Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C(O[CH:18](O)[C:19]([F:22])([F:21])[F:20])C.C(O)(=O)C>C(O)C>[ClH:1].[F:20][C:19]([F:22])([F:21])[CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: CCOC(O)C(F)(F)F
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3C(F)(F)F

Procedure:
A mixture of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (0.5 g), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL), acetic acid (0.32 mL) and ethanol (22.5 mL) was heated at reflux for 16 h. The solvent and excess reagents were evaporated to dryness under vacuum. The residue was washed with diethyl ether to afford 1-trifluoromethyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ol hydrochloride (0.5 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1F)[NH:10][C:9](=[O:15])[C:8]2=[O:16]>CN(C)C=O>[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[S:2][CH3:1])[NH:10][C:9](=[O:15])[C:8]2=[O:16]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(cc1F)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium thiomethoxide (5.93 g, 84.6 mmol) was added to a solution of 5,6-difluoroindole-2,3-dione (7.75 g, 42.3 mmol) in dimethylformamide (400 mL). The reaction was stirred at room temperature for 1 h, then poured onto ice (2 L). The resulting solid was collected by filtration, washed with water and dried at 40° C. under vacuum to give a brown solid (3.12 g, 35%): mp 296° C.; C9H6F1NO2S requires: C, 51.18; H, 2.86; N, 6.63; S, 15.18%. Found C, 50.95; H, 2.85; N, 6.58; S, 15.35%; IR νmax (Nujol)/cm−1 3285, 2925, 2854, 1760, 1714, 1611, 1465 and 1036; NMR δH (400 MHz, DMSO-d6) 2.58 (3H, s), 6.71 (1H, d, J 6.0 Hz), 7.38 (1H, d, J 9.0 Hz), 11.02 (1H, brs).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23].N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[C:14]([C:12]1[O:11][N:10]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=3)[N:7]=2)[CH:13]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nccc(Nc3cc(C(C)(C)C)on3)n2)cc(OC)c1OC
Temperature: 100 °C

Procedure:
A mixture of (2-chloropyrimidin-4-yl)-(5-tert-butyl-isoxazol-3-yl)amine (50 mg 0.198 mmol Step A) and 3,4,5-trimethoxyaniline (36.2 mg 0.198 mmol) was suspended in 0.15 mL of a 2M solution of Et3N-TFA in DMSO (stock solution prepared by combining 1.28 g of Et3N-TFA and 3 mL of DMSO) in a sealed tube. The resulting mixture was heated at 100° C. for 4 h, cooled to RT, diluted with CH2C12 (attempted crystallization), concentrated and purified via preparative HPLC to give N4-(5-tert-butylisoxazol-3-yl)-N2-(3,4,5-trimethoxy-phenyl)-pyrimidine-2,4-diamine as a green-gray amorphous solid. MS m/z=400. Calc'd for C20H25N5O4— 399.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]([NH:20]C(=O)OC(C)(C)C)[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:11]([C:29](=[O:45])[NH:30][C@H:31]([CH:37]([OH:44])[C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[CH2:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH2:10]2)=[N:6][CH:7]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[NH2:20][C@@H:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]([N:12]1[CH2:13][C@H:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10][C@H:11]1[C:29]([NH:30][C@H:31]([CH:37]([OH:44])[C:38]([NH:40][CH:41]1[CH2:42][CH2:43]1)=[O:39])[CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1)=[O:45])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl (2S)-1-((2S,4R)-4-(5-chloro-pyridin-2-yloxy)-2-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (313 mg, 0.482 mmol) in dichloromethane (2 mL) was added 4.0 M HCl in dioxane (3.0 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure and dried to give (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-(5-chloro-pyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide HCl salt as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C(C)=CC=CC=1>[Cl:30][C:26]1[CH:25]=[C:24]([C:19]2([N:18]3[C:8](=[O:16])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:12]([CH3:13])[O:11][CH2:10]3)[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC1(c2cccc(Cl)c2)CCCC1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C2(c3cccc(Cl)c3)CCCC2)CO1
Yield: 88.5 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1-(3-chlorophenyl)cyclopentylamine (0.78 g) and xylene (3 ml) was heated at reflux for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.97 g).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(NCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of {6-[2-(3-tert-butoxycarbonylamino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.39 g, 0.78 mmol) in THF (10 mL) was treated with lithium hydroxide (0.089 g, 3.90 mmol) in water (2 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated in vacuo. The residue was diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(3-tert-butoxycarbonylamino-propylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid as a yellow solid (0.27 g, 74%) after lyophilization. 1H NMR (400 MHz, CD3OD) δ8.09 (d, J=6.25 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.32 (m, 1H), 5.67 (d, J=6.25 Hz, 1H), 3.28-3.14 (br m, 2H), 3.17 (dd, J=15.24, 2.35 Hz, 1H), 3.10-2.90 (m, 2H), 2.38 (s, 3H), 2.36-2.25 (m, 1H), 1.70-1.50 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14](C(O)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:40]([O:42][C:43](=[O:48])[CH2:44][C:45]([K])=[O:46])[CH3:41].[Cl-].[Mg+2].[Cl-]>C1COCC1.Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][C@@H:14]([C:45](=[O:46])[CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:48])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[K]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)O)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
To a solution of (3R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2.25 g) in THF (60 ml) was added 1,1′-carbonylbis(1H-imidazole) (1.20 g) and the mixture was stirred at room temperature for 2 hr. (3-Ethoxy-3-oxopropanoyl)potassium (1.26 g) and magnesium chloride (700 mg) were added and the reaction mixture was stirred with heating to reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with 3.5 M aqueous potassium carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-80:20) and concentrated under reduced pressure to give the object compound (460 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][N:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:31]=[C:30]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:29]=2)=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: CC(C)c1ccc(NC(=O)c2ccnc(Br)c2)cc1
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3ccc(C(C)C)cc3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-(4-isopropyl-phenyl)-isonicotinamide were converted to the title compound.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[O:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>C1(C)C=CC=CC=1>[N:5]([S:2]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[O:8][CH:12]=[N:11][N:10]=1)(=[O:4])=[O:3])=[C:6]=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1-c1nnco1
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
By the procedure of Example 1, 7.1 g of chlorosulfonyl isocyanate was added to a suspension containing 8.1 g of 2-(1,3,4-oxadiazol-2-yl)phenol [prepared by the procedure of J. Maillard et al., Bull. Soc. Chim. France, 3, 529 (1961)] in 125 ml of dry toluene. The reaction mixture was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for about 0.5 hour. The resulting suspension containing a viscous oil was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 8 g of the title compound as a viscous, crude oil. The IR spectrum showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][C:22]2=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>O1CCOCC1.O>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH:21]([C:3]([O:6][CH3:7])=[O:8])[C:22]2=[O:27])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1CCc2c(OCc3ccccc3)cccc2C1=O
Temperature: 82.5 °C
Yield: 98.2 %

Procedure:
Under an argon atmosphere, 2.09 g of 60% sodium hydride was suspended in 30 ml of anhydrous dioxane and 11.51 g of dimethyl carbonate was added. While stirring with heating in an oil bath at 80 to 85° C., a solution of 6.58 g of 5-(benzyloxy)-1-tetralone in 15 ml of dioxane was added dropwise over about one hour. After stirring for one hour, the reaction solution was ice-cooled and 52 ml of an aqueous 1N acetic acid solution was added dropwise. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.95 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][CH:15]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:35].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:59]1([C:65](O)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>C(Cl)Cl>[CH:59]1([C:65]([N:13]([CH2:12][C:4]2[C:3](=[O:35])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:14][CH:15]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: O=C(O)C1CCCCC1
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 15 h

Procedure:
tert-butyl 4-(2-{[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate (1.61 g crude, 3.39 mmol), EDC (1.298 g, 6.77 mmol), HOAT (0.461 g, 3.39 mmol), DIEA (1.182 ml, 6.77 mmol), and cyclohexanecarboxylic acid (0.504 ml, 4.06 mmol) were combined in CH2Cl2 and the reaction stirred for 15 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was purified by silica gel chromatography on an Isco Companion. The desired fractions were combined and concentrated in vacuo. 1.63 g, 82% over two steps.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[C:27]([O:33][CH3:34])[CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COc1cc(O)ccc1C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)c(OC)c2)cc1
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4-(heptyloxy)benzoic acid (1.41 g, 5.98 mmol) in DCM (10 mL) was added DMF (3 drops) and oxalyl chloride (0.589 mL, 6.87 mmol). After stirring for 2 h, the reaction mixture was added to a solution of 4-hydroxy-2-methoxybenzaldehyde (1 g, 6.57 mmol) and TEA (1.25 mL, 8.96 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and was washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes) to afford 340 mg (15%) 4-formyl-3-methoxyphenyl 4-(heptyloxy)benzoate INT-25 as a white solid. LCMS-ESI (m/z) calculated for C22H26O5: 370; found 371 [M+H]+, tR=3.17 min (Method 10).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=O)[N:11]=2)[N:9]=1)[NH2:3].O.[NH2:21][NH2:22].C(OCC)(=O)C>C(O)C>[NH2:3][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:21][NH2:22])=[O:18])[N:11]=2)[N:9]=1)[NH2:1]
Reactant: NN
Reactant: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NNC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2-yl)thiazole (4.0 g) and 100% hydrazine monohydrate (1.05 ml) in ethanol (40 ml) was heated under reflux for 8 hours. To the reaction mixture was added ethyl acetate (60 ml) under stirring at ambient temperature. The isolated precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6-hydrazinocarbonylpyridin-2-yl)thiazole (3.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)OCC)cc1
Temperature: 100 °C

Procedure:
A stirred solution of ethyl 4-(4-chlorobenzylamino)-benzoate (5.8 g; 0.02 mole) in pyridine (50 ml) was treated dropwise with ethyl chloroformate (2.5 g; 0.023 mole) at room temperature. The mixture was heated to 100° C. for 30 minutes, cooled and added to iced water (100 ml). After neutralisation with dilute hydrochloric acid the product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and the solvent evaporated. The residual oil was purified by chromatography on silica-gel in dichloromethane to give ethyl N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-carbamate as a colourless oil (4.86 g; 56%) which solidifed on standing. M.p. 43°-6° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 84.5 %

Procedure:
A solution of Example 34B (0.053 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 84%). 1HNMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.74 (m, 7 H) 1.34 (m, 1 H) 1.57 (m, 3 H) 2.15 (m, 2 H) 3.08 (m, 3 H) 7.56 (m, 3 H) 7.75 (m, 3 H) 8.16 (m, 1 H) 10.26 (m, 1 H) 13.76 (m, 1 H).
Reaction SMILES: [C:1](=[S:3])=[S:2].C(N(CC)CC)C.[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2.C([O-])(=O)C.[Zn+2:25].C([O-])(=O)C>CS(C)=O.C(O)(C)C>[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH:17]([C:1]([S-:3])=[S:2])[CH2:16]2.[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH:17]([C:1]([S-:3])=[S:2])[CH2:16]2.[Zn+2:25]
Reactant: C1CCC2(CC1)NCCO2
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: S=C([S-])C1CCCC2(C1)NCCO2
Reaction time: 8 h

Procedure:
Thirty-eight grams (0.50 mole) of carbon disulfide was added with stirring at 10° - 20° C to a mixture of 500 g. isopropanol and 50.5 g. (0.50 mole) triethylamine. To this solution was added 70.5 g. (0.50 mole) of spiro(cyclohexane-1,2'-oxazolidine) [preparation described by A. Cope and E. Hancock, J. Am. Chem. Soc. 64, 1503 (1942)] followed by 46.0 g. (0.25 mole) of anhydrous zinc acetate. The reaction mixture was stirred 4 hours at room temperature. After overnight standing, the precipitate was filtered to give 97.4 g. of the desired carbodithioate melting at 198° - 200° C (decomp.). A sample, dissolved in hot dimethylsulfoxide and precipitated by addition of methanol, melted at 212° - 213° C and had the following analysis: Found: C, 42.80; H, 5.41; N, 5.75; Zn, 12.90%. Calcd for C18H28N2O2S4Zn. C, 43.43; H, 5.63; N, 5.63; Zn, 13.15%.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC.[Cu]I>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])=[O:5]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: Cc1ccccc1C(=O)CC(F)=C(F)F

Procedure:
To a solution of 3,4,4-trifluoro-3-butenoyl chloride (3.75 g, 23.65 mmol) in anhyd. ether (100 mL) was treated with copper(I)iodide (2.28 g, 12 mmol) followed by 24 mL of 1.0M solution of benzylmagnesium chloride in ether dropwise at -78° C. with stirring under nitrogen. The reaction mixture was stirred at -78° C. for 10 min and allowed to reach to r.t. and filtered. The filtrate was successively washed with 2N HCl, 5% sodium bicarbonate and brine, and dried. The residue, a mixture of several products, obtained after evaporation of the solvent was chromatographed over silica gel (20% hexanes in dichloromethane) and the major product (least polar) was isolated and further purified by kugelrohr distillation, b.p. 130°-140° C. (pot temperature)/12 mmHg. Proton and fluorine NMR spectra of this material was found to correspond to the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N+:4]([O-:8])=[C:5]([SH:7])[CH:6]=1.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[C:15](OC)(=O)C(C)=C.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH:1]1[CH:2]=[CH:3][N+:4]([O-:8])=[C:5]([SH:7])[CH:6]=1.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[CH2:15]=[CH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccccc1
Reactant: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [O-][n+]1ccccc1S
Solvent: ClCCl
Product: C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 6-ml flask was charged with 0.489 g of pyrithione methacrylate (2.5 mmole), 2.6 ml of methyl methacrylate (22.5 mmole) and 0.083 g of AIBN (0.5 mmole), and 3 ml of toluene. The flask was sealed and placed in an oven at 80° C. for 16 hours. After cooling to room temperature, the product was diluted with 10 ml of methylene chloride and filtered. The solution was concentrated via roto-evaporation and 2.32 g of the desired product was isolated as a yellow polymeric material for a 79.6% yield. The structure was confirmed by NMR and IR. Similar results were obtained by employing either acetyl peroxide, benzoyl peroxide, or lauryl peroxide as the radical initiator.