Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[H][H]>[Ni].C(O)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1Br
Yield: 63.2 %

Procedure:
Combine crude 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (32.4 g, 138 mmol), ethanol (100 mL) and Raney Nickel (1.00 g, 17.04 mmol) in a shaker flask. Charge the flask with hydrogen (275 kPa) and agitate until the absorption of hydrogen ceases. De-pressurize the reaction vessel, remove the catalyst by filtration, and evaporate the filtrate to dryness. Add MTBE, then filter again and evaporate the filtrate. Stir residue in hexanes. Collect the solids by filtration, wash with cold hexanes and dry in vacuo to provide the title compound (17.8 g, 63% yield) as a dark solid. MS (m/z): 204.0 (M+1)/206.0 (M+3).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([OH:22])=O)[CH2:4]1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2>>[CH3:18][C@H:7]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:3]([CH3:2])[CH2:4][N:5]([CH2:19][C:20]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]=[CH:29]3)=[O:22])[CH2:6]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Reactant: Nc1cccc2cnccc12
Agent: Cl
Product: C[C@@H]1CN(CC(=O)Nc2cccc3cnccc23)C[C@H](C)N1c1ncnc2sccc12

Procedure:
The title product was prepared from the product of step (ii) (0.2 g) and 5-aminoisoquinoline (0.084 g) by the method of Example 8 step (v) as a white solid. Yield 0.11 g.
Reaction SMILES: [C:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[NH:16]C(=O)C(F)(F)F)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)S(O[C:29]1[C:38]2[C:33](=[C:34]([O:39][CH3:40])[CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH:30]=1)(=O)=O>>[CH2:3]([C:2]1[NH:16][C:8]2[C:7]([C:1]=1[C:29]1[C:38]3[C:33](=[C:34]([O:39][CH3:40])[CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH:30]=1)=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:5][CH3:6]
Reactant: COc1cccc2c1CCC=C2OS(=O)(=O)C(F)(F)F
Reactant: CCCCC#Cc1ccc(C(=O)O)cc1NC(=O)C(F)(F)F
Product: CCCCc1[nH]c2cc(C(=O)O)ccc2c1C1=CCCc2c(OC)cccc21

Procedure:
The title compound was prepared according to the procedure outlined in Example 7, employing 4-(1-hexynyl)-3-trifluoroacetamidobenzoic acid on Wang resin (prepared according to Example 1) and 5-methoxy-3,4-dihydro-naphthalen-1-yl trifluoromethanesulfonate; 1H NMR (DMSO-d6) δ 0.80 (t, 3 H), 1.22 (m, 2 H), 1.60 (m, 2 H), 2.39 (m, 2 H), 2.70 (m, 4 H), 3.80 (s, 3 H), 6.02 (t, 1 H), 6.32 (d, 1 H), 6.85 (d, 1 H), 6.98 (m, 1 H), 7.08 (d, 1 H), 7.50 (d, 1 H), 7.95 (s, 1 H), 11.40 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccccn1
Solvent: CCO
Solvent: O
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and 2-pyridinesulphonylacetonitrile (0.2 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100 C. The mixture was cooled to room temperature and water was added for crystalization. The crude product was filtered and recrystalized from ethanol and water to give 0.15 g of (E)-3-(2-nitrothien-5-yl)-2-[(pyridin-2-yl)sulfonyl]acrylonitrile.
Reaction SMILES: Br[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24](=[O:25])[C:23]3[C@@H:22]4[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]4)[C:18]=3[NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O.CO>[CH2:2]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:3]
Reactant: CCBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of bromoethane (1.05 mL, 14.1 mmol), potassium carbonate (3.58 g, 25.9 mmol), and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.74 g, 6.5 mmol) in acetone (20 mL) and methanol (3 mL) was stirred at room temperature over the weekend then the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was evaporated, and the residue was chromatographed (0-50% ethyl acetate/hexanes) and recrystallized from ethyl acetate to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (168 mg, 9%) as a white solid. APCI-MS (M+H) 297.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccco1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCOCCc1ccco1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
2-Furanethanol (2 g) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (0.43 g) in DMF (20 ml). The mixture was stirred for 30 min and added dropwise to 1,6-dibromohexane (21.8 g). The resulting suspension was heated at 60°-70° for 18 h, poured into water (200 ml) and extracted with diethyl ether (3×100 ml). The dried extract was evaporated and the residue was purified on a column of silica eluted with cyclohexane. The resulting oil was fractionally distilled (Kugelrohr) to give the title compound as a colourless oil (1.7 g) b.p. 75°-80°/0.3 Torr.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[CH3:19][C:7]1[C:8]2[C:9](=[O:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]=2[C:4]2[CH2:1][CH:2]([C:36]([OH:37])=[O:39])[O:20][C:5]=2[CH:6]=1
Reactant: C=CCc1c(O)cc(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture of 4-allyl-3-hydroxy-1-methyl-9-oxo-9H-xanthene (3.0 g), m-chloroperbenzoic acid (8 g) and chloroform (500 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5.5 g), water (25 ml) and concentrated sulfuric acid (8.5 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 231°-234° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 298.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1.[I-].[Na+].[CH3:32][NH:33][CH3:34]>O1CCCC1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:33]([CH3:34])[CH3:32])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1
Reactant: CNC
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile and 0.055 g of sodium iodide in 15.6 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 2.5 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was treated with with ethyl acetate-ether depositing a solid and giving 0.51 g of the title compound as a off-white solid: mass spectrum (electrospray, m/e) M+H 445.0; (M+2H)+2 243.4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:44]=[CH:43][C:9]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)=[CH:19][C:14]=4[N:13]=[C:12]3[CH2:32][C:33]3([C:38]([O:40]CC)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:8][CH:7]=2)=[CH:2]1.C1COCC1.[Li+].[OH-]>CO>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]5[CH:31]=[CH:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)=[CH:19][C:14]=4[N:13]=[C:12]3[CH2:32][C:33]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:43][CH:44]=2)=[CH:2]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 20 mL vial were added ethyl 1-((1-(4-(furan-3-yl)benzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (60 mg, 0.1 mmol), THF (1.3 mL) and MeOH (1.3 mL) followed by LiOH (1.4 mL, 1 M). The reaction mixture was heated at 80° C. for 1.5 h. The mixture was cooled to RT and concentrated to dryness. Water (5 mL) was added and the pH was adjusted to ˜5-6 using 1 M HCl. To the mixture was added DCM (5 mL) and the mixture was stirred for 1 h at RT. The organic layer was separated then concentrated to dryness. The resulting residue was purified using FCC or reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C35H31N3O4, 557.23; m/z found, 558.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=8.5, 1H), 8.10 (d, J=8.5, 1H), 7.84 (d, J=8.1, 1H), 7.77-7.69 (m, 3H), 7.58-7.54 (m, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=8.1, 2H), 7.35-7.34 (m, 1H), 7.16 (d, J=8.8, 1H), 7.04-7.01 (m, 3H), 6.65 (s, 1H), 5.42 (s, 2H), 5.35 (s, 2H), 3.12 (s, 2H), 2.32-2.26 (m, 2H), 1.73-1.68 (m, 2H), 1.65-1.52 (m, 4H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 1-(3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-methylpentane, 30 ml of 47% hydrobromic acid and 30 ml of acetic acid was heated under reflux for 8 h. After cooling to room temperature, the reaction mixture was poured into water. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure and the obtained oily product was purified according to column chromatography (silica gel, developer: benzene) to obtain 4.2 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8](OC(=O)C)(=[O:10])[CH3:9].P(=O)(O)(O)O>O>[Cl:1][C:2]1[S:3][C:4]([C:8]([CH3:9])=[O:10])=[CH:5][C:6]=1[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1Cl
Agent: O=P(O)(O)O
Solvent: O
Product: CC(=O)c1cc(C)c(Cl)s1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 20 g (0,15 mol) of 2-chloro-3-methylthiophene and 18,6 g (0,18 mol) of acetic acid anhydride were heated to 70° C. and 1,8 ml of orthophosphoric acid were dropped thereto such that the reaction temperature remained below 75° C. Then it was stirred 3 hours at 100° C., 50 ml of H2O were added, the organic phase was extracted twice with 10 ml of saturated NaHCO3 -solution, dried over Na2SO4 and fractionated distilled in vacuo. Yield 15,8 g (60%), b.p. 85°-88° C./4 mbar.
Reaction SMILES: C(O[CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)C.[CH2:10]([SH:13])[CH2:11][CH3:12]>>[CH2:10]([S:13][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH2:11][CH3:12]
Reactant: CCOC1CCC(=O)N1
Reactant: CCCS
Product: CCCSC1CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4 g of 5-ethoxy-pyrrolidin-2-one, 30 cm3 of propanethiol and 2 g of Amberlite-15 resin is agitated for 2 hour 45 minutes at ambient temperature. The resin is filtered off, then the excess propanethiol is distillated. 2.8 g of the expected product is obtained, isolated from isopropyl ether. m.p. 40°-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH3:8])[N:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Cl:1][C:2]1[C:6]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:5][N:4]([CH2:7][CH3:8])[N:3]=1
Reactant: CCn1ccc(Cl)n1
Reactant: O=S(=O)(O)Cl
Product: CCn1cc(S(=O)(=O)Cl)c(Cl)n1
Temperature: 100 °C

Procedure:
3-Chloro-1-ethyl-1H-pyrazole (0.42 g, 3.2 mmol, the product of Step B) was added to chlorosulfonic acid (2.0 mL, 30 mmol) at room temperature and the mixture was slowly warmed to 100° C., and then heated at 100-110° C. for 2 hours. The reaction mixture was cooled, poured with stirring onto 150 mL of crushed ice, and extracted into diethyl ether (2×100 mL). The ether extracts were combined, washed with water (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.5 g of the title compound as an oil. 1H NMR (CDCl3) δ 8.00 (s, 1H), 4.20 (q, 2H), 1.56 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (3.15 g, 20 mmol), KI (0.1 g) and K2CO3 (8.28 g, 60 mmol) in DMF (100 mL) was added 4-methanesulfonyloxy-piperidine-1-caboxylic acid tert-butyl ester (7.26 g, 26 mmol). The mixture was heated at 100° C. for 2 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N NaOH (30 mL), water, and dried over anhydrous Na2SO4, concentrated to give the title compound as white solid (Yield: 5.3 g, 78%).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:19][CH:20]=[CH:21][CH2:22]Cl.[I-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:19][CH:20]=[CH:21][CH2:22][N:10]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C(NCC=Cc1ccccc1)C(F)(F)F
Reactant: ClC=CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(N(CC=CCl)CC=Cc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 250 g of N-cinnamyltrifluoroacetamide in 1 liter of hexamethylphosphoric acid triamide (HMPT) is added dropwise with ice-cooling and stirring under a nitrogen atmosphere, to a suspension of 27 g of sodium hydride in 400 ml of HMPT. After the evolution of gas has ceased, a solution of 130 g of 1,3-dichloropropene and 1 g of sodium iodide in 1 liter of HMPT is added dropwise and the mixture stirred for 16 hours at room temperature. The reaction mixture is then poured on to water and extracted with ether. The ethereal solution is dried over sodium sulphate, evaporated and the oily residue chromatographed on 3.5 kg of silica gel with toluene to yield N-(3-chloro-2-propenyl)-N-cinnamyl-trifluoroacetamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].BrC[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C(#N)C>[CH:22]1([C:20]([C:9]2[O:11][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[OH:10])=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1oc2ccc(F)cc2c1O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
1-(5-Fluoro-2-hydroxyphenyl)ethanone (4.0 g) was dissolved in acetonitrile (80 mL). To the reaction mixture were added potassium carbonate (4.8 g) and 2-bromo-1-cyclohexylethanone (7.3 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was filtered through celite, rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL) was added to the solution, and the mixture was stirred with heating at 110° C. for 1 hr. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-ethanol to give the title object compound (4.7 g, 76%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:13][CH:14]1[CH2:16][O:15]1.O>CN(C=O)C>[Cl:2][C:3]1[C:8]([O:9][CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCC1CO1
Reactant: Oc1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncccc1OCC1CO1
Reaction time: 0.5 h
Yield: 194.4 %

Procedure:
Reaction was carried out under nitrogen flow. A mixture of 2-chloro-3-pyridinol hydrochloride (1:1) (1.760 mol) in DMF (1000 ml) was added dropwise in 30 minutes to a mixture of NaH 60% (1.934 mol) in DMF (1200 ml) (temperature below 27° C.). The reaction mixture was stirred for 30 minutes. (Chloromethyl)-oxirane (3.530 mol) in DMF (1200 ml) was added dropwise over 30 minutes. The reaction mixture was stirred for 9 hours at 60° C. The mixture was cooled. Water was added dropwise on an ice bath. The mixture was extracted with DCM. The organic layer was dried, filtered and the solvent was evaporated. Petroleum ether was added to the residue, then decanted (3 times). This fraction was combined with analogously obtained fractions, then purified by HPLC over silica gel (eluent: hexane/ethyl acetate (50/50)). The desired fractions were collected and the solvent was evaporated, yielding 635 g of 2-chloro-3-(oxiranylmethoxy)-pyridine (intermediate 19).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CO.CS(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(C(F)(F)F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.50 g, 1.9 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.35 g, 1.9 mmol). The product was isolated as a white foam. Yield 250 mg (29%). mp 100°-105° C. FDMS m/e=457 (M+ of free base). α[D]589 =+8.13 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]1O.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]1
Reactant: CCOC(=O)C1CCC(=O)N(c2c(Cl)cccc2Cl)C1O
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CN(c2c(Cl)cccc2Cl)C(=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of the compound prepared in Example 1 in dichloromethane (150 mL) were added triethylamine (12.27 g) and methanesulfonyl chloride (6.65 g) on ice bath and the mixture was stirred at same temperature for 15 minutes. The reaction mixture was added by hydrochloric acid (1 mol/L), then the water layer was extracted with dichloromethane. The obtained extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (4.00 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([OH:14])=O)[NH:11][C:6]2=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:54][C:51]([CH3:53])([CH3:52])[C:48]([CH3:50])([CH3:49])[O:47]2)=[CH:42][C:41]=1[O:55][CH3:56]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([B:46]4[O:47][C:48]([CH3:49])([CH3:50])[C:51]([CH3:53])([CH3:52])[O:54]4)=[CH:42][C:41]=3[O:55][CH3:56])=[O:14])[NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
5-Methoxy-1 h-pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.602 mmol, 116 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.662 mmol, 252 mg) were added to a solution of 4-amino-3-methoxyphenylboronic acid pinacol ester (0.602 mmol, 150 mg) in dichloromethane (2.5 ml) and pyridine (0.5 ml) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Dichloromethane and water were added to the residue, the organic layer separated and washed with water. Both aqueous layers were extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane) to give 5-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (278 mg).