Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:11]#[N:12]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Oc1ccc(Cl)cc1I
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1O
Yield: 79.7 %

Procedure:
2-Amino-4-chlorophenol (50 g, 0.35 mol) was dissolved in 500 ml of 2.5N HCl. The resulting solution was cooled to 0° C., at which a solution of 25.25 g (0.37 mol) of sodium nitrite in 50 ml of water was added slowly. After stirring for 30 minutes, a chilled solution of 70 g (0.42 mol) of potassium iodide in 100 ml of water was added slowly. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure, whereby 89.7 g of 4-chloro-2-iodophenol were obtained (yield: 99%). Next, 85 g (0.33 mol) of the 4-chloro-2-iodophenol and 32.5 g (0.36 mol) of copper cyanide were dissolved in 150 ml of DMF. After the resultant solution was heated under reflux for 2 hours, the DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the extract was then washed with water. An insoluble matter was filtered off. The solvent was then distilled off under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%) (melting point: 150.3-152.6° C.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:49]=[C:48]([CH2:50][C:51](O)=[O:52])[O:47][N:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:51](=[O:52])[CH2:50][C:48]3[O:47][N:46]=[C:45]([CH3:44])[CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(CC(=O)O)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)on1
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-methyl-5-isoxazoleacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-methyl-isoxazol-5-yl)-acetamide (0.8 g, 84%) as a white solid: mp 179-181° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.71 min. (97%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.20 (s, 3H), 2.53-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.77 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.21 (s, 1H), 7.69-7.87 (m, 3H), 8.80 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 10.91, 21.95, 30.90, 33.46, 38.00, 48.85, 103.79, 121.99, 127.18, 131.54, 133.27, 134.75, 138.66, 159.51, 166.85, 166.90, 167.41, 169.77, 172.72; Anal. Calcd. for C20H18N4O6: C, 58.54; H, 4.42; N, 13.65. Found: C, 58.18; H, 4.19; N, 13.52.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:26]([CH3:39])=[CH:25][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:48]3[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=3)[C:15]2=[O:23])=[CH:29][C:28]=1[CH3:30]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.580 g, 0.963 mmol), 4-methoxyphenylboronic acid (0.293 g, 1.93 mmol), copper (II) acetate (0.175 g, 0.963 mmol), triethylamine (0.27 mL, 1.93 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 80% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.501 g, 0.708 mmol), in THF (5 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.80 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and add ethyl acetate (50 mL). Separate the layers, and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.285 g (62%) of the title compound: mass spectrum (FAB): m/z=480(M+1); 1H NMR(DMSO-d6): δ8.23 (s, 2H), 7.33-7.29 (m, 3H), 7.21 (td, 1H), 7.11-7.06 (m, 3H), 6.73 (s, 4H), 6.70 (d, 1), 3.70 (s, 3H), 2.07 (s, 12H).
Reaction SMILES: [ClH:1].[CH3:2][S:3]([N:6]1[CH2:22][CH2:21][C:9]2([CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4]>O1CCOCC1>[ClH:1].[CH3:2][S:3]([N:6]1[CH2:7][CH2:8][C:9]2([CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride in 1,4-dioxane (4.0M, 0.50 mL) was added to tert-butyl 8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (21.0 mg, 0.0000659 mol) at rt. The mixture was stirred at rt for 1 h and then the solvent was evaporated. and the residue was dried under high vacuum to afford the desired product. LCMS: m/z 255.5 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]=1[OH:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
5-Bromo-2-hydroxy-benzoic acid ethyl ester (40 g, 214 mmol) is suspended in sulfuric acid (200 mL) and the reaction cooled to zero in an ice bath. The reaction is equipped with an overhead stirrer and then the nitric acid (20 mL) in sulfuric acid (40 mL) is added dropwise to the solution over the course of 30 minutes. After the addition the ice bath is removed and the reaction warmed to room temperature. The reaction is stirred at room temperature for 16 hours. When complete the reaction is poured onto crushed ice and the resulting yellow solid is collected by vacuum filtration and washed with ice cold water. The solid dried in vacuum over overnight to give the 45 g (91%) of title compound that is used without further purification. LCMS (ESMS): m/z 291.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[N:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:23][C:22]([C:20]1[N:21]=[C:10]2[CH2:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]2[N:19]=1)=[O:24])[CH3:27]
Reactant: CCO
Reactant: O=C(O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Product: CCOC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
6.77 g (0.020 mole) of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid [cp. Example 1(a), (b) and (c)] is suspended in 250 ml of abs. ethanol. While being stirred and refluxed, the solution is saturated with hydrogen chloride gas. The obtained clear solution is refluxed for a further 10 hours, and afterwards concentrated at 40° in vacuo. The residue is dissolved in 100 ml of ice-cold 5% sodium bicarbonate solution and 100 ml of methylene chloride; the organic phase is separated, washed with water, dried over sodium sulphate and concentrated at 40° in vacuo. The crude greasy residue is refluxed for 1 hour with 100 ml of ether, whereby crystallisation occurs. After cooling to 0°, the crystals are filtered off under suction and washed with ether. 6-Phenyl-8-chloro-4H-s-triazolo[1,5-a] [1,4]benzodiazepine-2-carboxylic acid ethyl ester, M.P. 137°-138°, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27]OC1C=C(C=CC=1OC)C(C1C=CC(OC)=C(OCC)C=1)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH2:1][CH3:27])[CH:4]=2)=[CH:12][CH3:13])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OC)c2)ccc1OC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: CC=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OCC)c1

Procedure:
1-(3,4-Dimethoxyphenyl)-1-(3-ethoxy-4-methoxyphenyl)prop-1-ene was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3′-ethoxy-4′-methoxybenzophenone (1.6 g, 5 mmol), (ethyl)triphenylphosphonium bromide (2.04 g, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 10% hexane/methylene chloride) to afford 0.8 g (49%) of a mixture of the E and Z isomers as a white solid: mp 65.5-68° C.; 1H NMR (CDCl3) δ6.95-6.65 (m, 12 H), 6.14-6.00 (m, 2 H), 4.11-3.78 (m, 22 H), 1.86-1.74 (m, 6 H), 1.50-1.36 (m, 6 H); 13C NMR (CDCl3) δ148.5, 148.4, 148.1, 147.7, 141.8, 141.7, 136.1, 136.0, 132.6, 132.5, 122.5, 122.3, 119.7, 114.7, 113.1, 111.9, 111.0, 110.7, 110.4, 55.9, 55.8, 55.8, 55.7, 15.7, 14.7; Anal. Calcd for C20H24O4. Theoretical: C, 73.15; H, 7.37. Found: C, 73.33; H, 7.39.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:16])([O-])=O>[Pd].[C].C(O)C>[CH3:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[C:4]=1[NH2:1]
Reactant: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(OCC(F)(F)F)c1N
Yield: 99.5 %

Procedure:
To 60 ml of an ethanol solution containing 10 g (42.6 mmol) of 2-nitro-3-(2,2,2-trifluoroethoxy)toluene, 1 g of 5 wt% Pd-carbon catalyst, and catalytic reduction was performed at atmospheric pressure and room temperature. After performing thin-layer chromatography to confirm that all the starting material had been consumed, the catalyst was filtered off and the filtrate was concentrated to provide 8.7 g of 2-methyl-6-(2,2,2-trifluoroethoxy)aniline as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])O.[Na+].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 70 °C
Yield: 40.3 %

Procedure:
A mixture of 4-(3-indolyl)piperidine (7.47 g), N-(3-bromopropyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.45 g) in dry N,N-dimethylformamide (88 ml) was heated at 70° C. for 2 hours. After cooling, the reaction mixture was poured into water (880 ml) and extracted with a mixture of chloroform and methanol (10:1 V/V). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (290 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to give pale yellow crystals of 1-(3-phthalimidopropyl)-4-(3-indolyl)-piperidine (5.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: COc1ccc(Br)nc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(OC)cn2)cc1

Procedure:
Repeating the operations of Production Example 14 using 4-(methoxycarbonyl)phenylboronic acid and 2-bromo-5-methoxypyridine, methyl 4-(5-methoxy-2-pyridyl)benzoate was obtained. Hydrolyzing the same with 5N aqueous sodium hydroxide solution, the title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[S:27])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc2n1CCCCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=c1c2ccc(Cl)cc2nc2n1CCCCC2

Procedure:
10 g of 3-chloro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one was treated with 15 g of Lawesson's reagent in toluene at reflux under nitrogen, until the starting material was consumed, as checked by TLC, using chloroform as eluent (24 hours). The mixture was concentrated in vacuo and chromatographed on silica gel, using chloroform as eluent. The bright yellow material was recrystallized from hexane-ethyl acetate, giving lemon-yellow needles, m.p. 99° C.-101° C.
Reaction SMILES: [H-].[Na+].[C:3]([NH:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl[CH2:23][C:24]([CH2:26]Cl)=[CH2:25]>CN(C=O)C>[C:18]([O:17][C:15]([N:14]1[CH2:26][C:24](=[CH2:23])[CH2:25][N:13]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (3.81 g, 95.4 mmol) in DMF (80 mL) is add dropwise a solution of N-Cbz-N′-Boc-hydrazine (12.1 g, 45.4 mmol) in DMF (20 mL). The reaction mixture is stirred about 20 minutes and 3-chloro-2-chloromethyl-propene (5.8 mL, 50 mmol) is added dropwise and the reaction is allowed to stir at room temperature until the reaction is complete by TLC, approximately 12 hours. The reaction solution is partitioned between ethyl acetate and water, the water layer being extracted several times more with solvent. The combined organic layers are dried, filtered, and concentrated to afford the desired product as a clear oil which is used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([OH:18])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:19]([O-])([O-])=O.[K+].[K+].CN(C=O)C.CI>CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a stirred suspension of 14.56 g of ethyl 1-cyclopropyl-4-hydroxy-1H-indole-6-carboxylate and 16.2 g of K2CO3 and 220 ml of DMF was added 7.48 ml of MeI and the mixture was stirred at 60° C. for 3 hrs. The mixture was allowed to cool, diluted with EtOAc, washed with water and saturated brine successively, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (n-hexane-EtOAc) to afford 15.15 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate as a pale yellow oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:17]([N:19](CC)[CH2:20][CH3:21])[CH3:18].C(Cl)(=O)C(C)(C)C.N1CCCC1.Cl>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:19]1[CH2:20][CH2:21][CH2:18][CH2:17]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CC(C)C[C@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
3.46 g (15 mmoles) of BOC-Leu-OH are dissolved in 50 ml of ethyl acetate, 2.1 ml (15 mmoles) of triethylamine are added, and the mixture is cooled to -15° C. 1.97 ml (16 mmoles) of pivaloyl chloride are added dropwise to the stirred mixture at such a rate that the temperature remains below -10° C., the resulting suspension is stirred for 10 minutes, and then 1.37 ml (16.5 mmoles) of pyrrolidine are added dropwise to the suspension at the same temperature. When the addition is complete, the mixture is stirred at -10° C. for additional 30 minutes, and then allowed to stand at 5° C. for 3 hours. The reaction mixture is shaken thrice with 10 ml of n hydrochloric acid, each, thrice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is dissolved in 5 ml of ethyl acetate, and 10 ml of a 5 n hydrochloric acid solution in ethyl acetate are added. After one hour of standing the solution is diluted with ether and extracted with water. The aqueous solution is washed with ether, rendered alkaline with potassium carbonate, and then extracted with chloroform. The chloroform solution is dried over anhydrous sodium sulfate, evaporated, the oily residue is dissolved in 10 ml of ether, and the pH of the solution is adjusted to 3 with a concentrated solution of hydrochloric acid in ethyl acetate. The separated crystals are filtered off to obtain 2.41 g (73%) of H-Leu-pyrrolidine.HCl; m.p.: 170°-174° C. (decomposition), Rf5 =0.37.
Reaction SMILES: [BH4-].[Na+].C([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[B:23]1[O:27][C:26](C)(C)C(C)(C)[O:24]1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([O:18][CH3:19])[N:10]=1)=O>CO.C(Cl)Cl>[OH:24][B:23]1[C:22]2[CH:21]=[CH:20][C:7]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([O:18][CH3:19])[N:10]=3)=[CH:6][C:5]=2[CH2:26][O:27]1
Reactant: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(Oc2ccc3c(c2)COB3O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaBH4 (0.077 g, 2.0 mmol) in anhydrous methanol (10 mL) was added to a solution of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinamide (2.51 g, 6.30 mmol) in CH2Cl2 (40 mL) and stirred at room temperature for 5 minutes. Solid NaBH4 (0.400 g, 10.6 mmol) was then added portionwise over 45 minutes at room temperature. The reaction was stirred for an additional 30 minutes then quenched by the addition of 50% aqueous acetic acid (1 mL). After stirring for an additional 30 minutes at room temperature, the solution was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (AcOH/MeOH/CH2Cl2 1:3:100 v/v/v) to give the title compound as a white fluffy solid (0.220 g, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.I[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH2:21][CH3:22])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5-bromo-2-chloro-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)benzene (2.70 g) obtained in Reference Example 46 in dichloromethane (27 ml) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise boron tribromide (0.83 ml). The mixture was warmed to room temperature, and stirred for 30 minutes. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and subsequently, the reaction mixture was made acidic with a saturated aqueous citric acid solution. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from chloroform-hexane to give 5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (2.01 g) as pale green crystals. ESI-Mass m/Z 351/353 (M−H). (2) The above 5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzene (500 mg) was dissolved in N,N-dimethylformamide (5 ml), and thereto were added iodoethane (0.23 ml) and potassium carbonate (390 mg). The mixture was stirred at room temperature for 2 days. Added thereto was water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the desired 5-bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene (492 mg) as pale pink oil. APCI-Mass m/Z 381/383 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][Si](C=[N+]=[N-])(C)C>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 2.15 g (11.2 mmol) of 5,6-dichloronicotinic acid in 10 mL of v:v 1:1 CHCl2/CH3OH at rt was added dropwise 8.4 mL (16.8 mmol) of (trimethylsilyl)diazomethane (2.0 M in hexanes). The mixture was stirred at rt for 30 min and then concentrated. Chromatography on a Biotage 40M cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 1.85 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 3.98 (s, 3H), 8.35 (d, J=1.8, 1H), 8.88 (d, J=1.8, 1H).