Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:12]=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>N1C=CC=CC=1.[Cu](Br)Br>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Agent: Br[Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Reaction time: 20 h
Yield: 64 %

Procedure:
A 60% dispersion of sodium hydride (0.86 g, 22 mmol) was added to a mixture of copper bromide (2.6 g, 17.9 mmol) and phenol (1.7 g, 17.9 mmol) in pyridine (300 mL). After the effervescence subsided, the mixture was heated to reflux for 30 minutes. 3-Iodo-4-nitroanisole (5.0 g, 17.9 mmol) was added and stirring proceeded under nitrogen for 20 hours. The mixture was cooled and the reaction was quenched with saturated ammonium chloride (1 mL). The mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (250 mL) and washed with dilute aqueous HCl (2×200 mL), saturated sodium carbonate (2×200 mL) and water (200 mL), and was evaporated in vacuo. The residue was purified by ISCO silica gel flash chromatography in hexanes-ethyl acetate gradient, eluting 2.8 g of the product at 7:3 hexanes-ethyl acetate, in 64% yield; 1H NMR (CDCl3) δ 3.78 (s, 3H), 6.43 (d, J=2.3 Hz, 1H), 6.68 (dd, J=9.2, J=2.3 Hz, 1H), 7.03-7.07 (m, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.37-7.41 (m, 2H), 8.07 (d, J=9.2 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]1.O>CN1C(=O)N(C)CCC1>[OH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11]1
Reactant: N#Cc1cccc(F)c1
Reactant: O[C@@H]1CCNC1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: N#Cc1cccc(N2CC[C@@H](O)C2)c1
Temperature: 180 °C
Yield: 62.7 %

Procedure:
3-Fluorobenzonitrile (0.385 g, 3.18 mmol) and (3R)-pyrrolidin-3-ol (0.278 g, 3.19 mmol) were dissolved in DMPU (3 mL). The resulting mixture was subjected to microwave heating at 180° C. for 5 h. Water was added and the mixture extracted with ether. The organic layer washed with water, dried with MgSO4, filtered and concentrated. Purification on a 10 g Isolute Flash Si column (heptane/EtOAc 2:1→1:1) gave 0.375 g (63%) of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.22 (dd, 1H, J=8.5, 7.5 Hz), 6.82 (d, 1H, J=7.5 Hz), 6.72 (dd, 1H, J=8.5, 2.2 Hz), 6.69 (bs, 1H), 4.48 (m, 1H), 3.42-3.33 (m, 2H), 3.24 (ddd, 1H, J=8.8, 8.8, 3.4 Hz), 3.13 (bd, 1H, J=10.5 Hz), 2.14-1.94 (m, 2H). 13C NMR (MeOH-d4) δ 149.2, 130.9, 120.6, 119.5, 117.0, 114.9, 113.4, 71.4, 56.7, 46.5, 34.7.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([SH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C(O)C.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: COc1ccc(S)cc1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1OC
Reaction time: 24 h
Yield: 73.9 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (7.4 g) (see Preparation 4) was dissolved in absolute ethanol (150 ml), sodium tert-butoxide (8.5 g), 3,4-dimethoxybenzenethiol (5 g) and tetrakis(triphenylphosphine)palladium(O) (0.5 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 24 hours. A further portion of tetrakis(triphenylphosphine)palladium(O) (0.5 g) was then added and heating was continued for another 24 hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using 1:4 hexane: dichloromethane as the eluent to yield 6-(3,4-dimethoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.4 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[N:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[N:2]=1
Reactant: O=Cc1ccc(-c2cccnn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2cccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(3-pyridazinyl)benzaldehyde (prepared as described in Reference Example 16) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH3:17]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:14][CH2:15][O:16][CH3:17])=[C:4]([F:10])[CH:3]=1
Reactant: COCCBr
Reactant: OCc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1ccc(Br)cc1F
Temperature: 5 °C
Yield: 46.5 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanol (10 g, 49.02 mmol) in THF (250 mL) at 0° C., was added 60% NaH (2.93 g, 73.53 mmol) slowly in portions. After addition, the suspension was heated to 5° C. for 30 min, cooled to RT, then was added 1-bromo-2-methoxy ethane (5 mL, 53.92 mmol) and the mixture was stirred at RT for 20 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was diluted with ice cold water (100 mL) and concentrated under reduced pressure. The obtained aqueous residue was extracted with EtOAc (2×150 mL); the combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 4-bromo-2-fluoro-1-((2-methoxyethoxy)methyl)benzene (6 g, 47%) as yellow liquid (TLC solvent system: 30% EtOAc-PE; Rf: 0.4).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O-])([O-])=[O:33].[K+].[K+].C([O-])(O)=O.[Na+].C(OCC)(=O)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:32][OH:33])=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OCc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(CO)cc1)NC(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 62.1 %

Procedure:
Compound 11 (7.70 g, 16.70 mmol, 1 eq), Pd(OAc)2 (378 mg, 1.68 mmol, 0.1 eq) and 1,1′-Bis(diphenylphosphino)ferrocene (dppf) (1.86 g, 3.34 mmol, 0.2 eq) were dissolved in dry DMF (40 mL). K2CO3 (11.54 g, 83.5 mmol, 5 eq) was then added to the reaction mixture and CO gas was bubbled through for 15 min. The reaction mixture was then heated at 60° C. for 8 h under a CO balloon. The reaction mixture was then cooled and partitioned between ethyl acetate and saturated NHCO3. The aqueous layer was acidified with a 10% aqueous solution of citric acid and extracted with ethyl acetate (4×75 mL). The organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated to give the crude carboxylic acid as a tan-coloured solid (4.89 g). The acid was dried over P2O5 and was used in the next step without purification. The crude acid was dissolved in dry THF (70 mL) and cooled in an ice bath. The reaction was charged with BH3-DMS complex (10 M, 6.96 mL, 68.47 mmol, 4 eq) added dropwise. The reaction mixture was warmed to room temperature over 2 h. A solution of saturated NaHCO3 was added dropwise until the bubbling ceased. Ethyl acetate (70 mL) was added and the organic layer was separated and dried over Na2SO4 and then reduced. The crude product was purified on a silica column (3:2 hexane:ethyl acetate followed by 2:3 hexanes:ethyl acetate) to give 12 (3.56 g, 62%) as a white solid. [α]D25+50.56° (C=0.99, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 7.29-7.23 (m, 2H), 7.08 (d, J=8.0 Hz, 2H), 5.14-4.87 (m, 2H), 4.65 (dd, J=10.2, 5.8 Hz, 3H), 3.70 (d, J=18.6 Hz, 3H), 3.10 (qd, J=13.9, 5.8 Hz, 2H), 1.86 (t, J=5.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 172.17 (s), 155.86 (s), 140.04 (s), 136.45 (s), 135.29 (s), 129.68 (s), 128.75 (s), 128.43 (s), 128.32 (s), 127.49 (s), 67.22 (s), 65.20 (s), 55.03 (s), 52.59 (s), 38.12 (s). ESIMS calculated for C19H21NO5Na [M+Na]+366.13, found: 366.13; mp 74-77° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H]>O>[C:12]1([N:11]2[N:10]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]3=[N:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1N=Nc1ccccc1
Reactant: [H][H]
Solvent: O
Product: c1ccc(-n2nc3ccccc3n2)cc1

Procedure:
An o-nitroazobenzene derivative which is selected as a starting material is dissolved in a solvent contained in a reaction vessel into which water, a hydrogenation catalyst and a basic substance are then placed. After the air in the reaction vessel has been replaced by hydrogen, a given amount of hydrogen is charged into the reaction vessel, and the reaction is then allowed to proceed under atmospheric pressure or a given pressure at a temperature of room temperature to 170° C. under agitation. After the reaction has been completed, the catalyst is filtered off, the solvent layer is washed with water, and the solvent is distilled off. The crude product is then purified by recrystallization to obtain the corresponding 2-phenylbenzotriazole as a pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([S:13][CH2:14][C:15]2[C:19]([CH3:20])=[N:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[C:11]([S:13]([CH2:14][C:15]2[C:19]([CH3:20])=[N:18][N:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)[N:16]=2)=[O:39])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1cc(SCc2nn(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(S(=O)Cc2nn(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of Compound 100 (1 eq) in CH2Cl2 was added MCPBA (1.2 eg) at room temperature, the resulting mixture was stirred for 2 hrs, evaporated and chromatography on silica gel to give desired compound as a white solid. 1H NMR (400 MHz, DMSO) δ 8.01 (2H, d, J=8.4 Hz), 7.88(2H, d, J=8.4 Hz), 7.34˜7.28 (2H, m), 6.97 (1H, d, J=9.2 Hz), 4.77(2H, s), 4.42 (1H, d, J=13.6 Hz), 4.27 (1H, d, J=13.6 Hz), 2.14 (3H, s), 2.09 (3H, s).
Reaction SMILES: [I:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1.CO.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Zn]>[I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a stirred solution of 4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroaniline (7.10 g, 13.62 mmol) in tetrahydrofuran (100 mL), methanol (50 mL), and water (10 mL) was added ammonium chloride (5.83 g, 109.0 mmol) and iron (II) sulfate heptahydrate (13.25 g, 47.67 mmol). The bright orange suspension was treated with zinc (3.12 g, 47.67 mmol). The mixture was gradually warmed to reflux. After 20 min, the color of the reaction mixture had turned from orange to olie-green. At this point the reaction mixture was allowed to cool to room temperature. The mixture was filtered through Celite, and the filtercake was washed with chloroform. The filtrate was then washed with 5N ammonium hydroxide solution (75 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 6.49 g of 4-iodo-N1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1.C(N(CC)CC)C.C(O)C.O.[NH2:23][NH2:24]>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][NH2:24])[N:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: CCOc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1nc(Cl)cc(NN)n1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A mixture of 50.0 g of 95 percent purity (0.246 mol) 4,6-dichloro-2-ethoxypyrimidine, 26.9 g (0.266 mol) of triethylamine, 200 mL of ethanol, and 200 g of water was prepared and cooled to 5° C. To this was added 13.4 g (0.266 mol) of hydrazine hydrate over a 15-min period with stirring and cooling at about 5° C. The mixture was stirred and allowed to warm to ambient temperature overnight. It became very thick, but approximately 10 percent of the starting material remained. Another 1.3 g (0.026 mol) of hydrazine hydrate was added and stirring was continued for another 4 hours. The solids that formed were recovered by vacuum filtration and were washed twice with 100 mL portions of water and then with 100 mL of acetonitrile. The title compound, which was obtained as a white powder melting at 170°-173° C., amounted to 43.9 g (88 percent of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:20]([NH:23][NH2:24])(=O)[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:12]3[O:14][C:20]([CH3:21])=[N:23][N:24]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Reactant: CC(=O)NN
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(-c3nnc(C)o3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[(4-Methoxybenzyl)oxy]benzoic acid (9.26 g, 35.9 mmol), acethydrazide (3.98 g, 53.8 mmol), HOBT (6.59 g, 43 mmol) and EDC (10.3 g, 53.8 mmol) were weighed into a 200 mL RB flask. DMF (60 mL) was added. The mixture was stirred vigorously at room temperature. The solid dissolved within 5 min. LC-MS showed complete consumption of the acid after 30 min. DMF was removed at 60° C. under vacuum. The residue was treated with 100 mL EtOAc/water (1/1) and was allowed to stand overnight. The solid was collected via filtration and washed with EtOAc. The crude N′-acetyl-3-[(4-methoxybenzyl)oxy]benzohydrazide (8 g) was suspended in 100 mL THF and was heated under reflux in the presence of Burgess' reagent (12.8 g, 53.8 mmol) for 1 hour. The solution was cooled and directly passed through a plug of silica gel (300 gram) which was washed thoroughly with 20% acetone/hexanes. The eluent was concentrated to give the crude product as white solid.
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=CC)[C:13]=1[OH:21]>C(OCC)(=O)C.C(O)(=O)C>[OH:21][C:13]1[C:12]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Cl:4])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:18]=[O:1]
Reactant: CC=Cc1cccc(Sc2ccccc2Cl)c1O
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cccc(Sc2ccccc2Cl)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(2-chlorophenylthio)-6-(1-propenyl)phenol (26 g) in a mixture of ethyl acetate (200 ml) and acetic acid (10 ml) at temperature below 0° C. with stirring for an hour. The precipitates were collected by filtration, washed with ethyl acetate and then dried to give 2-hydroxy-3-(2-chlorophenylthio)benzaldehyde (15.9 g), mp. 111°-112.5° C. The filtrate and washings were combined, washed with dil. aqueous sodium hydrogen sulfite, saturated aqueous sodium bicarbonate and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was washed with methanol and dried to give the same product (3.2 g). Total yield 19.1 g.
Reaction SMILES: [F:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:13])=O>ClCCl>[F:1][CH:2]([CH:6]([CH3:9])[CH2:7][CH3:8])[C:3]([Cl:13])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C)C(F)C(=O)O
Solvent: ClCCl
Product: CCC(C)C(F)C(=O)Cl
Temperature: 40 °C

Procedure:
Finally, to the compound (v) was added 10 ml of dichloromethane and then 15 ml of oxalic acid chloride dropwise with ice cooling. The reaction was carried out under reflux at 40° C. for 3 hours. The reaction product was freed of chloromethane and oxalic acid chloride by atmospheric distillation, and the residues were purified by vacuum distillation. Thus there was obtained 2-fluoro-3-methylpentanoic acid chloride (vi), which has a boiling point of 58°-60° C. (at 20 mmHg).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[NH:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:30])[NH:7][C:6]1=[O:31])[CH2:2][CH2:3][CH3:4]>ClCCl>[CH2:1]([N:5]1[C:10]2[N:11]=[C:12]([CH:27]([CH3:29])[CH3:28])[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:30])[NH:7][C:6]1=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(c(=O)[nH]c1=O)C(c1ccc(F)cc1)C(C(=O)OCC)=C(C(C)C)N2
Solvent: ClCCl
Product: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(C(=O)OCC)c(C(C)C)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.35 g (50 mmol) of 2,3-dichloro-4,5-dicyanobenzoquinone are added to a mixture of 21.5 g (50 mmol) of the compound from Example 2 in 800 ml of dichloromethane and the mixture is stirred at room temperature for 1 h. The solution is filtered from a beige precipitate, the filtrate is washed four times with water, the organic phase is dried over sodium sulphate, filtered through a thin layer of active carbon and the filtrate is concentrated in vacuo. The residue is crystallized from ether/petroleum ether.
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[O:33])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:32]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[OH:33])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 2.04 ml, 3.27 mmol) was added dropwise to a solution of benzothiophene (0.48 g, 3.58 mmol) in anhydrous THF (10 ml) at −78° C. over 5 minutes. The reaction solution was stirred at −78° C. for 10 minutes, and then at room temperature for 20 minutes. A solution of 4-bromonaphathalene-2-carbaldehyde (0.73 ml, 3.11 mmol) in anhydrous THF (5 ml) was added dropwise to the resulting reaction mixture at −78° C. and stirred at −78° C. for two hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resulting mixture was extracted with diethyl ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.0 g, 75.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C1(C)C=CC=CC=1.[SH:17][CH2:18][C:19](O)=O.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:19][CH2:18][SH:17])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)CS
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: SCCNc1ccc(Cl)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 125.3 %

Procedure:
A 3-necked 2 L round bottomed flask equipped with an overhead stirrer, temperature probe and reflux condenser with Dean-Stark trap was charged with 100.0 grams (0.617 mol) of 3,4-dichloroaniline and 500 mL of toluene. The resulting solution was then treated with 64.4 mL (0.927 mol, 1.5 equivalents) of mercaptoacetic acid. The solution was heated to reflux (130° C.), while collecting water in the Dean-Stark trap for 20 hours, then cooled to room temperature. Ethyl acetate (250 mL) was then added followed by 123 mL of 1N hydrochloric acid. The layers were separated and the organic layer washed with 250 mL of water then 500 mL of saturated aqueous sodium bicarbonate and concentrated under vacuum to a volume of approximately 200 mL. After addition of 200 mL of toluene, the solution was again concentrated to approximately 200 mL, diluted with 1 L of tetrahydrofuran and filtered. This filtrate was added dropwise to a nitrogen-purged 3-necked 5 L round bottomed flask containing 1.73 L (1.73 mol, 2.80 equivalents) of 1N borane-tetrahydrofuran complex while maintaining a temperature of 10-15° C. Some gassing was observed. The reaction mixture was warmed to room temperature and stirred overnight then cooled to 10° C. A solution of 252 grams (6.91 mol, 11.2 equivalents) of anhydrous hydrogen chloride in 840 mL of ethanol was added at 10-15° C. during which time significant gas evolution was observed and solids precipitated. After stirring for 1 hour at 5-10° C. the solids were collected by filtration, washed with tetrahydrofuran, and dried under vacuum to yield 100.0 grams (62.6% yield) of the title compound as a white solid, mp 185-188° C. 1H NMR (DMF-d7) δ7.20 (d, J=8.7 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.78 (dd, J=2.7, 8.7 Hz, 1H), 3.18 (dd, J=6.4, 7.7 Hz, 2H) 2.61 (br s, 2H), 2.37 (br s, 1H). 13C NMR (DMF-d7) δ146.02, 132.94, 134.90, 122.70, 118.09, 117.19, 50.05, 23.07. HRMS (FAB) calcd for C8H9Cl2NS: 221.9911; found: 221.9893.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[C:19]([O:21]CC)=O)#[N:2].[BH4-].[Na+]>C1COCC1.CO.CCOC(C)=O>[O:21]=[C:19]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3][CH2:1][NH:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CCC#N)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 0 °C
Yield: 84.2 %

Procedure:
To a suspension of diethyl 1-(2-cyanoethyl)-1H-indole-2,6-dicarboxylate (1.5 g, 4.8 mmol) in THF (12 mL) and methanol (16 mL) is added CoCl2 (1.3 g, 9.6 mmol). The bright blue suspension/solution is cooled to 0° C., and NaBH4 (1.8 g, 48.0 mmol) is carefully added in small portions. As each portion is added H2 is formed violently and the suspension becomes black. After the addition of NaBH4 is complete, the mixture is warmed up room temperature for 60 min and is then heated at reflux for 16 h. The mixture is cooled to room temperature and is diluted with EtOAc. The mixture is filtered through Celite, and the gummy solids are washed with EtOAc. The combined EtOAc filtrate is washed with 3M HCl, water, NaHCO3, brine, dried (Na2SO4) and concentrated to afford the title crude compound (1.1 g, 85%) which is used in the next step without purification.