Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:26]([O:31][CH:32]([CH3:49])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:27][CH2:28][CH2:29][CH3:30].Cl>O.CN(C)C=O>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH:32]([O:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:49])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCCC)cc2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Separately, 3.12 g of 5-n-decyl-2-(4-hydroxyphenyl)pyrimidine and 0.53 g of potassium hydroxide were added to 14 ml of dimethylformamide, and the mixture was stirred for 3 hours at 100° C. To the mixture was added the above-prepared 2.98 g of 6-pentyloxyheptyl-p-toluenesulfonate followed by 5 hours of stirring under heating at 100° C. After the reaction, the reaction mixture was poured into 200 ml of cold water and acidified to about pH 3 with 6N-hydrochloric acid and extracted with benzene, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent, to obtain 4.71 g of crude product. The product was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/2) and recrystallized from hexane to obtain 1.56 g of 5-n-decyl-2-[4-(6-pentyloxyheptyloxy)phenyl]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:16]CC#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[OH-:20].[K+].Cl.[CH2:23]([OH:25])[CH3:24]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])[CH2:16][CH2:24][C:23]([OH:20])=[O:25]
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCCN(c1ccccc1N)c1ccccc1F
Agent: Cl
Agent: [K+]
Product: Nc1ccccc1N(CCC(=O)O)c1ccccc1F
Yield: 86 %

Procedure:
N-(2-Aminophenyl)-N-(2-cyanoethyl)-2-fluoroaniline (6.18 g) was dissolved in ethanol (40 ml), aqueous potassium hydroxide (12.5 g) solution (80 ml) was added, the mixture was refluxed for 3 hours. The reaction mixture was allowed to cool, adjusted to pH 3 with concentrated hydrochloric acid, and extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 5.6 g of the titled compound as brown amorphous (Yield: 86%).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:17][O:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccccc2cc1C(=O)O

Procedure:
Five grams of 2-hydroxy-3-naphthoic acid was dissolved in 220 ml of dimethyl formamide, 3.74 grams of sodium hydride was added thereto little by little with ice cooling and stirring, then 11.0 grams of methyl iodide was added, and the mixture was stirred at room temperature for twelve hours. The reaction solution was partitioned between benzene and water, the benzene layer was collected, dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom, and the residue was dried. To this were added 10 ml of water, 90 ml of methyl cellosolve and 5.0 grams of potassium hydroxide, the mixture was heated to reflux for forty minutes with stirring, the reaction solution was poured over ice water, the mixture was acidified with diluted hydrochloric acid, and the separated mass was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom, and the residue was crystallized from n-hexane to afford 2-methoxy-3-naphthoic acid. The yield was 4.62 grams.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 43 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (1.01 g, 2.94 mmol) in pyridine (10 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (500 mg, 2.67 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 108-109° C., in 43% yield (570 mg, 1.15 mmol); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 1.24-1.34 (m, 21H), 1.55-1.66 (m, 2H), 2.63 (t, 2H, J=7.2 Hz), 3.88 (s, 2H), 4.25 (q, 2H, J=7.5 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.1, 22.7, 29.3, 29.5, 29.6, 29.7, 31.2, 31.9, 35.9, 38.1, 61.9, 126.7, 128.4, 138.8, 147.2, 152.1, 168.3, 170.3; MS (LCQ, ESI+) Calcd for C24H38N3O4S2 496.2. found 496.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H38N3O4S2 496.2304. found 496.2295 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:5]2[Cl:24].C([Li])CCC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1>O1CCCC1>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)([C:39]3[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Oc1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (525 mg, 1.29 mmol, Intermediate 5, step d) in tetrahydrofuran (12 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 1.2 mL, 1.94 mmol) dropwise over 1 minute and stirred at this temperature for 5 minutes. To the resulting dark red solution was added (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (428 mg, 1.94 mmol, Intermediate 1, step b) and stirred in an ice bath (0° C.) for 0.5 hours. The yellow-orange solution was quenched with water and diluted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH-DCM), affording the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=2.02 Hz, 1H), 7.64-7.70 (m, 2H), 7.46 (dd, J=2.02, 9.09 Hz, 1H), 7.42 (d, J=9.09 Hz, 2H), 7.29-7.35 (m, 4H), 7.06 (t, J=7.33 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J=7.58 Hz, 2H), 6.16 (d, J=1.01 Hz, 1H), 3.51 (q, J=7.07 Hz, 4H), 3.34 (br. s., 3H), 1.05 (t, J=7.07 Hz, 6H)); MS m/e 548.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=O)[NH:7]2.P(Br)(Br)([Br:16])=O.C(=O)(O)[O-].[Na+]>>[Br:16][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]([CH3:12])[CH:10]=[N:11][C:2]=2[CH3:1])[N:7]=1
Reactant: Cc1ncc(C)c2[nH]c(=O)ccc12
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ncc(C)c2nc(Br)ccc12
Temperature: 110 °C
Yield: 22.1 %

Procedure:
A mixture of 5,8-dimethyl-1,6-naphthyridin-2(1H)-one (2.1 g, 12 mmol) and phosphoryl tribromide (5 g) was heated to 110° C. for 1 h, cooled, diluted with ice water, and neutralized with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM (100 mL×3), and the combined organic layers were dried with sodium sulfate and purified by column chromatography to give 0.63 g of the product as a pale white solid. MS (ESI): m/z 237.0 [M+H]+.
Reaction SMILES: [CH2:1]([P:5](=[O:14])([O:10][CH:11]([CH3:13])[CH3:12])[O:6][CH:7]([CH3:9])[CH3:8])[C:2]([CH3:4])=O.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].C(O)(=O)C.N1CCCCC1.[NH2:36]/[C:37](/[CH3:53])=[CH:38]\[C:39]([O:41][CH2:42][CH2:43][N:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:45])=[O:40]>C(O)(C)C>[CH3:53][C:37]1[NH:36][C:2]([CH3:4])=[C:1]([P:5]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])=[O:14])[CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:38]=1[C:39]([O:41][CH2:42][CH2:43][N:44]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH3:45])=[O:40]
Reactant: CC(=O)CP(=O)(OC(C)C)OC(C)C
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(P(=O)(OC(C)C)OC(C)C)=C(C)N1
Yield: 52 %

Procedure:
A mixture of 2.22 grams of diisopropyl acetonylphosphonate and 1.51 grams of m-nitrobenzaldehyde was added to 10 ml of isopropanol, 300 mg of piperidine acetate was added thereto, and the mixture was heated to reflux for three hours with stirring. To this was added 2.48 grams of 2-(N-benzyl-N-methylamino)-ethyl 3-aminocrotonate and the mixture was heated to reflux for another five hours with stirring. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, the solution was washed with 1N aqueous solution of sodium hydroxide, aqueous solution of sodium bisulfite, and water, successively, then separated after addition of 1N hydrochloric acid solution, to the lower layer was added chloform followed by separation, the chloroform layer was washed with 5% aqueous solution of potassium carbonate and then with water, and dried. Chloroform was evaporated therefrom in vacuo, the residue was purified by subjecting to silica gel column chromatography (100 grams of silica gel used; eluting solution: ethyl acetate) and the resulting crystals were recrystallized from ethyl acetate to afford 3.04 grams of 2-(N-benzyl-N-methylamino)-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-diisopropoxyphosphinyl-1,4-dihydropyridine-3-carboxylate, melting point 113°-15° C., melting point of the hydrochloride 119° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][CH:3]=1.C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N+:4]([O-:14])[CH:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1C
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(Cl)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (8.6 g, 46.1 mmol) and hydrogen peroxide urea adduct (8.1 g, 86 mmol) in dichloromethane (100 mL) was added 2,2,2-trifluoroacetic anhydride (10.9 ml, 78 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6 mmol, 95% yield) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (1H, s), 4.02 (3H, s), 2.65 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:32](=[O:33])[C:31]4[C:30]5[C:25](=[CH:26][C:27]([C:34]#[N:35])=[CH:28][CH:29]=5)[NH:24][C:23]=4[C:22]([CH3:37])([CH3:36])[C:21]=3[CH:38]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40].O1CCOCC1>O>[ClH:40].[CH3:36][C:22]1([CH3:37])[C:23]2[NH:24][C:25]3[C:30](=[CH:29][CH:28]=[C:27]([C:34]#[N:35])[CH:26]=3)[C:31]=2[C:32](=[O:33])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14](=[O:39])[N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:38][C:21]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)c2cc(OCC(=O)N3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound A9-15-1, 20 mg) was added with 4 N hydrochloric acid and dioxane solution (1 ml), and stirred in an water bath at 10° C. for 4 hr. Water was added to the reaction solution and the resulting precipitates were filtered and dried to obtain the title compound (15 mg, white powder).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][NH:14][CH2:13][CH2:12][C@H:4]13.Cl[CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].C(N(CC)CC)C.O1CCOCC1>C1(C)C=CC=CC=1>[CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C@H:3]1[CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:21])[CH2:13][CH2:12][C@H:4]13
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CC3)c1ccc(F)cc1
Yield: 64.7 %

Procedure:
A mixture of (±)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4.3-b]pyrrolo[3,2,1-hi]indole (2.8 g, 14 mmol), 4-chloro-4′-fluorobutyrophenone (4.21 g, 21 mmol), triethylamine (3 mL), KI (3.48 g, 21 mmol), dioxane (25 mL), and toluene (25 mL) was stirred and refluxed for 15 h under an atmosphere of nitrogen and then evaporated under reduced pressure to remove the volatiles. The residue was triturated with a small volume of dichloromethane and decanted from the insoluble material. The process was repeated two more times and the combined dichloromethane solution was added to 0.5N solution of hydrogen chloride in ether (200 mL). The salt that separated was filtered off, washed with ether, dissolved immediately in a minimum quantity of water and the solution extracted with ether. The ether extract was discarded and aqueous layer basified with 10% aqueous sodium hydroxide. The resulting mixture was extracted with dichloro-methane (2×) and the extract dried over magnesium sulfate and stripped of the solvent under reduced pressure to yield the title compound (3.3 g, 65%) as a highly viscous light brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.70-1.80 (m, 2H), 1.80-2.02 (m, 2H), 2.19 (t, J=10.9 Hz, 1H), 2.30-2.52 (m, 3H), 2.62-2.72 (m, 1H), 2.72-2.85 (m, 1H), 2.99 (t, J=7.0 Hz, 2H), 3.02-3.20 (m, 2H), 3.25-3.42 (m, 2H), 3.59-3.65 (m, 1H), 6.85 (s, 1H), 6.90 (s, 1H0, 7.01 (t, J=7.0 Hz, 2H), 7.98-8.03 (m, 2H) ppm. MS (CI): 365 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C)C=O>[C:3]([N:6]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]
Reactant: ClCc1ccccc1Cl
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccccc1Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a suspension of 400 mg of sodium hydride (60% in oil) in 30 ml of dimethylformamide was added 2.00 g of N-acetyl-2-phenoxyaniline at room temperature, followed by stirring at room temperature for 30 minutes. To the solution was added dropwise 1.64 g of 2-chlorobenzyl chloride at room temperature with stirring, followed by stirring for 30 minutes. After addition of ice-water, the reaction mixture was extracted with ether. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:4) to give 2.92 g of N-acetyl-N-(2-chlorobenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1.C(OCC)C>O1CCOCC1.O>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:15]=[C:14]2[CH2:13][CH2:12][OH:11]
Reactant: Cc1ccc(NN)cc1
Reactant: C1=COCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2[nH]cc(CCO)c2c1
Temperature: 95 °C
Yield: 17.6 %

Procedure:
To a suspension of 4-methylphenylhydrazine hydrochloride (2.50 g, 15.7 mmol) in 1,4-dioxane (25 mL) and water (1.5 mL) was dropped neat 2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixture was heated at 95° C. for 4 hours. After cooling to room temperature, it was poured into ethyl ether, dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 0.485 g (18%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.95 (br, 1H), 7.41 (s, 1H), 7.27 (d, 1H), 7.05 (m, 2H), 3.90 (dd, 2H), 3.01 (t, 2H), 2.46 (s, 3H), 1.50 (t, br, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][NH:39]3)O1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[N:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CNC(=O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with methylamine hydrochloride via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide (41 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 10.6 mg of 344. MS (Q1) 472.0 (M)+
Reaction SMILES: O.O.[OH-].C[N+](C)(C)C.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(=O)c1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
A solution of tetramethylammonium hydroxide dihydrate (TMA(H)·2H2O) (1.8 g, 14.0 mmole), benzamide (1.2 g., 9.9 mmole) and 10 ml of xylene was stirred under nitrogen at 70° C. Thewater and xylene was removed by vacuum distillation at 740 mmHg/70° C. Nitrobenzene (1.2 g., 9.7 mmole) was added dropwise and the solution was stirred for 4 hours under nitrogen after which time an aliquot was removed for HPLC analysis. 4'-Nitrobenzanilide, i.e., N-(4-nitrophenyl)benzamide, was produced in 98% yield based on benzamide. Azoxybenzene was also detected as a minor product in this reaction.
Reaction SMILES: C([O:4][CH:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:31])[CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)C#N)(=O)C.Cl.[O:33]1[CH2:38]COCC1.[OH2:39]>>[OH:4][CH:5]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:31])[CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:38]([OH:33])=[O:39]
Reactant: C1COCCO1
Reactant: O
Reactant: CC(=O)OC(C#N)CCc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC(O)C(=O)O)cc1

Procedure:
A mixture of 2-acetoxy-4-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]butyronitrile (1.72 g), 6 N HCl (20 ml) and dioxane (10 ml) was heated under refluxing conditions for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure to yield 2-hydroxy-4-[4-[3-(5-methyl-2-phenyl-4-oxazolyl) propionyl)phenyl]butyric acid as a solid substance. The solid was dissolved in ethanolic hydrogen chloride (10%, w/w, 20 ml), followed by stirring at 75°-80° C. for 2 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1), 2-hydroxy-4-[4-[3-(5-methyl-2-phenyl4-oxazolyl)propionyl]phenyl]butyric acid ethyl ester (1.54 g, 88%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless needles having a melting point of 87°-88° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O1CCOCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nn1-c1ccc(F)cc1
Yield: 8.2 %

Procedure:
A mixture of ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (1 g) and 4-fluorophenylhydrazine hydrochloride (0.67 g) in ethanol (10 ml) and dioxane (10 ml) was refluxed for 5 hours. The solvent was evaporated, and the residue was dissolved in chloroform and washed with water. The organic layer was dried over magnesium sulfate and concentrated. The residue (1.6 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give ethyl 1-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyrazole-5-carboxylate (0.11 g).