Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=S)[NH:8][C:7]=2[CH:18]=1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>C(O)CCC>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:25][C:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:18][C:7]=2[N:8]=1
Reactant: FC(F)(F)c1ccc2c(c1)NC(=S)c1ccccc1N2
Reactant: COC(CN)OC
Solvent: CCCCO
Product: COC(CNC1=Nc2cc(C(F)(F)F)ccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino] acetaldehyde dimethyl acetal.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]I)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[O:18]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](OCCC1(CCI)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)CC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(C(=O)OCC)C(=O)OCC
Yield: 65.8 %

Procedure:
Using tert-butyl-[2-[1-(2-iodoethyl]cyclohexyl]ethoxy]diphenylsilane (1.77 g) and triethyl 1,1,2-ethanetricarboxylate (2.51 g), the title compound (1.43 g) was obtained in the same manner as in Preparation Example 3B-1. This product was subjected to the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:14]1[C:15](=[O:27])[NH:16][C:17](=[O:26])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CN1CCCC1=O>Cl>[C:8](/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14]2[C:15](=[O:27])[NH:16][C:17](=[O:26])[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([OH:10])=[O:9]
Reactant: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Cl
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)/C=C/c1ccc(NC2=C(c3ccc(Cl)cc3)C(=O)NC2=O)cc1
Reaction time: 28.5 h

Procedure:
A mixture of trans-4-aminocinnamic acid (0.205 g, 1.26 mmol), 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (0.123 g, 0.51 mmol) and 1-methyl-2-pyrrolidinone (1.0 mL) was heated in a sealed tube in a hotblock set at 69° C., for 28.5 hours. The mixture was diluted with aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was triturated with a mixture of dichloromethane and ethyl acetate to afford the title compound as a solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21].O>C(O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:4](=[N:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOC1CCCCC1)C(=O)CCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Yield: 12 %

Procedure:
Ethyl 4-chloro-2-cyclohexyloxyimino-3-oxobutyrate (syn isomer, 27.8 g.), thiourea (7.7 g.), sodium acetate 3-hydrate (13.7 g.) water (70 ml.) and ethanol (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.6 g.), mp 125° to 126° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:14]([Cl:19])(Cl)(Cl)(Cl)[Cl:15].Cl.C(O)=[O:22]>C(Cl)(Cl)(Cl)Cl>[Cl:15][P:14]([Cl:19])([NH:11][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=1)=[O:22]
Reactant: O=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)NP(=O)(Cl)Cl)cc1

Procedure:
A mixture of 75 g (0.42 mole) of 4-tert-butylbenzamide, 88.1 g (0.42 mole) of phosphorus pentachloride and 750 ml of AR carbon tetrachloride was heated at 70° until the evolution of HCl had nearly ceased. The reaction was cooled to 30° and 19.5 g (0.42 mole) of 97% formic acid, added dropwise. After the 20 min. addition, it was chilled to 0°, filtered, washed with AR carbon tetrachloride and air-dired to give 82 g, m.p. 110°-111°.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:50])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:50])=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:48][CH2:47]5)=[O:45])[N:42]=4)[N:39]=3)[CH:49]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CCC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 64.4 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (150 mg, 64%) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1COCC1.C(Cl)Cl>[Cl:18][C:13]1[N:12]=[C:11]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[N:16]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:14]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Oc1cccnc1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a solution of 3-hydroxypyridine (950 mg, 10 mmol) in anhydrous THF (50 mL) at 0° C. under the nitrogen protection was added NaH (60% in oil) (480 mg, 12 mmol). The suspension was stirred for 0.5 h at 0° C., and 2,4,6-trichloropyrimidine (1.84 g, 10 mmol) was added. After the mixture warmed to room temperature and stirred for 2 h, the reaction was quenched by ice brine and extracted with EtOAc (300 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, evaporated in vacuo. The cure product was purified by flash chromatography on a column of silica gel (EtOAc-Hexane, 1:7). The product (1.80 g, 7.4 mmol) in CH2Cl2 (150 mL) at 0° C. was added slowly morpholine (2.5 g, 28 mmol). The reaction mixture was stirred at 0° C. for 1 h and another 1 h at room temperature. The mixture was washed with water. The organic phase was dried (Na2SO4), filtered and evaporated in vacuo and presented three isomers. The isomers was separated by flash chromatography on a column of silica gel (EtOAc-Hexane, 1:7 and 1:3) to obtain 4-[6-chloro-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-morpholine (320 mg, 14.7%).
Reaction SMILES: [CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:15]O>>[CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH2:3]1
Reactant: CO
Reactant: CC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc2c(c1)C=CCC2C
Reaction time: 8 h
Yield: 61 %

Procedure:
Following a similar procedure to that reported in Ferraz, which is hereby incorporated by reference, to a stirred solution of 4-methyl-α-tetralone (0.867 g, 4.98 mmol) in methanol (20 mL) was added NaBH4 (0.56 g, 14.9 mmol) portionwise. The reaction mixture was followed by TLC and, after complete consumption of the starting material (about 2 h), was quenched with saturated NaHCO3. The aqueous layer was extracted with diethyl ether, dried with magnesium sulfate (MgSO4), and filtered; and the solvent was removed under reduced pressure. The crude alcohol was dissolved in toluene (25 mL) and a few crystals of p-TsOH were added. The reaction mixture was stirred overnight, then neutralized by slow addition of saturated sodium bicarbonate (NaHCO3) and extracted with diethyl ether. The combined organic layers where washed with brine, dried with magnesium sulfate (MgSO4), and filtered; and the solvent was removed under reduced pressure. The product was purified by flash chromatography (SiO2, hexanes) to give 1,2-dihydro-1,6-dimethylnaphthalene ((±)-4) as a clear oil (0.479 g, 61% yield). This compound is volatile and cannot be dried for long periods (>30 min) under high vacuum. The spectroscopic data are consistent with previously reported data (Adachi et al., Bull. Chem. Soc. Jpn., 56:651ff (1983), which is hereby incorporated by reference).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[N:9]=[CH:10][N:11]=1)=[CH2:5])C.C1COCC1>CO>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([N:12]2[C:8]3[N:9]=[CH:10][N:11]=[C:6]([C:4](=[O:3])[CH3:5])[C:7]=3[CH:14]=[CH:13]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: C=C(OCC)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Yield: 89 %

Procedure:
[7.25 g, 21.12 mmol] of 4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50 mL each of methanol and THF and stirred with 10 mL of 6N HCL for 4.0 hours at ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic fraction was brined and dried with anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude material was triturated with a mixture of MTBE and petroleum ether (1:4) for several hours and the solid finally isolated via suction filtration and air dried. The 5.95 g of pale yellow material, representing a 89% yield was used without further purification. 1H NMR: 500 Mhz CDCL3 δ9.0(s,1H), 8.08(d,2H, J=8.4 Hz), 7.87(d, 1H, J=4.1 Hz), 7.3(m,3H), 2.8(s,3H), 2.4(s,3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>N1C=CC=CC=1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2
Yield: 81.3 %

Procedure:
A solution of 2-fluoronitrobenzene (10 g, 70.9 mmol) and 1,4-dioxa-8-aza-spiro[4.5]decane (10 g, 69.8 mmol) in pyridine (70 mL) was heated at 70° C. for 1 day, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, and filtered. The solvent was removed under reduced pressure to give the title compound (15 g) as a red oil; 1H NMR (300 MHz, CDCl3) δ 1.88 (t, J=5.6 Hz, 4H), 3.16 (t, J=5.6 Hz, 4H), 4.00 (s, 4H), 7.03 (dd, J=8.2, 8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.40 (ddd, J=8.2, 8.2, 1.7 Hz, 1H), 7.77 (dd, J=8.4, 1.7Hz, 1H); MS (ES) m/z: 265.1 (MH+); HRMS Calcd. for C13H17N2O4 (MH+): 265.1188. Found: 265.1164.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>ClC1C=CC=CC=1Cl>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(Br)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.33 g) and 2-bromo-4-methylphenol (2.5 ml) were dissolved in o-dichlorobenzene (3 ml), and the solution was stirred at 160° C. for 5 hr. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give the title compound (1.83 g, yield 82%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[C:4]=1[S:11]([NH:14][C:26]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])(=[O:12])=[O:13]
Reactant: CSc1cccc(SC)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNC(=O)NS(=O)(=O)c1c(SC)cccc1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A stirred suspension of 5.0 g (0.02 mol) of 2,6-bis(methylthio)benzenesulfonamide, 8.3 g (0.06 mol) potassium carbonate and 3.4 ml (0.03 mol) n-butyl isocyanate was heated at reflux for four hours. After stirring at 25° C. overnight, the mixture was poured into ice and 30 ml 10% HCl. The resulting precipitate was collected, washed several times with water and air dried to provide 6.5 g of the title compound, m.p. 151°-154°.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (32 g, 130 mmol) in DMF (100 mL) was cooled to 0° C. Triethylamine (27.5 mL, 198 mmol) was added, and 3-amino-1-propanol (11.9 g, 158 mmol) was slowly added. The reaction was stirred for two hours at room temperature and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. A solid was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 34.5 g of 3-[(2-chloro-3-nitroquinolin-4-yl)amino]propan-1-ol as a yellow and orange solid.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH2:5](O)[CH3:6].Cl[C:9](Cl)(Cl)[CH2:10][O:11][C:12](=[O:40])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=3)=[CH:23][C:22]=2[N+:37]([O-])=O)=[CH:16][CH:15]=1>CCOC(C)=O.O.[Fe]>[CH:2]1[C:1]2[CH:9]([CH2:10][O:11][C:12](=[O:40])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:36])[NH:28][C:29]5[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=5)=[CH:23][C:22]=4[NH2:37])=[CH:16][CH:15]=3)[C:5]3[C:6](=[CH:26][CH:21]=[CH:22][CH:23]=3)[C:16]=2[CH:15]=[CH:14][CH:19]=1
Reactant: CCO
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 97 %

Procedure:
A 5 liter, 3-neck round bottom flask equipped with a water condenser, heating mantle and overhead stirrer was charged with glacial acetic acid (0.75 L) and 200 proof ethanol (0.75 L) followed by addition of the product from Example 17C (40.0 g, 60 mmol) and iron powder (13.3 g, 240 mmol). The mixture was then heated to reflux for 6 hours, cooled to ambient temperature and diluted with 1.0-1.5 L of EtOAc, stirred for 10-15 minutes and diluted with 1.0 L of water. The two-phase mix was stirred vigorously for 5-10 minutes and the layers were allowed to separate. The red aqueous layer was removed and discarded. The remaining EtOAc layer with suspended solids was washed 6×1.0 L with water eventually removing all of the red color. The EtOAc layer was then filtered to collect a cream colored solid which was rinsed with 300 mL EtOAc and dried to constant mass in a vacuum oven (40° C., house vacuum, 24 hours) to give of the title compound (37 g, 97%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9](O)=[O:10])([CH3:3])[CH3:2].C(C1C=C(O)C=CC=1)(C)C.[Cl:25]CC(O)=O.[OH-].[Na+].O=S(Cl)Cl>C1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([Cl:25])=[O:10])([CH3:3])[CH3:2]
Reactant: O=C(O)CCl
Reactant: CC(C)c1cccc(OCC(=O)O)c1
Agent: CC(C)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)c1cccc(OCC(=O)Cl)c1

Procedure:
A mixture of 3-isopropylphenoxyacetic acid (prepared by the reaction of 3-isopropylphenol with chloroacetic acid in the presence of sodium hydroxide, 5.0 g, 25.8 mmol) and SOCl2 (5.0 mL, 8.2 g, 68.8 mmol) in 10 mL of benzene was refluxed for 2 h. Thereafter volatile materials were removed by vacuum distillation to give 3-isopropylphenoxyacetic acid chloride as a light brown oil. To an ice-bath cooled solution of 4-aminobutyric acid (5.3 g, 51.6 mmol, 2.0 eq) and NaOH (2.0 g, 51.6 mmol) in 60 mL of H2O and 80 mL of CH3CN were added drop-wise the acid chloride in 40 mL of CH3CN and NaHCO3 (3.3 g, 38.7 mmol, 1.5 eq) in 50 mL of H2O. The resulting mixture was stirred vigorously for 5 h.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]2[S:21]C(=S)N[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-:24].[Na+].Cl>C(OCC)(=O)C>[CH3:3][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH:17]([SH:21])[C:18]([OH:23])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:1]
Reactant: [OH-]
Reactant: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC(S)C(=O)O)cc(C(C)(C)C)c1O
Temperature: 15 °C

Procedure:
To 114.5 g of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-2-thioxo-4-thiazolidinone, 815 ml of 2M sodium hydroxide was added. The resultant mixture was heated to reflux temperature over the course of one hour and maintained at reflux for 2 hours. The mixture was cooled in an ice/water bath to 15° C. and 290 ml of 6M hydrochloric acid was added dropwise under a nitrogen atmosphere over 15 minutes, keeping the temperature of the mixture below 16° C. The resultant solid was dissolved by adding 600 ml of ethyl acetate to the mixture. The organic layer was separated, washed 3 times with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and then the solvent was removed in vacuo to yield 100.3 g (100% of yield) of the subtitled intermediate. mp 137°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH:36]1([NH:42][NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: NNC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NNC4CCCCC4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 10.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 7 hr. Next, cyclohexylhydrazine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 12 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (8 mg, yield 10%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(Cl)Cl.N1C=CC=CC=1>[C:8]([C:7]1[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1N
Reactant: O=C(Cl)CCCCCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cccnc1NC(=O)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To 2-amino-3-cyanopyridine [24517-64-4] (200 mg, 1.7 mmol) in CH2Cl2 (3 ml) and pyridine (3 ml) was added a solution of 6-phenylhexanoic acid chloride (1.5 eq) in CH2Cl2 (1 ml) and the reaction mixture was stirred overnight at ambient temperature. Water was added, the phases were separated and the pH of the inorganic layer was adjusted (pH 7). The inorganic phase was extracted with EtOAc (3 times), the combined organic layers were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Trituration from diethyl ether yielded 6-phenyl-hexanoic acid (3-cyano-pyridin-2-yl)-amide 360 mg (73%) as a white solid, MS (m/e): 294.3 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[CH2:7]([N:9]([CH2:16][CH2:17][Cl:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8]>O>[Cl-:18].[CH3:1][N+:2]([CH3:3])([CH2:17][CH2:16][N:9]([CH2:7][CH3:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][OH:6]
Reactant: CCN(CCCl)c1ccccc1
Reactant: CN(C)CCO
Solvent: O
Product: CCN(CC[N+](C)(C)CCO)c1ccccc1
Product: [Cl-]

Procedure:
A stirred mixture of 35.6 parts of dimethylaminoethanol in 60 parts of water was heated to 90° and 73.6 parts of N-ethyl-N-(2-chloroethyl)aniline was gradually added. The mixture was heated at 90°-95°. After two and one-half hours there was obtained N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-2-hydroxyethylammonium chloride in the form of an aqueous solution.