Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:6])[C:3](=[O:5])[CH3:4].[C:7]1(C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[OH:5][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])[C:2](=[O:6])[CH3:1]
Reactant: Cc1ccccc1
Reactant: CC(=O)C(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(C)(O)c1ccccc1
Yield: 56.6 %

Procedure:
The Grignard reagent (6.13 moles) was added to 480 g of 2,3-butanedione dissolved in 1.95 L of THF and 3.25 L of PhMe while maintaining the temperature at -6° C.±4° C. After the reaction was complete, it was quenched with 5% sulfuric acid to pH=4.5±1, then worked up as in Example I to give 689 g of crude product. Vacuum distillation (88°-93° C., 1.2-3 mm Hg) gave 3-hydroxy-3-phenylbutan-2-one in 56.6% yield.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH3:17][Mg]Cl.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>O1CCCC1>[CH2:24]([O:23][C:21]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3](=[O:2])[CH2:4][CH:5]1[CH3:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Mg]Cl
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc2nccc(OC)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
4,6,7-Trimethoxyquinoline (1.0 g, 4.6 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). The mixture was cooled to -78° C., and methyl magnesium chloride (2.3 mL of a 3.0M solution in tetrahydrofuran, 6.9 mmol) was added. The mixture was stirred at -78° C. for 1 h, then benzyl chloroformate (1.0 mL, 6.9 mmol) was added. The reaction was warmed to room temperature over 30 min, then 8 mL of a 1N aqueous HCl solution was added. After 30 minutes, the tetrahydrofuran was removed in vacuo, and the remaining aqueous phase was extracted with ethyl acetate (3×30 mL). The organic phases were combined and washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.5 g of crude product. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded 0.91 g of the desired product (57%). 1H NMR (CDCl3) δ 1.25 (d, 3H), 2.5 (d, 1H), 3.0 (dd, 1H), 3.7 (s, 3H), 3.9 (s, 3H), 5.1-5.3 (m, 5.2 (d, 1H), 5.4 (d, 1H), 7.3-7.5 (m, 7H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.CCOCC>C(COC)OC.CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:34]([C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:15]2(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CO
Solvent: COCCOC
Solvent: CCOCC
Product: O=S1(=O)c2ccccc2C(c2ccc(F)cc2)N1C1CCN(Cc2ccccc2)CC1
Reaction time: 0.58 h
Yield: 46 %

Procedure:
A solution of N-(l-benzylpiperidin-4-yl)benzenesulfonamide from Example 1 above, (18.7 g, 56.5 mmol) and 210 ml dimethoxyethane was chilled at 0° C. under N2, followed by a slow addition over 25 minutes of 2.3 equivalent of n-butyl lithium (52 ml, 2.5 N/hexanes, 130 mmol) keeping the temperature below 15° C. After mechanically stirring for 35 minutes longer, 4-fluorobenzaldehyde (7.4 g, 59 mmol) in 50 ml dimethoxyethane was added at 5° C., and the reaction was stirred for 2 hours. Ether (400 ml) was added, and the reaction was washed with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel eluting with CHCl3 to CHCl3 :5% MeOH to afford 11.85 g (46% yield) of the intermediate as a foam.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: COC(CSc1cccc(O)c1)OC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(CSc1cccc(OC(=O)Nc2cccc([N+](=O)[O-])c2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 3-Nitrophenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio) phenyl] N-3-nitrophenylcarbamate as the residue.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13]C=2)(C)C)=[CH:4][CH:3]=1.CC(C1C=CC(OCC2OC2)=CC=1)(C1C=CC([O:27]CC2OC2)=CC=1)C.C(P(CCCC)CCCC)CCC>>[CH:7]1[CH:6]=[C:5]([C:8]2[CH:11]=[CH:16][CH:15]=[C:14]([OH:17])[CH:13]=2)[C:4]([OH:27])=[CH:3][CH:2]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: CCCCP(CCCC)CCCC
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 160 °C

Procedure:
152 g of bisphenol A, 63 g of a diglycidyl ether of bisphenol A, having an epoxide equivalent weight of 189, and 0.1 g of tributylphosphine were heated at 160° C. for 1 hour. After this time, epoxide was no longer detectable and a chain-extending diphenol had formed. 53.8 g of isopropanol, 129 g of di-n-butylamine, 31.5 g of paraformaldehyde and 17.6 g of isobutanol were added and the mixture was heated at 80° C. for 2 hours. The product had a solids content of 80% by weight.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:17]([O:18][CH2:19]SC)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1.[N-:43]=[N+:44]=[N-:45].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:33]=2[N:34]=[CH:35][N:36]=1)[C@@H:15]1[O:32][C@H:22]([CH2:23][OH:24])[C@@H:17]([O:18][CH2:19][N:43]=[N+:44]=[N-:45])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [F-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To 0.4 g N6-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (0.76 mmol) dissolved in 7 mL dry CH2Cl2 was treated with 0.4 mL cyclohexene and 155 μL SO2Cl2 (1.91 mmol) at 0° C. for 2 h. During this time the starting material completely converted to 7a which was shown by disappearance of the starting material and appearance of 3′-OH analog (5a) in TLC (EtOAC:Hex/7:3, Rf˜0.3; the 3-CH2Cl (7a) could not detected in TLC due to decomposition in TLC plate to 5a). Then solvent was removed by rotary evaporation and kept about 10 minutes in high vacuum pump. Then dissolved in 5 mL dry DMF and treated with 400 mg NaN3 (6.6 mmol) at room temperature for 3 h. Then the reaction mixture was partitioned in H2O/CH2Cl2, the combined organic part was dried over Na2SO4 and concentrated by rotary evaporation. The crude sample was then dissolved in 5 mL MeOH and treated with 300 mg NH4F (8.1 mmol) more than 38 h. Then MeOH was removed by rotary evaporation. After partioning in H2O/EtOAc, the combined organic part was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (100% EtOAc to 98:2, EtOAc/MeOH) resulting 150 mg of 9a as white powder (48% yield in three steps). HR-MS: Obs. m/z 411.1530, calcd for C18H19O4N8 411.1529 [M+H]+. 1H-NMR (CDC3): δH 8.84 (brs, 1H), 8.70 (brs, 1H), 8.08 (m, 1H), 7.76-7.54 (m, 5H), 6.47 (t, J=5.6 Hz, 1H), 4.83 (m, 2H), 4.78 (m, 1H), 4.39 (m, 1H), 4.09 (d, J=12.78 Hz, H5′, 1H), 3.88 (d, J=12.78 Hz, H5″, 1H), 3.09 (m, H2′, 1H), and 2.65 (m, H2″, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:19])[C:5]=2[NH:4][N:3]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=[CH:42][C:29]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](=O)[CH2:38]CCl)[CH2:33][CH2:32]1>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:19])[C:5]=2[N:4]([C:20](=[O:23])[CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]3[CH:42]=[CH:43][C:44]([O:48][CH3:49])=[C:45]([O:46][CH3:47])[C:28]=3[O:27][CH3:26])[CH2:32][CH2:33]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: COc1ccc(CN2CCN(C(=O)CCCl)CC2)c(OC)c1OC
Agent: [K+]
Product: COc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5ccc(OC)c(OC)c5OC)CC4)c3C2=O)cc1

Procedure:
A target compound (136.1 mg, 0.235 mmol, 46.8%) was yielded as white solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (129.8 mg, 0.502 mmol) with potassium carbonate (104.0 mg, 0.753 mmol) and 1-{4-(2,3,4-trimethoxybenzyl)piperazin-1-yl}-3-chloropropan-1-one (196.9 mg, 0.552 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(C(N)Cc2ccccc2)n1

Procedure:
5-(1-tert-Butoxycarbonylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (1.5 g, 4.2 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (40 ml). After 5 h at 20° C. the reaction mixture was concentrated in vacuo to give 1.2 g of (R) 5-(1-amino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:58])([CH3:57])[C@H:42]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:58])([CH3:57])[C@H:42]([NH:46][C:47](=[O:56])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@H](NC(=O)COc1ccccc1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)COc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 54B (0.038 mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.011 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (d, J=2.94 Hz, 18 H), 1.53 (m, 2 H), 2.55 (m, 1 H), 2.73 (m, 3 H), 3.49 (s, 3 H), 3.65 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 4.05 (m, 1 H), 4.15 (m, 1 H), 4.33 (d, J=9.56 Hz, 1 H), 4.53 (m, 2 H), 4.81 (d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.95 (m, 3 H), 7.11 (m, 1 H), 7.18 (m, 6 H), 7.31 (m, 3 H), 7.48 (d, 9.56 Hz, 1 H), 7.84 (m, 6 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: CS(O)(=O)=O.CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[C:24]([NH:27][N:28]1[C:32]([SH:33])=[N:31][N:30]=[N:29]1)(=[O:26])[CH3:25].[OH-].[NH4+]>C(#N)C.O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:33][C:32]3[N:28]([NH:27][C:24](=[O:26])[CH3:25])[N:29]=[N:30][N:31]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)Nn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
Methanesulfonic acid (5.77 g, 60 mmol) was added dropwise to a solution of 7β-aminocephalosporanic acid (3.27 g, 12.0 mmol) and 1-acetamido-5-mercapto-1H-tetrazole (2.50 g, 15.7 mmol) in acetonitrile (15 ml). The mixture was stirred at room temperature for 30 minutes and at 50° C. for 4 hours. Water (20 ml) was added with cooling to the reaction mixture, which was then adjusted to pH 3.5 with 28% aqueous ammonium hydroxide. Precipitates formed were filtered, washed with water and acetone successively and dried to give pale brown powder of 7β-amino-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.36 g, 75. 3%), mp~195° C. (decomposition).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:15]1[CH2:14][CH2:13][N:12]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:4][CH:5]=2)=[O:11])[CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CCl)cc4)CC3)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CN5CCCCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.7 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:40][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Cl)c1

Procedure:
Compound 57 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-chloro-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [376 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.93 (d, 1H), 8.46 (dd, 3H), 7.51 (d, 1H), 7.36 (s, 1H), 7.20 (t, 1H), 6.58 (s, 1H), 5.34 (dd, 1H), 3.11 (dd, 1H), 3.00 (dd, 1H), 2.37 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.[ClH:28]>C(OCC)C>[ClH:28].[CH3:24][C:22]1[O:21][N:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=3[CH:15]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)no1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(-c2ccc3c(c2)CCNCC3)no1
Reaction time: 12 h
Yield: 81 %

Procedure:
7-(5-Methyl-isoxazol-3-yl)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (1.9 g, 5.8 mmol) was treated with ethanol (20 ml) followed by a saturated ethanolic hydrochloride solution (20 ml). The mixture was stirred for 12 h until a precipitate was observed. Diethyl ether (100 ml) was added and the precipitate filtered and dried in vacuo to give the title compound as a colourless solid (1.25 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([N:20](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:9]1[CH:18]=[C:17]2[C:12]([O:13][CH2:14][C:15](=[O:19])[NH:16]2)=[N:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.O.CC(O)=O>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH2:20])[C:9]1[CH:18]=[C:17]2[C:12]([O:13][CH2:14][C:15](=[O:19])[NH:16]2)=[N:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1cnc2c(c1)NC(=O)CO2
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@H](N)c1cnc2c(c1)NC(=O)CO2
Reaction time: 18 h

Procedure:
A mixture of the dibenzylamine 20-6 (0.22 g, 0.44 mmol) in EtOH/H2O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (100 mg). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (20% 20:1:1 EtOH/NH4OH/H2O—80% EtOAc) to give the tert-butyl ester 20-7 as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:12]([C:20]#[N:21])=[C:11](S(C)(=O)=O)[N:10]=1>COCCOC>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:12]([C:20]#[N:21])=[C:11]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:10]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1CCNCC1
Solvent: COCCOC
Product: CN1CCN(c2nc(N)nc(-c3ccco3)c2C#N)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile N-methylpiperazine in DME. ES-MS m/e (%): 2859 (M+H+, 100), 228 (35).
Reaction SMILES: [Na].O.O.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=O)=[O:12])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:18])(=[O:14])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: -30 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 7 g (30 mmol) of the sodium salt of 4-hydroxybenzenesulfonic acid dihydrate in 40 ml of dimethylformamide is added dropwise to a solution of 15.5 ml (181 mmol) of oxalyl chloride in 120 ml of dichloromethane cooled to −30° C. The reaction medium is slowly brought back to ambient temperature and then stirred at ambient temperature for 18 h. After the addition of 200 ml of ice, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. 6.2 g (100%) of 4-hydroxybenzenesulfonyl chloride are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4](O)[CH2:3]1.[P:9](Cl)([Cl:12])([Cl:11])=[S:10].N1C=CC=CC=1>ClC=C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([P:9]([Cl:12])([Cl:11])=[S:10])[CH2:3]1
Reactant: S=P(Cl)(Cl)Cl
Reactant: CC1CCCC(O)C1
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC1CCCC(P(=S)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 3-methylcyclohexanol (5.0 g, 43.8 mmol) in trichloroethylene (300 mL) is added dropwise to a 0°-4° C. mixture of thiophosphoryl chloride (11.13 g, 65.7 mmol) and anhydrous pyridine (5.20 g, 65.7 mmol) in trichloroethylene (125 mL) over a 1 hour period under a nitrogen atmosphere. The resultant reaction mixture is stirred at 0°-4° C. for 1 hour and is then warmed to room temperature and stirred at room temperature for 8 hours. A white solid gradually precipitates. The white solid is filtered from the reaction mixture. The resultant reaction mixture is concentrated in vacuo to a residue. Successive aliquots of toluene (100 mL) are added to the residue and then separately are evaporated in vacuo to give 7.57 g (70%) of (3-methylcyclohexyl)-thiophosphoryl dichloride which can be used directly without further purification as the starting material for Example 23.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22]>C(O)(C)C>[ClH:1].[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(N)cc1O
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Nc3cc(O)c(C)cc3F)c2cc1OC
Product: Cl
Yield: 68.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (76 mg, 0.28 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (40 mg, 0.28 mmol), (prepared as described for the starting material in Example 8), in isopropanol (2.5 ml) was stirred and heated at reflux for 7 hours. The reaction mixture was allowed to cool and the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (79 mg 66%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NS(=O)(=O)c1ccc2occc2c1
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2ccc3occc3c2)cc1
Yield: 33.8 %

Procedure:
The 5-benzofuransulfonamide (5.74 mmol) and 4-methylphenylisocyanate (5.74 mmol) were reacted as described in Method B above to obtain a solid. This residue was purified by reverse phase chromatography with 50% acetonitrile in water with 1% acetic acid on a C18 column to obtain 0.64 g of the title product as a solid. 1H NMR (CD3SOCD3): κ10.35 (bs, 1 H), 8.74 (s, 1 H), 8.38 (d, J =3 Hz, 1 H), 8.20 (d, J =3 Hz, 1 H), 7.96 (dd, J =3, 9 Hz, 1 H), 7.86 (d, J =9 Hz, 1 H), 7.22 (d, J =9 Hz, 2 H), 7.20 (d, J =3 Hz, 1 H), 7.06 (d, J =9 Hz, 2 H), 2.22 (s, 3 H).