Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH:17]=5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([O:40]CC)[CH3:39]>C(OC(C)=C)(=O)C>[C:38]([O:26][C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH:12]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:17]=1)(=[O:40])[CH3:39]
Reactant: CCOCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(c5cccnc5)=CC[C@@H]34)[C@@]2(C)CC1
Temperature: 80 °C
Yield: 44 %

Procedure:
17-(3-pyridyl)androsta-4,16-dien-3-one (174 mg, 0.50 mmol) was dissolved in isopropenyl acetate (2 ml). p-Toluenesulfonic acid (130 mg, 0.68 mmol) was then added and the mixture heated at 80° C. for 12 h. After allowing to cool the mixture was poured into diethyl ether, washed with saturated aqueous sodium bicarbonate, dried (Na2CO3) and concentrated. Chromatography on elution with light petroleum--diethyl ether (1:1), afforded the title compound (86 mg, 44%), IR νmax 1755 cm-1, 1H-NMR (CDCl3) inter alia δ1.05 (6H,s,18-CH3 and 19-CH3), 2.15 (3H,s,COCH3) 5.44 (1 H,m,6-H), 5.72(1H,m,4-H), 6.00 (1H,m,16-H), 7.25 (1H,m,Py 5-H), 7.66 (1H,m,Py 4-H), 8.47 (1H,M,Py 6H), 8.63 (1H,m,Py 2-H). MS m/z 389 (M+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[NH3:12].C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: Clc1nccc2occ(Br)c12
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nccc2occ(Br)c12
Temperature: 150 °C
Reaction time: 120 h

Procedure:
To the solution of 3-bromo-4-chloro-furo[3,2-c]pyridine (3.0 g) in 40 ml of dioxane was added 28% ammonia solution (15 ml) in an autoclave and put into the oil bath. The reaction mixture was allowed to heat up to 150° C. and stir for 5 days at 150° C. The resultant mixture was poured into ethyl acetate and brine. The organic phases was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford 3-bromo-furo[3,2-c]pyridin-4-ylamine (1.3 g). 1H NMR (400 MHz, CDCl3) ppm 7.93 (d, J=6.1 Hz, 1H), 7.52 (s, 1H), 6.87 (d, J=5.8 Hz, 1H). MS: m/z 213, 215 (M+H)+.
Reaction SMILES: [Si]([N:8]1[C@H:11]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH2:10][C:9]1=[O:18])(C(C)(C)C)(C)C.[ClH:19].[CH3:20][CH2:21][OH:22]>>[ClH:19].[CH2:21]([O:22][C:9](=[O:18])[CH2:10][C@@H:11]([C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1)[NH2:8])[CH3:20]
Reactant: CCO
Reactant: Cc1cc([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)on1
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cc(C)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-tert-butyldimethylsilyl-4(S)-(3-methyl-5-isoxazolyl)-2-azetidinone (0.9 g) in EtOH (10 ml) was added HCl (16.9 mmol)/EtOH (4.2 ml) at room temperature at 0° C. The reaction mixture was stirred at room temperature for 2 hours, then evaporated in vacuo. The residue was recrystallized from diethyl ether to give 3(S)-(3-methyl-5-isoxazolyl)-β-alanine ethyl ester hydrochloride (0.67 g) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=[O:14])[C@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8]1.[CH3:22][CH2:23]O>>[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH2:22][CH3:23])=[O:14])[C@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8]1
Reactant: O=C1CC[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1CCC(=O)C[C@H]1c1ccccc1
Reaction time: 14 h
Yield: 31 %

Procedure:
Sulfuric acid (0.073 ml, 1.375 mmol) was added to a mixture of (trans)-4-oxo-2-phenylcyclohexanecarboxylic acid (1.5 g, 6.87 mmol) in EtOH (15 ml). The reaction was aged at 77° C. for 14 h. The cooled reaction was quenched with NaOH (1/V) and extracted three times with CH2Cl2. The combined organic layers were dried under reduced pressure and purified via silica gel column chromatography (0-40% EtOAc:Hexanes) to afford ethyl(trans)-4-oxo-2-phenylcyclohexanecarboxylate (526 mg, 31%) as a colorless oil. MS ESI: [M+H]+ m/z 247.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:16])[CH3:15])=[O:5])[CH3:2].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.[NH2-].[Li+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]1([CH3:15])[CH3:16])=[O:5])[CH2:2][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCO
Reactant: CCOC(=O)CN1C(C)(C)CCCC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CCO
Product: CCCCCCCCOC(=O)CN1C(C)(C)CCCC1(C)C

Procedure:
A mixture of 45.4 parts of 1-ethoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine, 36.5 parts of 1-octanol and 0.5 part of lithium amide was heated at 110°-115°C for 48 hours, the ethyl alcohol formed during the reaction being removed by distillation. Fractional distillation of the reaction mixture gave 1-octoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine having a boiling point of 120°C/0.005 mm Hg.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38][C:39](=[O:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:48]>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:46].[ClH:48].[C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([NH:38][C:39](=[O:47])[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)(=[NH:8])[NH2:10]
Reactant: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=N)N)c2c1

Procedure:
A solution of 120 mg of cis-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorobenzoylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 5 mL of methanol and 5 mL of chloroform was combined with 3 mL of a 4N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 72 hours. After concentrating, treatment was performed with methanol-ethyl ether to obtain 22 mg of the desirable compound as pale yellow powder.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:20]=[C:19]([N:30]4[CH2:34][CH2:33][CH2:32][CH:31]4[CH3:35])[N:18]=3)[C@H:13]([CH3:36])[CH2:12]2)=[N:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[N:20]=[C:19]([N:30]3[CH2:34][CH2:33][CH2:32][CH:31]3[CH3:35])[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:7]4[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][C:8]=4[CH3:10])[CH2:12][C@H:13]3[CH3:36])[CH:22]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)[C@H](C)C2)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1cc(CO)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Temperature: -78 °C

Procedure:
Dissolve 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid methyl ester (78 mg, 0.155 mmol) in DCM and cool to −78° C. using a dry ice/acetone bath. Add diisobutylaluminum hydride (0.619 mL, 1M in hexanes) dropwise and continue stirring for 1 h at −78° C. Add excess Na2SO4.10H2O and stir at −78° C. for 5 min and then remove the cooling bath and allow to come to room temperature. Filter the mixture through celite washing with DCM, and then concentrate under reduced pressure. Purify the resulting oil using flash chromatography (30-50% EtOAc/hexanes eluent) to afford the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 1.32 (m, 3H, CH3); 1.40 (m, 3H, CH3); 1.69 (m, 1H, CH2CH2); 1.90 (m, 1H, CH2CH2); 2.05 (m, 2H, CH2CH2); 2.36 (s, 3H, Ar—CH3); 3.00 (m, 1H); 3.08 (m, 1H); 3.37 (m, 2H); 3.48 (m, 1H); 3.68 (m, 2H); 4.34 (m, 2H); 4.69 (s, 2H, CH2OH); 4.71 (m, 1H); 6.24 (s, 1H, Ar—H); 7.10 (m, 2H); 7.48 (d, 1H, J=2.0 Hz); 8.00 (m, 2H); 8.11 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2)[CH:12]=1
Reactant: COC(=O)c1cnc(-c2cccnc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2cccnc2)nc1
Yield: 29.9 %

Procedure:
A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.73 g, 3.32 mmol) and 1M aqueous LiOH (3.32 mL) in MeOH (5 mL) is stirred at rt overnight. The MeOH is removed in vacuo, and the aqueous solution is treated with 3 N aqueous HCl to adjust the pH ˜2-3. The solid is filtered off and washed with water and dried in vacuum to yield 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (0.2 g, 30%) as a solid. MS: 202 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:2]1([O:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:24]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=4)[O:27][N:26]=3)=[CH:36][CH:35]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.9 %

Procedure:
To a solution of 1-hydroxybenzotriazole (244 mg) and 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (528 mg) in dichloromethane (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD•HCl) (430 mg) and the mixture was stirred for 4.5 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[5-(4-pentyloxyphenyl)isooxazol-3-yl]benzoic acid benzotriazol-1-yl ester (640 mg).
Reaction SMILES: [CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[CH:16]([OH:18])=[CH2:17].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>N1C=CC=CC=1.C1C=CC=CC=1>[CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25]([O:18][CH:16]=[CH2:17])=[O:26])([O-:21])=[O:20]
Reactant: C=CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: C=Cn1c2ccccc2c2ccccc21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Copoly(N-vinyl carbazole-Vinyl alcohol) (II) (2.0 g) was dissolved in 50 ml of anhydrous pyridine. 3,5-Dinitrobenzoyl chloride (3.88 g) in 15 ml of anhydrous benzene was added with stirring to the pyridine solution. The resulting orange solution was stirred at room temperature for 4 hours. The small amount of solid remaining in the reaction mixture was collected on a filter and the filtrate was poured into 400 ml of methanol. The isolated polymer was purified by two precipitations from tetrahydrofuran into methanol to give 3.2 grams of a yellow powder. Nitrogen analysis demonstrated that the reaction of the alcohol groups with the acid chloride was nearly quantitative.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[NH2:19][C:15]1[CH:14]=[C:13]([CH:8]([C:9]([F:11])([F:10])[F:12])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)CC(c1cccc(N)c1)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
13.6 g (47.0 mmol) of (+/−)-tert-butyl-3-(3-aminophenyl)-4,4,4-trifluorobutanoate were initially charged in 100 ml of acetonitrile, and 6.28 g (47.0 mmol) of N-chlorosuccinimide were added at RT. The reaction mixture was initially stirred at 60° C. for 12 h and then allowed to stand at RT for 3 days. After concentration under reduced pressure, the residue was separated by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1), and the desired target product was isolated. This gave 4.49 g of the title compound (29.5% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.27 mmol) obtained in Example 18 was dissolved in THF (10 mL), and cyclohexylamine (132.86 mg, 0.15 mL, 1.34 mmol) was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 25 mg of the titled compound (yield: 24%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:30][C:31](OC(C)=O)=[O:32]>C1COCC1.O>[C:31]([N:24]1[C:25]([CH:27]2[CH2:28][CH2:29]2)=[CH:26][C:22]([NH:21][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]3[S:12][C:11]([S:13]([NH:16][C:17]([CH3:19])([CH3:20])[CH3:18])(=[O:14])=[O:15])=[CH:10][CH:9]=3)[N:4]=2)=[N:23]1)(=[O:32])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Br)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1.6 g, 3.21 mmol, 1.0 eq) in THF/H2O (30 mL/15 mL), Ac2O (0.64 g, 6.42 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered to afford compound 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-tert butylthiophene-2-sulfonamide (1.6 g, 92%). LC-MS (m/z)=539 [M+H]+
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:18]2[CH2:17][N:13]3[CH:14]=[CH:15][C:16]4[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=4)=[C:12]3[N:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(=Cc1cccn2cc(-c3cccc(OC)c3)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(c1cccc(OC)c1)=N3

Procedure:
From 6d (yield: 50%); mp 198-200° C.; IR (KBr) 3297, 1670, 1261 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.41 (t, 3H, J=7 Hz), 3.90 (s, 3H), 4.41 (q, 2H, J=7 Hz), 6.88 (m, 2H), 7.34 (t, 1H, J=8 Hz), 7.52 (d, 2H, J=8 Hz), 7.58 (s, 1H), 7.74 (s, 1H), 7.76 (s, 1H), 7.88 (d, 1H, J=7 Hz), 9.93 (brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.3, 54.9, 60.5, 101.8, 106.8, 110.0, 110.4, 112.9, 113.2, 117.6, 124.3, 125.9, 129.7, 133.2, 135.6, 141.0, 141.9, 159.6, 160.6; MS m/z 335 (M+, 69), 289 (100), 132 (15), 102 (17). Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C, 68.23; H, 5.04; N, 12.73.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[C:9]([CH3:16])[CH:8]=1>C(=O)(O)[O-].[Na+]>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:15])=[O:2])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(N)ccc1CC#N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(N)ccc1CC(N)=O
Temperature: 25 °C
Yield: 50 %

Procedure:
Sulfuric acid (26 mL) was added to 2-(4-amino-2-methylphenyl)acetonitrile (0.500 g, 3.42 mmol) at 0° C. The mixture was warmed to rt for 4 h, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford the title compound (0.252 g, 50%) as a tan solid. MW=164.20. 1H NMR (DMSO-d6, 500 MHz) δ 7.09 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.74 (s, 1H), 6.39-6.35 (m, 1H), 6.33-6.29 (m, 1H), 4.78 (s, 2H), 3.19 (s, 2H), 2.10 (s, 3H); APCI MS m/z 165 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=O)[CH2:21][CH3:22])=[C:15]([OH:24])[CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[CH2:29]([O:31][NH2:32])[CH3:30]>C(Cl)(Cl)Cl>[CH2:29]([O:31][N:32]=[C:20]([C:16]1[C:17](=[O:19])[CH2:18][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:14][C:15]=1[OH:24])[CH2:21][CH3:22])[CH3:30]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC(=O)c3ccccc3C)cc2)CC1=O
Reactant: CCON
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC(=O)c3ccccc3C)cc2)CC1=O
Reaction time: 15 h
Yield: 56.1 %

Procedure:
Into 30 ml of chloroform was dissolved 1.6 g of 5-[4-(2-methylbenzamido)phenyl]-2-propionyl-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.4 g of ethoxyamine. The mixture was kept for 15 hours at 40° C. and the reacting solution was washed with water and a surplus amount of ethoxyamine was removed from it. After dried, the chloroform was distilled off from it and ethyl ether was added in the residue. The crystal sedimented was collected with a filtering step and 1.0 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 139°-140° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1)[CH3:2].CC(C)([O-])C.[K+].[CH3:23][C:24]1[N:28]=[C:27]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[S:26][N:25]=1.[Cl-].[NH4+]>CN(C)C(=O)C>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:40][C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][N:31]=[C:30]3[NH:29][C:27]2[S:26][N:25]=[C:24]([CH3:23])[N:28]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Cc1nsc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4nc(C)ns4)c3c2)nc1)OCC
Temperature: 25 °C
Yield: 39.1 %

Procedure:
5-(2,2-diethoxyethoxy)-2-fluoropyridine (530 mg, 2.3 mmol) and potassium tert-butoxide (260 mg, 2.3 mmol) were added to an N,N-dimethylacetamide suspension (0.5 ml) of 4-[(3-methyl-1,2,4-thiadiazol-5-yl)amino]quinazolin-6-ol (300 mg, 1.2 mmol), and reacted at 200° C. for 30 minutes, using microwaves. The reaction solution was cooled to room temperature, aqueous saturated ammonium chloride solution was added, filtered, and washed with a mixed solution of chloroform/methanol (9:1). The obtained filtrate was extracted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=90:10) to obtain 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)quinazoline-4-amine (220 mg, yield: 40%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+].P(Cl)(Cl)([Cl:19])=O>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:19])(=[O:15])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Product: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 170 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A mixture of potassium 4-n-pentylbenzene sulfonate (65 g, 0.243 m) and phosphoryl chloride (75 g, 0.492 m) was heated to approximately 170° C. with stirring until the reaction mixture became less viscous. Heating continued for approximately one hour. The hot reaction mixture was poured into cold water (1600 ml) and the reaction product was extracted with chloroform (2×600 ml). The extract was washed with water until it was neutralized and dried over anhydrous sodium sulfate. The solvent (chloroform) was evaporated and the extract was vacuum-distilled to give 4-n-pentylbenzenesulfonyl chloride (52 g, 87%, boiling point 132°-134° C./0.3 mm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:8]=1[CH3:21])[CH3:2].[H-].[Na+].[CH3:25]I.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH3:25])=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1C
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To an ice-cooled and stirred solution of (4-tert-butoxycarbonylamino-2-methyl-phenoxy)-acetic acid ethyl ester (3.09, 10 mmol) in DMF (30 ml) was added within 10 min NaH (55% in oil, 0.65 g, 15 mmol) and after 1 h, CH3I (4.98 ml, 80 mmol). The reaction was warmed up over night to RT, neutralized at 0° C. with aqueous 10% KHSO4 and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 3.46 g (quantitative) of [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid ethyl ester containing ca 20% (1H-NMR) of [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester, MS: 323 (M, ethyl ester) and 309 (M, methyl ester).