Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:20]([O:21][CH3:22])[CH3:19])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
The product from Example 71A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly. The mixture was cooled to 0° C., stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise. The mixture was allowed to warm to 25° C., stirred for 16 hours, and treated with DCM (150 mL). The mixture was washed with saturated NaHCO3, brine, and water. The organic phase was dried, filtered, and the filtrate evaporated under reduced pressure to provide the title compound as a pale yellow solid (18.65 g, 95% yield). 1HNMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.56 (s, 3H) 6.98 (d, 2H, J=8.9 Hz), 7.33-7.46 (m, 5H), 7.76 (d, 2H, J=8.9 Hz); MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1OB(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to a suspension of 60 mg (0.16 mmol) 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine and 63 mg (0.32 mmol) 2,4-dichlorophenylboric acid in 4 mL 1,4-dioxane and 1 mL 2 M Na2CO3 solution and the reaction mixture is stirred for 1 h at 110° C. The mixture is evaporated down i. vac. and the residue is extracted twice with in each case 15 mL EtOH. The solvent is removed and the residue is purified by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:6]=2[CH:27]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:36]4[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=4)=[CH:27][C:6]=3[N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (150 mg, 0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (218.50 mg, 88.95 mmol), Cs2CO3 (218.5 mg, 0.67 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.5 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one (70 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.ClC(Cl)C>C(O)(=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Reactant: Brc1ccc2c(c1)NCC2
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
Triacetoxylated sodium borohydride (298 g) was added over 30 min to a mixture of 6-bromoindoline (175 g), 1-(4-fluorophenethyl)-4-piperidone (194 g), acetic acid (250 ml) and dichloroethane (2.5 l) followed by stirring 2 hr. Then the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (2 l), an 8 N aqueous solution of sodium hydroxide (1 l) and water (500 ml) and the layers were separated. The organic layer was washed successively with water (0.5 l) and brine (0.5 l), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot ethyl acetate (500 ml) and then cooled with ice water. The resulting crystalline precipitates were collected by filtration to give the title compound (205 g) (yield: 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(#N)C.CN(C1C=CN=CC=1)C>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[C:4](=[O:16])[CH:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of 4-amino-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.263 g, 1.2 mmol) in acetonitrile (7 mL) was added a DMAP (ca.), triethylamine (0.25 mL, 1.8 mmol) and 4-fluorobenzoyl chloride (0.213 mL, 1.8 mmol). The reaction mixture stirred at 0° C. for 25 minutes and then filtered. The solid was washed with 10% citric acid and water to afford the desired compound (0.326 g, 79%) after drying. 1H-NMR (d6DMSO, 400 MHz) δ 7.98 (m, 2H), 7.71 (d, 1H, J=7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98 (d, 1H, J=2.4 Hz), 6.61 (dd, 1H, J=2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m/z 341.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:26]([O:32][CH2:33][N:10]1[C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][N:4]=2)[C:8]([C:11](=[O:12])[NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:9]1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in DMF (5 mL) was added chloromethyl pivalate (288 mg, 1.92 mmol) followed by K2CO3 (353 mg, 2.56 mmol). The mixture was stirred at room temperature for 16 hours, then poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1, v/v) to give (2-bromo-7-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (305 mg, 44% over two steps) as a yellow solid. MS: (M+H)+=541; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 6.20 (s, 2H), 3.71 (s, 2H), 1.49 (s, 6H), 1.15 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH3:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Br:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Cc1cc(S)ccc1Br
Product: Cc1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)ccc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 189°-199° C.) and 3-methyl-4-bromo-thiophenol.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Ic1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
Following General Procedure A (120° C., 30 hours), phenyl acetylene (84 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol) to give 95% yield 1,1′-ethyne-1,2-diyldibenzene.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCCCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclohexyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Reaction time: 27 h

Procedure:
To a mixture of methyl 2-amino-5-bromobenzoate (9.00 g, 39.1 mmol) and Et3N (7.6 mL, 54.8 mmol) in CH2Cl2 (90 mL) at 4° C. was added 2-phenylacetyl chloride (7.26 g, 46.9 mmol) dropwise. After completion of the addition, the cooling bath was removed and the mixture was stirred for 27 hours. TLC showed that some of the starting material methyl 2-amino-5-bromobenzoate still remained. More 2-phenylacetyl chloride (1.88 g, 12.2 mmol) and Et3N (2.2 mL, 15.9 mmol) were added, and the mixture was stirred overnight. K2CO3 (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. CH3CN (100 mL) was added, and the precipitated solid was filtered, washed with Et2O, and dried to afford the title compound. The filtrate was concentrated in vacuo, and the solid was filtered, washed with Et2O, and dried to provide additional title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7](C)[C:8](=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[NH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][CH3:8])=[C:5]([CH:4]=1)[C:10]([NH2:16])=[O:9]
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2C
Reactant: N
Solvent: C1CCOC1
Product: CNc1ccc(OC)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.50 g (7.24 mmol) 6-Methoxy-1-methyl-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 20 ml tetrahydrofuran and 10.0 ml ammonia (25%) added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>O1CCCC1.CCCCCC>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: COC(=O)/C=C/C(OC)OC
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
3.4 ml of a 1.95 M of butyllithium per liter of hexane were added at -70° C. to a mixture of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and after stirring the mixture for 15 minutes, a solution of 1 g of methyl (E) 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred at -20° C. for one hour and was then poured into an aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an ether-petroleum ether (b.p. =40° to 70° C.) mixture to obain 1.1 g of methyl 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N+:3]=1[O-].C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1.C(OCC)(=O)C>ClC(Cl)C>[Cl:25][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
2-Methyl-6-nitroquinoline N-oxide (13.0 g, 63.72 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (13.5 g, 70.81 mmol) in dichloroethane (200 mL). The reaction was stirred overnight at 100° C. and then stirred at room temperature for 2 days. To the reaction mixture was added ethyl acetate. A solid precipitated and was filtered and recrystallized from acetone/water to afford 7.91 g (56%) of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: Clc1ccc(O[C@@H]2C[C@H]3CNCCN3C2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(CN2CCN3C[C@H](Oc4ccc(Cl)cn4)C[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 57 (76.2 mg, 0.3 mmol) and triethylamine (61 mg, 0.6 mmol) in dichloromethane (2 mL) was added 3-(trifluoromethyl)benzyl chloride (93 mg, 0.48 mmol). The mixture was stirred at 50° C. for 8 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (m, 3H), 2.16-2.26 (m, 3H), 2.38 (m, 1H), 2.70 (m, 1H), 2.86 (m, 2H), 3.60 (m, 3H), 5.24 (m, 1H), 6.83 (d, 1H, J=7 Hz), 7.60 (m, 4H), 7.80 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.40 (s, 1H); MS (ESI) m/z 412 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][OH:11]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: CN1CCC(=NO)CC1

Procedure:
1-Methyl-piperidin-4-one oxime was prepared from 1-methyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (1H, s), 2.45 (2H, t, 6.1 Hz), 2.38 (2H, t, 5.9 Hz), 2.31 (2H, t, J=6.0 Hz), 2.20 (2H, t, 6.4 Hz), 2.18 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][CH2:24][NH2:25])=[C:9]2[CH3:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][CH2:24][NH:25][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:9]2[CH3:26])=[CH:6][CH:7]=1
Reactant: Cc1c(CCN)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(CCNC(=O)c2ccccc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of 2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulphonyl)phenyl)-1H-pyrrol-3-yl)ethanamine (0.20 mmol) in dry DMF (10 mL) cooled at 0° C. and under an atmosphere of N2, TEA (0.20 mmol) was added and the mixture was stirred for 10 min. Then benzoyl chloride (0.20 mmol) was added at 0° C., and the reaction was stirred for 24 h at r.t.; the reaction mixture was washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The residue, purified by flash-chromatography (EtOAc/hexane 7:3 v/v), gave the expected compound as yellow oil (yield 70%). 1H-NMR (CDCl3) δ ppm: 2.03 (s, 3H), 2.80 (t, 2H, J=7.1), 2.97 (s, 3H), 3.67 (m, 2H), 6.43-6.48 (m, 2H), 7.10 (m, 6H), 7.34-7.46 (m, 3H), 7.64 (m, 2H), 7.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1>[Cl:30][C:31]1[N:36]=[C:35]([CH2:37][C:5]([C:4]2[C:3]([O:2][CH3:1])=[C:12]([NH:13][C:14](=[O:15])[O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH:34]=[CH:33][N:32]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1OC
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464 mmol,) in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol, 1440 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) in THF (150 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step E (109.9 g, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.64-13.68 (br, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:34]=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:38]=[C:37]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:36]=[N:35][CH:34]=2)[CH2:29][O:28]1
Reactant: CC1(C)OCC(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CO1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)CO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (80 mg, 0.23 mmol) in 1,4-dioxane (6 mL) and H2O (0.5 mL) under nitrogen was added 3-(2,2-dimethyl-1,3-dioxan-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.35 mmol), and potassium carbonate (96 mg, 7.0 mmol). The mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (12 mg, 0.015 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 20% EtOAc in hexanes to provide 2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (45 mg, 39%). LCMS Method T: retention time 1.75 min; [M+1]=504.2.