Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:21][CH:20]=2)=[O:26])[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 86.4 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzoyl)amino]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 455-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2 M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (590 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([Cl:28])=[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Cl:28][C:5]1[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:43]([NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[C:3]([F:29])[CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
To a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one (500 mg, 1.20 mmol) and pyridine (140 mg, 1.8 mmol) in DCM (20 mL) was added phenyl isocyanate (215 mg, 1.8 mmol). The mixture was stirred at RT overnight, concentrated, and purified by prep-HPLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (53 mg, 8.4% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28-7.23 (m, 3H), 6.98-6.95 (m, 1H), 6.35 (s, 1H), 4.39 (s, 1H), 4.11-4.09 (m, 2H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.36 (m, 2H), 2.26 (s, 3H), 2.23-2.20 (m, 1H), 1.68-1.62 (m, 1H), 1.64 (t, J=7.2 Hz, 3H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=CC(S)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)=[CH:3][CH:8]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Fc1ccc(S)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CNOC
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (10 g, 102.52 mmol) and ethyl chlorooxoacetate (13.77 ml, 123.02 mmol) in dichloromethane (163 ml) at 0° C. was added triethylamine (28.6 ml, 205.04 mmol) drop wise. The reaction was stirred at room temperature for 1.5 hrs. The reaction was quenched with 20 ml of methanol, and then concentrated. The resulting solid was triturated with THF and filtered away. The filtrate was concentrated. The residue was vacuum distilled bulb to bulb. At approximately 85° C. impurities were collected and then discarded. The title compound was collected at approximately 120° C. as a neat oil (11.6 g, 72.0 mmol, 70.2%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[N:16][O:17][CH2:18][CH2:19]Br)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]1>CC(CC(C)C)=O>[CH2:46]([O:45][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([CH2:19][CH2:18][O:17][N:16]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:38]1)=[O:44])[CH3:47]
Reactant: BrCCON=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Yield: 58.6 %

Procedure:
To a solution of 2-(((10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)oxy)ethylbromide (1.4 g, 4.2 mmol) in methyl isobutylketone (40 ml) was added potassium carbonate (4.7 g, 34 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (2.6 g, 8.5 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The oily residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). A 34% aqueous tartaric acid solution was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate (25 ml). The combined organic phases were extracted with a 34% aqueous tartaric 1/2acid solution (2×5 ml) and the organic extracts were discarded. The acidic aqueous phases were combined, diluted three times with water and ethyl acetate (40 ml) was added. A 4 N sodium hydroxide solution was added until pH 7 and the phases were separated. The organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 1 g of (R)-N-(2-(((10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.39 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
138 g. (1 mole) of 4-hydroxybenzoic acid was dissolved in 1 liter of 95% ethanol and 500 ml. of 2N sodium hydroxide solution. To this solution was added 346 ml. (3 mole) of benzyl chloride and the mixture was boiled under reflux. 1 liter of 5N sodium hydroxide was added dropwise over a period of 2 hours and the mixture heated a further hour with stirring. The solvent was distilled to half its volume, 2 liters of water added, the warm aqueous solution acidified with hydrochloric acid and the precipitated product recrystallised from 80% ethanol, m.p. 188° C.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: NN1CCCCC1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCCCC2)on1
Yield: 65.6 %

Procedure:
As described for example 18, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.33 mmol) was converted, using 1-aminopiperidine (127 mg, 1.27 mmol) instead of N,N-dimethylhydrazine, to the title compound (83 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=9:1 to 7:3). MS: m/e=384.2 [M+H]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[O:5]=[C:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7]1>O.Cl>[OH:3][N:1]=[C:7]1[C:6](=[O:5])[CH2:10][CH2:9][S:8]1(=[O:12])=[O:11]
Reactant: O=C1CCS(=O)(=O)C1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCS(=O)(=O)C1=NO
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of 8.4 g (120 mmol) of sodium nitrite in 25 ml of water is added dropwise at 0° C. to a suspension of 15.5 g (116 mmol) of 3-oxotetrahydrothiophene dioxide (M. A. Smith et al., J. Chem. Soc. (c) 1967, 2171) in 70 ml of water and 10 ml of conc. hydrochloric acid. After 1 hour at 0° C., the product is filtered off with suction, washed with water and dried in vacuo. 11.5 g (61%) of 2-hydroxyimino-3-oxotetrahydrothiophene dioxide, m.p. 148° C., are obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:15](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1>C(O)C>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:15](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 84 h
Yield: 86.2 %

Procedure:
10 ml of a 40% aqueous solution of dimethylamine are added to a solution of 5.37 g (12 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, in 10 ml of ethanol. The mixture is allowed to stand for 3-4 days, then evaporated, the residue is diluted with 50 ml of benzene, the resulting solution is washed with water until neutral, dried and evaporated. The residue is crystallized from hexane. 4.26 g (86.2%) of (E)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene are obtained; m.p.: 90°-91° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH3:2].[C:18]1([CH2:24][C:25]#[N:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.[OH-].[Na+]>O>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]#[N:26])=[CH:8][CH:7]=1)[CH3:2]
Reactant: N#CCc1ccccc1
Reactant: CCCCC(CC)COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CC)COc1ccc(C=C(C#N)c2ccccc2)cc1

Procedure:
70.2 Grams of 4-[(2-ethylhexyl)oxy]benzaldehyde (prepared as described in the preceding paragraph) and 38.6 g of phenylacetonitrile were added to 800 ml of methanol and stirred cold (10°-15° C.). To this was added (dropwise) 125 ml of aqueous sodium hydroxide (50 percent) with continued stirring at 10°-15° C. for an additional two hours. The mixture was then stirred overnight at room temperature and then poured into cold water and extracted with ethyl acetate. The extract was dried and evaporated to yield α-[[4-(2-ethylhexyloxy)phenyl]methylene]benzeneacetonitrile which was catalytically reduced as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:33][CH:32]=1
Reactant: O=C(c1ccc(O)c(F)c1)N1CCC[C@H]1CN1CCCC1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: CS(=O)(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2F)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (3-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone and 4-methylsulfonylbenzyl chloride. MS (ES+) 461.2
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C@H:11]2[S:15][C@H:14]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:13][S:12]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH2:30](Br)[CH:31]=[CH2:32].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:32]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C@H:11]2[S:15][C@H:14]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[CH2:13][S:12]2)=[CH:4][C:3]=1[O:28][CH3:29])[CH:31]=[CH2:30]
Reactant: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Reactant: C=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trans-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxy-phenyl)-1,3-dithiolane (21) (2.50 g, 5.69 mmole) was dissolved in 30 ml dry DMF and allyl bromide (0.963 g, 7.97 mmole) was added by syringe. To this solution was added 100 mg of 18-crown-6 and potassium carbonate (0.785 g, 5.69 mmole). The reaction was stirred at 50° C. under an argon atmosphere for 4 hours. The reaction was quenched with 10% HCl and extracted with diethyl ether. The organic layer was dried over MgSO4, and concentrated to a yellow oil in vacuo which was purified by flash column chromatography with 3:1-2:1 hexane/ethyl acetate as eluent. (2.60 g, 95% yield: colorless oil).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)nc(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)nc(-c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2,6-bis(4-methylphenyl)pyrimidine-4-carboxylate (0.31 g, 0.98 mmol) in THF (10 mL) and water (10 mL) were added sodium hydroxide (1.0 M in water; 2.05 mL, 2.05 mmol). The mixture was stirred at ambient temperature. After 18 h, HCl (1.0 M in water) was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. MS 305.1 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]3)O1.Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][N:29]=[CH:30]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:30]1[C:31]2[C:26](=[C:25]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]4)[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: COC(=O)c1cccc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Brc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Yield: 70.9 %

Procedure:
Methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (2.2 g, 7.0 mmol), 5-Bromoisoquinoline (1.33 g, 6.3 mmol), a 2M solution of sodium carbonate (9.6 mL) and palladium tetrakistriphenylphospine (0.37 g, 0.32 mmol) were heated in Toluene-EtOH (105 mL-21 mL) at 80° C. overnight. Solvent was evaporated and mixture was extracted with ethyl acetate. Organic phase was washed with brine, dried, filtered and evaporated. Residue was purified by chromatography (ethyl acetate-hexane 10:90->20:80->30:70->40:60->60-40. to give 1.4 g of the title compound as an off-white solid
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Yield: 106.2 %

Procedure:
A mixture of 4-nitro-phthalonitrile (4.00 g), 4-methoxy-phenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) was heated to reflux for 2 h. Reaction mixture was cooled and filtered. Filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1 N, 50 ml), water, and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product (6.14 g). 1H NMR (200 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1 H), 7.21 (m, 2 H), 6.96 (m, 4 H), 3.84 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Cl:15])=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)cs1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C)c(Cl)s1
Reaction time: 0.5 h

Procedure:
4-Methyl-2-thiophenecarboxylic acid ethyl ester (3.4 g) synthesized in accordance with the method of Reference Example 140 was dissolved in acetonitrile (30 ml), and sulfuryl chloride (2.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room-temperature for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g). 5-Chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) was dissolved in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml), and 1N aqueous sodium hydroxide (40 ml) was added. The mixture was stirred at 60° C for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N.S(=O)(=O)(O)[OH:17]>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)(=[O:17])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: N
Product: NC(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
1-(3-Cyanophenyl)piperazine (1.6 g, 8.3 mmol) was dissolved in 90% sulfuric acid aqueous solution (17 ml) and stirred at a room temperature for 2 days. The reaction solution was slowly added drbpwise to a mixture consisting of ice (65 g) and 28% aqueous ammonia (65 ml), and the reaction product was extracted with chloroform. The resulting extract was washed with saturated brine and dried with sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 990 mg of the title compound (4.9 mmol, 58% in yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of cis-2-aminocyclohexanecarboxylic acid amide (2.0 g, 14.0 mmol), and triethylamine (3.9 mL, 28 mmol) in dichloromethane (100 mL) was added 4-chlorobenzenesulfonyl chloride (2.95 g, 14.0 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction was then diluted with dichloromethane (200 mL) and washed with H2O, 1.0 M HCl, brine, and dried over Na2SO4. Further purification by flash chromatography (silica gel, 1% to 10% MeOH/CHCl3) afforded cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (2.0 g) as a white solid in 45% yield over three steps: 1H NMR (DMSO-d6) δ 7.82 (m, 2 H), 7.63 (m, 2 H), 7.56 (d, 1 H, J=7.0 Hz), 7.22 (s br, 1 H), 6.80 (s br, 1 H), 3.43 (m, 1 H), 2.37 (m,1 H), 1.72 (m, 2 H), 1.45 (m, 3 H), 1.15 (m, 3 H); MS m/e 317.05 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]>>[C:7]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C1NCCO1
Reactant: C=CCCC(=O)Cl
Product: C=CCCC(=O)N1CCOC1=O
Yield: 53 %

Procedure:
Using the method of preparation 20 and reagents oxazolidin-2-one (10.22 g, 117.3 mmol) and pent-4-enoyl chloride affords 10.62 g (53%) of the title compound as a colorless oil.