Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([S:26]([CH3:25])(=[O:28])=[O:27])=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1nc(C=NO)cs1)N(C1CCCCC1)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)C(=NO)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 1,1-dicyclohexyl-3-[4-(hydroxyimino-methyl)-thiazol-2-yl]-urea (0.15 mmol) in DCM (4 mL) was added methansulfonyl chloride (0.15 mmol) and DIEA (0.15 mL). The mixture was stirred at rt for 2 h and quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts was washed with water (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica, EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to give the desired product in 30% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C@@H:25]5[CH2:29][CH2:28][CH2:27][O:26]5)[CH:19]=4)[C:14]3=[O:30])=[CH:9][C:8]=2[F:31])[CH2:3]1.Br[CH2:33][CH2:34][CH2:35][O:36][CH3:37]>>[F:31][C:8]1[CH:9]=[C:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH:19]=3)[C:14]2=[O:30])[CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:3]1
Reactant: COCCCBr
Reactant: N[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Product: COCCCN[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1

Procedure:
2-[4-((R)-3-Amino-pyrrolidin-1-yl)-3-fluoro-phenyl]-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one was reacted with 1-Bromo-3-methoxypropane by method X. The product with the molecular weight of 497.62 (C28H36FN3O4) was obtained in this way; MS (ESI): 498 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:16])[CH3:17])[N:13]=[C:12]([CH2:18][O:19][C:31](=[O:32])[NH2:33])[C:11]=2[CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1nc(CO)c(COCc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1nc(COC(N)=O)c(COCc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a solution of 120 mg of 5-(3,5-Dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methoxymethyl]-1H-pyrazole-3-methanol in 1 ml of dichloromethane at 0° C. was added 11 mg of trichloroacetyl isocyanate. The mixture was stirred for 2 h at 0° C. then the solvent was removed. The residue was dissolved in 2 ml of methanol and 1 ml of water, 100 mg of potassium carbonate added, and the mixture stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography using methanol/dichloromethane for the elution to give 12 mg of carbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methoxymethyl]-1H-pyrazol-3-yl]methyl ester as a white solid. Mass spectrum (ES) m/z 481 [M]+. 1H NMR (DMSO-d6) 1.25 (d, 6H), 4.50 (s, 2H), 4.52 (s, 2H), 4.80 (m, 1H), 5.05 (s, 2H), 6.55 (br s, 1H), 6.75 (br s, 1H), 7.08 (m, 2H), 7.16 (d, 2H) 7.45 (m, 1H), 8.43 (d, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17]([OH:19])=O)=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:35]=[CH:36][CH:37]=[N:38]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.C1(N)CC1>C(OCC)(=O)C>[CH:37]1([NH:38][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:14]([C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][N:6]=[CH:7]4)[CH:15]=2)[CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C)nncc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 10-mL round-bottom flask was charged with 3-(1-isopropylphthalazin-6-yl)-4-methylbenzoic acid (32 mg, 0.10 mmol), HATU (60 mg, 0.157 mmol), and N,N-dimethylformamide (0.5 mL), followed by cyclopropylamine (0.03 mL, 0.52 mmol). The resulting golden yellow mixture was stirred at RT for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, then dried (MgSO4) and concentrated in vacuo. CombiFlash purification (20% to 70% ethyl acetate in Hexane) afforded the title compound as an off-white amorphous solid. MS (ES+): 346.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[N:16]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ncccn3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-(2-pyrimidyl)piperazine (9.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C19H19N5O2: 349.1539, found 349.1538.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36])[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(Cl)cc1C)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a solution containing (Benzhydrylidene-amino)-acetic acid ethyl ester (2.3 g, 8.6 mmol) in 50 mL of DMSO under a nitrogen atmosphere was added potassium t-butoxide (1.2 g, 11 mmol) After stirring for 20 minutes, 1-Bromomethyl-4-chloro-2-methyl-benzene (1.89 g, 8.6 mmol) was added and the reaction allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 2-(Benzhydrylidene-amino)-3-(4-chloro-2-methyl-phenyl)-propionic acid ethyl ester (1.75 g, 50%) as a yellow oil. LCMS (APCI+) m/z 406 [M+H]+; Rt: 4.16 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[S:24]>O1CCCC1.C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24]
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: S=C=Nc1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc(CNC(=S)Nc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and 2-chlorophenylisothiocyanate (0.09 g) in dry tetrahydrofuran (10 ml) was added 10 drops of triethylamine. The mixture was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo and the residue extracted with ethyl acetate and washed with 2M hydrochloric acid. The layers were separated and the organic phase was evaporated to dryness to give the title product, m.p. 126° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 379 (M{81Br}+H+, 100), 377 (M{79Br}+H+, 95).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N(C([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)[C@H](C(O)=O)CC1C=CC=CC=1.COC1C=CC(C[Mg]Cl)=CC=1>>[CH2:35]([O:34][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: COc1ccc(C[Mg]Cl)cc1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
Boc-Phe 7 is converted to the allylic alcohol 8 using the same procedures reported by De Lucca et al. for the conversion of Z-Phe to the corresponding Z-allylic alcohol (J. Med. Chem. 1997, 40, 1707-1719). The allylic alcohol 8 is reacted with 4-methoxybenzylmagnesium chloride to afford the alkene 9 (J. Med. Chem. 1997, 40, 1707-1719). The 4-methoxybenzylmagnesium chloride is prepared from 4-methoxybenzylchloride according to the procedure of Van Campen et al. (J. Amer. Chem. Soc. 1948, 70 p2296). The alkene 9 is converted to the tetrahydropyrimidinone 10 using the same series of procedures reported by De Lucca et al. (J. Med. Chem. 1997, 40, 1707-1719). Treatment of the nitrile 10 with hydrogen peroxide in DMSO affords the carboxamide 11 (Synthesis, 1989, 949-950). The carboxamide 11 is treated with trimethylsilylbromide to form the phenol 12 (Green) which is then alkylated with trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester in the presence of base (e.g. cesium carbonate) to yield the dibenzyl phosphonate 13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.[Cl:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:29][C:16]1[C:17]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:12]=2[C:13](=[O:18])[NH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (322.3 mg) obtained in Step A of Example 39 in DMF (10 mL) was added N-chlorosuccinimide (252 mg) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 day, and then at 100° C. for 1 day, and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane/methanol) to give the title compound (156 mg).
Reaction SMILES: C(OC([N:8]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([C:28]#[N:29])[CH:24]=2)[CH2:19]1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:31][O:30][C:22]1[C:23]([C:28]#[N:29])=[CH:24][C:25]2[CH2:26][CH2:27][CH:18]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]3=[O:14])[CH2:19][C:20]=2[CH:21]=1
Reactant: CCOC(=O)CNCCN(C(=O)OC(C)(C)C)C1CCc2cc(C#N)c(OC)cc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc2c(cc1C#N)CCC(N1CCNCC1=O)C2
Temperature: 25 °C

Procedure:
To a solution of Ethyl N-{2-[(tert-butoxycarbonyl)(6-cyano-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethyl}glycinate (100 mg, 0.232 mmol) in dioxane was added HCl (1.16 ml, 4.6 mmol). The mixture was allowed to stir at RT until there was no SM left. The volatiles were removed, and the residue was dissolved in EtOH (15 ml). To this solution was added Hunig's Base (0.20 ml, 1.16 mmol). The solution was sealed in a microwave tube and heated to 155° C. for 5 hours. The product was then purified by MPLC. LC-MS (IE, m/z): 286 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1.CCOC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(CO)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(CO)c1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a chilled suspension of 3-aminobenzyl alcohol (9.24 g, 75 mmol) in THF (50 mL) was added neat acetic anhydride (8.1 mL, 86 mmol). The reaction mixture was stirred cold for 1 hr, diluted with EtOAc, washed with aq. NaOH and brine, and concentrated in vacuo to give N-[3-(hydroxymethyl)phenyl]acetamide (10.5 g, 85%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[CH2:36][C:37](=O)[CH2:38][CH3:39])=[CH:31][CH:30]=1>>[CH2:38](/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35]([C:32]1[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=1)=[O:41])[CH3:39]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 49 mg (0.27 mmol) of Intermediate 32 to yield 83 mg of Example 35: TLC (EtOAc/MeOH (7:3): Rf=0.28; 1H NMR (DMSO-d6, 400 MHz) δ11.38 (d, 1H, J=7.00), 7.84 (m. 4H), 7.45 (m, 3H), 7.16 (t, 2H, J=8.72), 7.09 (d, 2H, J=7.69), 6.77 (d, 2H, J=7.69), 5.49 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (s, br, 1H), 2.30 (s, 3H), 1.62 (s, 3H); low resolution MS (ES+) m/e 529 (MH+); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 30-100% CH3CN in H2O) with 0.1% HCO2H buffer: 30 minutes; 1 mL/min: tr=20.10 min (to=1.53).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])SC1C=CC=CN=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23].C(Br)C(C)C.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12](=[O:20])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)Sc1ccccn1)C(=O)OC(C)(C)C
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CC(C)CBr
Solvent: C1CCOC1
Product: CC(C)CC(=O)CCN(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of S-2-pyridyl 3-(N-t-butoxycarbonyl-N-methylamino)propanethioate (490 mg) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added dropwise a solution of isobutylmagnesium bromide prepared from isobutyl bromide (1.13 g) and magnesium (200 mg) in dry tetrahydrofuran (30 ml), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride (50 ml). The resulting slurry was extracted with diethyl ether (50 ml×2), and the combined extract was dried over magnesium sulfate and concentrated to give 1-(N-t-butoxycarbonyl-N-methylamino)-3-oxo-5-methyl-hexane (400 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:9]2)=[CH:4][CH:3]=1.C([O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([CH2:35]Br)[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])C>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:33]4[CH:32]=[CH:31][C:30]([O:37][CH3:38])=[C:29]([CH:34]=4)[C:28]([OH:39])=[O:27])[CH2:23][CH2:24]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccc(Cl)s1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc2c(c1)c(C1CCN(Cc3ccc(OC)c(C(=O)O)c3)CC1)cn2Cc1ccc(Cl)s1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.13 mmol) 1-(5-chloro-thiophen-2-ylmethyl)-5-methoxy-3-piperidin-4-yl-1H-indole and 0.05 g (0.18 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column, and 0.002 g (99% of purity) of the expected acid were isolated.
Reaction SMILES: CN(C)[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[O:16]1CCCC1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH2:4][C:3]([S:7][C:6]=2[CH:8]=1)=[O:16]
Reactant: C1CCOC1
Reactant: COc1ccc2cc(N(C)C)sc2c1
Agent: Cl
Product: COc1ccc2c(c1)SC(=O)C2
Yield: 80 %

Procedure:
To tetrahydrofuran (200 mL) containing 2-dimethylamino-6-methoxybenzo-[b]-thiophene (cf. U.S. Pat. No. 5,420,349)(20.00 g, 96.5 mmol) was added 1N aqueous HCl (200 mL) and the resulting mixture was heated to reflux for 3 h. The mixture was cooled, the layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers washed with water (250 mL), dried (MgSO4), filtered and concentrated to give crude product, which was recrystallized from 3A-ethanol, and dried in vacuo at room temperature to afford the title compound (13.89 g, 77.0 mmol, 80%): mp 80-82° C.; IR (KBr) 1713, 1605, 1485, 1287, 1015, 865, 813 cm-1 ; 1H NMR (DMSO-d6) δ 7.22 (d, 1 H, J=8.4 Hz), 7.11 (s, 1 H), 6.78 (d, 1 H, J=8.4 Hz), 4.06 (s, 2 H), 3.71 (s, 3 H); 13C NMR (DMSO-d6) δ 203.5, 159.0, 136.9, 125.6, 124.6, 112.3, 108.4, 55.3, 46.2. Anal. Calcd. for C9H8O2S: C, 59.98; H, 4.47; S, 17.78. Found: C, 60.19; H, 4.57; S, 18.03.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>C(OCC)(=O)C>[CH3:18][O:10][C:9](=[O:11])[C@H:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:13][CH:12]=1)[NH2:8]
Reactant: CO
Reactant: Nc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(N)cc1
Yield: 88.5 %

Procedure:
To a stirred solution of p-aminophenylalanine (2.05 g, 9.9 mmol) in methanol (100ml) at 0° C. was added thionyl chloride (20ml) dropwise. Upon complete addition the reaction mixture was heated under reflux. After 24 hours the reaction mixture was cooled and reduced under pressure to give a brown oil. The brown oil was taken up in ethyl acetate (200 ml) and washed with saturated sodium bicarbonate solution (200 ml). The aqueous layer was further extracted with ethyl acetate (5×200 ml) . The combined organic layer was dried over MgSO4 and reduced under pressure to yield the title compound as a brown solid (1.7 g, 88.5%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[N:32](C(=O)C)[C:31]3[CH:36]=[CH:37][C:38](Br)=[CH:39][C:30]=3[N:29]=2)=[N:20]1)(=O)C>O1CCCC1.C(OCC)(=O)C>[C:7]1([C:37]2[CH:38]=[CH:39][C:30]3[N:29]=[C:28]([C:21]4[NH:20][N:19]=[C:27]5[C:22]=4[CH:23]=[CH:24][CH:25]=[CH:26]5)[NH:32][C:31]=3[CH:36]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)n1nc(-c2nc3cc(Br)ccc3n2C(C)=O)c2ccccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3nc(-c4[nH]nc5ccccc45)[nH]c3c2)cc1
Temperature: 25 °C
Yield: 122.9 %

Procedure:
40 mg of sodium carbonate, 7 mg of dihydrogendichlorobis(di-tert-butylphosphonite-κP)palladate(2-) (POPd[0]) and 46 mg of phenylboronic acid are added under an argon atmosphere to a solution of 50 mg of 1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone in 800 μl of anhydrous tetrahydrofuran. The reaction mixture is brought to reflux for 3 hours and then cooled to ambient temperature. The mixture is then diluted with 3 ml of ethyl acetate and then washed with 2 times 2 ml of water. The organic phase is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. 48 mg of a brown solid are obtained, which solid is dissolved in 500 μl of tetrahydrofuran, to which 500 μl of diethylamine are added. The reaction mixture is heated at 60° C. for 4 hours and then allowed to return to ambient temperature. The mixture is then concentrated to dryness and then the brown solid obtained is purified by LC-MS to produce 12.5 mg of 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole (6); analytical retention time 3.10, MS 311 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:13][C:14]1([F:58])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([OH:30])[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=3[N:23]=[C:22]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:44]=[CH:43][C:42]([OH:45])=[CH:41][N:40]=4)[CH2:35][CH2:34]3)[C:21]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:16][CH2:15]1>>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][O:45][C:42]1[CH:41]=[N:40][C:39]([N:36]2[CH2:35][CH2:34][CH:33]([C:22]3[C:21]([CH:46]([F:57])[C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:54])([F:55])[F:56])=[CH:49][CH:48]=4)=[C:20]([CH:17]4[CH2:18][CH2:19][C:14]([F:13])([F:58])[CH2:15][CH2:16]4)[C:29]4[CH:28]([OH:30])[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=4[N:23]=3)[CH2:38][CH2:37]2)=[N:44][CH:43]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCO[Si](C)(C)C(C)(C)C)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Example 13 were performed except for using (3-bromopropoxy) (tert-butyl)dimethylsilane instead of ethyl iodide, and from 61 mg (94 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 71 mg (87 μmol) of 2-{1-[5-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was obtained.