Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1-n1ccnc1SCCCOc1ccc2c(c1)CCC(=O)N2
Solvent: ClCCl
Product: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 56.7 %

Procedure:
In 1 liter of dichloromethane was dissolved 67 g of 6-{3-[1-(2-methylphenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril. Thereto was added 32.6 g of m-chloroperbenzoic acid with ice-cooling. The mixture was stirred overnight. After the completion of the reaction, the reaction mixture was washed five times with an aqueous solution saturated with sodium hydrogencarbonate, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/ethyl acetate/methanol=30/10/1). The crude crystals were recrystallized from ethanol-n-hexane to obtain 39.5 g of 6-{3-[1-(2-methylphenyl)-2-imidazolylsulfinyl]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl>[CH3:1][C:2]1([C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[O:7])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2(C)CC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
1-Methyl cyclopropane carboxylic acid (2.96 g, 29.54 mmol) was added to a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (5 g, 26.85 mmol) in dichloromethane (135 ml) at room temperature. Triethylamine (9.4 ml, 67.13 mmol) was then added. The reaction was cooled down to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate, 17.4 ml, 29.54 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was diluted in dichloromethane (100 ml) and a 20% aqueous potassium carbonate solution (80 ml) added. The mixture was stirred at room temperature for 18 hours and the layers separated. The organic layer was washed with 20% potassium carbonate solution (50 ml), brine (80 ml), dried over magnesium sulfate, concentrated in vacuo and azeotroped with diethyl ether to provide the title compound as a white solid (6.815 g, 95%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[N:9]([CH3:23])[C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.[OH-].[K+].Cl>C(O)C>[C:13]12([CH2:12][CH2:11][C:10]3[N:9]([CH3:23])[C:8]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[N:7][C:6]=3[C:4]([OH:5])=[O:3])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: CCOC(=O)c1nc(-c2ccccc2C)n(C)c1CCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Temperature: 50 °C
Yield: 94.6 %

Procedure:
To a solution of 5-(2-adamantan-1-yl-ethyl)-1-methyl-2-o-tolyl-1H-imidazole-4-carboxylic acid ethyl ester (397 mg, 0.98 mmol) in ethanol (30 ml) was added 2.0M potassium hydroxide solution (3.4 ml). The solution was heated at reflux for 16 h, cooled to 50° C. and acidified (1M hydrochloric acid, pH=3-4). The ethanol was evaporated, the residue was diluted with water (30 ml) and the product was extracted with DCM. The organic layer was dried (MgSO4) and the solvent was evaporated to afford the product as a white solid (351 mg, 95%). 1H NMR (300MHz, CDCl3) 7.41-7.27 (4H, m), 6.00 (1H, br s), 3.38 (3H, s), 3.01 (2H, m), 2.20 (3H, s), 2.01 (3H, s), 1.70 (6H, m), 1.61 (6H, s), 1.37 (2H, m).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Cl:16][C:17]1[C:18]([C:26]([NH2:28])=[O:27])=[N:19][C:20]([CH2:24][CH3:25])=[C:21](Cl)[N:22]=1>CN(C)C=O>[C:26]([C:18]1[N:19]=[C:20]([CH2:24][CH3:25])[C:21]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:22][C:17]=1[Cl:16])(=[O:27])[NH2:28]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Cl)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g) and N,N-dimethylformamide (30 mL) was added 55% oily sodium hydride (233 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.18 g) was added thereto, followed by further stirring for 1 hour under ice-cooling. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to obtain tert-butyl 3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (795 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]([CH3:29])[CH3:28].Cl.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([N:27]([CH3:29])[CH3:28])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(N(C)C)c3)nc2N1C1CCCC1
Temperature: 140 °C
Yield: 61 %

Procedure:
To the solution of (R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 200 mg, 0.56 mmol) in 5 mL of DMSO, (CH3)2NH HCl (200 mg 5.6 mmol) and Na2CO3 (130 mg, 1.2 mmol) were added. The mixture was heated to 140° C. for 18 hr in a sealed tube, quenched with water and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure, and chromatographed (CH2Cl2:CH3OH=15:1) to give the title compound as a white solid (130 mg, 60% yield). 1H NMR (CDCl3) δ: 8.27 (d, 1H), 7.97 (s, 1H) 7.49 (s, 1H), 7.43 (d, 1H), 4.35-4.29 (m, 2H), 3.39 (s, 3H), 3.18 (s, 6H), 2.1-1.7 (m, 10H) and 0.87 ppm (t, 3H); LCMS: 381.3 m/z (M+H)+; ret. Time: 1.44 min (Analytical Method E).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:11])[CH:9]=[CH2:10].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51]Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:38][CH2:39]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([O:11][CH2:49][O:50][CH3:51])[CH:9]=[CH2:10]
Reactant: COCCl
Reactant: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CC(OCOC)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a solution of 6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (210 mg, 0.37 mmol) in THF (7 mL) was added DIEA (0.084 mL, 0.48 mmol) and chloromethyl methyl ether (0.16 mL, 2.12 mmol). The reaction mixture was heated at 50° overnight. Another portion of DIEA (0.32 mL, 1.85 mmol) was added and heating was continued for another 5 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (175 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (q, 1H), 8.10 (s, 1H), 7.93-8.00 (m, 2H), 7.36-7.53 (m, 5H), 7.19 (s, 1H), 5.88 (ddd, 1H), 5.38 (d, 1H), 5.18-5.30 (m, 2H), 4.66 (d, 1H), 4.53 (d, 1H), 3.38-3.46 (m, 3H), 3.23 (s, 3H), 2.83 (d, 3H), 2.08-2.17 (m, 1H), 0.92-1.06 (m, 1H), 0.75-0.91 (m, 2H), 0.39-0.51 (m, 1H). LCMS (m/z, ES+)=613 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C(N(CC)CC)C.O.[NH2:45][NH2:46]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:45][NH2:46])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 4-(tert-butyl-dimethylsilanyloxy-methyl)-3-nitrobenzoic acid (1.00 g, 3.22 mmol), N,N,N′,N′-tetramethylfluoroformamidinium hexafluoro-phosphate (852 mg, 3.23 mmol) and triethylamine (0.90 mL, 6.44 mmol) in dimethylformamide (13 mL), hydrazine monohydrate (0.31 mL, 6.43 mmol) was added at 0° C., and then the reaction mixture was stirred at 0° C. for 8 hours To the reaction mixture was added water (10 mL), then the precipitated solid was filtrated and dried by means of a vacuum pump to give the desired product as a pale gray solid (461 mg, yield 44%).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:17][CH2:18]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:2]([N:9]([CH2:17][CH2:18][O:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:39][CH:38]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(COc2ccc(OCCN(Cc3ccccc3)Cc3ccccc3)cc2)cc1

Procedure:
The material given in Example 1 was prepared in accordance with the following. 20.0 g. of N,N-dibenzyl-2-chloroethylamine hydrochloride and 27.6 g of potassium carbonate were mixed in 250 ml of acetonitrile. The mixture was refluxed for 15 min. and 13.8 g of 4-benzyloxyphenol were added, whereupon the mixture was refluxed for 5 hours while stirred. After filtration and evaporation the residue was recrystallized from petroleum ether. 18.4 g of 1-(N,N-dibenzylamino)-2-(4-benzyloxyphenoxy)-ethane was obtained. The structure was determined using NMR.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]2=[CH:5][CH:4]=1.[CH2:15](O)[CH3:16]>>[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:6]2=[CH:5][CH:4]=1
Reactant: CCO
Reactant: O=C(O)c1cc2ccc(Cl)nc2[nH]1
Agent: Cl
Product: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Yield: 25 %

Procedure:
HCl gas is bubbled through a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (36 g, 183 mmol) in ethanol (500 mL) at 0° C. for 30 min. The reaction mixture is then heated at reflux for 16 h. The solvent is evaporated and the residue is diluted with CH2Cl2 and filtered. The filtrate is evaporated and the residue is washed with diethyl ether (2×250 mL). The organic layers are dried (Na2SO4) and concentrated. The crude residue is purified by passing through the column of neutral alumina, eluting with 10% EtOAc/hexane to afford the title compound as a white solid (10 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH2:21][CH2:22][CH3:23]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:21]([C:20]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:22][CH3:23]
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Yield: 102.3 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (10.0 g, 38.6 mmol) was treated according to a modification of the method described in Part B of Example 8. After the addition of trimethyl orthobutyrate (7.71 mL, 48.2 mmol) and pyridinium p-toluenesulfonate (0.200 g, 0.796 mmol), the reaction was heated at reflux for one hour and subjected to the work-up procedure to provide 12.3 g of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate, which was used without purification.
Reaction SMILES: Cl.[O:2](C1C=CC(S(N[C@@H]2[C@@H](S)CNC2)(=O)=O)=CC=1)[C:3]1C=CC=C[CH:4]=1.[C:25]([N:32]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([N:38]=[N+:39]=[N-:40])[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])(=O)C.[K+]>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:25]([N:32]1[CH2:36][C@@H:35]([O:37][C:3](=[O:2])[CH3:4])[C@@H:34]([N:38]=[N+:39]=[N-:40])[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: O=S(=O)(N[C@H]1CNC[C@@H]1S)c1ccc(Oc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 0 °C
Yield: 86 %

Procedure:
(3S,4S)-3-(4-Phenoxybenzenesulfonamido)-4-mercaptopyrrolidine Hydrochloride. A solution of (3S,4S)—N-Boc-3-azido-4-hydroxypyrrolidine (850 mg, 3.72 mmol) and triethylamine (622 μL, 4.46 mmol) in CH2Cl2 (10 mL) was cooled with stirring to 0° C., and methanesulfonyl chloride (331 μl, 4.28 mmol) was added dropwise. The solution was stirred at room temperature until no starting material was detected by TLC (25% ethyl acetate in hexane). The reaction mixture was washed with 10% aq. citric acid, water, dried over Na2SO4 and evaporated. The residual crude methanesulfonate was dissolved in anhydrous DMF (20 mL), potassium acetate (1.10 g, 11.2 mmol) was added, and the mixture was stirred at 105° C. under nitrogen for 6 hr. The reaction mixture was poured into ice water and was extracted with ethyl acetate (20 ml×3). The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (25% ethyl acetate in hexane) to give (3S,4R)—N-Boc-3-azido-4-acetoxypyrrolidine (860 mg, 86%): 1H NMR (300 MHz, CDCl3) δ 5.31 (br m, 1H), 4.07 (m, 1H), 3.60-3.71 (m, 2H), 3.36-3.50 (m, 2H), 2.16 (s, 3H), 1.46 (s, 9H); [α]20D=−34.5° (c=1.00, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][NH:15][CH2:16][C:17]1[CH:26]=[N:25][C:24]2[N:23]([CH3:27])[CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.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]>[Cl:13][C:5]1[CH:4]2[CH:9]([CH:10]=[CH:11][C:2]([N:15]([CH3:14])[CH2:16][C:17]3[CH:26]=[N:25][C:24]4[N:23]([CH3:27])[CH2:22][CH2:21][O:20][C:19]=4[CH:18]=3)=[CH:3]2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: CNCc1cnc2c(c1)OCCN2C
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(Cc1cnc2c(c1)OCCN2C)C1=CC2C(Cl)=NNC(=O)C2C=C1
Yield: 1.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (275 mg, 1.06 mmol), N-methyl-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methylamine (250 mg, 1.29 mmol), Pd2(dba)3 (113 mg, 0.123 mmol), xantphos (214 mg, 0.370 mmol) and NaOtBu (380 g, 3.696 mmol) in dioxane (6 mL) was heated at 80° C. for 3.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-[methyl-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylmethyl)-amino]-4a,8a-dihydro-2H-phthalazin-1-one (5 mg) as a yellow solid. 1H (400 MHz, d6-DMSO) δ: 2.98 (s, 3H), 3.18 (s, 3H), 3.38 (t, 2H), 4.18 (t, 2H), 4.6 (s, 2H), 6.81 (d, 1H), 6.90 (d, 1H), 7.37 (dd, 1H), 7.61 (d, 1H), 8.00 (d, 1H), 12.40 (s, 1H) ppm; m/z (M+1) 372.21.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:5]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:1][OH:2])=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(CO)(CO)CO
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(CC(CO)(CO)CO)(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 57.6 %

Procedure:
Trimethylolpropane (26.84 g, 0.2 mole) was treated with p-nitrobenzoyl chloride (117 g, 0.63 mole), following the general procedure described in Example 1. Part A. The product was worked up in the usual way, except that precipitation occurred during the treatment with saturated aqueous sodium bicarbonate. The mixture was therefore heated to effect solution, the phases separated, the organic phase washed with saturated sodium bicarbonate (3×), and dried over MgSO4. The product crystallized during drying and the mixture was therefore heated to boiling, filtered hot, the solid washed with hot ethyl acetate and hexanes added to the filtrate to induce crystallization. The product, tris-(4-nitrobenzoyl)-trimethylolpropane (67 g) was obtained at a pale yellow solid, m.p. 104°-106° C., which was homogeneous by TLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1.O.[Cl-].[Na+]>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N
Yield: 17.5 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (80 mg, 0.16 mmol, Example 272), potassium iodide (200 mg, 1.2 mmol), morpholine (200 mg, 4.3 mmol) in dioxane (12 mL) was heated at reflux under nitrogen for 48 hours. The resulting solution was diluted with 20 mL of cold water plus 20 mL of saturated aqueous sodium chloride. Solids were filtered and dissolved in methylene chloride. The organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (triethylamine/methanol/methylene chloride 1:10:90) and crystallized from methylene chloride/hexane to give [4-amino-2-[1-(3-morpholin-4-yl-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (15 mg, 17% yield). HRMS, observed: 537.2296; Calcd for (M+H)+: 537.2290
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH3:9])[NH:4][C:3]=1[CH:10]=[O:11].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:4]3[C:3]([CH:10]=[O:11])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH3:9])=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (3.0 g, 13.7 mmol), 4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (4.8 g, 13.7 mmol), and potassium carbonate (1.9 g, 13.7 mmol), were dissolved in DMF (60 mL, 780 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The resulting material was purified by silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate (17a) (5.6 g). MS m/z: [M+H+] calcd for C24H25BrN2O4, 485.1. found 485.3. 1H-NMR (CDCl3): 9.58 (1H, s), 7.80 (1H, d), 7.50 (1H, t), 7.40 (1H, t), 7.30 (5H, m), 5.42 (2H, s), 4.57 (2H, q), 1.46 (3H, t), 1.18 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 33 %

Procedure:
2-Hydroxycarbazole (0.5 g, 2.7 mmol), ethyl 6-bromohexanoate (0.6 g, 2.7 mmol), and potassium carbonate (0.4 g, 3.0 mmol) in dimethyl formamide (10 ml) were heated to 120° C. for 24 h. Water was added and extraction with ethyl acetate was performed. The combined organic phases were washed with water and dried (sodium sulfate). The solvent was removed i. vac. and the residue was purified by column chromatography (silica gel, ethyl acetate: heptane=1:1) to give ethyl 6-(9H-carbazol-2 yloxy)-hexanoate (290 mg, 33%) as a colorless solid. MS (M−H+)324.