Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N:18]([CH2:25][C:26]#[N:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>O1CCCC1>[OH:8][C:9]1[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(O)c(C#N)n2-c1ccccc1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
A mixture of 8.4 g (0.075 mole) of potassium tert.-butoxide in 200 ml of tetrahydrofuran (under a nitrogen atmosphere) was stirred and cooled in an ice bath. A solution of 13.7 g (0.046 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid methyl ester in 150 ml of tetrahydrofuran was added over two hours, the ice bath was removed, and the new mixture was stirred for an additional 42 hours. The total reaction mixture was added to 1.1 kg of ice/water and acidified with 12.0 ml of glacial acetic acid to precipitate the crude product. The solid was filtered, washed with water, and recrystallized from aqueous methanol to yield 10.3 g (84% yield) of the nitrile product. A sample recrystallized again as above was analytically pure, mp 182° C.-dec.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[C:9]1([N:15]2[C:19]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[C:9]1([N:15]2[C:19]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:31])=[O:2])[CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 24 h

Procedure:
18 mg of potassium carbonate and 40 μl of 30% hydrogen peroxide solution were added to a solution of 50 mg of 6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanonitrile in 1 ml of methanol, and it was allowed to stir for 24 hours. Then, ice-cold aqueous sodium thiosulfate solution was stirred in and extracted three times with ethyl acetate. After drying on sodium sulfate, it was concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:1][CH2:2]1
Reactant: COC(OC)c1ccccc1
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C(=O)O)COC(c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a round bottom flask was added sequentially 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (10.0 g, 74.5 mmol), acetone (75.0 mL), benzaldehyde dimethyl acetal (17.02 g, 111.0 mmol) and para-toluenesulfonic acid monohydrate (0.71 g, 3.7 mmol). The resulting mixture was stirred at ambient temperature for 4 h and then filtered. The filter cake was rinsed with cold acetone and dried under vacuum to give the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.46-7.48 (m, 2H), 7.34-7.36 (m, 3H), 5.49 (s, 1H), 4.65 (d, J=10.8 Hz, 2H), 3.70 (d, J=11.4 Hz, 2H), 1.11 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:39][S:36]([O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:38])=[O:37]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
Benzyl 3-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)phenylcarbamate (4 g) was dissolved in dry DCM (80 mL) and cooled to 0° C. under an argon atmosphere. Triethylamine (5 g) was added, followed by mesyl chloride (3.42 g) added drop-wise over a period of 2 hours. The reaction temp was maintained at 0° C. for further 2 hours. The reaction was quenched by addition of water, extracted into DCM and concentrated under vacuum at a temperature below 25° C. The crude product (3.5 g) was unstable and was used for next step as soon as possible.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:21][CH:20]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: OB(O)c1ccc(F)nc1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3ccc(F)nc3)cc2C1

Procedure:
The title compound was prepared by a similar process to the preparation of Example 1, starting from Intermediate 2 with (6-fluoro-3-pyridinyl)boronic acid, except that, instead of stirring the mixture at conventional reflux for 16 h, the reaction mixture was stirred in a microwave reactor at 160° C. for 20 minutes.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([NH2:17])[CH3:16])[N:8]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: COC(=O)Cl
Reactant: CC(N)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Reaction time: 0.08 h
Yield: 108 %

Procedure:
A solution of S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (0.25 g, 0.72 mmol) in THF-water (1:1, 8 mL) was cooled to 0° C. and then solid NaHCO3 (0.10 g, 1.2 mmol) was added with concomitant frothing. After 5 minutes, a THF solution of methyl chloroformate (0.1 M in THF, 4.3 mL, 0.43 mmol) was added dropwise to the mixture and the reaction was maintained overnight allowing the cooling bath to expire. LCMS indicate incomplete reaction and addition methyl chloroformate solution and NaHCO3 was added. After the reaction was deemed complete by LCMS, the reaction mixture was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4), and concentrated to give (S)-methyl 1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a yellow solid (0.19 g): LCMS (m/z) 409.0 (MH+), tR=0.63 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Cl)cc(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A mixture of 4,6-dichloro-2-nitrophenol(1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol(50 ml) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(685 mg, 80%). 1H NMR (CD3OD): d 6.75 (s,1H), 6.61 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[S:26])[CH2:21][CH2:20]1)=[O:18])[CH3:15]>O1CCCC1.C(N(CC)CC)C.C(Cl)Cl>[NH:9]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[NH:1][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH2:20][CH2:21]1)=[S:26]
Reactant: Nc1ccccc1Cc1ncc[nH]1
Reactant: CCOC(=O)N1CCN(C(=S)Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1

Procedure:
To a suspension of 3.8 g of 2-(2-aminobenzyl)imidazole in 38 ml of tetrahydrofuran and 3.23 ml of triethylamine is added dropwise a solution of 5.5 g of 4-ethoxycarbonyl-1-piperazinyl-thiocarbonyl chloride in 10 ml of methylene chloride at room temperature. The mixture is stirred for 1 week and the suspension filtered. The filtrate is washed with first 10% aqueous potassium carbonate, then with water, dried and evaporated to dryness to give amorphous 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine, characterized by NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]#[C:5][CH2:6][CH3:7].ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCl>[CH3:1][N:2]([CH3:8])[CH:3]=[CH:4][C:5](=[O:14])[CH2:6][CH3:7]
Reactant: CCC#CCN(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(=O)C=CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cold solution of 1-dimethylamino-2-pentyne (3.0 g) in dichioromethane (100 ml) was added 3-chloroperoxybenzoic acid (4.66 g) in small portions. After the reaction was stirred at 0° C. for 20 minutes, the mixture was passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 5% methanol in dichloromethane. All fractions containing 1-dimethylamino-2-pentyne N-oxide were combined and evaporated to near dryness in vacuo. The residue was treated successively three times with of methanol (ca. 100 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 90 mL by addition of methanol. One third of this methanolic solution (30 ml) of the N-oxide (9 mmol) was heated to reflux for approximately 4 hours, cooled, evaporated to dryness in vacuo, and the residue was chromatographed over silica gel (2% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent in vacuo the desired product as an oil. MS (+ES) m/z: 128 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]1[O:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:15][NH2:16]>CO>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[O:6][C@@H:4]2[C:3]([NH:16][CH3:15])=[O:2])=[CH:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Solvent: CO
Product: CNC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Yield: 91.6 %

Procedure:
To a mixture of (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionic acid methyl ester (1.92 g) and methanol (10 ml) is added dropwise a solution of 40% aqueous methylamine solution (2.37 g) in methanol (10 ml) under ice-cooling. The reaction mixture is stirred under ice-cooling for one hour, and concentrated under reduced pressure. To the residue is added ether, and the precipitated crystals are collected by filtration, washed, and dried at 50° C. to give (2S,3R)-3-(4-methylphenyl)-2,3-epoxy-N-methylpropionamide (1.75 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:36])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH:33]1([CH2:32][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[O:36])[CH:24]=2)[CH2:34][CH2:35]1
Reactant: O=C(Nc1cc(-c2ccccc2OCC2CC2)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2OCC2CC2)ncn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
4-[6-(2-Cyclopropylmethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XV) (0.41 g, 0.84 mmol) was dissolved in methanol (20 ml) and 10% Pd/C (0.2 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. Then the crude product was triturated with dry diethyl ether (10 ml) and the solid was filtered off to obtain piperidine-4-carboxylic acid [6-(2-cyclopropylmethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #8A) (0.11 g, 37%) as a white solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[N:15][CH:14]=[CH:13][C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][N:20](/[CH:22]=[C:10]1/[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]=2[NH:7][C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]/1=2)[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Solvent: C1CCOC1
Product: CN(C)/C=C1/C(=O)c2cccnc2Nc2cnccc21
Temperature: 60 °C

Procedure:
To a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (as described in WO 2007038215) (0.38 g) and dimethylformamide dimethylacetal (1.5 mL) in tetrahydrofuran (10 mL) were heated at 60° C. under nitrogen for 24 hours. Additional dimethylformamide dimethylacetal (2 mL) was then added and the mixture heated at 60° C. under nitrogen for an additional 48 hours. The reaction mixture was cooled and solvent removed under reduced pressure to give the desired product, (E)-6-((dimethylamino)methylene)-6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (0.745 g) as a brown solid, which was used without further purification in Step 2.
Reaction SMILES: [N:1]([CH2:4][C:5]1([F:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1([F:21])[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: [N-]=[N+]=NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 60 h

Procedure:
To a solution of benzyl 4-(azidomethyl)-4-fluoropiperidine-1-carboxylate (1.5 g, 5.1 mmol) in THF (10 mL.) at RT was added water (0.92 mL, 0.92 mmol) and triphenylphosphine (4.3 g, 15.4 mmol). The reaction mixture was stirred for 60 h, concentrated, dissolved in HCl (1 M) and extracted with Et2O four times. The aqueous layer was basified to pH 11 and extracted with EtOAc twice. The organic layer was dried over Na2SO4, filtered and concentrated. The crude mixture was chromatographed on silica gel (CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) to give benzyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate. M.S. (M+1): 267
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:15]1)=O)(C)(C)C>O1CCCC1>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[O:21][CH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:12])[CH2:15]1
Reactant: Cc1cccc(C)c1OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC[C@H]1CCCN(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
A solution of 1M lithium aluminum hydride in tetrahydrofuran (45 mL, 45 mmol) was added dropwise during 30 minutes to (S)-N-(tert-butoxycarbonyl)-3-(2,6-dimethylphenoxymethyl)piperidine (13.0 g, 40.6 mmol) in dry tetrahydrofuran (250 mL) under a dry nitrogen atmosphere. After the addition was complete, the reaction mixture was heated at reflux for 4 hours, stirred at room temperature for 20 hours, and quenched by the cautious addition of solid sodium sulfate decahydrate (70 g). The sodium sulfate was removed by filtration and washed with ethyl acetate (3×150 mL). The combined filtrates were concentrated, and the residue chromatographed on silica gel, eluting with dichloromethane/methanol (9.5:0.5) to give (S)-3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine as a clear oil (8.0 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH:18]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.[OH-].[Na+]>[OH:23][C@H:20]1[CH2:21][CH2:22][N:18]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)[CH2:19]1
Reactant: O[C@H]1CCNC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(N2CC[C@H](O)C2)CC1
Reaction time: 16 h
Yield: 103.4 %

Procedure:
A solution of phenylmethyl 4-oxo-1-piperidinecarboxylate (1 g, 4.29 mmol) and (3S)-3-pyrrolidinol (0.411 g, 4.72 mmol) in 1,2-dichloroethane (14.29 mL) was treated at room temperature under air with sodium triacetoxyborohydride (1.363 g, 6.43 mmol) and glacial acetic acid (0.245 mL, 4.29 mmol). After 16 h, the mixture was diluted with 1N NaOH (75 mL) and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with brine (1×75 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford phenylmethyl 4-[(3S)-3-hydroxy-1-pyrrolidinyl]-1-piperidinecarboxylate (1.35 g, 98% yield). This material was used in the next step without further purification. MS (m/z) 305.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH:13]([CH2:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][CH3:20])=[O:15])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: Oc1ccc2ccncc2c1
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ccncc2c1

Procedure:
In a similar procedure to Example 1, 7-hydroxyisoquinoline (commercially available) and 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide were reacted to give 2-(7-isoquinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (Compound No. 2 of Table 39) as a colourless solid, m.p. 149-50° C.
Reaction SMILES: [CH2:1]([C:3](=[CH:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6]C)=[O:5])[CH3:2].C(O)C.[OH-].[Na+].O>COC(C)(C)C>[CH2:1]([C:3](=[CH:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(=CSc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: O
Product: CCC(=CSc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
To methyl 2-ethyl-3-(phenylthio)acrylate (4.39 g) were added ethanol (40 mL) and then a 2N aqueous sodium hydroxide solution (20 mL), and the mixture was refluxed at room temperature for 2 hours. After the reaction mixture was cooled to room temperature, water (100 mL) was added thereto, and further tert-butyl methyl ether was added, thereby layers were separated. The aqueous layer was adjusted to pH 2 by addition of conc. hydrochloric acid, and then extracted with tert-butyl methyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and then concentrated to obtain 2-ethyl-3-(phenylthio)acrylic acid (4.07 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13]1)[N:8]1[CH:24]([CH3:26])[S:25][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32].II.[Cl:35]S(O)(=O)=O>>[Cl:35][C:10]1[C:11]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH2:13]2)=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]1[CH:24]([CH3:26])[S:25][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1c2n(c3cc(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Agent: II
Product: CCOC(=O)c1c2n(c3c(Cl)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2

Procedure:
To a solution of 1.50 g of ethyl 6-fluoro-1-methyl-4-oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate in 4.0 ml of chlorosulfonic acid, a trace of iodine was added, and the mixture was bubbled with chlorine gas for 1 hour under ice cooling with stirring. The reaction mixture was poured into ice water and was extracted with chloroform. The extract was washed with aqueous potassium carbonate and water, dried and evaporated. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as an eluent to give 1.61 g of the desired compound, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether. The obtained crystals were consistent with that of Example 1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC([CH:24]2[CH2:28][CH2:27]C[O:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:27][CH2:28][CH2:24][O:25]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: Cc1nc(C2CCCO2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCCO2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole (compound 173.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH3:19]>CO.[Cu]>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:19])[CH:7]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1cc(N2CCN(C3CCCC3)CC2)ccn1
Reactant: N
Agent: [Cu]
Solvent: CO
Product: Nc1cc(N2CCN(C3CCCC3)CC2)ccn1
Temperature: 150 °C
Yield: 24 %

Procedure:
A mixture of 5.84 g (22 mmol) 1-(2-chloro-pyridin-4-yl)-4-cyclopentyl-piperazine, 0.8 g copper powder in 41 ml 7M ammonia in methanol was heated to 150° C. for 18 h. After evaporation to dryness the residue was purified on silica eluting with a gradient formed from dichloromethane/methanol and NEt3. The evaporation of the combined product fractions yielded 1.29 g (24%) of the title compound as yellowish solid. (m/e): 247.3 (MH+; 100%).