Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[H-].[Na+].[Si:17]([O:24][CH2:25][C@H:26]1[CH2:37][CH2:36][C:35]2[S:34][C:33]3[C:28](=[C:29](Cl)[N:30]=[CH:31][N:32]=3)[C:27]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1>[Si:17]([O:24][CH2:25][C@H:26]1[CH2:37][CH2:36][C:35]2[S:34][C:33]3[C:28](=[C:29]([O:14][CH:11]4[CH2:10][CH2:9][CH:8]([N:6]5[CH2:7][C:4]6([CH2:1][O:2][CH2:3]6)[CH2:5]5)[CH2:13][CH2:12]4)[N:30]=[CH:31][N:32]=3)[C:27]1=2)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: OC1CCC(N2CC3(COC3)C2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexan-1-ol (250 mg, 1.27 mmol, 1.19 equiv) in 15 mL of freshly distilled THF was added sodium hydride (60% dispersion in mineral oil, 169.9 mg, 4.25 mmol, 4.00 equiv) in portions at 0° C. under nitrogen. The resulting solution was stirred for 0.5 h at this temperature. Then (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (377 mg, 1.06 mmol, 1.00 equiv) was added and the resulting solution was allowed to react, with stirring, for an additional 2 h at ambient temperature. After completion of the reaction, the reaction mixture was quenched by the addition of 20 mL of saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate to give the desired (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (0.5 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:42]1([CH:48]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:49][CH2:50][O:51][NH2:52])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:52][O:51][CH2:50][CH2:49][CH:48]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NOCCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCCC(c1ccccc1)c1ccccc1
Yield: 26.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (85 mg, 0.15 mmol) and 3,3-diphenylpropoxyamine hydrochloride (48 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (29 mg). 7.75 (s, 1H), 7.33 (d, J=9.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.71 (s, 2H), 4.39 (dd, 1H), 4.25 (m, 1H), 4.11 (t, J=8.0 Hz, 1H), 3.57 (m, 2H), 3.01 (m, 2H), 2.93 (m, 1H), 2.75 (m, 1H), 2.24 (m, 2H), 1.35 (s, 9H); IR (KBr) 3274, 2978, 1684 1651 cm−1; HRMS m/z 739.3126 (calc. of monoisotopic mass for C41H45N3O10 gives 739.3105).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].N1C2C(=CC=CC=2)C=C1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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.COCCOC.C(O)C.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[Si:27]([CH:28]([CH3:29])[CH3:30])([CH:34]([CH3:35])[CH3:36])[CH:31]([CH3:32])[CH3:33])[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[CH:7]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(-c3cccnc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Temperature: 100 °C
Yield: 46 %

Procedure:
To a 30 mL vial equipped with stir-bar was added 0.400 g (0.71 mmol) 4-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole followed by 0.096 g (0.78 mmol) 3-pyridinyl boronic acid, 3 mL toluene, 3 mL ethanol, 0.71 mL 2 M aqueous sodium carbonate and 0.011 g (0.035 mmol) tetra n-butylammonium bromide. The starting indole did not dissolve, so 3 mL DME (ethylene glycol dimethyl ether) were added. The reaction mixture was degassed for 30 min by bubbling nitrogen into the mixture. Pd(PPh3)4 (0.018 g, 0.022 mmol) was added and the reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled and filtered through Celite®, washing with ethyl acetate. The solvent was removed and the crude product was purified by preparative TLC (eluent: 30:70 ethyl acetate:hexane) to give 0.184 g of 4-[3-(4-methoxy-benzyloxy)-5-pyridin-3-yl-phenyl]-1-triisopropylsilanyl-1H-indole. This compound was deprotected as described in Example 34. 1H NMR (400 MHz, CDCl3): δ 10.07 (d, J=2.1 Hz, 1H), 9.74 (dd, J=4.9, 1.3 Hz, 1H), 9.30 (dt, J=4.9, 2.6 Hz, 1H), 8.70 (q, J=4.3 Hz, 1H), 8.65-8.61 (m, 2H), 8.53 (d, J=3.3 Hz, 1H), 8.45-8.36 (m, 3H), 8.29 (t, J=1.9 Hz, 1H), 7.89 (d, J=3.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:36]1[CH2:41][CH2:40]OCC1>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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:10]1[CH:9]=[CH:14][CH:13]=[C:40]([CH:41]=[O:36])[CH:11]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C=O)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-formalphenylboronic acid (82.5 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-formyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:3]=2)[CH2:9][CH:10]1[CH3:13]
Reactant: N#Cc1cccc(CO)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 3-(hydroxylmethyl)benzonitrile.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:21][CH:22]([O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a solution of 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (930 mg, 2.50 mmol) (obtained as described in Reference Example 35(4)) in methylene chloride (47 ml) were added methanesulfonyl chloride (480 μl, 6.20 mmol) (obtained as described in Reference Example 35(4)) and triethylamine (869 μl, 6.20 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.16 g, yield 100%) as a pale yellow oil.
Reaction SMILES: [BrH:1].C(OC([NH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)=[O:19])=O)C1C=CC=CC=1>C(O)(=O)C>[BrH:1].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)=[O:19]
Reactant: O=C(Nc1ccc(O)c(C(=O)Nc2nnn[nH]2)c1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(O)c(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic acid (100 ml) was saturated with hydrogen bromide at 10° C. and the mixture was treated with 5-benzyloxycarbonylamino-2-hydroxy-N-(tetrazol-5-yl)benzamide (1.77 g). The mixture was stirred at 25° C. for 20 hours, and then most of the hydrogen bromide was removed by passing a stream of air through the mixture for 6 hours. Any finely divided suspended solid was then removed by centrifuging and the supernatant liquid was decanted off. Removal of the acetic acid in vacuo gave a solid, which was triturated with diethyl ether and dried to give 5-amino-2-hydroxy-N-(tetrazol-5-yl)benzamide hydrobromide (1.0 g), m.p. above 330° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[N:7]([CH3:13])[C:6]=2[CH:14]=1.[O:15]=[C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][NH:17]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH:10]1([C:8]2[N:7]([CH3:13])[C:6]3[CH:14]=[C:2]([N:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]4=[O:15])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1cc[nH]c(=O)c1
Reactant: Cn1c(C2CC2)nc2ccc(Br)cc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccn(-c2ccc3nc(C4CC4)n(C)c3c2)c(=O)c1
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a mixture of 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (984 mg), methyl 2-oxo-1,2-dihydropyridine-4-carboxylate (600 mg), potassium carbonate (1.08 g) and dioxane (25 ml) were added CuI (298 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (223 mg), and the mixture was heated at 80° C. for 12 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to give the title compound (800 mg) as a white solid.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.[Br:33]C1C2SC(I)=NC=2C=CC=1>>[Br:33][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2nc(I)sc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(Br)c2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 7-bromo-2-iodo-1,3-benzothiazole and conducting the Suzuki coupling at 60° C. for 4 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.20-9.09 (brm, 1H), 9.02-8.90 (brm, 1H), 8.61 (very brs, 1H), 8.60 (s, 2H), 8.52 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 4.57-4.47 (mc, 1H), 3.40 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.2 Hz, 2H), 2.31-2.12 (m, 4H). MS(ES+): m/z=454.98/457.00 (79/83) [MH+], 371.94/373.95 (95/100) [MH+-piperidine]. HPLC: tR=2.22 min (polar—5 min, ZQ2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:19]([CH:16]1[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:17]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(C(=O)N1CCC(Oc2ccccc2)CC1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1

Procedure:
By following the manipulative procedure described in Example 4(c), 5.0 g of 1-(indol-3-ylglyoxyloyl)-4-phenoxypiperidine are reacted with 2.8 g of lithium aluminum hydride to give white flakes of 3-[2-(4-phenoxypiperidyl)ethyl]indole, m.p. 123°-125° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:35])([F:34])[C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([C:28]5([C:27]([F:35])([F:34])[F:26])[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(C(F)(F)F)CC1

Procedure:
The title compound, white solid (10 mg, 31.5%), MS (ISP) m/z=467.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[CH3:15][C:12]1[N:13]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=1
Reactant: Clc1ncccn1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2cn(-c3ncccn3)c(C)n2)ccn1

Procedure:
2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (87 mg, 0.44 mmol) dissolved in 3 mL dimethyl formamide. Potassium carbonate (122 mg, 0.88 mmol) and 2-chloro-pyrimidine (76 mg, 0.66 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was poured into 60 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was treated with ethyl acetate (2 mL) and diisopropyl ether (2 mL). The solid was filtered off and washed with little diisoppropyl ether. The desired compound was as an off-white solid (49 mg, 50%), mp=164–165° C., MS: m/e=276.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:3]=1[CH3:20].C=O.Cl.[CH3:24]NC>O1CCOCC1>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:14](=[O:19])[C:15](=[CH2:24])[CH2:16][CH2:17][CH3:18])[C:3]=1[CH3:20]
Reactant: CCCCC(=O)c1cc2oc(C(=O)O)cc2c(C)c1C
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: C=C(CCC)C(=O)c1cc2oc(C(=O)O)cc2c(C)c1C

Procedure:
A mixture of 4,5-dimethyl-6-valerylbenzofuran-2-carboxylic acid (15 g.) paraformaldehyde (3.5 g.) and dimethylamine hydrochloride (7 g.) in p-dioxane (100 ml.) is refluxed for 8 hours and cooled. The 4,5-dimethyl-6-[(2-dimethylaminomethyl)valeryl]benzofuran-2-carboxylic acid hydrochloride which separates is filtered, dried, and dissolved in acetic acid (200 ml.) containing sodium acetate (20 g.). The reaction mixture is refluxed for two hours then poured into water (250 ml.) containing hydrochloric acid (25 ml.) affording 4,5 -dimethyl-6-(2-methylenevaleryl)-benzofuran-2-carboxylic acid which melts at 172° after recrystallization from butyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][C:16]=3[F:25])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[C:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=3)[CH2:13][CH2:12]2)=[C:16]([F:25])[CH:17]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
9.0 g of 1-(4-chlorobenzoyl)-4-[2-fluoro-4-methoxycarbonylbenzylidene]piperidine in 150 ml of methanol are treated with a solution of 4.0 g of 84% caustic potash in 100 ml of water and the mixture is stirred overnight at ambient temperature. The methanol is evaporated off, the residue is mixed water with cooling and the mixture is acidified with dilute hydrochloric acid. The precipitate is suction-filtered, washed with water and dried in vacuo. 8.6 g (95% of theory) of 4-(4-carboxy-2-fluorobenzylidene)-1-(4-chlorobenzoyl)piperidine of melting point 170°-173° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]=1Br)[CH2:9][CH2:8][C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[C:5]2=[O:17].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH:3]1[CH:2]=[CH:11][N:10]2[CH2:9][CH2:8][C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=3[C:5](=[O:17])[C:4]=12
Reactant: [H][H]
Reactant: O=C1c2ccccc2CCn2c1cc(Br)c2Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2CCn2cccc21

Procedure:
A suspension of 25 g. (0.070 mole) of 2,3-dibromo-6,11-dihydro-5 H-pyrrolo[2,1-b][3]benzazepin-11-one in 200 ml. ethanol containing 25 ml. of triethylamine and 1 gm. of 10% Pd on charcoal was hydrogenated under 3 atmospheres of hydrogen to yield 6,11-dihydro-5H-pyrrolo-[2,1-b][3]benzazepin-11-one, m.p. 54°-55° C. after removal of catalyst, recrystallization from petroleum ether and drying under vacuum. The same compound is also obtained by hydrogenolysis of the 2,3-dichloro ketone and the 1,2,3-tribromoketone.
Reaction SMILES: ClC1N(CC2C=CC=CC=2C#N)C(=O)NC(=O)C=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[N:31]([CH2:32][C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[C:35]#[N:36])[C:30](=[O:41])[N:29](C)[C:28](=[O:43])[CH:27]=2)[CH2:21]1>>[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[N:31]([CH2:32][C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[C:35]#[N:36])[C:30](=[O:41])[NH:29][C:28](=[O:43])[CH:27]=2)[CH2:21]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Agent: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)[nH]c1=O

Procedure:
The title compound 6 was prepared from compound 2 by the procedure used in the preparation of compound 4. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.65 (d, J=7.5 Hz, 1 H), 7.58 (t, J=7.8 Hz, 1 H), 7.39 (t, J=7.5 Hz, 1 H), 7.27 (d, J=7.8 Hz, 1 H), 5.32 (s, 1 H), 5.13-5.13 (ABq, 2H, J=30.0, 15.0 Hz), 3.39 (m, 2 H), 2.95 (m, 2 H), 2.69 (m, 1 H), 2.12 (m, 1 H), 1.85 (m, 1 H), 1.64 (m, 2 H). MS (ES) [m+H] calc'd for C17H20N5O2, 326.2; found, 326.2.