Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][B-:26]([F:29])([F:28])[F:27].[CH3:30][O+](C)C.C(O)C>ClCCl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH3:30])[CH:17]=3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[O+](C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: Cn1c[n+](-c2ccc(S(=O)(=O)c3ccccc3)cc2)c2ccccc21
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 1-(4′-phenylsulfonylphenyl)benzimidazole (6.7 g, 20 mmol) in dichloromethane (100 ml) is admixed at −10° C. with trimethyloxonium tetrafluoroborate (3.3 g, 22 mmol) and stirred under argon for 16 h. After adding ethanol, the precipitate formed is filtered off and washed with cold petroleum ether. Yield: 80%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1C=N[N:12]=[N:11]1>>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[N:11][NH:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: c1nnn[nH]1
Reactant: N#Cc1cccc(I)c1
Product: Ic1cccc(-c2nn[nH]n2)c1

Procedure:
The 3-iodobenzonitrile (3.6 g, 16.6 mmol) was converted to the corresponding tetrazole (4.1 g, 91%) utilizing reaction conditions previously described in Step (a) of example 1. CI-MS: C7H51N2 [M+1] 273.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN1CCCC1=O>[C:13]1([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1ccccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-bromophenylacetic acid (25 mmol) was added to a mixture of 50 mmol of aniline, 50 mmol of anhydrous potassium carbonate, (7%) mmol of activated copper powder, and 3 ml of N-methylpyrrolidone at 120° C. The mixture was kept at 120° C. for 4 h with stirring. The resulting slightly grayish mixture was filtered while hot through a bed of Celite and the Celite was washed with water (200 ml) and hexane (200 ml). The filtrate was transferred to a separating funnel and extracted with hexane and cooled to room temperature. The aqueous layer was removed, cooled to 5° C., and neutralized with dilute hydrochloric acid (1:3) which was also kept at 5° C. The precipitated 2-[(phenyl)amino]phenylacetic acid was collected by filtration, thoroughly washed with water, and dried under suction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:20][C:21](=[O:22])[N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-Bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (1.8 g, 5.14 mmol) was dissolved in dry THF (50 mL) and 1,1′-carbonyl-diimidazole (0.92 g, 5.65 mmol) was added. The dark brown solution was stirred at room temperature under nitrogen overnight. The mixture was diluted with ethyl acetate and washed with water then brine and dried over anhydrous magnesium sulfate. After filtration and concentration the crude product was chromatographed on silica gel eluting with 5-50% ethyl acetate in hexanes to give 6-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-benzo[d]imidazol-2(3H)-one as a purple oily foam (1.14 g, 2.96 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[N:8]([C:45](=[O:46])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=NN(C(=O)Nc2ccc(Cl)cc2)C(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.520 g) in methylene chloride (12 ml) was added pyridine (4 equiv.) and 4-chlorophenyl isocyanate (1.25 equiv.). Stirred at room temperature for 16 hours. Evaporated and recorded crude 1H: 80156×134 RM1—revealed expected product and relatively clean. Purified by silica gel chromatography, eluant 10-100% EtOAc in hexane over 25 mins. Collected 1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.480 g).
Reaction SMILES: C([NH:4][C@@H](CS)C(O)=O)(=O)C.[C:11]([C:13]1([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)#[N:12].C([O-])(=O)C.[NH4+]>CO>[C:11]([C:13]1([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14]1)(=[NH:4])[NH2:12]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(NS(=O)C(C)(C)C)C1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(C(=N)N)C1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of (R)-2-acetamido-3-mercaptopropanoic acid (N-acetylcycteine, 0.812 g, 4.98 mmol), tert-butyl 3-cyano-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (1.5 g, 4.98 mmol), and ammonium acetate (1.918 g, 24.88 mmol) in MeOH (5 ml) in a 15 ml sealed tube was heated at 70° C. overnight. Analysis of the reaction mixture by LCMS showed 38% desired product with other impurities but no starting material present. The reaction mixture was used for the next step without workup.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)=O)(C)(C)C.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[N:44]3[C:39]([CH:40]=[N:41][C:42](OS(C(F)(F)F)(=O)=O)=[N:43]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C(O)(C(F)(F)F)=O>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[N:44]3[C:39]([CH:40]=[N:41][C:42]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([CH:9]5[CH2:10][NH:11][CH2:12][CH2:13][NH:8]5)[CH:22]=4)=[N:43]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2cccc(N)c2)C1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(C5CNCCN5)c4)nn23)cn1
Yield: 43.2 %

Procedure:
Analogous to Example 1528d, 2-(3-Amino-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (204 mg, 0.540 mmol) and Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (162 mg, 0.432 mmol) were reacted to afford [7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-piperazin-2-yl-phenyl)-amine (75 mg, 33%) as the TFA salt. LCMS: 402 (M+H); 1H-NMR (DMSO-d6): 9.74 (s, 1H), 9.5 (br s, 3H), 9.03 (s, 1H), 9.00 (s, 1H), 8.50 (m, 1H), 7.93 (d, 1H, J=8.1 Hz), 7.65 (s, 1H), 7.48 (m, 1H), 7.26 (d, 1H, J=4.8 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.03 (m, 2H), 1.41 (m, 1H), 3.94 (s, 3H), 3.71 (m, 1H), 3.60 (m, 2H), 3.2-3.4 (m, 3H).
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])#[N:3]>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:1])=[O:8])#[N:3]
Reactant: N
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: N#Cc1cccc(C(N)=O)c1
Reaction time: 0.33 h

Procedure:
0.88 Ammonia solution (30 ml) was slowly added to a solution of 3-cyanobenzoyl chloride (10 g, 60.3 mmol) in dichloromethane (100 ml) at 0° C. under nitrogen and the reaction was stirred for 20 minutes. The mixture was filtered and the solid was washed with water (50 ml) then diethylether (50 ml), azeotroped with toluene and dried in vacuo to provide the title compound (9 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O.[OH-].[Na+]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:10]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Temperature: 50 °C

Procedure:
Refer to synthesis of (D46) for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (1.85 g, 9.70 mmol) and morpholine (1.69 mL, 19.4 mmol) in anhydrous dimethylformamide (20 mL) was heated to 50° C. for 2.5 h. The reaction was then cooled to room temperature and diluted with 0.1 M NaOH (600 mL) and extracted with ethyl acetate (3×500 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound (2.49 g) as an orange oil, which later solidified upon standing. Compound 6-Chloro-2-morpholin-4-yl-nicotinamide (2) was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ7.89 (br s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.56 (br s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.67 (br t, J=4.7 Hz, 4H), 3.31 (br t, J=4.7 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2c1CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) was dissolved in dichloromethane (0.5 ml), TFA (0.5 ml) was added, and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (10 ml×2), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (45 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([N:9]([CH2:8][C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(N)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br
Temperature: 100 °C

Procedure:
A suspension of 4-bromo-2-fluoro-5-methylbenzenamine (1 g, 4.9 mmol), (bromomethyl)benzene (2.5 g, 14.7 mmol) and potassium carbonate (2 g, 14.7 mmol) in acetonitrile (80 mL) was heated in a sealed tube at 100° C. for 16 hours. After concentration, the residue was diluted with ethyl acetate (80 mL), washed with water (20 mL), dried over anhydrous sodium sulfate filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 50/1 petroleum ether/ethyl acetate to give the title compound. MS: 384 (M+H+).
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]([O:20]C)=O)[CH:9]=1)C1C=CC=CC=1.[CH2:22]([Mg]Cl)[CH:23]([CH3:25])[CH3:24].CCOCC>C1COCC1>[CH3:22][CH:23]([CH3:25])[CH2:24][C:18](=[O:20])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CC(C)C[Mg]Cl
Reactant: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(=O)Cn1ccc2ccccc21
Temperature: 0 °C

Procedure:
To a solution of methyl indol-1-ylacetate (1.13 g, 5.9 mmol) from Example 1, Step 1, in THF at -78° C. was added dropwise a solution of 2M isobutyl magnesium chloride in Et2O (3.3 mL, 6.6 mmol). The reaction mixture was warmed up to 0° C. and kept at this temperature until the starting material disappeared. The reaction mixture was quenched with a 0.5M solution of Na and K tartrate and extracted with EtOAc. The extract was washed with a solution of NH4OAc, dried over MgSO4 and evaporated to dryness. The crude residue was chromatographed on flash silica gel column eluting with EtOAc-hexane (1:9) to afford the pure title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][O:11][CH:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]1[CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=2)[N:9]=[CH:10]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc(-c2cocn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a stirred solution of 4-(4-bromophenyl)-1,3-oxazole (469 mg, 2.09 mmol) in dioxane (20 ml) was added tributyl(1-ethoxyvinyl)tin (906 mg, 2.51 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.207 mmol), lithium chloride (221 mg, 5.23 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. To the residue was added THF (10 ml), 2N HCl aqueous solution (10 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (256 mg, 65% yield).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([OH:25])[CH3:24].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: COC(=O)C[C@H](C)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl(chloro)diphenylsilane (15.282 g, 55.6 mmol) was added dropwise to an ice-cooled and stirred solution of (S)-3-hydroxybutanoic acid methyl ester (5.473 g, 46.3 mmol) and 1H-imidazole (6.939 g, 102 mmol) and DMAP (0.566 g, 4.63 mmol) in DMF (250 mL). After 10 min., the cloudy reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was taken up in EtOAc, then washed successively with H2O (3×), 1N HCl and a sat. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to give a viscous colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].Br[CH:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]1=[O:24]>O1CCCC1>[CH:18]1([N:15]2[CH2:16][CH2:17][CH:13]([S:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:14]2=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1C(Br)CCN1C1CCCCC1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(Sc2ccc(Cl)cc2Cl)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Place 2,4-dichloro-benzenethiol (728 mg, 4.1 mmol) in tetrahydrofuran (10 mL) and cool to 0° C. Slowly add sodium hydride (98 mg, 4.1 mmol) and stir for 30 minutes. To this solution, add a solution of 3-bromo-1-cyclohexyl-pyrrolidin-2-one (Preparation 1) in tetrahydrofuran (2 mL) and stir at room temperature for 30 minutes. Pour reaction mixture onto ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-30% ethyl acetate in hexane) to yield 641 mg (92%) of the title compound: Mass spectrum (apci) m/z=344.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(Cl)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(Cl)cc2)n1
Yield: 14 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (8 mg, yield 14%). 1H NMR (CDCl3) δ 8.59 (t, J=1.7 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.12 (d, J=6.7 Hz, 1H), 7.99 (d, J=6.6 Hz, 2H), 7.64 (t, J=7.7 Hz, 2H) 7.49 (s, 1H), 7.38 (d, J=4.9 Hz, 1H), 2.03 (s, 2H), 1.40 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O3: 490.10. found: 491.1 (M+H)+.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[OH:30])=[O:22]>>[CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[OH:30])=[O:22])[CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1
Reactant: O=C(CCCCl)c1ccc(F)cc1O
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3)c1ccc(F)cc1O

Procedure:
The title compound was prepared by the method of Example 361 as a yellow oil (8 mg, 17%) from (±)-cis-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (30 mg, 0.12 mmol) and 4-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-butanone (52 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ1.85-2.13 (m, 5H), 2.25-2.47 (m, 3H), 2.63-2.95 (m, 3H), 2.99 (t, J=7.0 Hz, 2H), 3.17-3.35 (m, 3H), 4.43 (dd, J=6.9, 2.2 Hz, 2H), 6.59-6.75 (m, 5H), 7.81 (dd, J=8.7, 6.6 Hz, 1H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[K+].O>CS(C)=O>[CH2:34]([O:41][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCc6ccccc6)ccn45)cccc32)n1
Temperature: 90 °C
Yield: 94.6 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.2 mmol; prepared as in Example 65, step C), benzyl alcohol (1.2 g, 11 mmol) and potassium hydroxide (0.61 g, 11 mmol) was dissolved in DMSO (7 mL). The reaction mixture was heated at 90° C. for 20 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) with stirring, and the resulting solid was collected by vacuum filtration and dried under vacuum to give the product (1.1 g). MS (ES+APCI) m/z=529.7 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.Cl.[NH2:17]O.O>N1C=CC=CC=1>[C:10]1([CH2:9][CH:7]([NH2:17])[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NC(Cc1ccccc1)c1ccncc1
Reaction time: 4 h

Procedure:
5.34 g of benzyl 4-pyridyl ketone and 3.75 g of hydroxylamine hydrochloride in 50 ml of pyridine are heated to boiling for 4 hours. After cooling, the mixture is stirred into 600 ml of water, and the oxime (5.6 g) of melting point 194°-196° C. is filtered off. The oxime is hydrogenated with hydrogen in isopropanol with Raney nickel at 50° C. and under normal pressure. After the customary working up, the amine is obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1Cc2ccc(OC)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Methyl 2-(t-butyloxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylate (0.615 g, 2.0 mmol) in DMF (7 mL) was added K2CO3 (0.304 g, 2.2 mmol) and iodomethane (0.137 mL, 2.2 mmol). The mixture was stirred for 18 hr at 25° C. Approximately 14% of the starting material remained. An additional amount of iodomethane (0.050 mL) was added and stirring continued for 18 hr. The DMF was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (30 mL). The ethyl acetate layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and evaporation in vacuo gave the title compound.