Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:19][CH3:20])[S:12][C:13]([C:14]([O:16]CC)=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:19][CH3:20])[S:12][C:13]([C:14]([OH:16])=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1nc(C)oc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1sc(C(=O)O)c2c1-c1oc(C)nc1CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylate (1.88 g) was suspended in a mixed solvent of ethanol (15 ml) and tetrahydrofuran (10 ml); a 2 N aqueous solution of sodium hydroxide (9.1 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 2 hours, the solution obtained was poured over water (300 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylic acid (1.61 g, 94.2%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point over 300° C.
Reaction SMILES: [OH:1][CH:2]([CH2:22]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11].[BrH:24].[C:25]([OH:28])(=O)[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[C:25]([O:1][CH:2]([CH2:22][Br:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])(=[O:28])[CH3:26]
Reactant: CC(=O)O
Reactant: Br
Reactant: Cn1cnc2c1c(=O)n(CCCCCCC(O)CO)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A mixture of 1-(7,8-dihydroxyoctyl)-3,7-dimethylxanthine, prepared as described above, (2.11 g, 6 mmol) was stirred with a 30% solution of hydrogen bromide in acetic acid (3.58 mL, 18 mmol) for 90 minutes. The mixture was then added to a flask containing aqueous sodium bicarbonate solution (4 g in 50 mL) and dichloromethane (30 mL). After 10 minutes of vigorous stirring the layers were separated and the aqueous portion was washed with dichloromethane (2×50 mL). The combined organic portions were dried over sodium sulfate and the solvent was evaporated under vacuum, yielding 2.51 g (94%) 1-(7-acetoxy-8-bromooctyl)-3,7-dimethylxanthine (inventive compound no. 1514) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[O-]CC.[Na+]>C(O)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:11][CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(=O)n2ccsc2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (200 mg, 1.206 mmol) in ethanol (30 ml) was added 4-chlorobenzaldehyde (253 mg, 1.795 mmol) followed by sodium ethoxide (122 mg, 1.795 mmol) in ethanol at room temperature. The reaction mixture was heated to reflux for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue obtained was partitioned between chloroform (100 ml) and water (50 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 2% acetone in chloroform to give 59 mg of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 6.25 (s, 1H), 6.87 (d, J=15.6 Hz, 1H), 6.94 (d, J=4.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.73 (d, J=15.6 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 289.37 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCSC[C@@H]12
Temperature: 90 °C

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (70 mg, 0.279 mmol) in propiononitrile (Volume: 696 μl) was added (cyanomethyl)trimethylphosphonium iodide (81 mg, 0.334 mmol), DIEA (146 μl, 0.836 mmol) and finally 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64.1 mg, 0.279 mmol). The vial was heated to 90° C. for 12 hours. Cooled to rt and concentrated to a brown residue which was treated with MeOH (5 mL). The precipitate was filtered, the solids were collected, taken up in EtOH (15 mL) and refluxed 2 hours. Let sit at RT ON. Filtered, dried in vacuum and retrieved 75.6 mg (63.6%) of the title compound as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.80 (d, J=1.8 Hz, 1H), 7.66 (br. s., 1H), 7.30 (d, J=3.8 Hz, 5H), 7.04 (br. s., 1H), 6.02-6.09 (m, 1H), 5.06 (ddd, J=13.5, 2.8, 2.7 Hz, 1H), 4.42 (dd, J=10.5, 3.2 Hz, 1H), 3.54 (br. s., 2H), 3.10-3.26 (m, 3H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.85-2.92 (m, 1H), 2.75 (br. s., 2H), 2.56 (br. s., 2H), 2.35-2.44 (m, 1H). [M+H] calc'd for C22H23ClN4OS, 427. found, 427.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO.C(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1
Reactant: COCCCO
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@H]2C)c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COCCCN1C(=O)[C@@H](C)N(Cc2ncc(C)c(OC)c2C)c2nc(N)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
(7R)-2-Amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 2[2])(60 mg, 0.18 mmol) was suspended in THF (10 mL) and the 3-methoxy-1-propanol (70 μL, 0.73 mmol) was added, followed by triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol). The mixture was stirred at room temperature for 2 hours. A further quantity of triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol) were added and stirring continued for 2 hours. A further quantity of triphenylphosphine (192 mg, 0.73 mmol) and DIAD (144 μL, 0.73 mmol) were added and stirring continued overnight. TLC and LCMS analysis showed complete reaction; the mixture was diluted with methanol (5 mL) and loaded onto an SCX-2 column which had been equilibrated with 30% methanol in DCM. The column was eluted with 30% methanol in DCM to remove impurities, then with 30% (3M NH3 in methanol) in DCM to elute the product. The appropriate fractions were concentrated in vacuo; the residue (about 40 mg) was found to be a mixture of N- and O-alkylated products. The sample was dissolved in methanol (5 mL) and 6N HCl (2 mL) was added. The mixture was stirred at room temperature for 2 hours. LCMS showed complete hydrolysis of the O-alkylated material; the desired N-alkylated material was unchanged. The mixture was concentrated in vacuo and the residue was purified by chromatography, eluting with 0 to 5% (10:1 methanol/concentrated NH3 (aqueous)) in DCM. The appropriate fractions were concentrated under reduced pressure to give the title compound as a pale yellow gum (20 mg, 27%); 1H NMR spectrum (400 MHz, CDCl3) δ 1.36 (3H, d), 1.89 (2H, ddt), 2.17 (3H, s), 2.25 (3H, s), 3.39 (2H, td), 3.75 (3H, s), 3.81 (1H, dd), 3.97 (1H, dd), 4.03 (1H, q), 4.09 (1H, d), 4.67 (2H, s), 5.70 (1H, d), 7.70 (1H, s), 8.18 (1H, s); Mass spectrum: (M+H) 401.
Reaction SMILES: [Cl:1][C:2](=[O:8])[C:3]([O:5]CC)=O.[CH3:9][N:10]([CH3:26])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19])=[CH:13][CH:12]=1>ClCCl>[ClH:1].[CH3:26][N:10]([CH3:9])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:2](=[O:8])[C:3](=[O:5])[N:20]([CH2:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:18]2=[S:19])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CN(C)c1ccc(NC(=S)NCC(C)(C)C)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(N2C(=O)C(=O)N(CC(C)(C)C)C2=S)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Ethyl chlorooxoacetate (3.4 mL, 30 mmol) was added dropwise to a stirring solution of N-[4-(dimethylamino)phenyl]-N′-(2,2-dimethylpropyl)-thiourea (3.98 g, 15 mmol) in dichloromethane (100 mL) and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was treated with ether (100 mL) and the mixture was stirred for one hour. The solid was collected by filtration, washed with fresh ether and dried to give 5.3 g (100%) of the title compound: mp. 244–246° C.; 1H NMR (DMSO-d6): δ7.28 (d, 2H), 7.20 (br s, 2H), 3.74 (s, 2H), 3.02 (s, 6H), and 0.98 ppm (s, 9H); IR (KBr) 3640, 3080, 2350, 1775 cm−1; MS (m/z) 319 (M+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C([C:17]([O-:19])=[O:18])C.C(O)(=O)C.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[Cl:24][S:25]([C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[C:11]3[NH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[C:10]=3[C:9]=2[CH:8]=1)(=[O:27])=[O:26]
Reactant: CCC(=O)[O-]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Solvent: CC(=O)O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Temperature: 85 °C
Yield: 100 %

Procedure:
In a sealed tube, 1.42 g (4.5 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid (synthesis 1) is dissolved in 6 mL (90 mmol) of chlorosulfonic acid. The reaction mixture is placed on an oil bath heated beforehand to 85° C. for 20 minutes, cooled on an ice bath then poured slowly onto crushed ice. The solid is filtered, rinsed with water, diisopropyl ether and pentane then dried under vacuum to give 1.47 g (quantitative) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example l(a)), (0.15 g, 0.61 mmol) and 5-hydroxyindole (0.24 g, 1.8 mmol, Aldrich) in 1,4-dioxane (12 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 4 h, and after cooling to room temperature, the solvent was removed in vacuum. EtOAc (15 mL) was added to the residue, and the organic layer was washed with 1 N NaOH (10 mL), water (10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (3 mL). Water (5 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 143-145° C. MS (ESI, pos. ion) m/z: 344 (M+1). Anal. Calcd for C22H21N3O·(H2O)1/8: C, 76.44; H, 6.20; N, 12.16. Found: C, 76.63; H, 6.20; N, 12.12.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:3]1[CH:4]=[CH:5][C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cccc(-c3ccc4ccccc4c3)c2C1
Yield: 2472.1 %

Procedure:
The crude product was taken up in 500 cm3 of toluene, admixed with 1.5 g of p-toluenesulfonic acid and heated under reflux for 2 hours with a water separator. The reaction mixture was washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 18.4 g (72%) of 17 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O[C@@H:18]1[CH:23]2C[CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>C1(C)C=CC=CC=1>[N:20]12[CH2:21][CH2:22][CH:23]([CH2:18][CH2:19]1)[C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:25]2
Reactant: CCCCCC(O)(C(=O)OC)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: CCCCCC(O)(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1

Procedure:
2.7 g of 2-Hydroxy-2-thien-2-ylheptanoic acid methyl ester (Intermediate I-9) (0.011 mol) were dissolved in 70 ml of toluene. To this solution were added 1.63 g (0.0128 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.18 g (0.0045 mol) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 1 hour. The cooled mixture was extracted with 1N HCl acid, the aqueous layer washed with ether, basified with K2CO3 and extracted with CHCl3. The organic layer was washed with water, dried over MgSO4 and evaporated. The yield was 2.85 g (76%) of the title product as a mixture of diastereomers, structure confirmed by 1H-NMR.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(O)C.C(=O)([O-])[O-].[NH4+:49].[NH4+]>ClCCl.C(O)C>[ClH:41].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:49])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 25 from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 61% of theory, C33H34N6O2 (546.7); Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=547; (M+H+Na)++=285.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1)C.O.[NH2:13][NH2:14].[CH:15]([C:17]1[CH:26]=[N+:25]([O-:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N+:18]=1[O-:28])=[O:16].Cl>CO.C(O)C>[C:4]([NH:13][N:14]=[C:26]1[N+:25]([O-:27])=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]2)=[N+:18]([O-:28])[CH:17]1[CH:15]=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: O=Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=CC1C(=NNC(=O)c2cccnc2)[N+]([O-])=c2ccccc2=[N+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
7.55 g. (0.05 moles) of nicotinic acid ethyl ester are dissolved in 60 ml. of ethanol, then 2.6 g. (0.05 moles) of 96% hydrazine hydrate are dropped to the obtained solution. The reaction mixture is boiled for 2 hours, then the warm solution of 9.5 g. (0.05 moles) of 2-formyl-quinoxaline-1,4-dioxide and 1 ml. of concentrated hydrochloric acid in 140 ml. of methanol is dropped to it. The reaction mixture is allowed to cool to room temperature, then it is stirred for two hours at this temperature. The separated crystals are filtered and washed with methanol. In this way 13.2 g. (85.4%) of the title product are obtained with a melting point of 279° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:15]([Cl:17])=[O:16])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Brc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cl)N(c1ccccc1)c1cccc(Br)c1
Temperature: 90 °C

Procedure:
A solution of 15.0 g (60.4 mmole) of 3-bromodiphenylamine [i.e., N-(3-bromophenyl)aniline] [S. Kurzepa and J. Cieslak, Roczniki Chem., 34, 111 (1960)] in 30 ml of toluene and 50 ml (116 mmole) of 1.93M phosgene in toluene were combined and heated at 90° C. under nitrogen for 2 hours with stirring. The red orange colored solution was cooled, flushed with nitrogen for 2 hours to remove excess Phosgene and concentrated in vacuo to 18.0 g (58.0 mmole, 96%) of red orange oil which was homogeneous by TLC (4:1 hexane-ethyl acetate, Rf =0.80).
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19].Cl.Cl.C(OC([N:32]1[C:36]([NH:37][C:38](=[O:52])[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)=[CH:41][CH:40]=2)=[C:35]2[CH2:53][NH:54][C:55]([CH3:57])([CH3:56])[C:34]2=[N:33]1)=O)C.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][C:1]([N:54]1[CH2:53][C:35]2[C:34](=[N:33][NH:32][C:36]=2[NH:37][C:38](=[O:52])[C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)=[CH:41][CH:40]=2)[C:55]1([CH3:56])[CH3:57])=[O:2]
Reactant: Nc1c(F)cccc1Cl
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1)CNC2(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)Nc3[nH]nc4c3CN(C(=O)Nc3c(F)cccc3Cl)C4(C)C)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
To a solution of di-tert-butyl dicarbonate (101 mg, 0.46 mmol, 1.1 eq) in DCM (2 mL) was added 2-chloro-6-fluoroaniline (61 mg, 0.42 mmol, 1 eq) and N,N-dimethylpyridin-4-amine (51 mg, 0.42 mmol, 1 eq). After 1 hour of agitation at room temperature, 6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4Hpyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (189 mg, 0.38 mmol, 0.9 eq), triethylamine (0.23 mL, 1.68 mmol, 4 eq) and an additional 2 mL of DCM (4 mL total). The cocktail was placed in a Personal Chemistry, Smith Creator microwave reaction station and the vial contents were irradiated at 125° C. for 10 minutes with application of continuous, simultaneous cooling. After the 10 minutes of heating time had elapsed, the solution was washed twice with water. The organic phase was collected and the solvent was removed in vacuo. The residue was dissolved in methanol (3 mL), treated with triethylamine (0.3 mL, 2.2 mmol, 5 eq) and agitated for 6 hours at 50° C. After evaporation of the solvent, the solid was purified by preparative HPLC to afford 0.012 g of the title compound in 5% overall yield.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[C:5]([O:8]C(=O)C)(=[O:7])[CH3:6]>O>[C:5]([OH:8])(=[O:7])[CH3:6].[C:5]([OH:8])(=[O:7])[CH3:6].[C:5]([OH:8])(=[O:7])[CH3:6].[B:1]([OH:4])([OH:3])[OH:2]
Reactant: CC(=O)OC(C)=O
Agent: OB(O)O
Solvent: O
Product: CC(=O)O
Temperature: 73.8499984741211 °C
Reaction time: 0.5 h

Procedure:
86.4 g (1.40 mol) of boric acid (for production of a catalyst) was added to 17.9 L (190 mol) of acetic anhydride in a nitrogen atmosphere, and the mixture was heated and stirred at 70.0 to 77.7° C. for 30 minutes. Then the mixture was cooled to an internal temperature of 24.7° C. (warm water temperature setting: 23.0° C.). Then boric acid was added in four portions to the solution mixture. More specifically, 842 g (13.6 mol) of boric acid (the first portion) was added to the solution mixture, and the resultant mixture was stirred at 24.7 to 27.4° C. for 30 minutes. Then 842 g (13.6 mol) of boric acid (the second portion) was added to the solution mixture, and the resultant mixture was stirred at 24.3 to 26.3° C. for 30 minutes. 842 g (13.6 mol) of boric acid (the third portion) was added to the solution mixture, and the resultant mixture was stirred at 24.3 to 26.8° C. for 30 minutes. 842 g (13.6 mol) of boric acid (the fourth portion) was added to the solution mixture, and the resultant mixture was stirred at 25.1 to 28.3° C. for 30 minutes. The solution mixture was stirred at 50.0 to 54.9° C. for 30 minutes to obtain a boric acid triacetate adjusting solution.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.[Cl:12]CCCl.[Cl-].[P+]=O>CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: ClCCCl
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Agent: O=[P+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 100 ml three-necked round-bottomed flask equipped with a magnetic bar, a thermometer, a dropping funnel and a reflux condenser is charged with 4-methyl-5-nitro-pyridin-2-ol (5.0 g), and 1,2-dichloroethane (30 ml). Phosphorous oxide chloride (3.6 ml) is added dropwise. Into this mixture DMF (2.5 ml) is added dropwise at ambient temperature. The reaction mixture is heated at 70° C. under stirring for 0.5 hours. After cooling the mixture to ambient temperature, it is concentrated in vacuo at 50° C., to obtain a brown oily gum. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 4.91 g of the compound as a light yellow solid (MP: 35-38° C.).
Reaction SMILES: C1(C2SC(NC3C=CC(OCCN4CCCC4)=CC=3)=NC=2)C=CC=CC=1.[S:27]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([CH2:38][CH:39]=O)[CH:35]=[CH:36][CH:37]=2)=[CH:28]1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH2:57])=[S:56])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>>[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:55]3[S:56][C:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:29]5[CH:30]=[CH:31][S:27][CH:28]=5)[CH:33]=4)=[CH:39][N:57]=3)=[CH:52][CH:53]=2)[CH2:44][CH2:43]1
Reactant: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Reactant: O=CCc1cccc(-c2ccsc2)c1
Agent: c1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Product: CN1CCN(c2ccc(Nc3ncc(-c4cccc(-c5ccsc5)c4)s3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 1 for (5-phenyl-thiazol-2-yl)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine but using (3-thiophen-3-yl-phenyl)-acetaldehyde and [4-(4-methyl-piperazin-1-yl)-phenyl]-thiourea (Example 5). MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 435.0 [M+3]+; single peak at tR=3.09 min (System 2); Rf=0.25 (CH2Cl2/MeOH, 90/10).