Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=N[CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:14]([I:15])=[CH:13][N:12]=[CH:11][N:10]=1.[CH2:16]1COCC1>C(Cl)Cl>[I:15][C:14]1[C:9]([N:1]2[CH:5]=[CH:16][CH:3]=[N:2]2)=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: C1CCOC1
Reactant: Clc1ncncc1I
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Ic1cncnc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of 1H-1,2,4-triazole (0.158 g, 2.288 mmol) in THF (Volume: 6.03 ml) cooled to 0° C. was added NaH (0.100 g, 2.496 mmol). The reaction mixture was stirred for 30 min at this temperature and then 4-chloro-5-iodopyrimidine (0.500 g, 2.080 mmol) was added. The reaction mixture was allowed to warm to room temperature. After 16 hr, reaction quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous and organic layers were separated. Aqueous phase was extracted with EtOAc (3×). The organics layers were combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 20-80% EtOAc in hexanes over 20 min, tr=13 min) gave 5-iodo-4-(1H-pyrazol-1-yl)pyrimidine (113 mg, 20%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].[I-].[K+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][NH:32][CH2:31][C:30]([F:34])([F:33])[F:29])[CH:6]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Reactant: NCC(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCNCC(F)(F)F)c3)cc12
Yield: 51.7 %

Procedure:
In a 10 mL microwave vial was added 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (50.0 mg, 0.128 mmol), 2,2,2-trifluoroethylamine (0.100 ml, 1.279 mmol), potassium iodide (42.5 mg, 0.256 mmol), and N,N′-diisopropylethylamine (0.045 ml, 0.256 mmol) in DMF (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 20 min. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water (1×20 mL) and brine (1×20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with (CH2Cl2/CH2Cl2-MeOH-NH4OH=100:20:1 1:0 to 0:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallization from IPA-H2O to give 30 mg of N-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2-trifluoroethylamino)ethoxy)phenyl)quinazolin-4-amine as a yellow powder (42%). LCMS m/z=454 (M+1) (Method C) (retention time=2.26 min). 1H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s, 1H), 9.13-8.98 (m, 2H), 8.93 (d, J=5.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28-4.07 (m, 2H), 3.59-3.39 (m, 2H), 3.30 (d, J=2.8 Hz, 3H).
Reaction SMILES: C(#N)C.Cl.[CH3:5][N:6](/[C:8](=[CH:12]\[CH3:13])/C(O)=O)[CH3:7].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C=O)C>[CH3:7][N:6]([CH2:8]/[CH:12]=[CH:13]/[C:15]([Cl:17])=[O:16])[CH3:5]
Reactant: C/C=C(/C(=O)O)N(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C1C=CC=CC=1.C(OCC)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([O:4][CH3:3])[O:16][CH3:17])=[CH:7][CH:8]=2)[C:13](=[O:15])[CH3:14])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(OC)c1ccc(CC(C)=O)cc1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(OC)c1ccc(C(Cc2ccc(Cl)c(Cl)c2)C(C)=O)cc1
Yield: 46 %

Procedure:
0.15 g of 60% oily sodium hydride was dissolved in a liquid mixture of 1.5 ml of dimethylformamide and 1.5 ml of benzene, and a dimethylformamide 2 ml/benzene 2 ml solution of 0.72 g of 4-dimethoxymethylphenylacetone was dropwise added thereto with stirring under cooling with ice. The mixture was stirred at the same temperature for 15 minutes. To this solution, a dimethylformamide 2 ml/benzene 2 ml solution of 0.65 ml of 3,4-dichlorobenzyl chloride was dropwise added with stirring under cooling with ice. The mixture was stirred at the same temperature for 40 minutes. Then, a 3% citric acid aqueous solution and ethyl ether were added for liquid separation. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography (Lobar column™, size B, Lichroprep™ Si60F, manufactured by Merck Co.; hexane/ethyl acetate=10/1→6/1) to obtain 0.64 g (yield: 46%) of 4-(3,4-dichlorophenyl)-3-(4-dimethoxymethylphenyl)-2-butanone as colorless oily substance.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[CH2:13]([N:2]([CH3:1])[CH:3]1[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CNC1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
N-Methyl-1,4-dioxaspiro[4.5]decan-8-amine (4.0 g, 23.39 mmol, 1.0 eq.) was dissolved in DCM (70 ml); benzaldehyde (2.83 g, 28.07 mmol, 1.2 eq.) and AcOH (0.2 ml) were added and the mixture was stirred for 30 minutes at RT. NaBH(OAc)3 (14.8 g, 70.17 mmol, 3.0 eq.) was added at 0° C. and the reaction mixture was stirred for a further 14 hours at RT. After monitoring by TLC, water (100 ml) was added to the reaction and the phases were separated. The aqueous phase was extracted with 10% MeOH in DCM (2×100 ml). The combined org. phases were washed in succession with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 4% MeOH in DCM). Yield: 49% (3.0 g, 11.49 mmol)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([O:15][CH2:21][CH:20]=[CH2:19])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
N-tert-Butoxycarbonyl(4R)-hydroxyproline (9.25 g, 40 mmol) was added to a solution of 60% sodium hydride (3.36 g, 84 mmol) in 100 ml of anhydrous tetrahydrofuran and stirred for 2 hours at room temperature. Allyl bromide (6.9 ml, 80 mmol) was added to the mixture and refluxed for 6 hours. The mixture was quenched with the addition of ice chips, then additional water was added and the mixture was washed with hexane. The aqueous layer was acidified with 10% sodium hydrogen sulfate and extracted with ethyl acetate (2×150 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give 5 g of the title product with no further purification.
Reaction SMILES: [OH-].[Na+].C([N:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([C:9]1[C:10](=[O:24])[N:11]([CH3:23])[C:12]2[C:17]([C:18]=1[O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])(=O)C.Cl>CO.C1COCC1.O>[C:25]1([NH:6][C:7]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:8])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)Oc1c(C(=O)N(C(C)=O)c2ccccc2)c(=O)n(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(=O)Nc2ccccc2)c(=O)n(C)c2ccccc12
Reaction time: 0.05 h

Procedure:
A solution of NaOH in MeOH (0.50 mL, 0.20 M, 0.10 mmol) was added to a solution of N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (38 mg, 0.10 mmol) in MeOH (1.0 mL) and THF (0.5 mL). After stirring for 3 min, the solution was neutralized with aq. HCl (0.2 mL, 0.5 M) and further diluted with water (ca 10 mL). The precipitated product (29 mg, 86%) was collected by filtration and washed with water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Reaction time: 2 h

Procedure:
A round-bottom flask was charged with 3-bromo-4-chloroanisole (1.625 ml, 7.34 mmol), (3-fluorophenyl)boronic acid (1.129 g, 8.07 mmol), potassium carbonate (3.04 g, 22.01 mmol), and tetrakistriphenylphosphine palladium (0) (0.424 g, 0.367 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (19.57 ml) and water (4.89 ml) were added. A reflux condenser was attached, and the flask was lowered into a 90° C. heating bath. After 2 h, the mixture was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 0-10% EtOAc/Heptane) to give an oily solid as product that was used directly in the next step. m/z (ESI) 281.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: OB(O)c1ccccc1F
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4F)c3)cn2)CC1

Procedure:
5′-(2′-Fluoro-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-fluorophenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C27H28N3O3F [M+H]+: 462.2188. Found: 462.2187.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][NH:48]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:20]([N:48]2[CH2:49][CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CN1CCn2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCn2nc(C(=O)N3CCc4ccccc4C3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (60 mg, 0.199 mmol) in DMF (2 mL) under an atmosphere of nitrogen was added HATU (152 mg, 0.398 mmol) and 1,2,3,4-tetrahydroisoquinoline (32 mg, 0.239 mmol). The reaction was stirred at room temperature for 1 hour. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.69-7.58 (m, 1H), 7.53-7.48 (m, 1H), 7.33-7.30 (m, 1H), 7.22-7.10 (m, 4H), 7.08-7.06 (d, 1H), 6.94-6.92 (d, 1H), 5.24-5.22 (d, 2H), 4.81 (s, 1H), 4.60 (s, 1H), 4.39-4.35 (t, 2H), 3.90-3.87 (m, 1H), 3.78-3.75 (t, 2H), 3.64-3.61 (t, 1H), 3.18 (s, 3H), 2.93-2.90 (t, 1H), 2.82-2.79 (t, 1H); ES MS (M+1)=417.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.6 %

Procedure:
62 mg of the compound (198) obtained in Example 69 and 50 mg of benzylamine were added to 2 ml of toluene, and the solution was heated at 80° C. for 24 hours. The reaction solution was added to chloroform and was washed with aqueous 5% citric acid solution. After drying over magnesium sulfate, the solvent was removed by distillation. Obtained solids were dispersed in ether and filtered off to obtain 59 mg of the subject compound (200) in a 74% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.[H-].[Na+].O.[C:35]1(C)[CH:40]=CC=C[CH:36]=1>BrCCC.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:26][CH2:27][CH:28]([O:31][CH2:36][CH2:35][CH3:40])[CH2:29][CH2:30]2)[CH2:21][CH2:20]1
Reactant: Cc1ccccc1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCBr
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(OCCC)CC4)CC3)c(F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The compound (15) (8.2 g), dimethyl sulfoxide (40 ml) and sodium hydride (1.0 g) were put in a reaction vessel under a nitrogen atmosphere, and heated to 60° C. The stirring was continued for 1 hour, and then a dimethyl sulfoxide solution in which 1-bromopropane (16) (2.6 g) was dissolved in dimethyl sulfoxide (5 ml) was added dropwise thereto, and the mixture was heated to 120° C. The stirring was continued for 2 hours, and then the mixture was cooled slowly to room temperature, and water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using toluene as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume) and dried, giving 2.8 g of 4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-4′-propoxybicyclohexane (No. 54). The yield based on the compound (12) was 31.4%.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:17]([O:3][C:4]1[CH:9]=[C:8]([O:10][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][N:5]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccnc(OC(=O)c2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To 4.0 g of 2,4-bis(trimethylsilyloxy)-pyridine in 50 ml of dichloromethane were added 2.65 g of benzoyl chloride and 0.2 ml of stannic chloride, and the mixture was stirred at room temperature for one hour. The solvent was distilled off and the residue was subjected to silica gel chromatography using ethyl acetate-benzene (2:3) as an eluent to produce 0.74 g of the title compound in a yield of 14.8%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:15]1([C:21]#[N:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:18]3[CH2:19][CH2:20][N:15]([C:21]#[N:22])[CH2:16][CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: N#CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.48 g, 15.65 mmol), piperazine-1-carbonitrile (2 g, 17.99 mmol) and DIPEA (3.54 mL, 20.34 mmol) in DMF (20 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and triturated with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carbonitrile (4.29 g, 92%) as a cream crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)[CH3:17].C(OC(ON=C(C#N)C(N)=O)=O)C>CN(C)C=O>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:17]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.73 ml) in dimethylformamide (9 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.11 g) is added, and the resulting mixture is stirred for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine ethyl ester (0.2 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)nc23)CC1
Yield: 44 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 gm (0.56 mMol) 4-cyanobenzoyl chloride, 0.068 gm (44%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:18][C:19]([O:21]CC)=[O:20])[O:3]1.[Li+].[OH-]>C1COCC1.CO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:18][C:19]([OH:21])=[O:20])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OCC(=O)NC)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
The mixture of ethyl 2-(1-hydroxy-4-methyl-6-(2-(methylamino)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (321 mg, 1 mmol), LiOH (119.5 mg, 5 mmol) in THF/MeOH/H2O (5 ml/5 ml/10 ml) was stirred at room temperature for 4 hrs. The reaction mixture was quenched with 3N HCl. Filter the precipitate and washed with water. Dried to give desired product 150 mg as white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 9.14 (s, 1H), 7.97 (s, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 5.42 (d, J=9.6 Hz, 1H), 4.42 (s, 2H), 3.20 (dd, J=15.6, 2.4 Hz, 1H), 2.63 (d, J=3 Hz, 3H), 2.48 (s, 3H), 2.05 (dd, J=9.6, 15.6 Hz, 1H). MS (ESI) m/z=292 [M−H]−.