Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl:27][C:28]1[C:29]2[C:36](I)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:27][C:28]1[C:29]2[C:36]([C:8]3[CH:7]=[CH:6][C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[C:4]([O:3][CH3:2])[CH:9]=3)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 81.3 %

Procedure:
A mixture of water (25 ml) and tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (65% pure) (4.25 g, 7.92 mmol) was frozen and subjected to vacuum followed by filling with nitrogen while defreezing. 4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.83 g, 5.28 mmol), tetrakis (triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), sodium carbonate (1.40 g, 13.20 mmol) and ethylene glycol dimethyl ether (50 ml) were added and the resulting mixture was heated at 80° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate twice. The combined ethyl acetate extracts were dried over magnesium sulfate and evaporated to give a dark oil which was purified by flash column chromatography on silica using n-heptane/ethyl acetate (3:1) with 2% triethylamine as the mobile phase. Appropriate fractions were collected, combined and concentrated to give tert-butyl N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate as white solids (1.90 g, 4.29 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 7.94 (s, 2H), 7.74 (d, 1H), 7.19 (d, 1H), 7.07 (dd, 1H), 5.22 (m, 1H), 3.87 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.73 (m, 2H), 1.48 (s, 9H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.58.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH2:11].O=[C:13]1[CH2:17][S:16][CH2:15][CH:14]1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:6]([Cl:10])=[CH:5][C:4]2[NH:11][C:18](=[O:20])[C:14]3[CH2:15][S:16][CH2:17][C:13]=3[N:2]([CH3:1])[C:3]=2[CH:8]=1
Reactant: CNc1cc(Cl)c(Cl)cc1N
Reactant: COC(=O)C1CSCC1=O
Solvent: Cc1ccccc1
Product: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)c(Cl)cc21

Procedure:
A solution of 2.7 g. of N-methyl-4,5-dichloro-o-phenylenediamine and 1.85 g. of methyl tetrahydro-4-oxo-3-thiophenecarboxylate in 150 ml. of toluene is heated under reflux for 3 hours during which 100 ml. of distillate is collected in a Dean-Stark trap. The solution is cooled and the solid which separates is recrystallized from ethyl acetate to give yellow crystals, m.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][C:23](=O)OCC4C=CC=CC=4)=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.Br.[C:36](O)(=O)C>>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH2:23][CH3:36])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(Nc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12)OCc1ccccc1
Agent: Br
Product: CCNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate in acetic acid was added HBr (30% in AcOH). The solution was stirred at room temperature for 2 hours and afterwards the solvent was removed under reduced pressure. The residue was dissolved several times in toluene and the solvent removed under reduced pressure. The resulting solid was dissolved in 1,2-dichloroethane-MeOH (1:1), acetaldehyde and sodium cyanoborohydride were added, and the mixture stirred at room temperature. After 30 minutes the solvent was removed under reduced pressure and the residue washed with H2O.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c(C)cc1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 2,5-dimethyl-4-hydroxyaniline gave N2-(2,5-dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.69 (d, 1H, J=3.9 Hz), 7.16 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 7.02 (d, 1H, J=1.2 Hz), 6.66 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 4.19 (s, 4H), 2.12 (s, 3H), 2.10 (s, 3H); LCMS: ret. time: 19.80 min.; purity: 90%; MS (m/e): 383 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (4.50 g) in THF (41.7 mL) were added triethylamine (3.49 mL) and methanesulfonyl chloride (1.94 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.01 g).
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.[Cl-].Cl[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][NH+:18]=1.[OH-].[Na+]>C(O)C.O>[CH3:24][O:23][C:21]1[C:20]([O:25][CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[CH:22]=1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)cc1OC

Procedure:
A brownish solid is obtained by the procedure described in Example 13 by reaction of 0.85 g of 5H-[1,3]-dioxolo[4,5-f]-benzimidazole-6-thiol with 0.98 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 10 ml of ethanol and 10 ml of water, with the addition of 8.5 ml of 1N sodium hydroxide solution, after a reaction time of 20 hours and after concentration, by removing the solvent in vacuo, to a volume of 10 ml. The crude product is dissolved in 30 ml of methylene chloride, the solution is clarified with fuller's earth (for example, Tonsil®), and concentrated. The residue is crystallized by addition of diisopropyl ether and the now pale yellow solid is boiled up in 5 ml of methanol. 0.90 g (60% of theory) of the title compound is obtained as a colorless solid of m.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH:33]3[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1COCCN1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (960 mg, 2.076 mmol; Example 210, Step A) in 1,2-dichloroethane (15 mL) was added 3-methylmorpholine (Enamine Ltd, Kiev, Ukraine) (0.471 mL, 4.15 mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[S:1]1[C:5]2=[CH:6][N+:7]([O-:18])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cc2ccsc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2ccsc2c1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 18 g of thieno[2,3-c]pyridine in 300 ml of chloroform was added 33 g of 3-chloroperbenzoic acid portionwise with ice-cooling over a period of 1 hour, and the mixture was stirred for further 1 hour under the same conditions. The reaction mixture was diluted with 400 ml of chloroform, washed successively with water, a saturated sodium carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 16.6 g of thieno[2,3-c]pyridine-N-oxide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([OH:21])[C:18]=1[CH2:19][OH:20].[CH2:23](I)[CH3:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([O:21][CH2:23][CH3:24])[C:18]=1[CH2:19][OH:20]
Reactant: CCI
Reactant: Cc1ncc(Cn2cnc3c(Cl)nc(N)nc32)c(CO)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C)ncc(Cn2cnc3c(Cl)nc(N)nc32)c1CO
Temperature: 50 °C

Procedure:
A mixture of 6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine (see previous example), EtI (excess), K2CO3 (excess) and DMF was heated to 50° C. for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the title compound. HPLC Rt: 3.720 min. 1H-NMR (CDCl3) δ 8.27 (s, 1H), 7.90 (s, 1H), 5.40 (s, 2H), 5.11 (s, 2H), 4.85 (d, 2H), 4.50 (t, 1H), 3.95 (q, 2H), 2.51 (s, 3H), 1.45 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>Cl>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(=O)[nH]c2ccccc12
Agent: Cl
Product: Cc1nc(Cl)nc2ccccc12

Procedure:
Prepared analogously to Example 27c from 4-methyl-1H-quinazolin-2-one and phosphorus oxychloride in hydrochloric acid.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:31]=[O:32]>CCN(CC)CC>[CH2:1]([CH:8]1[CH:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[CH2:12][CH2:11][N:10]([C:31]([NH:30][C:33]2[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1N=C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)N1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccccc2)C1
Yield: 57456.6 %

Procedure:
The compound (0.15 g) obtained in Example 404 and ethyl 2-isocyanatobenzoate (0.076 mg) were reacted and treated in the same manner as in the method described in Example 6 excluding Et3N to obtain the title compound as pale yellow oil (0.139 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[C:36]([OH:38])=[O:37])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 51.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellowish solid (0.30 g, 52%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 4-(hydrazinocarbonyl)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 334 mg of the title compound (86%) as a yellow solid in 98.3% purity by HPLC (Rt: 5.21, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:29]=[N:30][CH:31]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)C>[CH3:17][N:15]1[CH:16]=[C:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)(=[O:34])=[O:35])[CH:29]=[N:30][CH:31]=2)=[CH:3][CH:4]=3)[CH:13]=[N:14]1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)cn1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (5.98 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (6.78 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.18 mmol) in 2M aqueous sodium carbonate (15 mL) and 1,4-dioxane (40 mL) was heated at 100° C. for 22 h. Additional N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.83 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.09 mmol), and 2M aqueous potassium carbonate (3 mL) were added and the reaction mixture was heated at 100° C. for 22 h for complete consumption of starting material. The reaction mixture was cooled, diluted with diethyl ether (30 mL), and filtered through a pad of Celite while rinsing with (2×30 mL) diethyl ether. The organic layer was poured into a separatory funnel containing water (100 mL) and the layers were separated. The aqueous layer was acidified with 6N aqueous HCl until the pH was approximately 7 and then further extracted with (3×200 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate with decolorizing activated carbon, filtered through a pad of Celite while rinsing with (2×100 mL) ethyl acetate, and concentrated in vacuo. The filtrate was separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the residue from hot ethyl acetate afforded the title product as an ivory solid (804 mg, 30%). Additional product was obtained from the concentrated mother liquors after purification by silica gel chromatography (70-100% ethyl acetate/hexanes) followed by precipitation from cold ethyl acetate (534 mg, 20%). MS(ES)+ m/e 443 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=1)([O-:21])=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[N:26][CH:27]=1)([O-:21])=[O:20]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ccc([N+](=O)[O-])cn4)cc23)CC1
Yield: 42.5 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.212 g, 0.88 mmol), 5-nitro-2-chloropyridine (0.314 g, 1.98 mmol), and 4-dimethylaminopyridine (0.085 g, 0.7 mmol) in dry DMF (2 mL) was refluxed 8 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated 0.5N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×4 inches). Gradient elution with from 50% to 90% ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.136 g of orange oil. Recrystallization from isopropanol followed by recrystallization from nitromethane gave 0.005 g (1.4%) of the title product as orange crystals: mp 121°-125° C. Analysis calculated for C20H21N5O2 ·H2O; C, 62.98; H, 6.08; N, 18.36. Found: C, 62.86; H, 5.84; N, 18.13.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH3:13])[C:7]2=[O:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:15])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=S)[nH]c2c(I)cccc2c1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2c(I)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
At RT, to a mixture of 8-iodo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (11.2 g g, 35.3 mmol) and K2CO3 (9.76 g, 70.6 mmol) in THF (100 mL) was added MeI (6.58 mL, 106 mmol). The reaction was heated to reflux for 6 h, and then cooled to RT. The mixture was poured into ice/water (300 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) followed by cold ether (20 mL). The solid was dried to give 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 11.4 g, 97% yield) as an off-white solid. Crude material was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (1H, dd, J=7.6, 1.4 Hz), 8.08 (1H, dd, J=7.8, 1.4 Hz), 7.19 (1H, t, J=7.7 Hz), 3.51 (3H, s), 2.73 (3H, s). m/z (ES, +ve) 332.9 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])(=[O:35])=[O:34])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=S(=O)(Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1)c1ccccc1F

Procedure:
N-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was prepared according to the procedure outlined in Example 44, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (150 mg) and 2-fluorobenzenesulfonyl chloride (55 mg). The resultant white solid was purified using an ISCO autocolumn eluting with 100% ethyl acetate. N-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 511 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[CH3:28][N:29]([CH3:39])[C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CN(C)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(=O)N1CCC(Cc2ccc3nc(-n4c(N(C)C)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone from Example 148 (0.125 g) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 47.5 mg of 165 following reverse phase HPLC purification. MS (Q1) 515.2 (M)+
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)[CH2:9]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
To the obtained (−)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (27.5 g) were added 50% aqueous 10% palladium-carbon (6 g) and ethanol (400 ml), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 6 hr. After celite filtration, the filtrate was concentrated and ethyl acetate was added to the obtained residue. The precipitated crystals were collected by filtration to give (−)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (16.8697 g)