Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CCN(C(C)C)C(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCCl>[CH3:19][C:16]1([CH3:20])[C:17](=[O:18])[N:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([NH:1][C:40](=[O:41])[CH2:39][Cl:38])[CH:3]=2)[C:14](=[O:28])[N:15]1[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)CCl)c2)C(=O)N1Cc1ccncc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
500 mg (1.27 mmol) 3-(3-amino-4-trifluormethoxy-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione and 172 mg (1.33 mmol) Hünig's base were dissolved in 20 ml 1,2-dichloroethane. The mixture was cooled to −20° C. and treated with a solution of 143 mg (1.27 mmol) chloroacetylchlorid in 15 ml 1,2-dichloroethane. After stirring 1 h at 0° C., 5 ml ethanolic hydrochlric acid were added and the mixture evaporated to dryness. The raw material, containing huening's base hydrochloride was used without further purification.
Reaction SMILES: C(C1C=CC([C:16]2[NH:17][C:18]3[CH:24]=[C:23](N)[C:22](N)=[CH:21][C:19]=3[N:20]=2)=CC=1)(OC1C=CC=CC=1)=O.C1(S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C1(O)C=CC=CC=1>CO>[N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][CH:16]=1
Reactant: Nc1cc2nc(-c3ccc(C(=O)Oc4ccccc4)cc3)[nH]c2cc1N
Agent: O=S(=O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Oc1ccccc1
Product: c1ccc2[nH]cnc2c1
Temperature: 250 °C
Yield: 169.3 %

Procedure:
A polymerization flask equipped with nitrogen inlet and outlet tubes and mechanical stirrer was thoroughly flamed and purged with nitrogen. To this was added a mixture containing 5.0 g (14.5 mmole) of 2-[p-carbophenoxyphenyl]-5,6-diaminobenzimidazole and 25 g of diphenyl sulfone. The reaction flask was then slowly heated to 250° C and maintained at that temperature for 6 hours. During this time, phenol sublimed from the reaction mixture, and a precipitate formed. The flask was cooled to 125° C and the polymer suspension poured into 500 ml of methanol. The polymer thus precipitated was collected on a filter frit, washed several times with small portions of methanol, and dried. Reprecipitation from methane sulfonic acid into methanol, followed by successive washings with 5% ammonium hydroxide, methanol and benzene, yielded 2.9 g of benzimidazole polymer as a dark tan powder, exhibiting an inherent viscosity of 1.1 dl/g in methane sulfonic acid (0.35 g/dl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccccn1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccn4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 81 mg (yield 82%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]12([CH:26]([CH3:30])[C:27](Cl)=[O:28])[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:27](=[O:28])[CH:26]([C:19]34[O:25][CH:22]([CH2:23][CH2:24]3)[CH2:21][CH2:20]4)[CH3:30])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(C(=O)Cl)C12CCC(CC1)O2
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C(C)C34CCC(CC3)O4)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-(7-oxa-bicyclo[2.2.1]hept-1-yl)-propionyl chloride, the title compound was obtained as white solid (67% yield). MS: m/e=418(M+H+), mp 195-197° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]([NH:19][C:20](N1C=CN=C1)=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:20]([NH:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCCCNC(=O)n1ccnc1
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)NCC(O)CO

Procedure:
The preparation was carried out, according to the same process described in Example 1, from 2.3 g of 3-amino-1,2-propanediol of corresponding formula R2—NH—R3, where R2 denoted H and R3 denoted —CH2—CHOH—CH2OH, and 7 g of 1-N-(dodecylaminocarbonyl)imidazole of corresponding formula (II), where R1 denoted C12H25, in 100 cm3 of methanol.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:7][N:6]([CH3:21])[CH:5]=1)(=[O:3])C.ClN1C(=O)CCC1=O.[Cl:30][CH2:31][Cl:32]>>[Cl:30][CH:31]([Cl:32])[C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[CH:7][N:6]([CH3:21])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Product: Cn1cc(C(=O)C(Cl)Cl)c(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
A 4.5 g. portion of 3-acetyl-1-methyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was dissolved in 125 ml. of dichloromethane, and 2 g. of N-chlorosuccinimide was added. The mixture was stirred under reflux for 60 hours. The mixture was then cooled, and washed successively with 150 ml. each of 1 N sodium hydroxide, 1 N hydrochloric acid, and saturated sodium chloride solution. It was then dried over magnesium sulfate, and evaporated under vacuum to obtain a tan solid. The residue was chromatographed on a 350 g. silica gel column, with 1:10 ethyl acetate:dichloromethane as the eluting solvent. The first product off the column was the dichloroacetyl compound of Example 22, m.p. 184°-186° C., of which 0.6 g. was obtained. Nmr analysis in DMSOd6 showed the following peaks: δ8.4 (s, 1H, CHCl2); 7.6-8.3 (m, 6H, aromatic); 3.9 (s, 3H, N--CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[O:5])(=[O:28])=[O:27])=[CH:24][CH:25]=1)#[N:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1

Procedure:
10 g of 2-amino-2',5-dichlorobenzophenone and 7.7 g of 4-cyanophenylsulfonyl chloride are heated in pyridine at 100° C. for 48 hours in the presence of 4.6 g of DMAP, the mixture is evaporated to dryness, water and ethyl acetate are added, the organic phase is washed with dilute hydrochloric water, water and an aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is evaporated off under vacuum. The precipitate formed is filtered off and then recrystallized twice from a DCM/isopropyl ether mixture to give the expected product.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[N+:24]([C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (10 g) was dissolved in methanol (75 ml) and with the addition of aqueous 1N-sodium hydroxide (75 ml), the mixture was stirred at 30° C for 2 hours. With the slow addition of 3N-hydrochloric acid for neutralization (pH=˜5), water (110 ml) was slowly added to the mixture for precipitate. After 2-hours stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 8.66 g (yield: 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[C:24]([NH2:31])=[N:23]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:8]([C:6]1[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=[C:2]([NH:31][C:24]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:22][N:23]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Reactant: Nc1n[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1cc(Nc2n[nH]c3ncccc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 5.3 %

Procedure:
A mixture of 4-chloro-6-tert-butyl-2-(2-trifluoromethylphenyl)-pyrimidine (0.10 g, 0.32 mmol) and 1H-pyrazolo[3,4-b]pyridin-3-ylamine (0.064 g, 0.48 mmol) was heated neat at 160-170° C. for 16 hours. The resulting residue was cooled, dissolved in N-methyl-pyrrolidinone (2 mL), then poured into water (20 mL) and sodium bicarbonate (5 mL) and extracted twice with ethyl acetate. The combined organic layers were washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to provide the title compound (0.007 g, 4% yield) as a yellow solid. 1H-NMR (500 MHz, DMSO-d) δ 13.2 (br s, 1H), 10.6 (br s, 1H), 8.49 (m, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.76 (m, 2H), 7.68 (m, 1H), 7.12 (m, 1H), 1.32 (s, 9H) ppm; LC-MS 413.08 (M+H); Rt (Method A) 3.112 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (1 g, 4.3 mmol) was added to a mixture of morpholine (435 μL, 5 mmol) and potassium carbonate (690 mg, 5.0 mmol) in 5 mL of DMSO. The mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 950 mg of 4-[2-(4-nitro-phenyl)-ethyl]-morpholine, which was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (880 mg, 99%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.98 (d, J=8.2 Hz, 2H), 6.61 (d, J=8.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.57 (br, 2H), 2.64-2.71 (m, 2H), 2.45-2.56 (m, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([O:13][CH3:14])[O:10][C:9]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]([C:11]([O:13][CH3:14])=[O:10])[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:29][C:9]2=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cn(C(c2ccccc2)c2ccccc2)c(=O)o1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1C(c2ccccc2)OC(=O)N1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 141 mg (0.5 mmol) of 3-diphenylmethyl-5-methoxy-2(3H)oxazolone, and after cooling the solution to −78° C., 53.1 mg (0.5 mmol) of benzaldehyde and 0.05 ml (0.05 mmol) of a methylene chloride solution containing 1.0 M-trimethylsilyl triflate were added to the solution and the mixture was reacted under stirring for one hour. After the temperature of the mixture was raised up to 0° C., 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 20 ml of methylene chloride. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 184 mg (0.476 mmol) of 3-diphenylmethyl-4-methoxycarbonyl-5-phenyl-2-oxzolidinone as white crystal. (Yield based on 3-diphenylmethyl-5-methoxy-2(3H)oxazolone: 95%.) According to HPLC analysis, a formation ratio of cis/trans-isomers of the formed product was 5/95.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][OH:11].CCN(C(C)C)C(C)C.Cl[C:22](OCC)=[O:23]>C1COCC1>[O:23]=[C:22]1[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][O:11]1
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(N)c(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 mmol of 4-Amino-3-hydroxymethyl-benzonitrile were dissolved in THF. 1.2 eq. of DIPEA were added and the reaction cooled to 0° C. 3.5 eq of ethyl chloroformate were added dropwise and the reaction warmed to rt and stirred for another 15 min. The crude material was extracted form etyhlacetate and sat. NaHCO3. After separation, and drying of the organic layer the solvent was evaporated and the crude taken up in toluene. 2.5 ml of DBU were added and the reaction mixture refluxed for 4 h. The organic layer was extracted with water and the organic layer separated and reduced resulting in a yellow oil. Crude material was not further characterized.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:35]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Sulfone 9.1 (1.0 g, 2.41 mmol) was taken up in 5 mL ethyl 4-amino-1-piperidinecarboxylate (29 mmol) and stirred at 150° C. After 1 hour, the reaction slurry was cooled to room temperature, poured into 50 mL methanol, and filtered to collect a white solid. The solid was washed with an additional 50 mL methanol and dried in vacuo to yield 0.569 g of 3-(2-chlorophenyl)-7-(1-ethoxycarbonylpiperidin-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:23]=4)[C:18]([S:33][CH3:34])=[CH:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)(=O)C.ClCCl>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:23]=4)[C:18]([S:33]([CH3:34])=[O:1])=[CH:17]3)=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1cn(-c2ncc(-c3ccnc(C)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen peroxide (30%, 0.4 mL, 3.595 mmol, 4.0 eq) was added to a stirred solution of (1-(5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (400 mg, 0.898 mmol, 1.0 eq, synthesized analogously to procedure 1d) in acetic acid (10 mL). The reaction mixture was stirred for 1 h at room temperature and then diluted with dichloromethane (20 mL). The mixture was washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated under vacuum. The remnant was purified by preparative silica gel TLC [dichloromethane with 3% methanol]. White solid. Yield: 250 mg
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18]>CCCCCC>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1cccc(CCl)c1N
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CCCCCC
Product: COc1ccc2[nH]c(SCc3cccc(C)c3N)nc2c1
Yield: 48.5 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.75 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 4.00 g of 2-(chloromethyl)-6-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Trituration with hexane gave 3.02 g of the title compound: m.p. 132-134° C. Analysis. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 64.21; H, 5.77; N, 14.00; S, 10.38.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[S:32](N)([NH2:35])(=[O:34])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(S(N)(=O)=O)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), sulfamide (3.35 mg, 0.0349 mmol) and dioxane (2 mL) was heated to 90° C. overnight in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.09-2.25 (m, 4 H), 2.76-2.91 (m, 2H), 3.78 (d, J=12.4 Hz, 2 H), 4.30 (dt, J=10.4, 5.3 Hz, 1 H), 5.29 (q, J=7.4 Hz, 1 H), 7.15-7.23 (m, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.38-7.53 (m, 2 H), 7.58 (s, 1 H), 7.92 (s, 1 H), 8.32 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 537.02 (100) [MH+]. HPLC: tR=3.36 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[O:13]CC(C)(C)CO2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH3:33][N:34](C)C=O>[Cu+]>[C:23]([C:22]1[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH2:16][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:33]#[N:34])=[CH:7][CH:6]=1)=[O:13])#[N:24]
Reactant: CN(C)C=O
Reactant: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Agent: [Cu+]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(C(=O)CCCOc2cccc(C#N)c2)cc1

Procedure:
500 mg (1.16 mmol) of 3-[3-[2-(4-bromophenyl)-5,5-dimethyl-1,3-dioxane-2-yl]propoxy]benzonitrile and 114 mg (1.27 mmol) of copper (1) cyamide were stirred in 1 ml of dimethylformamide at 140° C. overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the resultant mixture. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated. 10 ml of ethanol and 2 ml of 6 N hydrochloric acid were added to the residue, and the resultant mixture was heated under reflux for 5 hours. The solvent was evaporated. 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate, the extract was washed with saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel chromatography with ethyl acetate hexane as the extractant to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzeneacetamide (3.0 g, 0.022 mol) was dissolved in dichloromethane (60 mL) and N-bromosuccinimide (4.0 g, 0.022 mol) was added. The reaction was stirred at room temperature under UV light for 24 hr. The mixture was poured into water and the layers were separated. The organic layer was washed with water (2×50 mL) then with brine (1×50 mL). The organic layer was dried (magnesium sulfate) then chromatographed on silica (40% ethyl acetate/hexanes) to give 2-Bromo-2-phenylacetamide, compound h Rf 0.37, 40% ethyl acetate/hexanes; MS m/z 216 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][C:20]([OH:24])=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[C:20]([OH:24])=[N:19][CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc(Cl)cnc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Temperature: 160 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (226 mg), 3-chloro-5,6-dihydroxypyridine (290 mg), and 4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (83 mg, yield 25%).