Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH3:11].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C[O-].[Na+].Cl>CO.O.CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:11])[C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (5.00 g), methyl bromoacetate (3.13 mL) and N,N-dimethylformamide (50 mL) was added potassium carbonate (12.5 g), and the mixture was stirred overnight at room temperature. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a brown oil. To a solution (50 mL) of the obtained oil in methanol was added sodium methoxide (1.63 g), and the mixture was stirred with heating under reflux for 3 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.25 g, 19%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[N:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]([CH2:31][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 10 min. After addition of 1-(bromomethyl)naphthalene (1.511 g, 6.83 mmol), the mixture was warmed to 80° C. and stirred for 3 h at this temperature. The resulting mixture was cooled to rt and poured over ice. The precipitate formed was collected by filtration and air dried (2.4 g total). The crude material was purified on silica gel (ISCO, 0-5% MeOH in DCM) to give methyl 6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate (1.48 g, 3.15 mmol, 69.2% yield). A portion of this material (138 mg) was purified by reverse phase-HPLC (25 to 95% AcCN in water, plus 0.1% TFA) to give the desired product (93.4 mg, 0.195 mmol, 4.28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J=8.34 Hz, 1H), 8.01 (d, J=7.33 Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.60-7.73 (m, 3H), 7.39 (d, J=2.27 Hz, 1H), 7.31 (t, J=7.83 Hz, 1H), 6.24 (br. s., 1H), 6.22 (s, 2H), 3.95 (s, 3H), 3.64-3.73 (m, 4H), 3.06-3.19 (m, 4H). MS(ES+) m/e 470 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:35]=[CH:36][C:29]=12.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][O:18][C:28]3[N:33]=[CH:32][N:31]=[C:30]4[N:34]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][O:38]5)[N:35]=[CH:36][C:29]=34)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: OCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OC(COc1ncnc2c1cnn2C1CCCCO1)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A toluene solution (30 mL) of 3-[4-[bis(4-fluorophenyl) methyl]-1-piperazinyl]-1,2-propanediol (3.98 g, 11 mmol) was added dropwise to a stirred mixture of 4-chloro-1-(tetrahydropyran-2-yl)-pyrazolo[3,4-d]pyrimidine (2.387 g, 10 mmol), powdered KOH (0.485 g, 8.51 mmol), 18-crown-6 (3, 90.2 mg, 0.34 mmol) in toluene (70 mL) over a 20 min period. The mixture was stirred at room temperature for 3 h and washed with water (3×70 mL). The organic layer was dried (Na2SO4), filtered and evaporated to dryness. The oily residue (7.0 g) was purified on a medium pressure silica gel column eluting with increasing proportions of methanol in methylene chloride. The title compound was obtained as the major product (1.49 g, 41%), mp 101°-105° C. IR (KBr) cm-1 : 2466, 2446, 2401, 1603, 1568, 1506, 1347, 1222. 1H NMR (CDCl3) δ: 8.35 (s, 1H, 3 or 6-H), 8.12 (s, 1H, 3 or 6-H), 6.9-7.4 (m, 8H, Ar--H), 5.0 (m, 1H, N--O--CH--C), 4.6 (m, 2H, OCH2), 4.23 [s, 1H, CH(O)2 ], 4.15 (m, 2H, HCOH, O--CHN), 3.8 (m, 1H, OCNH), 1.6-2.9 (m, 16H, CH2, NCH2 ; MS(DCI): 565 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][N:6]2[C:9](=[O:20])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1.[O-:21]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+]>O>[CH3:1][CH:2]1[CH2:8][CH2:7][N:6]2[C:9](=[O:20])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:21])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O

Procedure:
To compound 14 (4.0 g, 13.9 mmol), potassium peroxodisulfate (11.3 g, 41.6 mmol) and CuSO4.5H2O, 250 ml of acetinitrile/water 1:1 were added. The reaction mixture was heated to reflux for 30 minutes. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with 10% sodium thiosulfate and brine, and dried over Na2SO4. After filtration the solvent w as evaporated and the product purified by flash chromatography using CH2Cl2/EtOAc 9:1 as an eluent.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][C:8]3[C:12]4[NH:13][C:14]([C:21]([O:23]C)=[O:22])=[CH:15][C:16](=[O:20])[C:17]=4[CH:18]=[CH:19][C:7]=3[C:6]=2[NH:5][C:4]([C:25]([O:27]C)=[O:26])=[CH:3]1.[OH-].[Na+:30]>O.CO>[O:20]=[C:16]1[C:17]2[CH:18]=[CH:19][C:7]3[C:6]4[NH:5][C:4]([C:25]([O-:27])=[O:26])=[CH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][C:8]=3[C:12]=2[NH:13][C:14]([C:21]([O-:23])=[O:22])=[CH:15]1.[Na+:30].[Na+:30]
Reactant: COC(=O)c1cc(=O)c2ccc3c(ccc4c(=O)cc(C(=O)OC)[nH]c43)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc(=O)c2ccc3c(ccc4c(=O)cc(C(=O)[O-])[nH]c43)c2[nH]1

Procedure:
1.0 gram of the diester prepared in Example 1 is heated in 50 ml. of 1.0N NaOH for 30 minutes. The mixture is cooled, diluted with water, and methanol added. The precipitate is filtered and collected.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CC([O-])(C)C.[K+].[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20].S(=O)(=O)(O)O>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:17]([O:18][CH2:19][CH3:20])=[O:21])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
200 g (1.29 mol) of 4-chloroacetophenone (dissolved in 500 ml of diethyl carbonate) were added dropwise at 60° C. to a mixture of 296.4 g (2.59 mol) of potassium tert-butylate and 2.25 1 of diethyl carbonate. Thesuspension, which could be stirred with difficulty, was stirred at 60° C. for 3 h and then introduced into 2.7 1 of 10% strength sulfuric acid. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and concentration in vacuo gave the crude product, which was purified further by distillation (b.p. 130° C., 0.4 mbar). Yield: 268 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9][C:8]=2[CH:33]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9][C:8]=2[CH:33]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCc1cc([N+](=O)[O-])ccc1-2
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCc1cc(N)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
To the solution of 8-nitro-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide (80 mg, 0.18 mmol) in ethanol (20 mL) was added 10% w/w Pd/C (20 mg), the reaction was stirred at RT under H2 for about 3 hr. Filtered and washed with CH3OH (20 mL), the filtrate was concentrated under reduced pressure, the residue was purified by Pre-TLC (DCM/CH3OH=20/1) to afford the product as a white solid (20 mg, 26.8%). 1H NMR (400 MHz, DMSO-d6) δ 7.73-7.69 (m, 1H), 7.59-7.55 (m, 2H), 7.45-7.40 (m, 3H), 7.21-7.16 (m, 1H), 7.13-7.07 (m, 4H), 6.59-6.54 (m, 1H), 6.50-6.47 (m, 1H), 5.70-5.40 (br s, 2H), 3.64-3.59 (m, 2H), 2.99-2.94 (m, 2H). MS (ESI) m/e [M+1]+ 412.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Temperature: 0 °C

Procedure:
3-(4-Methoxyphenylsulfonyl)-2-phenylbenzofuran (1.9 g.) was combined with 12 g. of freshly distilled pyridine hydrochloride and heated at 210° for 3.5 hours. The hot mixture was poured onto an ice-dilute hydrochloric acid mixture and the precipitate formed was collected by filtration and dissolved in chloroform. The chloroform solution was extracted three times with water and then with a saturated sodium chloride solution, refluxed with decolorizing charcoal, filtered and dried (MgSO4). Evaporation of the solvent gave 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran, m.p. 166°-168°.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH2:29][CH3:30])=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH2:29][CH3:30])=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCOC4(CNC(=O)OC(C)(C)C)C3)c(F)c21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCOC4(CN)C3)c(F)c21

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 218°-223° C. (with decomposition).
Reaction SMILES: C(O)(=O)C.Cl.O.O.[Sn](Cl)(Cl)(Cl)Cl.[F:13][C:14]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:17]([C:18]#[N:19])=[C:16]([CH3:25])[CH:15]=1.[OH-].[Na+]>CO>[NH2:22][C:20]1[CH:21]=[C:14]([F:13])[CH:15]=[C:16]([CH3:25])[C:17]=1[C:18]#[N:19]
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1C#N
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(F)cc(N)c1C#N
Reaction time: 1 h
Yield: 104.9 %

Procedure:
Acetic acid (16.0 ml, 28 mmol) was added to a concentrated hydrochloric acid (90 ml) solution of tin chloride dihydrate (63.1 g, 280 mmol), and 4-fluoro-2-methyl-6-nitrobenzonitrile (I-263) (16.8 g, 93.3 mmol) was added, then methanol (8 ml) was added. Since the reaction liquid greatly generated heat, it was cooled with ice. After stirring for 1 hour, the reaction mixture liquid was poured into aqueous sodium hydroxide solution (4.6 M, 500 ml) with ice therein. The precipitated solid was collected by filtration, washed with water, then dried to obtain the entitled compound (14.7 g, 99%) as a gray solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O-]CC.[Na+].C1(O)C=CC=CC=1.[Cl:15][C:16]1[N:25]=[C:24](Cl)[C:23]2[C:18](=[C:19]([O:30][CH3:31])[C:20]([O:28][CH3:29])=[C:21]([Cl:27])[CH:22]=2)[N:17]=1>>[Cl:15][C:16]1[N:25]=[C:24]([O:3][CH2:1][CH3:2])[C:23]2[C:18](=[C:19]([O:30][CH3:31])[C:20]([O:28][CH3:29])=[C:21]([Cl:27])[CH:22]=2)[N:17]=1
Reactant: COc1c(Cl)cc2c(Cl)nc(Cl)nc2c1OC
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: CCOc1nc(Cl)nc2c(OC)c(OC)c(Cl)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 5 liters of ethanol containing 0.2 mole of sodium ethoxide is added slowly with stirring 0.1 mole each of phenol and 2,4,6-trichloro-7,8-dimethoxyquinazoline. The mixture is heated to boiling then allowed to stand at room temperature overnight, poured into ice-water, stirred 15 minutes and the precipitate collected by filtration. The cake is washed with water, then cold ethanol, dried and recrystallized from ethanol/hexane to obtain 2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[CH:12]([CH3:15])[O:11][C:10]([CH3:17])([CH3:16])[C:9]2=[O:18])=[C:4]([CH2:19][CH3:20])[CH:3]=1.[F-].[Cs+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:19]([C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[CH:8]1[C:13](=[O:14])[CH:12]([CH3:15])[O:11][C:10]([CH3:17])([CH3:16])[C:9]1=[O:18])[CH3:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
To a mixture of 4-(4-bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione (0.5 g, 1.48 mmol), cesium fluoride (0.70 g, 4.4 mmol), 4-fluorophenylboronic acid (0.31 g, 2.23 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.19 g, 0.23 mmol) is added degassed dimethoxyethane (15 ml) and the resulting suspension is stirred under nitrogen for 45 minutes then heated at 80° C. for 24 hours. After cooling to room temperature the reaction mixture is acidified with 1N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×25 ml) and then all organic fractions are combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to afford 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethylpyran-3,5-dione (0.27 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:27]1([C:30]([N:15]2[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]2)=[O:31])[CH2:29][CH2:28]1
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(C1CCN(C(=O)C2CC2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (250 mg, 0.841 mmol) was dissolved in dichloromethane (5.0 mL). To this, triethylamine (0.176 mL, 1.26 mmol) and cyclopropanecarbonyl chloride (0.114 mL, 1.26 mmol) were added at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-cyclopropanecarbonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (259 mg, yield: 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)[CH:3]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+]>O1CCOCC1>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:17]([OH:21])[OH:18])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CN(C)C1CCN(c2cc(Br)ccn2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2cc(B(O)O)ccn2)CC1
Yield: 125.9 %

Procedure:
In a Schlenck vessel 1-(4-bromopyridin-2-yl)-N,N-dimethylpiperidin-4-amine (1.55 g, 5.45 mmol) was treated with bis(pinacolato)diboron (1.65 g, 6.50 mmol), potassium acetate (1.6 g, 16.3 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.22 mg, 0.24 mmol) and dioxane (20 ml) as a solvent according to the method described in Preparation 174a to give 1.71 g (85% yield) of the title compound that was used in the next synthetic step without further purification. Purity 90%.
Reaction SMILES: [H-].[Na+].CS([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9](O)[CH2:8]1)(=O)=O.C1(O)C=CC=CC=1>CN(C)C=O>[C:13]([N:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 80 °C

Procedure:
Sodium hydride (Aldrich, 2 g, 50 mmol) was added to a solution of 4-(methylsulfonyl)hydroxy-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester of Example 14, B (10 g, 25 mmol) and the phenol from part 2 (5.5 g, 50 mmol) dissolved in dimethylformamide (60 mL) at 25° C. and under N2. The mixture was stirred and heated to 80° C. for 16 hours. After this time, the solvent was removed by roto-evaporation, followed by taking the residue up in ethyl acetate (150 mL) and H2O (100 mL). The layers were separated and the aqueous was extracted via ethyl acetate (2×-150 mL). The organics were washed with saturated K2CO3 (2×-100 mL), H2O (1×-150 mL), and brine (1×-150 mL), then dried over Na2SO4, filtered, and concentrated to afford a crude oil. The oil was purified on silica gel to give log of the N-boc piperidine as a clear oil. 1H NMR and mass spectroscopy was consistent with the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH2:7]([Mg]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:7]([C:2]1[CH2:3][CH2:4][CH2:5][N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCCCBr
Reactant: Br[Mg]Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(CC2=NCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.6 %

Procedure:
To a solution of 4-bromobutyronitrile (2.0 g, 13.5 mmol) in toluene (70 ml) was added 1.0 M benzylmagnesium bromide (20.0 ml, 20.0 mmol) in diethyl ether (70 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was partitioned between 0.1N hydrochloric acid and ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford 5-benzyl-3,4-dihydro-2H-pyrrole (2.85 g). This compound was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([O:25]CC)=[O:24])[C:13]1=[CH:12]2)[CH3:2].[Li+].[OH-].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][CH:21]([CH2:22][C:23]([OH:25])=[O:24])[C:13]1=[CH:12]2)[CH3:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OCC)c(OCC)c3)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1OCC
Temperature: 23 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of ethyl 2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.100 g, 0.221 mmol) in 1,4-dioxane (4 mL) was added 1.0 M LiOH (aq) (1.107 mL, 1.107 mmol). The reaction was stirred at 23° C. for 16 h in a 20 mL sealed scintillation vial. The mixture was poured into 1 M HCl and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over MgSO4, and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure to give the title compound (0.0831 g) as a tan solid. LCMS m/z=424.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.36 (m, 6H), 1.49 (d, J=11.37 Hz, 1H), 1.87-1.95 (m, 1H), 1.99-2.07 (m, 1H), 2.07-2.16 (m, 1H), 2.40-2.49 (m, 1H), 2.77-2.87 (m, 1H), 3.24-3.35 (m, 1H), 3.73-3.84 (m, 1H), 3.96-4.06 (m, 4H), 4.07-4.16 (m, 1H), 4.96 (s, 2H), 6.14 (s, 1H), 6.76 (dd, J=8.78, 2.34 Hz, 1H), 6.88-6.96 (m, 2H), 7.01-7.07 (m, 2H), 7.21 (d, J=8.84 Hz, 1H), 12.27 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:39]3[CH2:44][CH2:43][N:42]([S:45]([CH3:48])(=[O:47])=[O:46])[C@@H:41]([CH3:49])[CH2:40]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](C)(C)[O:31][SiH2]C(C)(C)C)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:50])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:39]3[CH2:44][CH2:43][N:42]([S:45]([CH3:48])(=[O:47])=[O:46])[C@@H:41]([CH3:49])[CH2:40]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=1
Reactant: C[C@H]1CN(c2cc(-c3ccccc3C(C)(C)O[SiH2]C(C)(C)C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CCN1S(C)(=O)=O
Agent: Cl
Solvent: CO
Product: C[C@H]1CN(c2cc(-c3ccccc3CO)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CCN1S(C)(=O)=O

Procedure:
A solution of 73 mg (0.093 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml of a 1 M solution of hydrochloric acid in methanol was stirred at room temperature. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with a 1 M aqueous solution of sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 62 mg (quantitative) of the title compound as a light yellow solid.