Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([PH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[BrH:16].C1C[O:20][CH2:19][CH2:18]1>>[BrH:16].[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([P:7]([CH2:18][CH:19]=[O:20])[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(Pc2ccc(C)cc2)cc1
Reactant: C1CCOC1
Agent: Br
Product: Cc1ccc(P(CC=O)c2ccc(C)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A Schlenk flask was charged with KH (0.524 g, 13.1 mmol), and dry THF (13 mL). Di(p-tolyl)phosphine (2.331 g, 10.9 mmol) was added, and the solution turned red in colour. The solution was stirred for 30 min, and then cooled to −78° C. Bromoacetadehyde diethyl acetate (1.68 mL, 10.9 mmol) was added over 20 min, and the solution turned yellow. The solution was warmed to room temperature and 48% HBr (2.5 g, 14.8 mmol) was added. A white precipitate formed, and the solution turned colourless. The mixture was heated at 45° C. for 2 hours, and then left in the freezer overnight. The precipitate was filtered off and washed with 15 mL cold H2O, as well as 15 mL of a 1:1 mixture of cyclohexanol:ethyl acetate. The precipitate was then recrystallized in MeOH and ether, and dried under high vacuum. Yield: 2.698 g, 87.8%. Diastereomer 1: 1H NMR (CD3OD, 400 MHz, δ): 8.06 (dd, J=8.2, 12.3, aromatic CH, 4H), 7.63-7.58 (m, aromatic CH, 8H), 7.48 (dd, J=2.5, 8.2, aromatic CH, 4H), 6.19 (dd, J=6.8, 21.5, PCH(OH), 2H), 4.37-4.15 (m, H1 of PCH(OH)CH2, 2H), 3.99-3.81 (m, H2 of PCH(OH)CH2, 2H), 2.53 (s, CH3, 6H), 2.44 (s, CH3, 6H). 31P NMR (CD3OD, 400 MHz, δ): 11.12. 13C NMR (CD3OD, 400 MHz, δ): 146.8 (aromatic C—P), 146.7 (aromatic C—P), 133.7 (aromatic CH), 133.1 (aromatic CH), 130.6 (aromatic CH), 130.4 (aromatic CH), 113.9 (CH3C), 113.0 (CH3C), 61.1 (PCHOH), 22.1 (PCH2), 20.5 (CH3), 20.3 (CH3). Diastereomer 2: 1H NMR (CD3OD, 400 MHz, δ): 7.96 (dd, J=8.3, 12.5, aromatic CH, 4H), 7.86 (dd, J=8.3, 12.0, aromatic CH, 4H), 7.63-7.58 (m, aromatic CH, 4H), 7.56 (dd, J=3.2, 8.3, aromatic CH, 4H), 5.80 (ddd, J=2.5, 9.4, 16.3, PCH(OH), 2H), 4.37-4.15 (m, H1 of PCH(OH)CH2, 2H), 3.99-3.81 (m, H2 of PCH(OH)CH2, 2H), 2.50 (s, CH3, 6H), 2.49 (s, CH3, 6H). 31P NMR (CD3OD, 400 MHz, δ): 16.06. 13C NMR (CD3OD, 400 MHz, δ): 147.5 (aromatic C—P), 146.9 (aromatic C—P), 133.3 (aromatic CH), 132.9 (aromatic CH), 131.3 (aromatic CH), 130.5 (aromatic CH), 112.5 (CH3C), 111.7 (CH3C), 62.2 (PCHOH), 23.6 (PCH2), 20.4 (CH3). Anal. Calcd for [C32H36P2O2][Br]2[CH3OH][H2O]: C, 54.71; H, 5.84. Found: C, 54.65; H, 6.04. MS (ESI, methanol/water; m/z+): 257.1 [C32H36O2P2]2+. The diastereomeric excess was found to be 13%, as determined by 1H NMR, and 31P NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][CH3:25])[N:18]=2)=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[NH4+].[Cl-].[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:6]2[C:5]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][CH3:25])[N:18]=3)=[CH:4][N:3]=[C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[N:7]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: OB(O)c1ccncc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccncc3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A mixture of 2-chloro-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (38 mg, 0.101 mmol), pyridine-4-boronic acid (14.91 mg, 0.121 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (8.26 mg, 10.11 μmol) and cesium carbonate (39 mg, 0.121 mmol) in dioxane (1 mL) was stirred at 100° C. for 1 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude product as an orange solid. The crude product was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyridin-4-yl)pyrimidin-4-amine (11 mg, 0.026 mmol, 26.0% yield). 1H NMR (300 MHz, CDCl3) δ 11.69 (s, 1H); 9.78 (s, 1H); 8.62-9.02 (m, 2H); 8.46 (s, 1H); 8.29-8.43 (m, 1H); 8.24 (d, J=4.53 Hz, 1H); 8.04-8.14 (m, 1H); 6.79-6.93 (m, 1H); 5.30 (s, 2H); 4.00 (s, 3H); 2.69 (s, 3H); 2.67 (s, 3H). m/z (ESI, +ve ion) 419.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C([Li])CCC.[CH3:12][C:13]1[S:17][C:16]([C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27](F)(F)F)[CH3:19])=[CH:15][CH:14]=1>CCOCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:27]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[C:18]([C:16]2[S:17][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:19]=1
Reactant: CN(C)CCN
Reactant: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(-c2cc(NCCN(C)C)c3ccccc3n2)s1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
A solution of N,N-dimethylethylenediamine (0.66 ml, 6.0 mmol) in ether (15 mL) was treated with a commercial solution of n-butyllithium (6.0 mmol) in hexanes at -10° C., and the resultant mixture was stirred at -10° C. for 20 minutes before treatment with a solution of ketimine 12q (0.42 g, 1.5 mmol) in ether (5 mL). The mixture was stirred at -10° C. for an additional 45 minutes, and then quenched with water (0.5 mL). The organic layer was concentrated on a rotary evaporator to give a crystalline residue. Removal of colored polymeric materials on a short silica gel column by eluting quinoline 9g with hexanes/Et3N/EtOH (7:2:1) was followed by crystallization of the purified 9g from hexanes; yield 82%, mp 103°-105° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:18][C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[O:28][C:29]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:30][N:31]=2)[CH:24]=[CH:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([S:15][CH3:16])[N:10]=[CH:11][C:12]=3[CH:13]=[C:20]([C:21]3[CH:26]=[C:25]([C:27]4[O:28][C:29]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:30][N:31]=4)[CH:24]=[CH:23][C:22]=3[CH3:36])[C:19]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1cc(-c2nnc(CC(C)C)o2)ccc1C
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (0.05 g, 0.22 mmol, from Preparation 4), [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid methyl ester (0.06 g, 0.21 mmol) and cesium carbonate (0.14 g, 0.43 mmol) in N,N-dimethylacetamide (4 mL) was heated in a microwave reactor at 100° C. for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The combined organic phase was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (Yield: 0.04 g, 40%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([OH:15])=O)([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[F:34])[NH2:30]>>[NH2:7][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([F:34])=[C:27]([F:26])[CH:28]=1)=[O:15]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Yield: 89.8 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid from Example 17, Step A (3.85 g, 19.74 mmol), DMF (1.0 mL, 12.92 mmol), and 3,4-difluoroaniline (4.0 mL, 40.34 mmol) to afford the product (4.9 g); m.p. 108-110° C. after trituration in hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH2:8][O:9][CH3:10])[CH3:2].C(N(CC)CC)C.[N:19]#[N:20].[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[S:26][C:25]=2[CH:24]=[CH:23][C:22]=1[S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[N:19]#[N:20].[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([C:46](=[O:47])[C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])[NH:37][S:34]([C:22]1[CH:23]=[CH:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[CH:21]=1)(=[O:35])=[O:36])[CH2:7][CH2:8][O:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CNCCOC
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2sc3ccccc3c2c1)C(=O)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.42 g of N-(2-methoxyethyl) glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 5.5 g of powdery N2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
363 mg of methyl 10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate were hydrogenated at room temperature in 50 ml of ethyl acetate in the presence of 36 mg of 10 percent palladium/carbon. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel and the product was crystallized from methanol. There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate of m.p. 138°-139°.
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:8][CH2:9][CH3:10])([CH2:6][SH:7])[CH2:4][SH:5].[CH:11](OCC)(OCC)OCC>C1C=CC=CC=1>[CH2:8]([C:3]12[CH2:6][S:7][CH:11]([S:5][CH2:4]1)[S:1][CH2:2]2)[CH2:9][CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CCCC(CS)(CS)CS
Solvent: c1ccccc1
Product: CCCC12CSC(SC1)SC2

Procedure:
2-Mercaptomethyl-2-n-propylpropan-1,3-dithiol (4.0 g.) and triethyl orthoformate (3.6 g.) were refluxed, with stirring, in dry benzene (120 ml.) containing Amberlyst "15" (1.0 g.). The mixture was cooled and filtered. The filtrates were evaporated in vacuo and the residue was purified by chromatography on alumina eluting with 1:10, dichloromethane: hexane saturated with ammonia. 4-n-Propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtained as a colourless solid (3.1 g., m.pt. 139°).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[O:31]1[C:28]2[CH:29]=[CH:30][C:25]([NH:1][C:2]3[CH:14]=[C:13]([N:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:26][C:27]=2[O:33][CH2:32]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-(indolin-1-yl)benzoate 0.12 g were added 1-bromo-3,4-methylenedioxybenzene 0.12 mL, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 110° C. for 6 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added at room temperature, and it was stirred at 110° C. for 18 hours 30 minutes. 1-Bromo-3,4-methylenedioxybenzene 0.12 mL, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(indolin-1-yl)benzoate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:32]([NH:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:33])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[NH2:20])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(N)=O)c2)n1
Yield: 68.3 %

Procedure:
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea as a white solid (0.22 g). mp: 230 (dec.); 1H NMR (200 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.92 (s, 1H), 8.32–8.08 (m, 3H), 7.94–7.44 (m, 8H), 6.44 (s, 1H), 3.51 (s, 2H), 1.31 (s, 9H); MS:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[NH2:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:35][OH:36])[C:24]([N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[C:25]([F:26])[C:20]=2[O:19][N:18]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:35][OH:36])[C:24]([N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[C:25]([F:26])[C:20]=2[O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2c(CO)cc3c(N)noc3c2F)C[C@H](C)O1
Reactant: O=Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2c(CO)cc3c(NCc4ccccc4)noc3c2F)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To an ice cooled solution of benzaldehyde (0.08 mL, 2.54 mmol) in TFA (5 mL) was added triethylsilane (0.4 mL, 2.5 mmol) followed by {3-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzisoxazol-5-yl}methanol (Intermediate 7, 250 mg, 0.84 mmol), and slowly allowed to reach room temperature and stirred for 12 hour. The reaction mixture was concentrated and the residue thus obtained was purified column chromatography using EtOAc in petether to give the title compound as solid. Yield: 70 mg (21%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=CC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(NCCCCNCC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with cyclohexane carboxaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0240 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]>[Pd].CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1C#N
Yield: 108.8 %

Procedure:
A solution of 2-methoxy-4-nitrobenzonitrile (750 mg, 4.21 mmol) and palladium on carbon (50 mg, 0.47 mmol) in methanol (15 mL) was stirred at room temperature for 48 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-amino-2-methoxybenzonitrile (679 mg, 4.58 mmol, quantitative) as a brownish-red powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([CH2:14]S([O-])(=O)=O)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22].[OH-].[Na+]>>[Cl:29][C:25]1[CH:24]=[C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:12]([CH3:14])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(C[C@H](C)CS(=O)(=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] was added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 161 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 46%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the title compound was 95.8% [(R,R)/(R,S)=95.8/4.2].
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K].[C:25]1([CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2Cl)c1
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2NS(=O)(=O)CCc2ccccc2)c1
Yield: 90.3 %

Procedure:
A solution of 4-[4,6-dichloro-5-(3-methoxy-phenoxy)-pyrimidin-2-yl]-morpholine (1.0 g) and 2-phenyl-ethanesulfonic acid amide potassium salt (1.57 g, Referential Example 1e) in DMSO (15 ml) was stirred at 60° C. for 24 h. The solution was diluted with water (75 ml) and extracted twice with diethyl ether (75 ml) before it was acidified with 10% aq. citric acid. The mixture was extracted twice with EA (150 ml). The organic phase was washed with water (50 ml). The product precipitated upon evaporation of the solvent. The solid was collected, washed with diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.28 g) as off-white powder. LC-MS: tR=5.34 min, [M+1]+=505.12, [M−1]−=502.97.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:23]=[C:24]([CH3:26])[CH:25]=2)[C:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[CH3:22])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:11][NH:13][C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=3[CH3:20])[CH:23]=[C:24]([CH3:26])[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)Nc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 61.1 %

Procedure:
To a solution of 3-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-5-methyl-benzamide (288 mg, 0.82 mmol, 1.0 eq) in THF (10 mL) under N2 was added a solution of BH3 (1M in THF, 5.0 mL, 5.0 mmol, 6.0 eq) at 0° C. The reaction mixture was heated at 60° C. overnight. After cooling, the resulting mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 50:1 to 20:1) to give the title compound as a colorless oil (168 mg, 61%).