Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.COC1C=C(B(O)O)C=CC=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:41]=1>>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][C:40]1[N:41]=[C:37]([NH:36][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:12]=2)[S:38][CH:39]=1)[CH3:47]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(OC)c2)cc(C(=O)O)c1
Agent: COc1cccc(B(O)O)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3cccc(OC)c3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(3-Methoxy-phenoxy)-5-(S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[3-methoxy-phenyl]oxy}benzoic acid (prepared in analogy to the method described in general synthetic descriptions F, using 3-methoxyphenylboronic acid in step D)) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:16]([CH2:18][C:19]([O:21]C)=[O:20])[CH:17]=2)=[O:11])=[C:8]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>CO.O>[CH2:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=2)=[O:11])=[C:8]([O:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1cc(OCC(C)C)ccc1C(=O)c1ccc(OCC(C)C)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
In 2 ml of methanol is dissolved 0.13 g of methyl 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]acetate, to which is added 0.2 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour and then at 50-60° C. for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 0.07 g of 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]acetic acid as a white-colored solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1ccnc(Cl)c1F
Temperature: 25 °C
Yield: 87 %

Procedure:
A stirred solution of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (4.27 g, 12.9 mmol) in thionyl chloride (60 mL) was heated at 85° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in petroleum ether (40-60° C.), to afford the title compound as a cream solid (3.90 g, 87% yield). 1H NMR (400 MHz, CDCl3): δ 8.27-8.20 (m, 2H), 7.88 (dd, J=1.1, 8.1 Hz, 1H), 7.66 (t, J=8.2 Hz, 1H), 6.95 (t, J=5.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])[CH3:2].[Br:13]N1C(=O)CCC1=O>CO>[Br:13][C:7]1[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]([O:11][CH3:12])=[N:5][C:6]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1c(C)cc(C)nc1OC
Solvent: CO
Product: CCc1c(OC)nc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A mixture of 3-ethyl-2-methoxy-4,6-dimethylpyridine (265 mg, 1.61 mmol), N-bromosuccinimide (346 mg, 1.93 mmol) and methanol (5 mL) is stirred at room temperature for 5 hr. The solvent is removed and the residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 5-bromo-3-ethyl-2-methoxy-4,6-dimethylpyridine (285 mg, 73%) as a white semi-solid. LC/MS: MS m/e=244/246 (M+H); RT 4.78 min.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[N:15]1[NH:16][CH:17]=[C:18]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20][C:19]=12>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:16]2[CH:17]=[C:18]3[C:19]([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)=[N:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(NS(C)(=O)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To {4-[(methylsulfonyl)amino]phenyl}boronic acid (commercially available from e.g. Combi-Blocks) (127 mg, 0.29 mmol) in dichloromethane (3 ml) was added copper(II) acetate (107 mg, 0.59 mmol) and 4 Å molecular sieves (190 mg), and the reaction stirred at room temperature, open to air, for 10 minutes. 1,1-Dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (70 mg, 0.29 mmol) was added and the reaction stirred at room temperature, open to air, overnight. The reaction mixture was diluted with methanol and filtered through a celite pad, washing with methanol. Solvent was evaporated in vacuo. Ethyl acetate and water were added, and the product was extracted into ethyl acetate (×3), washed with water (×1), then saturated sodium bicarbonate solution (×1), and then dried over magnesium sulfate. Solvent was evaporated in vacuo. The resulting crude product was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate in hexane (0-50%). Relevant fractions were combined and solvent evaporated in vacuo. The resulting crude product was purified further by Mass Directed Autopreparation to afford the title compound (D39). MS (ES+) m/e 407 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(Cl)Cl>[CH2:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: BrCCOc1cccc2c1CCC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc2c1CCC2
Yield: 85.4 %

Procedure:
A solution of 54.01 g (0.226 mole) of 4-(2-bromoethoxy) indan and 41.81 g (0.226 mole) of potassium phthalimide in 1200 ml of dimethylformamide was stirred overnight at 85° C. The reaction was filtered and dimethylformamide removed in vacuo in a rotary evaporator to give a white solid. The solid was dissolved in methylene chloride and extracted with water. Methylene chloride was evaporated to give a light brown solid. The solid was triturated with diethyl ether to give 59.3 g light brown solid. A portion of the solid was recrystallized from methylene chloride-ethanol-diethyl ether to give a white crystalline solid, m.p. 128.5°-132.0° C.
Reaction SMILES: [F:1][C:2]([F:17])(S(F)(=O)=O)[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5]([F:8])(=[O:7])=[O:6].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[F:10][C:4]([F:9])([S:5]([F:8])(=[O:6])=[O:7])[C:3]([F:11])([F:12])[CH:2]([F:1])[F:17]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.4 Gram of 4-(2-aminoethyl)phenol and 9.15 g of triethylamine were dissolved in 100 mL of N-methylpyrrolidone, and the solution was cooled to 0° C. in a nitrogen stream. Thereto, 9.45 g of methacryloyl chloride was added dropwise over 0.2 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 4 hours. After adding 500 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 12.2 g of N-(4-hydroxyphenethyl)methacrylamide as a brown oil. Thereafter, 7.49 g of the oil and 11.5 g of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of THF, and the resulting solution was cooled to 0° C. Thereto, 4.43 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated, and the brown oil as residue was dissolved in 100 ml of methanol. Thereto, 10 g of sodium hydrogencarbonate as solid was added, and the mixture was stirred at 50° C. for 6 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with saturated brine and twice with water and dried over sodium sulfate to obtain 15.7 g of 3-((4-(2-methacrylamido)ethyl)phenoxy)sulfonyl)-1,1,2,2,3,3-hexafluoropropane-1-sulfonylfluoride as a brown oil. Thereafter, 7.29 g of this brown oil was dissolved in 100 mL of methanol, and 4.81 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, and the solvent was concentrated, as a result, 10.1 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 2.87 (t, 2H), 3.50 (quartet, 2H), 5.27 (s, 1H), 5.66 (s, 1H), 6.39 (bs, 1H), 7.14 (d, 2H), 7.23 (d, 2H), 7.67-7.76 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −107.4 (m, 2F), −114.0 (m, 2F), −118.1 (m, 2F).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:28])=[O:27]>>[CH3:39][O:38][C:36]([CH2:35][CH:30]1[CH2:31][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:33][CH2:34][N:29]1[S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:27])=[O:28])=[O:37]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: COC(=O)CC1CNCCN1S(=O)(=O)c1ccc2ccccc2c1
Product: COC(=O)CC1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with methyl 2-[1-(2-naphthylsulphonyl)piperazin-2-yl]acetate to give 2-methoxycarbonylmethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 90% yield as a glass;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[NH2:39])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[NH:39][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (137 mg, 473 μmol), 2,5-dimorpholinobenzeneamine (125 mg, 473 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 473 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.23-8.51 (1H, m), 7.96 (1H, d, J=8.2 Hz), 7.53-7.69 (2H, m), 7.42-7.53 (1H, m, J=7.8, 7.8, 5.5, 2.0 Hz), 7.31-7.40 (1H, m), 7.13-7.26 (2H, m), 7.10 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.4, 2.9 Hz), 6.12-6.27 (1H, m), 3.92 (4H, t, J=4.7 Hz), 3.75-3.87 (4H, m), 3.12-3.21 (2H, m), 3.00-3.12 (4H, m), 2.69-2.98 (2H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.3 (M+1).
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:17]1=[O:31].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])([CH3:8])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[C:17]3=[O:31])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=C(n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)c2cc(C#N)ccc2O1
Yield: 48.2 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 16. Then, 0.12 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for 3 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/25 mixture of methanol/methylene chloride as a developing solvent to obtain 0.61 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=2)[C:4]([CH3:17])=[N:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
2.0 Grams (0.00855 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.65 g (0.0116 mole) of powdery potassium hydroxide, the resulting mixture was stirred at 30° C. for 30 minutes. To this solution was added 2.32 g (0.00855 mole) of tert-butyl 4-bromomethylbenzoate, and reaction was carried out at from 50° to 60° C. for 1 hour. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain crude crystals. The crystals were recrystallized from methanol to obtain 2.4 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=1.C(N(CC)CC)C.[CH2:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]>C(#N)C.O.Cl>[CH2:18]([N:22]([C:6]1[C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Reactant: CCCCNCC
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc(Cl)c1C
Yield: 64.3 %

Procedure:
A mixture of 2,5-dimethyl-4,6-dichloro-pyrimidine (0.999 g, 5.64 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.570 g, 5.65 mmol) and heated at reflux overnight. The mixture was cooled, diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate, washed with brine, dried and concentrated to give 0.877 g (64%) of title compound as a yellow oil. 1H NMR (CDCl3) δ0.90 (t, 3H), 1.15 (t, 3H), 1.22-1.36(m, 2H), 1.5-1.6(m, 2H), 2.20 (s, 3H), 2.45 (s, 3H), 3.25-3.48 (m, 4H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1([CH2:18][OH:19])[CH2:17][CH:16]=[CH:15][CH2:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:19][CH2:18][CH:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCC1CC=CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitrobenzoyl chloride (3.46 g, 18.7 mmol) was added to a dichloromethane solution (34 mL) of cyclopent-3-en-1-ylmethanol (1.67 g, 17.0 mmol) and triethylamine (3.55 mL, 25.4 mmol). The solution was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate solution was added, and the solution was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CHCl3) δ 2.21 (dd, J=4.9, 14.8 Hz, 2H), 2.57 (dd, J=8.6, 15.1 Hz, 2H), 2.71-2.82 (m, 1H), 4.28 (d, J=7.2 Hz, 2H), 5.69 (s, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.27 (d, J=8.6 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(O[CH2:39][CH3:40])(=O)C>CCCCCC>[CH:4]1[C:5]2[N:6]([C:16]3[CH:21]=[CH:20][C:19]4[N:6]([C:40]5[CH:39]=[CH:12][CH:7]=[CH:8][CH:9]=5)[C:5]5[C:13]([C:18]=4[CH:17]=3)=[CH:14][C:2]([N:33]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]4[C:34]3=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:3][CH:4]=5)[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(C)=O
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1ccccc1
Solvent: CCCCCC
Product: c1ccc(-n2c3ccc(-n4c5ccccc5c5ccccc54)cc3c3cc(-n4c5ccccc5c5ccccc54)ccc32)cc1

Procedure:
The Rf values of the objective substance, 3,6-dibromo-9-phenyl-9H-carbazole, and carbazole were respectively 0.32, 0.73, and 0.18 which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:10 ratio).
Reaction SMILES: [C:1]1([O:11]C2C3C(=CC=CC=3)C=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[OH:11])[CH:6]=1
Reactant: c1ccc2c(Oc3cccc4ccccc34)cccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Oc1cccc2ccccc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Naphthylether 10 (19.8 g, 81 mmol) was dissolved in a dry DCM (400 mL) and the solution cooled to −70° C. A solution of BBr3 (1M in DCM, 160 mL, 160 mmol) was added dropwise while maintaining an internal temperature below −60° C. The mixture was aged at this temperature for an additional 30 min, then allowed to warm up to RT and aged for additional 2 h at rt. The mixture was then again cooled to −70° C., treated with absolute ethanol (20 mL), and the resulting mixture was aged at rt overnight. The solution was poured into a cold NaHCO3 solution (500 mL, saturated aq) and vigorously stirred. The organic layer was washed with dilute HCl solution (0.1N, 200 mL) and with water (200 mL), and the solvent removed. Column chromatography of the resulting residue using 20% ethyl acetate in hexanes yielded the naphthylester 12 (17.6 g, 76.4 mmol) in 94% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:16][C:17]1(OCC)[CH:22]=[CH:21][C:20](O)=[CH:19][CH2:18]1.[CH3:27][CH2:28]OC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:27][CH2:28][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: COC(=O)C(C)(C)Sc1ccc(O)cc1
Reactant: CCOC1(Cl)C=CC(O)=CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Sc1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
The title product was prepared according to the procedure described in Method B starting from methyl 2-(4-hydroxyphenylthio)isobutyrate (prepared as described above) (0.800 g, 3.54 mmol) and 4-chlorophenetyl alcohol (0.554 g, 3.54 mmol) in 20 mL of anhydrous THF. DEAD (0.801 g, 4.6 mmol) and triphenylphosphine (1.205 g, 4.6 mmol) were added piecemeal in small portions, maintaining the temperature below 30° C. The reaction was left overnight under magnetic stirring at room temperature. After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/ethyl acetate 9/1 as eluent. 0.416 g of oily product were obtained (yield: 32%); TLC: silica gel, eluent hexane/ethyl acetate 9/1, Fr: 0.32; 1H NMR (CDCl3, 300 MHz) δ: 7.40-7.19 (m, 6H), 6.80 (d, 2H), 4.15 (t, 2H), 3.65 (s, 3H), 3.08 (t, 2H) 1.45 (s, 6H); HPLC: Column: Symmetry—C18, (5 μm) 4.6×250 mm, T: 30° C., mobile phase CH3CN/H2O 70/30 (v/v), pH: as is, flow rate: 0.75 mL/min, 205 nm UV detector, retention time 31.40 min; KF: 0.4% H2O; E.A. conforming for C19H21ClO3S.
Reaction SMILES: [C:1](CC(N)=O)#[N:2].[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:1]#[N:2])[CH:21]=2)[S:10][N:9]=1
Reactant: N#CCC(N)=O
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Product: N#Cc1cccc(Nc2snc(O)c2C#N)c1

Procedure:
The title compound was prepared from 1-isothiacyanato-3-cyano-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (CD3OD) δ: 7.5–7.7 (m, 4H) ppm; MS (ES, m/z): 242.9, [M-H]+, 241.1 [M-H]−.