Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([Br:25])[C:17]=2[CH3:26])=[O:15])=[CH:10][C:9]=1[C:27]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:28]>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[Br:25][C:18]1[C:17]([CH3:26])=[C:16]([C:14]([C:11]2[CH:10]=[C:9]3[C:8](=[CH:13][CH:12]=2)[NH:7][C:2](=[O:3])[N:29]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:27]3=[O:28])=[O:15])[N:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[CH:23]2
Reactant: COC(=O)CNC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Ethyl chloroformate (1.3 mL; 13.5 mmol) is added dropwise to a solution of methyl N-({2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]phenyl}carbonyl)glycinate (2 g; 4.5 mmol) in 9 mL of pyridine at 0° C. After 15 min of stirring at ambient temperature, the reaction medium is concentrated to dryness and then diluted with ethyl acetate. The solution is washed with a 0.1 M hydrochloric acid solution and a saturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness. The yellow solid obtained is dissolved in 20 mL of anhydrous tetrahydrofuran and heated at reflux in the presence of diaza(1,3)bicyclo[5,4,0]undec-7-ene (1.35 mL; 9 mmol) for 1 h. The reaction medium is diluted with ethyl acetate, washed with a 0.1 M hydrochloric acid solution and a saturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness to give 2 g (95%) of a yellow powder.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[F:15])([CH3:5])[CH3:4].[CH3:16][C@@H:17]1[CH2:19][O:18]1.O>O1CCCC1.CCOCC>[CH:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:16][C@H:17]([OH:18])[CH3:19])=[CH:8][C:7]=1[F:15])([CH3:5])[CH3:4]
Reactant: C[C@@H]1CO1
Reactant: CC(C)c1cc2[nH]ccc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1cc2c(ccn2C[C@@H](C)O)cc1F
Reaction time: 1 h
Yield: 27 %

Procedure:
A suspension of 0.05 g of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.23 g of 6-isopropyl-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.18 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 70 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 15 g of silica gel with toluene-ethyl acetate (19:1). 0.08 g (27%) of (R)-1-(6-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CC(C)=O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(COc2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
6-Hydroxyindole (0.90 g, 6.8 mmol) and potassium carbonate (1.04 g, 7.5 mmol), were suspended in 13 mL of acetone. 4-Fluorobenzyl bromide (0.93 mL, 7.5 mmol, prefiltered through basic alumina) was added dropwise via syringe. The reaction mixture was heated at reflux under N2 atmosphere for 24 hours. The reaction mixture was cooled to ambient temperature and partitioned between H2O and methylene chloride. The aqueous phase was extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel to give 6-(4-fluorophenylmethoxy)indole (1.4 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Int. H) (150 mg, 0.502 mmol) in NMP (4 ml) was added phenylacetic acid (57 mg, 0.419 mmol) followed by DIPEA (366 ul, 2.093 mmol). To this solution was added HATU (239 mg, 0.628 mmol) portionwise and the reaction mixture was left to stir at RT for 1 h. The reaction mixture was added to EtOAc (25 ml) and the organic portion was separated and washed with 0.1M HCl (2×15 ml), water (25 ml), 0.1M NaOH (2×15 ml), water (25 ml), brine (25 ml) dried (Mg SO4) and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 1:1 EtOAc/iso-hexane to afford the title compound as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.30 (1H, s), 10.20 (1H, s), 7.70 (1H, s), 7.38 (4H, m), 7.25 (3H, m), 3.55 (2H, s). LC-MS Rt=1.43 min [M+H]+ 417.1 Method 2minLC_v002.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].[H][H]>CC(O)=O.[Pt]>[C:18]([NH:15][C:11]1[NH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:13][C:12]=1[CH3:14])(=[O:20])[CH3:19]
Reactant: COc1ccc(-c2nc(C)c([N+](=O)[O-])[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)c(NC(C)=O)[nH]2)cc1
Yield: 84 %

Procedure:
A solution of 41 (3.5 g, 0.015 mole) dissolved in glacial HOAc (35 ml)--acetic anhydride (105 ml) was hydrogenated at 50 psi over 5% platinum on charcoal catalyst (0.75 g) until uptake of hydrogen was complete. Catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in H2O (50 ml) and heated on a steam bath for 1 hour. The cooled solution was washed with ether (4×10 ml) and then evaporated to dryness in vacuo. Recrystallization of the residue from CHCl3 gave 3.07 g (84%) of 42 in two crops; m.p. 202°-204° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCOCC4)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-196 using 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone and morpholine. (0.050 g, 56.18%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10](Cl)=[O:11].O>CN(C=O)C>[CH3:1][N:2]1[CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: C=C(C(=O)Cl)C(F)(F)F
Reactant: CNC(=O)NC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 1,3-dimethylurea (423 mg; 4.8 mmoles) in DMF (5 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (792 mg; 5.0 mmoles) was added dropwise. The mixture was stirred at room temperature for 1 hour. Then, water (20 ml) was added, and the mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhhdrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform) to give 508 mg (yield: 50%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:18].[CH3:19][C:20](OC(C)=O)=[O:21]>N1C=CC=CC=1>[Cl:18][C:3]1[CH:4]=[C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][C:2]=1[NH:1][C:20](=[O:21])[CH3:19]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 10 h
Yield: 96.4 %

Procedure:
A solution of 1 g (3.4 mmol) of 2-(4-amino-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 5 mL of pyridine was treated with 0.42 mL (4.4 mmol) of Ac2O and stirred at 70° C. for 10 hours. The solvent was evaporated, the residue dissolved in THF, treated with a 2M aqueous solution of NaOH and stirred for 1 h at RT. After acidification of the mixture to a pH of ca. 7 by adding aqueous HCl, Et2O and H2O were added, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.1 g (ca. 94%) of crude N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide, which was dissolved in 20 mL of DMF and treated with 0.65 mL (4.37 mmol) of DBU and then at 0° C. dropwise with 0.73 mL (4.37 mmol) of TESCl. The mixture was stirred overnight and poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.53 g (93%) of crude N-[2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide, yellow oil, MS: 450 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccc(F)cc1)C2
Yield: 62.4 %

Procedure:
A mixture of 7-(4-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.2 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.2 ml), water (0.2 ml) and ethanol (30 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate and then recrystallized from ethanol-water to give 7-(4-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 77) (0.17 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.CC(C)=O.[C:22]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][C:22]([CH3:24])([CH3:23])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:3]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thirty grams (0.11 mole) of 3-(4,6-dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane is dissolved in 300 ml. of acetone and then 370 ml. of water is added followed by 20 g. (0.15 mole) of tert-octylamine. After stirring for 10 minutes, 4.4 g. (0.11 mole) of NaOH in 30 ml. of water is added over 20 minutes. The reaction is then heated to reflux for 19 hours. After cooling to room temperature, one liter of water is added, stirred for one hour and the white precipitate filtered off. The precipitate is washed with water, dried overnight, dissolved in dichloromethane and filtered through Magnesol®. The Magnesol® is then washed with dichloromethane, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 20 g. of colorless crystals, m.p. 159°-162.5° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCSCC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CCSCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of N,N-diisopropylamine (1.51 g, 2.1 mL, 15 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (6 mL, 15 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of tetrahydro-thiopyran-4-carboxylic acid methyl ester (1.60 g, 10 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (1.32 g, 1.7 mL, 30 mmol) was then added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:3 to afford the title compound (1.77 g, 87%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 0.96 (d, J=6.5 Hz, 3H), 1.46-1.73 (m, 2H), 2.12-2.28 (m, 2H), 2.43-2.57 (m, 4H), 3.50-3.58 (m, 1H), 3.63 (s, 3H), 4.85 (d, J=5.8 Hz, 1H). LCMS (m/z) 227.1 [M+Na], Tr=1.53 min.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:6][C:7]2[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=2)[N:23]=1
Reactant: CCOC(=O)c1c(O)csc1CSC
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)csc1CSC
Reaction time: 2 h
Yield: 50.1 %

Procedure:
50 ml of N,N-dimethylformamide was added to 3.5 g (15.1 mmol) of ethyl 4-hydroxy-2-methylthiomethylthiophene-3-carboxylate, 3.3 g (15.1 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 2.1 g (15.2 mmol) of potassium carbonate, and the mixture was heated and stirred at from 90° to 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2.8 g (yield: 50.0%) of the desired product.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:45])[CH:44]=1>CN1C(=O)CCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:45][C:43]1[CH:44]=[C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:40]=[N:41][CH:42]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: C[Sn](C)(C)c1cncc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3cncc(Cl)c3)C(=O)CC2)cc1
Temperature: 60 °C
Yield: 30.9 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (0.630 g, 2.0 mmol), Pd2 (dba)3 (0.037 g, 0.04 mmol), and AsPh3 (0.098 g, 0.32 mmol) in 5 mL NMP was added a degassed NMP solution (5 mL) of 3-trimethylstannanyl-5-chloropyridine (~2.0 mmol). The resulting mixture was heated to 60° C. for 16 h. The mixture was then cooled to r.t., diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (80% EtOAc/hexanes) followed by a CH2Cl2 /Et2O swish to provide 0.215 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.Br[CH2:21][CH2:22][F:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH2:22][F:23])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: FCCBr
Reactant: Cc1ccc(Br)cc1Cc1cc2cc(O)ccc2s1
Product: Cc1ccc(Br)cc1Cc1cc2cc(OCCF)ccc2s1

Procedure:
5-Bromo-1-(5-methoxybenzo[b]thiophene-2-yl methyl)-2-methylbenzene obtained in Reference Example 158 was treated in a manner similar to Reference Example 132-(1) to give 5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene as colorless powder. ESI-Mass m/Z 331/333 (M−H). (2) The above 5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene and 1-bromo-2-fluoroethane were treated in a manner similar to Reference Example 132-(2) to give the desired 5-bromo-1-(5-(2-fluoroethyloxy)benzo[b]thiophene-2-ylmethyl)-2-methylbenzene.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1)[CH2:18][CH3:19]
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cnc(-c2cc(C#N)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
A solution of 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (90 mg, 0.53 mmol) in anhydrous DMF (2 mL) was cooled in an ice-water bath. Sodium hydride (60%, 32 mg, 0.8 mmol) was added carefully at 0° C. The reaction mixture was stirred for 10 minutes, after which 1-bromopropane (73 μL, 0.8 mmol) was added. The reaction mixture was warmed up to r.t. and stirred for 1 hr and it was then purified by ISCO flash column (MeOH/DCM=0-5%). 80 mg title compound was obtained as white solid (71%). [M+H] Calc'd for C12H12N4, 213. Found, 213.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3s2)cc1
Yield: 71.5 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (293 mg, 1 mmol) and 2-chloro-benzothiazole (169 mg, 1 mmol) to afford the title product (305 mg, 75% yield); LCMS; 100% APCI+, Calcd: 426.50; Found m/z: 427.26 (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.41 (s, 9H), 1.78-2.13 (m, 4H), 3.24-3.36 (m, 2H), 3.89-4.12 (m, 3H), 7.08 (d, J=9.2 Hz, 2H), 7.31 (t, J=8.4 Hz, 1H), 7.37 (d, J=9.2 Hz, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:17].[Na+].[CH3:21][CH2:22][O:23][CH2:24]C>ClCC(OC)=O>[CH3:24][O:23][C:22](=[O:17])[CH2:21][NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: CCOCC
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C([O-])O
Agent: COC(=O)CCl
Agent: [Na+]
Product: COC(=O)CNc1cccc(OCc2ccccc2)c1
Reaction time: 16 h

Procedure:
A suspension of 3-benzyloxyaniline (69.0 g) and sodium bicarbonate (58.1 g) in methyl chloroacetate (45.4 ml) was stirred at 80°-90° under nitrogen for 16 h. The resultant solid was poured into ether (400 ml) and the suspension was filtered. The collected solid was partitioned between water (400 ml) and dichloromethane (200 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried and concentrated to give the title compound (66.9 g) as a solid, m.p. 92°-94°.
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].CN(C)CCN(C)C.I[CH2:25][CH2:26][O:27][CH2:28][CH2:29]I>C1COCC1>[O:27]1[CH2:28][CH2:29][C:8]2([C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][C:7]2=[O:15])[CH2:25][CH2:26]1
Reactant: O=C1Cc2ccccc2N1
Reactant: ICCOCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H2O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1).
Reaction SMILES: Cl.[CH2:2]([CH:4]1[C:24]2[C:7](=[CH:8][C:9]3[NH:13][C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=4[O:21][CH3:22])=[N:11][C:10]=3[CH:23]=2)[NH:6][C:5]1=[O:25])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].C([O-])(=O)C.[Na+]>>[CH2:2]([CH:4]1[C:24]2[C:7](=[CH:8][C:9]3[NH:13][C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:26](=[O:28])[CH3:27])=[CH:16][C:15]=4[O:21][CH3:22])=[N:11][C:10]=3[CH:23]=2)[NH:6][C:5]1=[O:25])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1C(=O)Nc2cc3[nH]c(-c4ccc(N)cc4OC)nc3cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCC1C(=O)Nc2cc3[nH]c(-c4ccc(NC(C)=O)cc4OC)nc3cc21

Procedure:
0.7 g. (1.8 mmol) 7-ethyl-2-(2-methoxy-4-aminophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride, 15 ml. acetic anhydride and 0.3 g. sodium acetate were stirred for 3 hours at 40° C. After cooling, the product was filtered off with suction and, after treatment with charcoal, crystallised from methanol. There was obtained 0.44 g. (69% of theory) of the title compound; m.p. 245°-249° C.