Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:12])[NH:2]1.C(O[BH-](O[C:36](=[O:38])[CH3:37])OC(=O)C)(=O)C.[Na+].N>O>[O:38]([CH2:36][CH2:37][N:2]1[C@@H:3]([C:11]([NH:13][C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH3:15])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Agent: N
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 147.6 %

Procedure:
To a stirring mixture of silica gel (200 g, 3.33 mol) and dichloromethane (1100 mL) at 22° C., add a solution of sodium periodate (56.2 g, 260 mmol) in water (352 mL) in a dropwise fashion. After the end of the addition, stir the mixture for an additional 30 minutes, then add 3-phenoxyl-1,2-propanediol (34.5 g, 195 mmol), resulting in a slight exotherm. Stir the mixture for an additional 30 minutes, then filter to remove the solids, discard the aqueous layer, and dry the organic layer over MgSO4, filter to remove the solids, and treat the filtrate with methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate (44 g, 130 mmol). Then, add sodium triacetoxyborohydride (57.4 g, 260 mmol) in small portions. Upon completion of the addition, stir the mixture for one additional hour, then add water (200 mL). Add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Separate the layers, dry the organic layer over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure. Dissolve the resulting crude oil in TBME (300 mL), then add water (250 mL) and 1 M aqueous hydrochloric acid (200 mL). Stir the resulting slurry for 30 minutes, concentrate under reduced pressure to remove the TBME, and isolate the resulting white precipitate by filtration. Pour this precipitate into a stirring mixture of water (400 mL) and TBME (400 mL), and add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Remove the aqueous layer, and wash the organic layer with a saturated aqueous sodium chloride solution (200 mL). Isolate the organic layer, dry over MgSO4, filter to remove the solids, and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel using a 30% to 70% EtOAc/hexanes gradient. Consolidate the fractions containing the product, and concentrate them under reduced pressure to furnish the title compound as a white solid (44 g, 74% yield). Mass spectrum (m/z): 459 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]1[CH2:50][CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43][CH2:42]1)=O>>[O:48]1[C:44]2([CH2:49][CH2:50][N:41]([CH2:39][CH2:38][O:1][C:2]3[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=4[CH:18]4[CH2:27][CH2:26][C:25]5[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=5[CH2:19]4)=[CH:4][CH:3]=3)[CH2:42][CH2:43]2)[O:45][CH2:46][CH2:47]1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC4(CC3)OCCO4)cc2)c1
Yield: 45.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCBr)cc1
Temperature: 0 °C

Procedure:
4-(2Hydroxyethyl)benzonitrile (3.0 g, 20 mmol) was combined with triphenylphosphine (6.42 g, 24.5 mmol) imidazole (1.39 g, 20.4 mmol) and carbon tetrabromide (8.11 g, 24.5 mmol) in DCM (10 mL) and stirred at 0° C., monitoring the reaction progress to completion by TLC. Silica gel was added to the mixture and the solvent was removed. Purification by MPLC eluting with 20% ethyl acetate/hexanes afforded the tide compound.
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH3:50])=[O:48]>ClCCl>[CH3:50][O:49][C:47](=[O:48])[N:11]([CH2:12][C:13]1[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)[CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36]
Reactant: COC(=O)Cl
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C(OC)C1CCCCC1
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 22 mg, 0.042 mmol) in dichloromethane (1 ml) was added diisopropylethyl amine (8.09 mg, 0.063 mmol) followed by methyl chloroformate (3.94 mg, 0.042 mmol) at room temperature and stirred for overnight. Reaction mixture was then concentrated in vacuo and the product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (7 mg, 30%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.4(m, 1H) 1.5(m, 2H) 1.7(s, 1H) 1.9 (d, J=11.2 Hz, 1H) 3.0 (s, 3H) 3.8(s, 3H) 4.0 (d, J=17.9 Hz, 1H) 4.6 (m, 4H) 7.25 (d, J=10.4 Hz, 1H) 7.45 (d, J=7.5 Hz, 1H) 7.53 (m, 3H) 7.7 (s, 1H) 7.8 (s, 1H). MS (ES+) Calc: 585.2, Found: 630.3 (M+45).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:31]([F:43])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C@@H:31]([F:43])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C[C@@H]1F
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1S*,2S*,4S*)-4-amino-2-fluorocyclohexyl]carbamate (example C22) the title compound is obtained as pale yellow foam.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][C@H:3]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)OC(C)(C)O1
Reaction time: 2.5 h
Yield: 130.1 %

Procedure:
To a stirring, 0°-5° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 38 mmol) in methylene chloride (250 mL) containing triethylamine (10 mL, 72 mmol) is added 4-chlorobenzenesulfonyl chloride (12.7 g, 60 mmol). Stirring is continued at 0°-5° C. for 2.5 hours and the solution slowly warmed to 20°-25° C. over a period of 2 hours. The solution is poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 200 mL of methylene chloride and the combined organic layers are washed with 200 mL each of saturated sodium bicarbonate solution to ensure complete removal of 4-chlorobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 21.5 g of the product as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[OH:22][C:23]1[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.CN(C)C=O.[H-].[Na+]>O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:13]1[O:14][C:15]([CH3:16])=[C:11]([CH2:10][O:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][O:22][C:23]3[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:24]=3)=[CH:4][CH:5]=2)[N:12]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridine (0.58 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)=[CH:26][C:25]=1[O:32][C:33]([F:34])([F:36])[F:35]
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(Cl)c(OC(F)(F)F)c1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(OC(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 4-chloro-3-trifluoromethoxybenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.
Reaction SMILES: [N:1]([C@H:4]([CH:6]([CH3:8])[CH3:7])[CH3:5])=[C:2]=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([NH:1][C@@H:4]([CH3:5])[CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: CC(C)[C@H](C)N=C=O
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)[C@H](C)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from (2S)-2-isocyanato-3-methylbutane (Alfa Aesar, Cat. #L20354) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=438.3.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[C:24]([CH3:28])[N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][C:25]([CH3:27])=[C:24]([CH3:28])[N:19]3[C:20](=[O:23])[C:21]=2[C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cccc(/C=C/c2nc3sc(C)c(C)n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 75.2 %

Procedure:
The title compound was prepared from Intermediate 18 (100 mg, 0.196 mmol) and 4-trifluoromethoxyphenylboronic acid (56 mg, 0.275 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.009 mmol) and sodium carbonate (125 mg, 1.187 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 80 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.28 (m, 2H), 0.46-0.52 (m, 2H), 0.90-1.01 (m, 1H), 2.30 (s, 3H), 2.59 (s, 3H), 3.67 (d, J=7.5 Hz, 2H), 3.76 (s, 3H), 6.82 (d, J=15.6 Hz, 2H), 6.88-6.91 (m, 1H), 6.98-7.00 (m, 4H), 7.43 (s, 4H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 543.19 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1/[C:8](=[CH:10]/[CH:11]([CH3:13])[CH3:12])/[CH3:9].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH2:9]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: Cl
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
Into a solution obtained by dissolving 3-aminothiophene (1.8 g, 18.1 mmol) in 4-methyl-2-pentanone (30.1 g), which was obtained in the same manner as in Example 14 using methyl 3-aminothiophene-2-carboxylate as a starting material was added concentrated hydrochloric acid (9.3 g, 90.5 mmol) at room temperature, and the resulting solution was stirred under nitrogen atmosphere at 60 degree centigrade for 5 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution, and separated. As a result of the analysis by the HPLC internal standard method of the obtained organic layer, 0.5 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 14%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[CH:42]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[CH:42]5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4ccnc4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4ccnc4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[2-(imidazol-1-yl)ethyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) was dissolved in methylene chloride (15 ml), and a solution of m-chloroperbenzoic acid (0.20 g) in methylene chloride (10 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[2-(imidazol-1-yl)ethyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 266) (60 mg).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:27][C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CO.[OH-].[K+]>C(O)(=O)C>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH2:27][NH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)=[CH:25][N:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3c(F)cccc3Cl)nc2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cccc(Cl)c1CNc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 80 °C

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine 617 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0210. MS (ESI) [M+H+]+=367.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 56.5 %

Procedure:
This product was prepared by a modification of the general procedure described in Diana et al. J.Med.Chem. 1995, 38, 1355. A mixture of 4-chlorobenzonitrile (5 g, 36.34 mmol), EtOH (90 mL), hydroxylamine hydrochloride (2.52 g, 36.34 mmol) and K2CO3 (2.51 g, 18.17 mmol) was refluxed for 20 h. The reaction mixture was concentrated, cold water was added, and it was filtered and dried to give 4-chlorobenzoamidoxime as a white solid (3.5 g, 56%). Next, this product (1.7 g, 10 mmol) was taken up in pyridine (34 mL) and treated with ethyl oxalyl chloride (2.22 mL, 20 mmol) at 0° C. The reaction mixture was stirred for 1 h, then poured into pH 7 phosphate buffer, concentrated and partitioned between CHCl3 and water. The organic phase was washed with 10% aqueous NaHCO3 solution, dried over Na2SO4, filtered, concentrated and purified by flash chromatography to give ethyl 3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carboxylate as an amorphous solid (2.14 g, 85%): 1H NMR (300 MHz, CDCl3) δ (TMS) 8.18 (dt, Jt =2.2, Jd =8.6, 2H, arom), 7.56 (dt, Jt =2.2, Jd =8.6, 2H, arom), 4.66 (q, J=7.1, 2H, OCH2), 1.57 (t, J=7.1, 3H, OCH2CH3).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=O)[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(Cl)(=O)C([Cl:16])=O>ClCCl>[CH2:1]1[CH:8]2[C:4]3([C:10]([Cl:16])=[O:12])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Solvent: ClCCl
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of commercially available hexahydro-2,5-methano-pentalene-3a-carboxylic acid (10 g, 0.06 mol) in dichloromethane (200 mL) was added oxalyl chloride (8.7 g, 0.066 mol). The mixture was stirred overnight and then concentrated under reduced pressure to afford the title compound as a colorless oil (11 g, 99%). MS (DCI/NH3) m/z 184 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][OH:33]>C(#N)C.O>[OH:33][CH2:32][CH2:31][N:22]1[CH2:21][CH2:20][C:6]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1
Reactant: OCCBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CCO)C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (100 mg, 0.325 mmol) in acetonitrile (3 mL), potassium carbonate (135 mg, 0.977 mmol) and 2-bromoethanol (61 mg, 0.488 mmol) were added and the reaction mixture stirred at 60° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2-[2-(2-hydroxy-ethyl)-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, formate salt) δ (ppm): 8.41 (d, 2H), 7.38 (d, 2H), 7.2 (m, 2H), 6.99 (d, 1H), 5.03 (t, 1H), 4.4 (bs, 2H), 4.3 (d, 2H), 3.93 (t, 2H), 3.45-3.62 (m, 2H), 3.2 (m, 2H), 2.9 (m, 2H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-64a-b.