaction SMILES: OC1C=C(CCC[N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])C=CC=1.O1C(CCC)C1>>[C:12]1(=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[NH:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: CCCC1CO1
Product: O=C1NC(=O)c2ccccc21

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxypentane gave 2434342-hydroxypentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.93 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=6.0 Hz, 1H), 7.53-7.60 (m, 1H), 7.47-7.52 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.14-7.19 (m, 1H), 6.78-6.83 (m, 2H), 6.73 (d, J=8.2 Hz, 1H), 3.81 (d, J=4.8 Hz, 2H), 3.73-3.79 (m, 1H), 3.18-3.24 (m, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.73-1.81 (m, 2H), 1.30-1.52 (m, 4H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:30])[C@H:10]([CH:11]=O)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=1[F:29])=[O:14].C(OP([CH:39]([Cl:42])[C:40]#[N:41])(=O)OCC)C>O1CCCC1>[Cl:42]/[C:39](/[C:40]#[N:41])=[CH:11]\[C@H:10]1[C@@H:9]([C:13]([O:15][CH2:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=2[F:29])=[O:14])[C:8]1([CH3:7])[CH3:30]
Reactant: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Reactant: CCOP(=O)(OCC)C(Cl)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](/C=C(\Cl)C#N)C2(C)C)c(F)c1F
Yield: 3.7 %

Procedure:
A solution of 0.27 g of potassium tert-butoxide in 2 ml of tetrahydrofuran was added dropwise to a mixture of 0.70 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3R)-2,2-dimethyl-3-formylcyclopropanecarboxylate, 0.42 g of diethyl(chlorocyanomethyl)phosphonate and 5 ml of anhydrous tetrahydrofuran with ice-cooling under a nitrogen atmosphere. After stirring with ice-cooling for 15 minutes, the reaction mixture was poured into a saturated saline solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subject to silica gel column chromatography to obtain 0.03 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3R)-3-((Z)-2-chloro-2-cyanovinyl)-2,2-dimethylcyclopropanecarboxylate represented by the formula (3):
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].Cl>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(C=C2CCCCC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C=C2CCCCC2O)cc1
Temperature: 0 °C
Yield: 17.4 %

Procedure:
2.0 g of (+)-2-[4-(2-oxocyclohexylidenemethyl)phenyl]-propionic acid and 0.6 g of sodium cyanoborohydride were dissolved in 50 ml of methanol. The pH of the mixture was adjusted to a value of 3 with 6N hydrochloric acid, whilst ice-cooling. The mixture was then stirred, with heating, for 40 minutes. Ice-water was added to the reaction mixture, which was then extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate, and the solvent was distilled off, to give 350 mg of (±)-2-[4-(2-hydroxycyclohexylidenemethyl)phenyl]propionic acid as crystals [compound of formula (VI)]. These crystals were dissolved in 10 ml of ethyl acetate, 50 mg of palladium chloride were added, and the mixture was subjected to catalytic reduction whilst bubbling hydrogen through the mixture. After the theoretical amount of hydrogen had been absorbed, the catalyst was removed by filtration and the solvent was distilled off, to give 330 mg of a mixture of the cis- and trans-isomers. This mixture was treated in the same manner as in Example 1, affording crystals of the cis- and trans-isomers of the title compound, having the same properties as the product of Example 1.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH2:28][O:29]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH2:28][OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCOC3CCCCO3)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCO)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-indole-6-carboxylate (1.38 g, 2.81 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 6N hydrochloric acid (4 ml), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1-1:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethylsulfanyl)phenyl]-1H-indole-6-carboxylate (1.00 g, yield 87.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:23]
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CCOCC
Product: S=C(Nc1c(Cl)cccc1Cl)N1CCN(c2cnccn2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 6.12 g. of 2,6-dichlorophenyl isothiocyanate in 50 ml. of anhydrous ether over 10 minutes. The mixture is stirred for 15 minutes and the resulting solid collected. This solid is dissolved with heat in a mixture of 200 ml. of acetone and 150 ml. of methanol and then cooled. The resulting solid is collected giving 5.29 g. of the desired product as white crystals, m.p. 225°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@H:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CC1(C)[C@@]23C4(ON4S(=O)(=[O:47])C2)C[C@H]1CC3>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C@H:11]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:13][C@H:14]([OH:47])[C:15]1=[O:16])=[O:4]
Reactant: CC1(C)[C@@H]2CC[C@]13CS(=O)(=O)N1OC13C2
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a solution of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.2 g, 7.97 mmol, 1.0 equiv) in THF (15.0 ml) was added NaHMDS (1.0 M in THF) at −78° C. and the resulting solution was stirred at −78° C. for 1.5 hours. To this solution was then added a solution of (S)-(+)-(camphorsulfonyl)oxaziridine (3.65 g, 15.94 mmol, 2.0 equiv) in THF (10 ml) and the reaction mixture was stirred at −78° C. for 3 hours. The reaction was quenched by addition of sat. NH4Cl aq. solution. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, and concentrate. The residue was purified by silica gel column chromatography, (Et2O/DCM 5%˜40%) to give 1.5 g of the desired product (yield 45%). MS: 418 [M+H+]