Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(O)(=O)C.[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH:29]=O)[CH3:25])([CH3:21])([CH3:20])[CH3:19].[Na]>CO.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH2:29][N:11]1[CH2:12][CH2:13][CH:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH2:9][CH2:10]1)[CH3:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: O=C1CCCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of [1,4′]bipiperidinyl-2-one (4.5 g) in methanol (100 mL) was added acetic acid (1.49 mL). The solution was stirred for several minutes before (S)-[2-(3,4-dichloro-phenyl)-4-oxo-butyl]-methyl-carbamic acid tert-butyl ester (26 mmole) was added in methanol (25 mL). Stirring was continued for 20 minutes after which time, sodium cyanoborohyuride (1.64 g) was then added in methanol (5 mL). The mixture was stirred for two days and then diluted with aqueous sodium bicarbonate and concentrated. It was then partitioned between layers of water and dichloromethane. The aqueous layers were washed with dichloromethane and the organic phases were combined, dried and evacuated to viscous oil which was purified by flash chromatography eluting with methanol:dichloromethane (5:95). This material formed a white foam upon drying under vacuum (9.4 g). MS: m/z=512(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C1C(=O)N([Br:21])C(=O)C1>>[Br:21][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1

Procedure:
4-Methyl-3-trifluoromethylbenzonitrile is brominated with NBS according to Example 1A to give 4-bromomethyl-3-trifluoromethylbenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 4.63 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:13]>>[CH3:11][S:8]([C:6]1[CH:7]=[C:2]([NH2:13])[CH:3]=[N:4][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: [NH4+]
Agent: [OH-]
Product: CS(=O)(=O)c1cncc(N)c1
Temperature: 170 °C
Yield: 31 %

Procedure:
A mixture of 3-bromo-5-(methylsulfonyl)pyridine (0.50 g, 2.1 mmol) and CuSO4 (H2O)5 (53 mg, 0.21 mmol) in concentrated ammonium hydroxide (3 mL) was heated in a sealed tube at 170° C. for 16 hours. The reaction was cooled to room temperature and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a brown solid. The solid was purified by column chromatography on silica gel using 0-5% MeOH in dichloromethane to give 5-(methylsulfonyl)pyridin-3-amine (0.11 g, 31% yield) as a tan solid. LC/MS: m/z 173.3 (M+H) at 0.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.[C:14](Cl)(Cl)=[S:15]>CC(N(C)C)=O.CCOC(C)=O.O>[N:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1)=[C:14]=[S:15]
Reactant: N#Cc1ncc(N)c2ccccc12
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ncc(N=C=S)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A mixture of 4-aminoisoquinoline-1-carbonitrile (500 mg, 2.95 mmol) and thiophosgene (0.34 mL, 4.44 mmol) in DMA (5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc/water. The two layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 553 mg of 4-isothiocyanatoisoquinoline-1-carbonitrile as an orange oil. 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 8.12 (td, 1H), 8.05 (td, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.[C:27]([O:34][CH3:35])(=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH:22]=[C:28]([C:27]([O:34][CH3:35])=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)CC(=O)OC
Reactant: CC1(C)CCC(C)(C)c2cc(OCCOc3ccc(C=O)cc3)ccc21
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)OC
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzaldehyde (1.50 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution is concentrated under a vacuum to give title compound (1.95 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cccc(Cl)c1

Procedure:
To a refluxing solution containing 43.9g (0.25 mole) of 3-chlorobenzoyl chloride in 120 ml. of dry benzene is added 30.0 g. (0.225 mole) of anhydrous aluminum chloride in several portions over a period of 10 minutes. When the reaction is complete, as indicated by vapor phase chromatographic (vpc) techniques, the mixture is cooled to 25° and diluted with ether. Extraction with dilute base is followed by thorough drying (magnesium sulfate) and concentration in vacuo. Final purification is effected by recrystallization from ether-hexane to afford 13.7g (0.06 mole) of 3-chlorobenzophenone, m.p. 84°-85°.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Br[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: O=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (120 grams), the diethyl acetal of 2-bromoacetaldehyde (78.8 grams) and sodium carbonate (42.4 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture was heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture was cooled to room temperature and was filtered. The filtrate was then distilled under vacuum to yield the desired product the diethyl acetal of 2-(2,6-diethylanilino)acetaldehyde as the residue having a boiling point of 130°C at 1 mm of Hg pressure.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(O)=[O:11].O>>[Br:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(Cl)c1Br
Reactant: O=CO
Solvent: O
Product: Cc1cc[nH]c(=O)c1Br
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To a resealable pressure vessel charged with 3-bromo-2-chloro-4-picoline (1.200 g, 5.81 mmol) was added formic acid (13.1 ml, 348 mmol) and water (4.00 ml, 222 mmol). The tube was sealed and the solution heated to 120° C. After 72 hrs, the solution was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase chromatography (neutral) to afford 3-bromo-4-methylpyridin-2(1H)-one as a white solid. M+H+=188.0.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.Cl.[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.CCOC(C)=O>[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2CC2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (0.19 g, 3.02 mmol) and tetrahydro-pyran-4-carbaldehyde (0.26 g, 2.26 mmol) is added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.4 g, 1.51 mmol) in DMF (5.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 364 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]4=O)[CH:16]=3)[CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][CH2:19]4)[CH:16]=3)[CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)C3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Cool a solution of tert-butyl 4-[(2S,3S)-3-[(4-fluorobenzoyl)amino]-2-hydroxy-indan-5-yl]-3-oxo-piperazine-1-carboxylate (8.85 g, 18.9 mmol) in anhydrous tetrahydrofuran (40 mL) in an ice bath for 30 min. and add borane-dimethyl sulfide complex (2 M, 37.7 mL, 75.40 mmol) under nitrogen. Warm the mixture to room temperature and stir for 1.5 hr. Add a second portion of borane-dimethyl sulfide complex (2 M, 9.42 mL, 18.9 mmol) at room temperature and stir for one hour. Cool in an ice bath for 10 min and carefully add water dropwise, followed by addition of saturated sodium bicarbonate solution (50 mL). Dilute the resulting suspension with ethyl acetate (150 mL). Wash the organic portion with brine, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by flash chromatography (120 g silica, 40 to 50% ethyl acetate/hexanes) to obtain the title compound (6.8 g, 79%). LC-ES/MS m/z 456 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Reactant: O=C=NCc1ccccc1
Product: CC1(C)CN(Cc2ccncc2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (11.7 mg, 38%) having the following characteristics.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH:14]=[C:13]([C:15]([CH3:39])=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH:15]([CH3:39])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH2:12][NH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=C(C)c2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CC(C)C2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC
Yield: 23 %

Procedure:
A solution of 84.4 mg of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-1-enyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 0.42 g of 5% Pd/C at room temperature for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting residue was taken up in chloroform and was extracted with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then subjected to thin layer chromatography using a 5% methanol:chloroform mixture as the eluent. After elution of a first fraction, there was obtained 19.6 mg of the title compound, NMR (CDCl3 250 MHz), d 1.20-1.33(m, overlapping methyls, 9H), 2.45-3.36(m, 15H), 4.11(q, 2H, J=7.14 Hz), 4.23(q, 2H, J=7.10 Hz), 4.89(m, 1H), 5.44(brs, 1H), 7.24(d, 2H, J=7.54 Hz), 7.72(d, 2H, J=7.54 Hz), 9.77(brs, 1H), 11.26(brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:18])=O>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Cl:18])[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a suspension of 6-chloro-3-nitro-1,5-naphthyridin-4-ol (5 g, 22.1 mmol) in 15 mL of DMF, was added a solution of phosphorous oxychloride (2.7 mL, 28.8 mmol) in anhydrous DMF (10 mL) over 3 min. The mixture was stirred at room temperature overnight. The mixture was then poured onto crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 2,8-dichloro-7-nitro-1,5-naphthyridine as yellow solid (4 g, yield 74.0%). MS (m/z): 244 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.Cl[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:20]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)=[O:21])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CCOC(=O)CCCCCC(=O)Cl
Product: CCOC(=O)CCCCCC(=O)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(6-Carboethoxyhexanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 6-(chloroformyl)hexanoate.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccccc2)CC1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C2CCNC(C3CCCCC3)C2)cc1
Reaction time: 10 h

Procedure:
Benzyl 2-cyclohexyl-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.7 g, 12.52 mmol) in EtOH (25 ml) was added Pd/C (1.18 g, 0.554 mmol) and hydrogenated with a balloon for 10 hours. Filter through celite and concentrate. The crude piperidine was not purified. LRMS (M+H)=217.10
Reaction SMILES: ClCCl.[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([NH:8][CH3:9])=[O:7].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)(Cl)Cl>[CH3:4][N:5]([CH2:10][CH2:11][CH3:12])[C:6]([N:8]([CH3:9])[C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])=[O:7]
Reactant: O=C=Nc1ccccc1
Reactant: CCCN(C)C(=O)NC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 74.6 %

Procedure:
Into 300 ml of anhydrous dichloromethane, 13.0 g (0.1 mol) of 1,3-dimethyl-1-propylurea and 12.0 g (0.1 mol) of phenylisocyanate were added and dissolved. The mixture was ice-cooled under stirring and 26.0 g (0.1 mol) of stannic chloride was added drop-wise. The reaction was then continued at a room temperature for 15 hours and the precipitate formed was separated by filtration. The precipitate thus obtained was added into a mixture of 60 ml of 20% hydrochloric acid/120 ml of chloroform and the stirring was continued until the mixture became transparent. Then the chloroform layer was separated and was washed with water and the chloroform layer was dried with anhydrous sodium sulfate. The chloroform was removed by distillation under reduced pressure and the residue thus obtained was recrystallized from ligroin to obtain 18.6 g (yield: 75%) of 1,3-dimethyl-1-propyl-5-phenylbiuret having a melting point of 63° to 64° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[OH2:10]>>[C:4]1([CH2:1][CH2:2][OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: CC(=O)c1ccccc1
Product: OCCc1ccccc1
Yield: 50 %

Procedure:
Acetophenone (120 mg, 1 mmol) was reacted with yeast (5 g) and water (5 ml) according to method I. The product was obtained in 50% yield. Reaction according to Method II gave the product in 52% yield.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[N:24]1([CH:30]=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH:30]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26][CH2:25]1)=[O:31]
Reactant: O=CN1CCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCN(C=O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and piperazine-1-carbaldehyde (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-45% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (35 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 3.59-3.82 (m, 8H) 6.39 (d, J=2.02 Hz, 1H) 7.43 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.34 Hz, 2H) 8.08-8.15 (m, 2H) 10.94 (s, 1H). ESI-MS: m/z 409.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:15]1[CH:14]=[C:3]2[C:2](=[CH:17][CH:16]=1)[N:1]=[C:21]([CH2:20][Cl:19])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:4]2=[O:5]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Yield: 91.8 %

Procedure:
Prepared according to Procedure B with 1d (500 mg, 1.78 mmol) and chloroacetyl chloride (0.42 mL, 5.33 mmol) in acetic acid (10 mL). Purified by recrystallization from isopropanol to afford 555 mg of a yellow solid (92%). 1H NMR (CDCl3) δ: 8.27 (d, J=1.9 Hz, 1H); 7.74-7.78 (m, 2H); 7.60-7.66 (m, 1H); 7.48-7.57 (m, 3H); 4.37 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 339.0 (M+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([OH:24])=[O:23])=O.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[Na]>CO.C1COCC1.C(O)(=O)C>[C:30]([NH:34][CH2:1][C:3]1[C:4]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=3)[CH2:8][CH2:7][N:6]2[C:21]=1[C:22]([OH:24])=[O:23])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(C=O)c(C(=O)O)n1CC2
Reactant: CC(C)(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CNC(C)(C)C)c(C(=O)O)n1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution of 500 mg of 15d and 110 mg of tert-butyl amine in 20 ml of methanol and 5 ml of THF was added 140 mg of sodium cyanoborohydride and 90 mg of acetic acid. The mixture was stirred for 3 hr at RT, then 140 mg of sodium cycanoborohydride was added additionally and stirring was prolonged for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography over silica gel, using a gradient of dichloromethane and methanol, to provide 520 mg of 15e; MS-ESI: [M+1] 469.23.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.B(O)(O)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[N:20][CH:19]=1>>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:2]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.