Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>N1C=CC=CC=1.C1CCCCC1.C(OCC)C>[CH3:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of N-tert-butoxycarbonylpyrrolidin-3-ol (19.8 g, 0.106 mol) in pyridine (200 ml) at 0° C. under nitrogen was added tosyl chloride (22.3 g, 0.117 mol) portionwise. Stir at 0° C. for 2 hr, warm to room temperature and stir at room temperature overnight. The pyridine was evaporated in vacuo and the residue was partioned between EtOAc and saturated aqueous citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2×200 ml) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave an oil which was purified by flash silica gel column chromatography using 10% EtOAc/cyclohexane as eluent to give in F40-85 an oil. The oil was dissolved in a small volume of cyclohexane/diethylether (5:1, 50 ml), cooled and scratched with a spatula to induce crystallisation. The resulting solid was filtered to give tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate (10.5 g, 29%) as a white solid. Rf in EtOAc/cyclohexane=0.13. 1H NMR (CDCl3, 250 MHz): 7.79 (2H, d), 7.35 (2H, d), 5.04 (1H, m), 3.43 (4H, m), 2.46 (3H, s), 2.03-2.20 (2H, bm), 1.43 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=Cc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CCNCc2ccccc2Cl)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)-ethylamine (80.3 g, 0.443 mol) and o-chlorobenzaldehyde (62 g, 0.443 mol) are boiled (1 hour) in toluene (500 ml) using a water separator. The reaction mixture is evaporated, the oily residue is taken up in methanol (500 ml) and combined, under vigorous stirring and intensive cooling, with a solution of sodium borohydride (16.9 g, 0.443 mol) in water (50 ml). After it has all been added, the resulting mixture is stirred (1 hour) at ambient temperature, concentrated in vacuo and the residue is distilled in vacuo. Yield: 108.8 g. Bp16.9 Pa : 188°-190° C.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15]C(=O)C)=[CH:7][C:6]=1[O:19]C(=O)C)(=O)C.C[O-].[Na+]>CO>[OH:19][C:6]1[C:5](=[O:4])[C:14]2[C:9]([C:8](=[O:15])[CH:7]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(=O)Oc1cc(OC(C)=O)c2ccccc2c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)C(=O)c2ccccc21
Reaction time: 1 h

Procedure:
1,2,4-Triacetoxynaphthalene (75.5 g) was added to a clear solution of sodium methoxide (from 26.6 g Na) in methanol (625 mL). After 1 hour, the resulting red paste was collected by filtration, then dissolved in water and acidified with concentrated hydrochloric acid. The yellow precipitate was collected, recrystallized from acetic acid to give 2-hydroxy-1,4-naphthoquinone, m.p. 195° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:13]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:12]1[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][NH:8]2
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(I)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (611 mg, 1.10 mmol) in DCM (5 ml) was added TFA (1.2 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (367 mg, 84%). LCMS (Method B): RT=3.23 min, [M+H]+=398.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)(OCC)[O:20]CC.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH:15]([CH2:16][OH:17])[O:18][C:19]3=[O:20])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)OCC
Reactant: OCC(O)CNc1ccc(C2CCCCC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1OC(CO)CN1c1ccc(C2CCCCC2)cc1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
2.4 g (9.62 mmol) of (RS)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol were dissolved in 50 ml of toluene, treated with 1.25 g (10.6 mmol) of diethyl carbonate and 0.4 ml of a 1 molar sodium methylate solution in methanol and stirred overnight at an oil bath temperature of 110°. The solvent was distilled off in a water-jet vacuum and the residue was treated with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. 1.4 g of product in the form of yellowish crystals were obtained from ethyl acetate/hexane. A further 0.9 g of pure product was obtained from the mother liquor. M.p.: 167°-167.5°.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]#[N:9]>CCOC(C)=O.[Pd]>[CH:1]12[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]#[N:9]
Reactant: N#CC1CC2C=CC1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CC1CC2CCC1O2
Yield: 100.5 %

Procedure:
The exo/endo-mixture of 7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile (4.70 g, 38.8 mmol) in EtOAc (30 mL) was dissolved in EtOAc (30 mL), treated with 10% Pd/C (0.300 g, 0.282 mmol) and hydrogenated (20 psi) for 2 h. The solids were removed via filtration, washed with EtOAc and the filtrate concentrated in vacuo to afford an exo/endo-mixture of 7-oxabicyclo[2.2.1]heptane-2-carbonitrile (4.80 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3]CCCCC.[CH2:11]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][NH2:13]>>[C:1]([OH:10])(=[O:9])[CH2:2][CH3:3].[CH2:11]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][NH2:13]
Reactant: CCCCCCCC(=O)O
Agent: NCCCNCCCN
Product: CCC(=O)O

Procedure:
In manner analogous to Example 3, polyester and polyacrylonitrile fibre may be treated with the product obtained by using, in place of the acylation product from caprylic acid and dipropylene triamine, 17.6 parts of a product formed by thermal condensation of 14.8 parts of propionic acid with 26.2 parts of dipropylene triamine, having a viscosity of about 150 cp (approximately 50% solution).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[O:12][C:11]1[C:2]([NH:33][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)c1ccccc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-Chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (73 mg, 0.21 mmol) was dissolved in dimethyl sulfoxide (2 mL). To this, benzenesulfonamide (33 mg, 0.21 mmol) and potassium carbonate (29 mg, 0.21 mmol) were added at room temperature and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (20 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was subjected to slurry purification using methanol, to give N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoxalin-2-yl}benzenesulfonamide (Compound 137) (31 mg, 320).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34]COC)=[CH:30][CH:29]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]([CH3:27])[C:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:7][CH:6]=1>C(OCC)(=O)C.Cl>[OH:34][C:31]1[CH:30]=[CH:29][C:28]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]([CH3:27])[C:19]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:20])=[CH:33][CH:32]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2N(C)C(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)C1CCCCC1)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 1 h
Yield: 17.2 %

Procedure:
In 50 ml of ethyl acetate saturated with hydrogen chloride was dissolved 2.18 g of Compound 137 obtained by Example 137, and the solution was stirred for 1 hour. Thereafter, the solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol to afford 0.31 g of the desired compound (Compound 138).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[O:21])=[CH:18][CH:17]=1>CO.COCCOC.CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25][S:12][C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]=3[N:6]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: COCCOC
Product: Cc1c[nH]c2nc(SCc3cccc(C(=O)c4ccc(Cl)cc4)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.1 %

Procedure:
In methanol (18.7 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.88 ml) for dissolution. Then, under ice-cooling, a solution of 3-(4-chlorobenzoyl)benzyl bromide (2.79 g) in DME-DMF (6:5; 22 ml) was added dropwise. The mixture was stirred at room temperature for 20 hours, at the end of which time it was poured in ice-water (200ml). The resulting precipitate was collected by filtration and rinsed with water. Then, it was further washed with 50% ethanol/water, methanol and ether in that order, dried, and purified by flash column chromatography (chloroform, containing 1% methanol) to provide the title compound (1.94 g). 1H-NMR (DMSO-d6) δ: 2.25(3H,s), 4.50(2H,s), 6.65(1H,s), 7.50(2H,d,J=8.OHz), 7.69(2H,d,J=8.6Hz), 7.51-7.82(4H,m), 11.38(1H,s), 11.95(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21]([O:26][CH3:27])(=[O:25])/[CH:22]=[CH:23]/[CH3:24].CC(C)([O-])C.[K+].O>C1COCC1.C(OCC)(=O)C>[CH3:27][O:26][C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=1[F:18]
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(C)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(4-Chloro-phenylsulfanylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 1.0 g, 3.1 mmol) and methyl crotonate (1.55 g, 15.5 mmol) were dissolved in 50 mL of THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for five hours. 100 mL of water and 100 mL of EtOAc were added. The organic layer washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%). The product is a mixture of diastereomers. 1H NMR (CDCl3 400 MHz) δ 7.60 (m, 2H), 7.37 (m, 2H), 7.07 (m, 1H), 6.83 (m, 0.5H), 6.63 (m, 0.5H), 5.03 (t, J=10.2 Hz, 0.5H), 4.80 (d, J=10.2 Hz, 0.5H), 3.71 (s, 1.5H), 3.60 (s, 1.5H), 3.33 (m, 1H), 3.10 (m, 0.5H), 2.89 (m, 0.5H), 2.42 (m, 0.5H), 2.15 (m, 0.5H), 1.49 (t, J=6.6 Hz, 1.5H), 0.95 (dd, J=8.8 and 7.3 Hz, 1.5H).
Reaction SMILES: C(N1CC(O)C1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC1C=CC(C(O)C2C=CC(Cl)=CC=2)=CC=1.[CH:35]([N:48]1[CH2:51][CH:50]([O:52][CH:53]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][C:55]=2Cl)[CH2:49]1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:35]([N:48]1[CH2:51][CH:50]([O:52][CH:53]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)[CH2:49]1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Agent: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (45.0 mmol) and 4,4′-dichlorobenzhydrol (90.0 mmol) using the procedure described for compound (3) (8.6 g, 40%).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.[Cu][C:24]#[N:25].O>CN(C=O)C>[C:24]([C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1)#[N:25]
Reactant: COc1ccc(-c2coc3cc(OC)cc(Br)c3c2=O)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3cc(OC)cc(C#N)c3c2=O)cc1
Temperature: 120 °C
Yield: 98.7 %

Procedure:
A suspension of 5-bromo-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1 benzopyran (150 mg), copper(I) cyanide (55.5 mg) in DMF (4 mL) was heated at 120° C. for 3 h. The mixture was cooled, poured into cold water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over MgSO4. Evaporation of the solvents afforded the title compound (126 mg) as a white solid. 1H NMR (DMSO-d6): 8.52 (s, 1H), 7.67 (d, 1H, J=2.7 Hz), 7.54 (m, 3H), 7.01 (d, 2H, J=8.7 Hz), 3.97 (s, 3H), 3.80 (s, 3H); MS: 308 (MH+); HPLC tR: 2.29 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(OCC)C>[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: CN1CCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3C)cc1
Reaction time: 0.03 h
Yield: 14.5 %

Procedure:
To a solution of 1-methylindolin-5-ol (18 mg, 0.12 mmol) in 0.6 mL of dry diethyl ether was added sodium hydride (55%, 19 mg, 0.43 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, 4-isopropylphenylisocyanate (29 μL, 0.18 mmol) was added with additional stirring for 5 min to 10 min. After the reaction mixture was quenched with water (1 mL), the solution was extracted with diethyl ether (10 mL). The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40) to obtain the title compound (5.4 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH3:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(Cl)c2Cl)cc1
Yield: 72.5 %

Procedure:
(E)-Ethyl 3-(2′,3′-Dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 73% yield) was prepared from 2,3-dichlorophenylboronic acid (1.26 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][CH:6]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2].Cl.[C:27](OCC)(=O)[CH3:28].CCCCCC>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:5]1[CH:28]=[CH:27][C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=2)[CH:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:25])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a stirred solution of (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester (3.7 g, 8.55 mmol) in acetone (150 mL) was added 6N hydrochloric acid (38 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with water. The solvent was evaporated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (1.17, 37% yield) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:27])[CH:6]([S:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].Br[C:29]1[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:6]([S:11][C:12]1[CH:13]=[CH:14][C:15]([C:29]2[CH:30]=[CH:31][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:27])#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CC(C)CC(Sc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)NCC#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(Sc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1)C(=O)NCC#N
Temperature: 80 °C

Procedure:
N-(cyanomethyl)-4-methyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thio}pentanamide (1.64 g, 4.22 mmol) and tert-butyl 4-bromobenzylcarbamate (1.33 g, 4.64 mmol) were mixed in DMF (12 mL). After addition of sodium carbonate (7.4 mL of a 2.0 M solution, 14.8 mmol), the reaction flask was thoroughly degassed with dry nitrogen. PdCl2dppf (103 mg, 0.13 mmol) was added and the reaction mixture was heated at 80° C. for 4 h. Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (40% EtOAc/hexanes) to afford tert-butyl {4′-[(1-{[(cyanomethyl)amino]carbonyl }-3-methylbutyl)thio]-1,1′-biphenyl-4-yl}methylcarbamate.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:14]Br>C(O)(=O)C>[Br:14][CH:10]1[CH2:11][CH2:12][N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:7][CH2:8][C:9]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCCN(C(=O)C2CC2)CC1
Solvent: CC(=O)O
Product: O=C1CCN(C(=O)C2CC2)CCC1Br
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A solution of 1-Cyclopropanecarbonyl-azepan-4-one (2.7 grams, 14.9 mmol, obtained in above step) in acetic acid (30 mL) was cooled to 10° C. and treated with bromine (0.71 mL, 14.9 mmol) over a period of 15 minutes. The resulting slurry was stirred for 18 hours under nitrogen atmosphere. After completion of reaction, mass was concentrated to dryness to obtain the title compound (3.87 grams).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10](=[O:17])[CH2:11][C:12](=O)[CH2:13][CH2:14][CH3:15])[CH3:8].O>C1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:17])[CH:11]=[C:12]([Cl:2])[CH2:13][CH2:14][CH3:15])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC(Cl)=CC(=O)OCC
Temperature: 0 °C

Procedure:
280 g of phosphorus pentachloride are added in portions over the course of 2 hours to a solution of 200 g of 3-oxo-hexanoic acid ethyl ester in 200 ml of absolute benzene whilst stirring at 0° C. 200 ml of water are then added dropwise with intense cooling so that the temperature never rises above 0° C. The mixture is stirred for a further 12 hours at 0° C. The organic phase is then separated off, washed with twice 100 ml of ice-cold 2 N sodium hydroxide solution and with twice 100 ml of water, dried over sodium sulphate and evaporated in vacuo. Fractional distillation of the evaporation residue gives, in the fraction boiling at 98°-102° C (20 mm), crude 3-chloro-2-hexenoic acid ethyl ester, which is used direct for further conversion.