Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccccc1
Yield: 81.1 %

Procedure:
A mixture of intermediate (9) (0.1 mole) in methanol (500 ml) was hydrogenated for two hours with palladium-on-carbon (10%) (10 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in 2-propanol. The precipitate was filtered off and dried, yielding 29 g of N-[4-(1-piperazinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 10, melting point 176° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:30](=[O:31])[C:29]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=1
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) and using a gradient of n-heptane:EtOAc (100:0 to 0:80) for the chromatographic purification. Colorless solid (30%). MS (ESI): m/z=559.096 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: Cc1cccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.02 (s, 1H), 12.91 (s, 1H), 8.98 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.78 (d, J=6.3 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.24 (d, J=7.0 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:11][C:12]([F:18])([F:17])[C:13]1([NH2:16])[CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:13]2([C:12]([F:18])([F:17])[F:11])[CH2:15][CH2:14]2)=[O:10])=[N:6][CH:7]=1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(F)(F)F)CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol), 1-(trifluoromethyl)cyclopropanamine (93 mg, 0.74 mmol) (Oakwood, Cat. #: 038175), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (345 mg, 0.780 mmol) and triethylamine (310 μL, 2.2 mmol) in methylene chloride (1 mL) was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (124 mg). LCMS (M+H)+: m/z=309.0.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Sc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 2.76 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 1 g of p-(bromomethyl)benzoic acid followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of water, made acidic with diluted hydrochloric acid and, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (1:1) gave 400 mg of p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[Cl:10][CH2:11][S:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: Nc1ccc(F)cc1Cl
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCl)Nc1ccc(F)cc1Cl
Temperature: 7.5 °C
Yield: 75 %

Procedure:
72.8 g (0.5 mol) of 2-chloro-4-fluoroaniline were dissolved in 400 mL of toluene and cooled to 5-10° C., and then 79 g (0.53 mol) of chloromethylsulfonyl chloride were added slowly with stirring. The temperature was kept below 10-15° C. The mixture was then heated to 40° C. for 30 minutes and cooled again to 5-10° C. At this temperature, 101 g (1 mol) of triethylamine was added with stirring and cooling. After the addition was complete, the mixture was stirred at 40° C. for an additional 8 hours and then poured into 1050 mL of 6 N hydrochloric acid. The organic phase was separated and the aqueous phase was washed with toluene. The combined organic phases were poured with vigorous stirring into 12.5% sodium hydroxide solution. The basic aqueous phase was separated and the organic phase was washed with aqueous sodium hydroxide solution. The combined aqueous phases were treated with active carbon and filtered. 6 N hydrochloric acid was added with cooling until the pH was below 7. The precipitated product was filtered off, washed with water and dried to yield 96.8 g (75%) of the title compound as a solid melting at 83-85° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1 g, 4.02 mmol) in N,N-dimethylacetamide (13.4 mL) was added 2-fluoroaniline (1.551 mL, 16.08 mmol) dropwise over 1 minute at room temperature. The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (38 mL) was added to the reside, and the mixture was concentrated to give ethyl 3-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: N[C:2]([NH2:4])=[NH:3].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([C:20](Cl)=[N:21][OH:22])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7]>C(O)C>[NH2:4][C:2]1[O:22][N:21]=[C:20]([C:11]2[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]([OH:15])=[C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])[CH:10]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(C(Cl)=NO)cc(C(C)(C)C)c1O
Reactant: N=C(N)N
Solvent: CCO
Product: CC(C)(C)c1cc(-c2noc(N)n2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.6 g (0.044 mole) of guanidine in absolute ethanol (100 ml) is added dropwise a solution of 6.2 g (0.022 mole) of 3,5-bis(1,1-dimethylethyl)-N,4-dihydroxybenzenecarboximidoyl chloride in absolute ethanol (60 ml). The mixture is stirred at room temperature for 18 hours, then evaporated to dryness (vacuum). The oil is dissolved in ethyl acetate (125 ml) and poured into water (125 ml). While stirring, the solution is acidified (pH 4.0-5.0) with 1N hydrochloric acid. The organic layer is separated, washed with water (2×100 ml), and dried (anhydrous magnesium sulfate). Evaporation of the organic layer leaves 5.0 g of crude material. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) gives 1.0 g (16%) of analytically pure 4-(5-amino-1,2,4-oxadiazol-3-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 202°-204° C.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:13][CH:14]([CH3:19])[CH2:15][C:16]([N:9]1[CH2:10][CH2:11][O:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:17]
Reactant: CC(C)CC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-methyl-butyryl chloride (301.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 3-methyl-1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>C(O)(C)C>[CH2:5]([C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:2]([OH:1])[CH2:3][NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Reactant: COc1cccc(CN)c1
Solvent: CC(C)O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1

Procedure:
tert-Butyl 1-(2-oxiranyl)-2-phenylethylcarbamate (V, commercially available, 20 g, 76 mmole) is dissolved in i-propanol (380 ml). To this mixture is added 3-methoxybenzyl amine (49 ml, 380 mmole). The reaction mixture is heated to reflux for 1 hr (when HPLC indicated complete reaction). The reaction mixture is concentrated under reduced pressure and the residue is treated with hexane (500 ml). The product is isolated by filtration. The mother liquors are concentrated under reduced pressure to give additional crude material which is partitioned between ethyl acetate (50 ml) and water (50 ml). The mixture is acidified with concentrated hydrochloric acid (to pH=4), the organic phase is separated and washed with water, saline, dried over sodium sulfate and then concentrated under reduced pressure to give additional title compound, M+H=401.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[OH-].[K+].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Yield: 97.6 %

Procedure:
5-Cyanoindole (Aldrich, 20.0 g) was added to a solution of KOH (22.4 g) in methanol (200 ml). N-Methyl-4-piperidone (Aldrich, 40.4 g) was then added dropwise and the resulting mixture refluxed for 4 hours, then cooled and poured into water. The resulting precipitate was filtered off and dried to give the desired product as a pale pink crystalline solid (32.6 g).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:13][CH:14](C(OCC)=O)[C:15](OCC)=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:25]([OH:29])([CH3:28])([CH3:27])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CO>[C:3]1([CH2:13][CH2:14][C:15]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)O
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
18.7 g (0.333 mmole) of potassium hydroxide were added to a solution of 20 g (66.6 mmole) of diethyl (1-naphthyl)methylmalonate dissolved in 200 ml of 80% v/v aqueous methanol, The mixture was then stirred at room temperature for 1 hour, after which it was concentrated by evaporation under reduced pressure. The residue was dissolved in water, and the resulting solution was washed with ethyl acetate. The aqueous solution was acidified with concentrated hydrochloric acid and then extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was decarboxylated by heating at 200° C. for 30 minutes, and was then suspended in 200 ml of diethyl ether. 19 ml of t-butanol, 16.5 g (80 mmole) of dicyclohexylcarbodiimide and 0.8 g of N,N-dimethylaminopyridine were added to the suspension. The mixture was allowed to stand for 24 hours. The precipitated insoluble materials were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: methylene chloride), to afford 12.18 g (71.4%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[CH2:15][O:14]2)=[C:8]([Cl:21])[CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:21][C:8]1[CH:7]=[C:6]([N:5]=[C:1]=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[CH2:15][O:14]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(N=C=O)cc2Cl)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of 7.9 grams (0.08 mole) of phosgene in toluene was added dropwise a solution of 5.0 grams (0.02 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in tetrahydrofuran. Upon completion of addition the reaction mixture was warmed to 80° C. where it stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give 5.6 grams of 2-(2-chloro-4-isocyanatophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as a residual solid.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[N:20]1([CH2:26][CH2:27][OH:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][C@@H:3]([CH2:1][N:23]2[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:22]2)[NH:4]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: OCCN1CCN(C[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(piperazin-1-yl)ethanol (33 μL, 0.267 mmol) provided a crude oil which was used without purification in the preparation of Example 115. MS(ESI+) m/z 276.2 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C(Cl)Cl>[CH:2]1([CH2:5][C:6]2([C:12]#[N:13])[CH2:7][CH2:8][N:9]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:11]2)[CH2:4][CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: N#CC1(CC2CC2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Reaction time: 2 h

Procedure:
A suspension of 4-(cyclopropylmethyl)piperidine-4-carbonitrile hydrochloride (I-3, 2.5 g, 12.5 mmol) in CH2Cl2 (130 mL) at 0° C. was treated with i-Pr2NEt (8.7 mL, 50 mmol) and EtSO2Cl (1.8 mL, 18.7 mmol) dropwise. After 2 h, the reaction was quenched with the addition of 1 M aqueous NaOH (40 mL) and stirred 18 h before being extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4-carbonitrile (I-4, M+H+=256.1) as an off-white amorphous solid. This material was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)C(=O)CCl
Product: CC(C)Oc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:40]([O:42][CH3:43])=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To 1.5 g (3.3 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 1.2 g (15 mmole) of pyridine and, finally, 1.3 g (13 mmole) of methyl chloroformate in 10 ml of ethyl acetate was added over 30 minutes. After an additional 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.7 g of the desired compound, mp 142°-145° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7].[H][H]>CO.Cl.[Pt]=O>[OH:7][CH:6]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: O=C(c1ccncc1)c1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: OC(c1cccc(C(F)(F)F)c1)C1CCNCC1

Procedure:
A solution of 25.1 g (0.1 mole) of 4-(m-trifluoromethylbenzoyl)pyridine in 150 ml methanol and 10 ml concentrated hydrochloric acid was shaken with one gram of platinum oxide at an initial pressure of fifty psi of hydrogen. The hydrogen uptake was complete in ten hours. The catalyst was filtered off. After removal of the methanol under reduced pressure, the residue was dissolved in water and made basic with sodium hydroxide. Extraction with benzene and concentration of the benzene solution gave crude 4-(alpha-hydroxy-m-trifluoromethylbenzyl)piperidine. Yield 20.2 grams.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22]C(C)([O-])C.[K+].CI>O1CCCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]([CH3:22])[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a suspension of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.0 g), with stirring. After 20 mins, methyl iodide (1.66) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with 2-butanone. The organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was adhered to silica (methanol) and flash chromatographed (50% ethyl acetate/hexane). The appropriate fractions were concentrated and the residue was triturated with diethyl ether to give 3.59 g (68%) of 3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][OH:7])[CH:15]=[CH:14][CH:13]=1)[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: OCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(CCO)c1)OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Caesium carbonate (8.84 g) was added to a solution of 3-(2-hydroxyethyl)phenol (2.5 g) and 2-bromo-1,1-diethoxyethane (3.74 g) in DMF (50 mL), and the resulting mixture was stirred at 90° C. overnight, then allowed to cool. The mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, then dried over anhydrous sodium sulphate and purified by flash chromatography on silica eluted with a gradient of diethyl ether in isohexane to afford the subtitled compound as a pale yellow oil. Yield 3.0 g.