Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCCNc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=O)NCCCCCNc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 1 h

Procedure:
Part B. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylamino)-aminopentane (1.7 g, 0.00531 mol) and triethylamine (0.58 g, 0.0058 mol) in methylene chloride cooled to 0° under a nitrogen atmosphere, heptanoyl chloride (0.788 g, 0.00531 mol) was added slowly. The reaction mixture was stirred for 1 hour at 0°, poured into water and extracted with methylene chloride (2×50 mL). The combined organic extract was washed with water, brine, dried over magnesium sulfate and concentrated to give N-[5-(4,5-diphenyl-1H-imidazol-2-ylamino)pentyl]heptanamide as a viscous oil. The product was purified by flash chromatography on silica gel (250 mL) eluting methylene chloride:methanol (95:5 v:v), to give an amber foam (1.3 g, 0.003 mol). 1H NMR (CDCl3) δ 7.43-7.15(m,10H), 6.3(m,1H), 3.24-3.1(m,4H), 2.09(t,2H), 1.6-1.16(m,14H), 0.84(t,3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:23][N:24](C)[CH:25]=[O:26]>>[CH3:23][NH:24][C:25](=[O:26])[NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrochloride (1.0 g) was suspended in dimethylformamide (30 ml) and triethylamine (1.2 ml) was added. The dark solution was filtered. Methyl isocyanate (0.53 ml) was added and the mixture was stirred for 17 hours at room temperature. The mixture was evaporated to dryness and the black residue washed with water; the insoluble material was collected by filtration and then reprecipitated from dimethylformamide solution with water. The precipitate was filtered off and the filtrate evaporated to dryness. The cream-coloured residue was collected to afford the title compound, m.p.>300° C.; C12H12N4O2Calculated: C 59.01; H 4.95; N 22.94: Found: C 59.09; H 4.94; N 22.90: νmax (liquid paraffin) 1675, 1642 cm-1 ; N.m.r. δ(DMSO-d6) 2.76 (d, 3H, CH3), 5.98 (q, 1H, --NHCH3), 7.91, 8.08 (2d, 2H, pyridine H's).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][Si](C)(C)C)[C:7](=[O:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[F-].[K+].C(Cl)(Cl)Cl.O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[CH:15])[C:7](=[O:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 58.8 %

Procedure:
18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate and 9.7 g of potassium fluoride are stirred for 3 hours at room temperature in a mixture of 300 ml of dimethylformamide, 200 ml of chloroform and 15 ml of water. The mixture is then filtered, the filtrate is treated with 120 ml of water, and the mixture is acidified with dilute aqueous hydrochloric acid. After extraction by shaking with chloroform, the organic phase is dried over sodium sulphate and concentrated. The residue obtained is recrystallised from methanol. In this way, 9 g of ethyl 1-cyclopropyl-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (59% of theory) are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH2:18]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: CCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg) in 1-methyl-2-pyrrolidone (0.8 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→95/5). The object fraction was concentrated under reduced pressure. To the residue was added a mixed solvent of diisopropyl ether and chloroform. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (96 mg) as a pale-purple powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.F[C:14]1[CH:15]=C2C(=C[CH:23]=1)NC(=O)C=N2.C(=O)([O-])[O-].[K+].[K+].C(I)C=C>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:15][CH:14]=[CH2:23])=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: O=c1cnc2cc(F)ccc2[nH]1
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1:2 mixture of 7-fluoro-2(1H)-quinoxalinone and 6-fluoro-2(1H)-quinoxalinone (20 g, 0.122 mol) in dry DMF (250 ml) and anhydrous potassium carbonate (50.5 g, 0.38 mol) was treated with allyl iodide (12.3 ml, 0.134 mol) and the mixture was stirred at rt for 2 hours. The reaction mixture was evaporated to dryness, water was added and the mixture was extracted (3×) with DCM, washed with water, dried (sodium sulphate) and evaporated. It was chromatographed, twice, on silica gel, eluting with 0-40% ethyl acetate-hexane. The early fractions gave 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinoxalinone (4.7 g) [later fractions contained the isomeric 6-fluoro-isomer (6.7 g)].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Product: O=c1[nH]c2ccc(-c3cccc(Cl)c3)cc2s1

Procedure:
Prepared from 6-bromo-2-benzothiazolinone, 3-chlorophenyl boronic acid according to the procedure of example 12. A white solid: mp 195-196° C.; 1H-NMR (DMSO-d6) δ11.95 (s, 1H), 7.96 (d, 1H, J=1.17 Hz), 7.7 (t, 1H, J=1.76 Hz), 7.62-7.59 (m, 2H), 7.46 (t, 1H, J=7.65 Hz), 7.4-7.38 (m, 1H), 7.18 (d, 1H, J=8.24 Hz); MS (EI) m/z (M+, 30%); Anal. Calc. For C13H8ClNOS.H2O: C, 57.67; H, 3.35; N, 5.17. Found: C, 57.98; H, 3.11; N, 4.98.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[CH2:52]([CH2:54][NH2:55])[OH:53].C(=O)(O)[O-].[Na+]>O1CCOCC1>[OH:53][CH2:52][CH2:54][NH:55][C:2]1[N:3]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:36][C:37]([CH3:50])([CH3:51])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:39]([CH3:42])([CH3:41])[CH2:40]2)[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:29])([CH3:28])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:7]=1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Yield: 87.4 %

Procedure:
A mixture of 10.0 g (13.6 mmol) of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperdin-4-yl)butylamino]-1,3,5-triazine, 3.3 g (54.6 mmol) of ethanolamine and 30 ml of dioxane is heated at reflux for four hours. The reaction mixture is then poured into 200 ml of saturated aqueous sodium bicarbonate solution. A precipitate forms. The supernatant liquid is decanted, and the precipitate is partitioned between ether (250 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The ether layer is dried over anhydrous magnesium sulfate and evaporated to obtain a glassy material. Purification by flash chromatography on silica gel (4:1 heptane:ethyl acetate) affords 9.0 g (87% yield) of the title compound as a colorless glass.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29][CH3:30])=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>ClCCl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH3:30][O:29][C:18]1[N:19]=[N:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:22][C:17]=1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1

Procedure:
A solution of 5.5 g 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 5 ml TFA in 10 ml dichloromethane stirred for 18 h at room temperature. The solvent is evaporated and the crude product purified by suspensing in water and collecting the precipitate.
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:42])C(=O)C1.S([O-])([O-])=S.[Na+].[Na+]>C(=O)([O-])[O-].[K+].[K+]>[CH3:1][N:2]1[C:9]([C:10]([F:13])([F:11])[F:12])=[C:8]([I:42])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1c(C(F)(F)F)cc(=O)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)c(I)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of 1,3-dimethyl-6-(trifluoromethyl)uracil (16.91 mmol, 3.52 g), trifluoroacetic acid (20 mL) and trifluoroacetic anhydride (5 mL) was refluxed for 5 min. Then, NIS (16.91 mmol, 3.8 g) was added and the resulting mixture was stirred for 15 h at which time the TLC analysis of the reaction mixture indicated the presence of some starting material. Another portion of NIS (8.45 mmol, 1.9 g) was added and reflux was continued for another 5 h. The reaction mixture was cooled to room temperature and was poured slowly into a saturated potassium carbonate solution (100 mL). Then, sodium thiosulfite solution was added to remove the excess iodine color. The resulting solids were collected by filtration and washed with water. After air drying, 3.73 g (66% yield) of 1,3-dimethyl-5-iodo-6-(trifluoromethyl)uracil was obtained as a white solid: mp 149-151° C. EI-HRMS m/e calcd for C7H6F3IN2O2 (M+) 333.9426, found 333.9436.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([O:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][CH:27]=[N:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:29]2[N:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=[CH:27][CH:28]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1OCc1ccccc1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2OCc2ccccc2)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.17 mmol) in dioxane (15 mL) were added 1-benzyloxy-5-tributylstannanyl-1H-pyrazole (1.24 g, 2.60 mmol) and Pd(dppf)2Cl2 (177 mg, 0.217 mmol) and the resulting mixture was stirred at 100° C. for 16 h. An additional portion of catalyst (0.1 equiv) was added and the mixture was stirred at 100° C. for an additional 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to provide the title compound as an off-white solid (263 mg, 31%). ES-MS: m/z 392.3 [M+H]+, rt 6.48 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC(C)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
4-Bromo-α-methylbenzylamine (8.15 g, 40.73 mmol) and (4.15 g, 41.00 mmol) triethylamine dissolved in 150 ml dichloromethane was treated slowly with ethanesulfonyl chloride (5.27 g, 41.00 mmol) and stirred for 15 minutes. The reaction mixture was extracted with 50 ml 1N HCl/15 ml brine. The organic layer was separated, dried sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 7.52 (d,2H,J=12 Hz), 7.25 (d,2H,J=12 Hz), 4.77 (m,1H), 4.63 (m,1H), 2.77 (m,2H), 1.56 (d,3H,J=8 Hz), 1.27 (t,3H,J=8 Hz). MS calcd. 292.2; MS (M+−1) 291.1.
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][N:22]=1.C[O-].[Na+]>C(#N)C.CO>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[N:7]([CH2:20][C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][N:22]=2)[CH:6]=[N:5][CH:9]=1
Reactant: BrCc1noc2ccccc12
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: OCCCc1cncn1Cc1noc2ccccc12
Reaction time: 3 h

Procedure:
A solution containing 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl)-imidazole (6.7 g, 0.025 mole), and 3-bromomethyl-1,2-benzisoxazole (5.3 g, 0.025 mole) in anhydrous acetonitrile (30 mL) is stirred at reflux for 72 hours. The reaction mixture is cooled and mixed with a solution of sodium methoxide (3 g, 0.055 mole) in methanol (30 mL). The resulting solution is stirred at reflux for 26 hours. The solvents are evaporated and the residue is taken up in 1N hydrochloric acid (30 mL). This solution is allowed to stand at ambient temperature for 3 hours and is then made basic (pH 9) by addition of 50% aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride (2×25 mL) and the combined extracts are washed with water (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated to give crude 3-[(5-(3-hydroxypropyl)-1H-imidazol-1-yl)-methyl]-1,2-benzisoxazole which is purified by trituration with acetone (15 mL), m.p. 129-131° C. The compound forms a hydrochloride hemihydrate, m.p. 155-157° C. when its solution in isopropanol is treated with ethereal hydrogen chloride.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]([C:12]#[N:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].N>CO.[Ni]>[NH2:13][CH2:12][C:8]1[C:9](=[O:11])[NH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCCc1ccc(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
intermediate (24a) (180 mg, 1 mmol) was dissolved in MeOH (10 mL). Aqueous ammonia (1 mL) was added, followed by wet Raney Nickel (100 mg). The mixture was stirred at room temperature under hydrogen for 3 hours. The mixture was then filtered and the filtrate evaporated to yield intermediate (24b) (157 mg, 870 μmol, which was used without further purification. MS m/z: [M+H+] calcd for C10H17N2O, 181.3; found 181.3.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C@@:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:22])[CH:3]=1.C([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:6]([SH:36]([C:28]1[CH:29]=[C:30]([CH3:35])[C:31]([CH2:33][OH:34])=[CH:32][CH:27]=1)[C:3]1[C:4](=[O:22])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:14])([CH3:8])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)C[C@@](CCc2ccccc2)(c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([SH](C2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)C(C)(C)C)ccc1CO

Procedure:
The title compound was prepared as described in General Method 9 using 0.12 g (0.40 mmol) of (S)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one (prepared in Example VV), 0.16 g (0.44 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.22 g (1.6 mmol) of K2CO3, and DMF (2 mL). Upon standard work-up, the residue was chromatographed on silica gel, eluting with 4:1 CHCl3 :EtOAc, to give the title compound, m.p. 186-187° C. 1H NMR (DMSO-d6) δ (s, 9 H), 1.75 (s, 3 H), 2.25 (m, 3 H), 2.55 (m, 1 H), 3.51 (q, partially obscured by H2O, 2 H), 4.32 (br s , 2 H), 4.90 (br s , 1 H), 6.17 (s, 1 H), 7.09 (m, 2 H), 7.15 (m, 1 H), 7.23 (m, 3 H), 7.37 (m, 1 H), 7.44 (m, 4 H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH2:12]([C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:16](=[S:17])[NH:15][CH3:14])[C:11]=2[N:10]=1)[CH3:13]
Reactant: CN=C=S
Reactant: CCc1ccc2c(n1)C(N)CCC2
Product: CCc1ccc2c(n1)C(NC(=S)NC)CCC2

Procedure:
The amino compound of Example 17 may be converted to the title compound by treatment with methylisothiocyanate according to the procedure of Example 4.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:30][CH2:31][O:32][Si](C)(C)C.Cl>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:30][CH2:31][OH:32])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: C[Si](C)(C)OCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(CCO)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of (2-chloro-ethoxy)-trimethylsilane (1.06 mL, 8.95 mmol). The reaction mixture is stirred for 48 h at 60° C. After cooling to room temperature, aqueous 1M HCl (30 mL) is added and the mixture is stirred at room temperature for 30 min, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:4) to afford 2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethanol as a solid. 1H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 3H), 3.69 (t, J=5.9 Hz, 2H), 4.18 (t, J=5.8 Hz, 2H), 7.21 (dd, J=8.6, 2.0 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.61-7.67 (m, 1H), 8.01 (dt, J=7.9, 2.0 Hz, 1H), 8.61-8.71 (m, 2H). HRMS (ESI) m/z 287.0953 [(M+H)+ Calcd for C16H16ClN2O: 287.0951].
Reaction SMILES: O[CH:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:9]2[C:8]3[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([CH3:31])=[C:4]([CH:2]=[CH2:3])[C:12]=3[O:11][CH2:10]2)=[CH:14][CH:15]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.23 g, 3.02 mmol) obtained in Example 22 and p-toluenesulfonic acid monohydrate (20 mg) in toluene (20 mL) was refluxed with heating at 80° C. for 1 hour under an argon atmosphere. The reaction solution was washed with an aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 1.09 g (yield: 89%) of the title compound. Melting point: 171-172° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]([C:19]1[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=1[CH:34]([CH3:36])[CH3:35])[CH3:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:40]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:40])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]([C:19]1[O:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[N:21][C:20]=1[CH:34]([CH3:35])[CH3:36])[CH3:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC(C)c3oc(-c4ccc(C(F)(F)F)cc4)nc3C(C)C)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(OCC(C)c3oc(-c4ccc(C(F)(F)F)cc4)nc3C(C)C)ccc2n1C

Procedure:
5-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-1H-indole-2-carboxylic acid ethyl ester (0.117 g, 0.234 mmol) is stirred with sodium hydride, 60% mineral oil (0.011 g, 0.28 mmol) and NN-dimethyl formamide (12 mL). Iodomethane (16 uL, 0.26 mmol) is added and the mixture is stirred at 80 deg C. 2 hr, and room temperature 18 hr. The mixture is diluted with water (50 mL), and the product is extracted into ethyl acetate (2×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica gel chromatography eluting with 8:2 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate to afford the title compound as a tan solid, 0.062 g, 51%). MS M++1 515. The structure is confirmed by 1H NMR spectroscopy.