Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[C:8](OCC)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][N:1]=[C:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: NCCNCCO
Reactant: CCCCCCCCCCCC(=O)OCC
Product: CCCCCCCCCCCC1=NCCN1CCO
Yield: 69.3 %

Procedure:
58.7 g (564.4 mmoles) of 2-(2-aminoethylamino)ethanol and 122.8 g (538.6 mmoles) of ethyl dodecanoate were heated at 125° C. and ethanol was removed by distillation. 100 ml of toluene was cautiously added and water was removed azeotropically on further reflux. The reaction mixture was fractionally distilled to give 100.2 g (69.5%) of pure product, m.p. 40°-42° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[N:14]1[CH:15]=[CH:16][C:11]([S:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: Nc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccncc2)c1
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90 mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K2CO3 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was back-extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et2O/hexane solution to afford the desired product (4.6 g, 66%): TLC (100% ethyl acetate) Rf 0.29; 1H-NMR (DMSO-d6) δ 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8, 2H). A4b. General Method for Substituted Aniline Synthesis Via Nucleophilic Aromatic Substitution Using a Halopyridine
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH3:15])=[CH2:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:46]N1C(=O)CCC1=O>ClCCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]([N:16]2[CH:19]([S:20][N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[CH:18]([NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]2=[O:43])[C:13]([CH2:15][Br:46])=[CH2:14])=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Yield: 25 %

Procedure:
A mixture of 1.26 g (2 mmoles) of 1-(1-p-nitro-benzyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 0.71 g (4mmoles) of N-bromosuccinimide, 50 mg (0.3 mmole) of azoisobutyronitrile and 80 ml of 1,2-dichloroethane was heated in the dark under nitrogen at 70° C for 3 hours. After washing twice with a sodium metabisulfite solution and with water, the reaction mixture was dried and concentrated to a small volume. After treating the residue with hexane, 1.2 g of crude material was isolated which was purified with column chromatography [sillica gel, 10:1 (v/v) methylene chloride ethyl acetate] to obtain 0.33 g o (0.5 mmole; 23% yield) of 1-(1-p-nitrobenzyloxycarbony-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothioazetidin-2-one.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:34][CH:35]=[C:36]([CH2:38][CH3:39])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:36]1[N:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:34][CH:35]=1)[CH3:39]
Reactant: CCc1coc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1coc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 2-(chloromethyl)-4-ethyl-1,3-oxazole (255 mg; compound D5) in the presence of potassium carbonate (242 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[C:5]1(C)[C:10]([SH:11])=[CH:9][CH:8]=C[CH:6]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:14]([S:11][C:10]1[CH:5]=[CH:6][C:2]([CH3:3])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Cc1ccccc1S
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCCSc1ccc(C)cc1

Procedure:
Sodium (44 g, 1.92 mol) was added in small portions to 1.5 liter of absolute ethanol containing 217 g (1.75 mol) of thiocresol, with stirring, uinder nitrogen. After the addition was completed, 640 g (1.92 mol) of bromooctadecane was added, and the mixture was heated at reflux for 2 hours. The hot reaction mixture was filtered, and the ethanol was removed under reduced pressure. The residue was crystallized from heptane yielding 595 g (91%) of white crystals. mp 54°-55° C.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\C(=O)OC(C)(C)C)/[N:7]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nn(C[C@H]2CCCO2)c(=N)s1

Procedure:
A mixture of Example 69B (7.50 g, 22.0 mmol) and 2,2,2-trifluoroacetic acid (13.5 mL, 176 mmol) was stirred at 22° C. for 8 hours. The volatiles were removed under reduced pressure and the residue was diluted with dichloromethane and washed with saturated aqueous NaHCO3. The organic extract was dried over Na2SO4 and concentrated to give the title compound. MS (ESI+) m/z 242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26]([NH:25][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 27 %

Procedure:
According to the procedure of Example 71, (1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with ethyl isocyanato-acetate. The crude product is purified by column chromatography (silica gel, 1:4 ethyl acetate:methylene chloride) to give pure N-[[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]carbonyl]glycine, ethyl ester (27%) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].C(OCC)(=O)C>>[ClH:27].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(OCc3ccccc3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(COc2ccc3c(n2)OCCNC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of the compound obtained in step 1 (0.40 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.28 g, 83%) as a white powder.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+].[ClH:27]>O.C(O)C>[ClH:27].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)=[O:24]
Reactant: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1F)C1CCNCC1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solutiion of 40.5 g of 1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine, 500 ml of ethanol and 500 ml of 30% of potassium hydroxide solution was stirred at a temperature slightly below reflux overnight. The reaction mixture was cooled to room temperature, diluted with 250 ml of water, and the ethanol partially removed under reduced pressure. The aqueous suspension was extracted with ether (2×150 ml) and the ether fraction subsequently extracted with 1N hydrochloric acid (2×200 ml). The aqueous solution was basified with 25% sodium hydroxide solution, extracted with ether (2×150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil was dissolved in a minimum amount of ethanol and a solution of ethereal hydrogen chloride was added dropwise until a precipitate formed. The solid was collected and dried to give 9.7 g (40%) of product. Recrystallization twice from ethanol-ether gave the analytical sample, mp 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(N)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)COc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
10 g of 3-aminophenoxyacetic acid methylester are solved in 19 g benzyl chloride. Subsequently, 14 g of sodium carbonate are added portionwise and the temperature is raised to 100° C. The reaction mixture is stirred at this temperature for 3 hours. The insoluble salt is filtered off and washed with 100 ml of ethyl acetate. The combined filtrates are kept at 5° C. for 12 h. After the extraction with water and brine, the organic phase is dried with sodium sulfate and the solvent is removed in vacuum (50° C., 10−2 mbar). Yield: 22 g (dark oil).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1OCC1CO1
Reactant: CC(C)(C)N
Product: COC(=O)CCC(=O)c1ccc(C)cc1OCC(O)CNC(C)(C)C

Procedure:
Methyl 3-[2-(2,3-epoxypropoxy)-4-methylbenzoyl]-propionate was treated with t-butylamine in a similar manner to the procedure described in Example 2(i) to give methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methylbenzoyl]-propionate, m.p. 82°-84.5°.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([F:9])[C:7]=1[C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14]
Reactant: COc1cc(OC)c(F)c(I)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (740 mg, 2.47 mmol), (trimethylsilyl)acetylene (0.697 mL, 4.93 mmol), copper(I) iodide (38 mg, 0.20 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (DMF) (4 mL, 50 mmol), bis(triphenylphosphine)palladium(II) chloride (86 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 70 hours. The reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (630 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cn1ccnc1SCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nccn1C
Temperature: 90 °C
Yield: 18.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 0.9 mmol), (prepared as described for the starting material in Example 24), 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (203 mg, 0.95 mmol) and potassium carbonate (303 mg 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline (75 mg, 17%) as a solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:15]3[C:10](=[CH:11][C:12]([NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[C:5]1[S:4][C:3]([C:1]#[N:2])=[N:7][C:6]=1[CH:8]=[CH:9]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(ccc3nc(C#N)sc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#Cc1nc2ccc3cc(N)ccc3c2s1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of tert-butyl (2-cyanonaphtho[2,1-d]thiazol-7-yl)carbamate (72 mg, 0.22 mmol) and thioanisole (0.5 mL) in 2 mL of DCM in an ice bath, 2 mL of trifluoroacetic acid was added. After 1 h, the reaction was concentrated under reduced pressure, and the product (47 mg, 94%) was isolated by silica gel chromatography eluting with 0→75% EtOAc in heptanes. 1H NMR (CD2Cl2) d 8.01 (d, 1H); 7.90 (dt, 1H); 7.76 (d, 1H); 7.09-7.16 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:14]([Cl:13])(=[O:16])=[O:15])[C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reaction time: 0.67 h

Procedure:
12.3 g (0.075 mol) of 4-(1,1-dimethylethyl)anisole, dissolved in 30 ml of methylene chloride, are added dropwise, while cooling in ice, to 16.5 ml of chlorosulfonic acid dissolved in 20 ml of methylene chloride. The mixture is stirred for 40 minutes and then poured onto ice-water. The organic phase is separated off, washed with water, dried with MgSO4 and evaporated. Recrystallization from toluene/petroleum ether provides crystals of melting point: 75°-77° C.
Reaction SMILES: O[C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[O:6][N:5]=[CH:4][CH2:3]1.S(=O)(=O)(O)O>O>[N+:17]([C:8]1[CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=[CH:12][C:7]=1[C:2]1[O:6][N:5]=[CH:4][CH:3]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C1(O)CC=NO1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccno1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
5-Hydroxy-5-(2-nitro-4-trifluoromethylphenyl)-isoxazoline (8.47 g) was added in portions to concentrated sulphuric acid (85 ml). The mixture was stirred for 2 hours and poured into a mixture of ice and water (200 ml). It was extracted with ether (2×100 ml) and the combined organic extracts were washed with water (2×75 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) and filtered to give 5-(2-nitro-4-trifluoromethylphenyl)-isoxazole (7.45 g) as a white solid, mp 62°-63° C.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][C:38]([CH:41]([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[CH:37][CH:36]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.[OH2:48].[NH2:49][NH2:50]>CO>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[C:29]5=[N:49][NH:50][C:31](=[O:32])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][C:38]([CH:41]([O:42][CH2:43][CH3:44])[O:45][CH2:46][CH3:47])=[CH:37][CH:36]=4)=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH2:11]2)=[O:48])[CH2:2][CH2:3]1
Reactant: NN
Reactant: O
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of methyl 3-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (526 mg, 0.82 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3 mL) was stirred at 25° C. for 2 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (330 mg, yield 65%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.72-0.76 (m, 4H), 1.09-1.12 (m, 6H), 1.99 (s, 1H), 3.39-3.73 (m, 12H), 4.70 (s, 1H), 5.40 (s, 1H), 5.99 (s, 1H), 6.68-7.31 (m, 9H), 7.41-7.61 (m, 3H), 12.19 (s, 1H); LC-MS (ESI) m/z: 622 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[N+:16]([CH3:19])([O-:18])=[O:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:19][N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Yield: 75.4 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.50 g, 25.9 mmol) in 14 mL of dry THF was treated by nitromethane (2.10 mL, 38.9 mmol) followed by a 1M solution of tetrabutylammonium fluoride in THF (26.5 mL, 26.5 mmol). The resulting mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was diluted with water and extracted with three portions of ether. The etheral portions were combined, washed with a 10% aqueous solution of potassium hydrogensulfate, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (8-Nitromethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (5.34 g, 75%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH3:18]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCNC(=O)Nc1nc2ccc(Br)c(OC)c2s1
Yield: 2 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and iodomethane in DMF was reacted to give 0.0034 g (2%) of the desired compound 10. 1H NMR (DMSO) δ 10.88 (br s, 1H, NH), 7.55 (d, 1H, J=8.5 Hz, ArH), 7.33 (d, 1H, J=8.5 Hz, ArH), 6.82 (br s, 1H, NH), 3.93 (s, 3H, CH3), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 330 (MH+); RP-HPLC RT 3.04 minutes.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 110.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (1.5 g, 7.49 mmol, supplier Aldrich) in DCM (30 ml) was added DIPEA (1.962 ml, 11.23 mmol) and then portionwise addition of 4-(trifluoromethyl)benzenesulfonyl chloride (2.2 g, 8.99 mmol) at room temperature. The resultant mixture was stirred under an atmosphere of Ar for 2 hours before addition of 1M HCl solution (75 ml) and DCM (75 ml). The layers were separated and the aqueous layer was then re-extracted with DCM (75 ml), the organic layers were combined and washed with saturated brine solution (100 ml). The organic layers were then separated, dried (MgSO4) and concentrated to dryness giving the title compound (3.39 g).