Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH3:3][N:4]([CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:6]=1[Br:1]
Reactant: BrBr
Reactant: CN(C)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)c1ccc(OC(F)(F)F)cc1Br
Reaction time: 1 h

Procedure:
Bromine (0.15 ml) was added dropwise to a stirred, cooled (0° C.) mixture of 1-dimethylamino-4-(trifluoromethoxy)benzene (Description 77, 600 mg) and sodium carbonate (620 mg) in chloroform (15 ml). The mixture was stirred for 1 h. and diluted with water. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (99:1 increasing to 95:5) to give the title compound as an oil (300 mg). 1H NMR (360 MHz, CDCl3) δ2.79 (6 H, s), 7.06 (1 H, d, J 9 Hz), 7.14 (1 H, dd, J 6, 1.5 Hz), and 7.44 (1 H, d, J 2.0 Hz). m/z (ES+) m/z 270, 272 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH2:33][CH:32]=[CH2:31]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C=CCCBr
Product: C=CCCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and 4-bromo-1-butene, white powdery N-[2-(3-but-3-enyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 24.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(4,5-difluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM extracts were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (10 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](=[O:25])[CH3:24].O>O1CCCC1>[C:23]([CH:22]([C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14])[C:10](=[S:11])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:25])[CH3:24]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
2,4-Difluorophenyl isothiocyanate (0.27 mL, 2.0 mmol) was added to a stirred suspension of sodium hydride (60% in mineral oil) (112 mg, 2.8 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice-water bath under a nitrogen atmosphere. A solution of 1-(2,4-dichlorophenyl)-2-propanone (570 mg, 2.8 mmol) in tetrahydrofuran (4 mL) was added dropwise over 5 min. The resultant yellow solution was stirred at 5-10° C. for 1 h. Water (10 mL) was carefully added, and the reaction mixture was extracted with ethyl acetate (10 mL). The aqueous phase was acidified to pH 3 with 1 N aqueous HCl, then extracted with ethyl acetate (20 mL). The organic extract was washed with water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid. The solid was triturated with hexanes/ethyl acetate (2:1), collected on a glass frit, and air-dried to give the title compound as a white solid (240 mg). MS: 373 amu (AP+).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[N:14]=1)[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:30])[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:23]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:8]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(OC)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1cncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(5-methoxy-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.091 mmol), β-alanine (651 mg, 7.30 mmol) and NaOMe solution (11 mL, 5.48 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 35 mg of the title compound as a light tan solid. MS: (+) m/z 551.32 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(-c2cnccn2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 2-(tributylstannyl)pyrazine: MS (m/z) 345.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.O>O1CCCC1>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:23][CH2:22][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([OH:14])=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=C1CCC(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
60% suspension mixed with NaH mineral oil (7.6 g, 0.19 mol) was added to trimethyl phosphonoacetate (22.8 mL, 0.15 mol) solution dissolved in anhydrous tetrahydrofuran (655 mL) under 0° C. nitrogen gas. 4-(4-hydroxyphenyl)cyclohexanone (25 g, 0.13 mol) solution dissolved in tetrahydrofuran (525 mL) was slowly added thereto at 25° C. Then, the reaction mixture was stirred at room temperature for 5 hours, cooled with water, and extracted with ethyl acetate. The mixed organic phase was washed with brine and dried with Na2SO4. The solvent was reduced under reduced pressure to obtain [4-(4-hydroxyphenyl)cyclohexylidene]acetic acid methyl ester as a white solid (31.3 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>ClCCl>[Br:49][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[CH:5][C:6]=1[Cl:10]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(c1ccc(-c2cc(Cl)c(CO)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CBr)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Yield: 53.7 %

Procedure:
Dissolve (3′,5′-Dichloro-4′-hydroxymethyl-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (13 g, 1 eq.) in dichloromethane (200 mL) and cool to 0° C. Add triphenylphosphine (12.2 g, 1.5 eq.) followed by carbon tetrabromide (15.4 g, 1.5 eq.) in portions. Filter the reaction mixture and concentrate the filtrate. Chromatograph the filtrate on silica gel to afford 8.0 g (54% yield) of the titled compound.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22](=[O:24])[CH3:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:25][C:26]1[CH:27]=[CH:28][C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]([NH2:32])[CH:31]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:32][C:30]1[CH:31]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[C:2]1[N:3]([CH2:21][C:22](=[O:24])[CH3:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C)=O)c2c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(C)cc3N)n(CC(C)=O)c2c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (700 mg, 1.78 mmol) and 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (456 mg, 1.96 mmol) in 1,2-dimethoxyethane (6 ml) and water (2 ml) were added sodium hydrogen carbonate (177 mg, 2.14 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give methyl 2-(2-amino-4-methylphenyl)-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (727 mg, yield 97%).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]2[CH:25]=[C:26]([Cl:28])[CH:27]=[C:7]2[C:6]=1[OH:29])=[O:4].[NH2:30][C@@H:31]([C:33]([OH:35])=[O:34])[CH3:32].C[O-].[Na+]>>[Cl:28][C:26]1[CH:27]=[C:7]2[C:6]([OH:29])=[C:5]([C:3]([NH:30][C@H:31]([CH3:32])[C:33]([OH:35])=[O:34])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[N:8]2[CH:25]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O
Reactant: C[C@@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(-c3ccccc3)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-phenyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, D-alanine and NaOMe. ESI (m/z): 466 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]2[CH2:34]N[CH2:32][CH2:31][NH:30]2)=[CH:23][CH:22]=1>>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:32][CH2:31][NH:30][C@@H:29]([CH2:28][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH2:34]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(C)C)nc43)CCN2)cc1
Yield: 38.4 %

Procedure:
By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.48 g, 5.7 mmol) and (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (1.26 g, 5.7 mmol) to give 1.01 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=462 (M+1); Analysis for C26H31N5OS(0.3 H2O): calcd: C, 66.87; H, 6.82; N, 15.00; found: C, 66.58; H, 6.35; N, 14.96.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1>CO>[NH2:1][C:3]1[C:4]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Reactant: N
Solvent: CO
Product: Nc1ncnc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To an ammonia solution in methanol (5 ml of a 6 M solution) was added 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (26 mg, 0.1 mmol). The mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:30, yielding the title compound (20 mg, yield 83%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 241 ([M+H]+, 100).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)=[CH:37][CH:38]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NCc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1
Yield: 28.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.298 mmol), acetic acid (17 μL, 0.29 mmol), (4-amino-phenyl)-acetic acid ethyl ester (14 mg, 0.45 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol) to afford 43 mg (30%) of the desired product after purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:23]1[N:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][C:29]([O:33][CH3:34])=[CH:28]2>>[F:20][C:5]1[C:4]([F:21])=[CH:3][C:2]([NH:1][C:23]2[N:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][C:29]([O:33][CH3:34])=[CH:28]3)=[CH:7][C:6]=1[C:8]1([CH3:19])[CH2:13][CH:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: COc1cnc2c(Cl)nccc2c1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: COc1cnc2c(Nc3cc(F)c(F)c(C4(C)CC(C(F)(F)F)OC(N)=N4)c3)nccc2c1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, example 163, Method Y, step 9) and 8-chloro-3-methoxy-1,7-naphthyridine (intermediate 31) in step 2. MS m/z=468.2 [M+H]+. Calculated for C21H18F5N5O2: 467.4
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20][C@@H:21]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O.Br[C:39]#[N:40]>C(Cl)Cl.[Cl-].[Na+].O>[C:39]([N:25]1[CH2:24][CH2:23][CH:22]([C@H:21]2[N:16]3[N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20]2)[CH2:27][CH2:26]1)#[N:40]
Reactant: N#CBr
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC[C@H]2C1CCNCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC([C@@H]2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of (S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (417 mg, 1 mmol) in DCM (20 mL) was added NaHCO3 (168 mg, 2 mmol) and water (5 mL), followed by BrCN (127 mg, 1.2 mmol). The mixture was stirred at RT for 16 h. To the mixture was added DCM (50 mL) and brine (20 mL). The organic phase was further washed with brine (100 mL), dried over Na2SO4. Concentrated and purified by Pre-TLC (DCM/MeOH, 50/1) to afford 330 mg (75%) of white solid. MS (ESI) m/e [M+1]+ 443.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3](=C=O)[CH2:4][C:5]#[N:6].[CH3:10][NH:11][NH2:12]>>[CH3:10][N:11]1[C:5]([NH2:6])=[CH:4][C:3]([CH:2]([CH3:1])[CH3:9])=[N:12]1
Reactant: CC(C)C(=C=O)CC#N
Reactant: CNN
Product: CC(C)c1cc(N)n(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Under nitrogen atmosphere, the compound of Example 2A (8.03 g, 72 mmol) was dissolved in alcohol (50 mL). Methylhydrazine (3.32 g, 72 mmol) was added. The resultant mixture was slowly warmed and refluxed with stirring. The reaction was kept for 3 hr. The reaction was stopped and cooled to room temperature. Alcohol was rotary-evaporated to obtain a crude product as oil. The crude product was purified with column chromatography (eluant: petroleum ether/ethyl acetate=1:1) to give 5.2 g of the title compound. MS (ESI): m/z 140 (M+H)+
Reaction SMILES: N1C=CC=CC=1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (0.37 mL, 4.6 mmol) was added to a suspension of N-hydroxyphthalimide (664 mg, 4.1 mmol), 4-chlorophenylboronic acid (635 mg, 4.1 mmol), and powdered 4 Å molecular sieves (1.02 g) in CH2Cl2 (20 mL). Cupric acetate monohydrate (812 mg, 4.1 mmol) was added, and the mixture was stirred open to the atmosphere at room temperature for 18 hours. Silica gel (10 g) was added, and the slurry was concentrated to dryness under vacuum. The residue was applied to the top of a flash chromatography column, and eluted with hexanes:ethyl acetate (80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.11-7.17 (m, 2 H), 7.27-7.34 (m, 2 H), 7.79-7.87 (m, 2 H), 7.88-7.95 ppm (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCc1ccncc1
Reactant: BrCCCc1ccccc1
Product: CC(CCCc1ccccc1)c1ccncc1
Yield: 55.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.86 g (9.35 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.17 g of the desired compound (yield: 55.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[CH3:16][S:17]([O-:19])=[O:18].[Na+]>[Cu]I>[CH2:12]([C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:3]=2)[N:8]=1)[CH3:13]
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Product: CCc1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Temperature: 25 °C
Yield: 24.8 %

Procedure:
The substrate of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (50.0 mg, 0.189 mmol), sodium methanesulfinate (28.8 mg, 0.29 mmol) and copper (I) iodide (53.7 mg, 0.29 mmol) was placed in a flask, which was flushed with N2. DMF (2 ml) was added via syringe. The resulting mixture was irradiated at 180° C. for 30 minutes in the SmithSynthesizer Microwave reactor (Personal Chemistry) with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, diluted with ethyl acetate (5 ml), and then filtered. The filtrate was washed with water and brine, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-Ethyl-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (Yield 12.5 mg, 25.1%). 1H NMR (400 MHz, CDCl3): δ 1.35 (t, 3H, J=7.58 Hz), 2.83 (dd, 2H, J=14.65, 7.58 Hz), 3.02 (s, 3H), 3.58 (s, 3H), 7.73 (d, 1H, J=8.84 Hz), 8.12 (dd, 1H, J=8.84 Hz), 8.77 (d, 1H, J=2.02 Hz). MS m/z calc. 265.1, found (ESI); 266.0 (M+1)+. Retention time 2.41 minutes.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][C:10]([C:13]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:14]=1[O:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21])([CH3:12])[CH3:11].Cl[CH2:31][C:32]([O-:34])=[O:33].[Na+]>CS(C)=O>[CH3:12][C:10]([C:13]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:14]=1[O:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[O:21][CH2:31][C:32]([OH:34])=[O:33])([CH3:9])[CH3:11]
Reactant: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reactant: O=C([O-])CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2OCC(=O)O)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To 103 mg of 60% sodium hydride, prewashed with hexane, in 10 ml of dimethyl sulfoxide was added 500 mg of the title product of Example 100. The mixture was stirred at 40° C. until gas evolution ceased, and then 290 mg of sodium chloroacetate was added, the resulting mixture stirred at room temperature overnight and then at 80° for 1 hour. After cooling, the mixture was partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer further extracted with ether, the combined organic extracts washed with several portions of water and then brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 30% ethyl acetate-2% acetic acid-68% hexane gave the title compound (155 mg) as a pure white crystalline solid, DSC 96.5° C.