Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13](C(Cl)=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2].[N-:19]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:19][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:11]=2[CH:12]=1
Reactant: CC(=O)NCCc1coc2ccc(C(=O)Cl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)NCCc1coc2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product obtained in Step F (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice-bath. After the addition of sodium azide (25 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0° C. for 2 hours. The organic phase is separated off, washed with water (2×5 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with a saturated sodium hydrogen carbonate solution (2×5 ml) and concentrated under reduced pressure. The residue is then taken up in methanol (20 ml), and water (80 ml) and then potassium carbonate (30 mmol) are added. After stirring at ambient temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml, and is then extracted 3 times with ether (3×50 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:6]1.C(=O)([O-])O.[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)(Cl)Cl>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[CH2:8][CH2:9][O:10][C@@H:5]([CH2:4][NH:3][C:27](=[O:28])[CH2:26][Cl:25])[CH2:6]1
Reactant: O=C(Cl)CCl
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-2-Aminomethyl-4-(3,4-dichlorobenzyl)morpholine dihydrochloride (30.5 g) was added to chloroform (400 mL) and saturated aqueous sodium hydrogen carbonate solution (400 mL). After dropwise addition of chloroacetyl chloride (7.7 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. After completion of the reaction, the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (31.6 g) as a colorless oil.
Reaction SMILES: C(Cl)(Cl)=O.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>[O-2].[O-2].[Ti+4]>[C:13](=[O:14])([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Ti+4]
Agent: O=C(Cl)Cl
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1
Yield: 2036 %

Procedure:
In a plane-joint jar with flow spoilers, a gas-dispersion stirrer and reflux condenser, 0.75 mol/h phosgene was continuously bubbled into 141 g (1.50 moles) of phenol at 140° C. in the presence of 14.1 g (10 wt % relative to phenol) of a powdered titanium dioxide from the Riedel de Haen company. After about 2 h reaction time, the phenol conversion was 12.5%, whereby 0.7 g phenyl chloroformate and 19.5 g diphenyl carbonate were formed. The selectivity to carbonate esters was >99%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:18])[CH2:13]2)[N:3]=1.CS(O[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH2:36][CH2:35][O:34][C:33]2=[O:37])[CH:27]=1)(=O)=O>>[CH3:18][C@@H:14]1[CH2:13][N:12]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]3)[CH2:17][CH2:16][N:15]1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:36][CH2:35][O:34][C:33]2=[O:37])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(N3CCN[C@H](C)C3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCOC2=O)c1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCOC5=O)c4)[C@H](C)C3)cccc2n1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield using a similar procedure to E124 starting from 2-methyl-5-[(3R)-3-methyl-1-piperazinyl]quinoline and 2-[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl methanesulfonate.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1cccc(Nc2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a mixture of (3-anilinophenyl)methanol (1.12 g, 5.62 mmol), methyl 3-(4-hydroxyphenyl)propanoate (1.22 g, 6.75 mmol), triphenylphosphine (1.92 g, 7.31 mmol) and tetrahydrofuran (20 mL) was added diethyl azodicarboxylate toluene solution (40%, 3.32 mL) with stirring at 0° C. and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (1.01 g, yield 50%) as beige crystals.
Reaction SMILES: COC([C:5]1[C:9](=[O:10])[O:8][CH2:7][C:6]=1O)=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=1.S([O-])(O)(=O)=O.[K+].O>C(#N)CCC.ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:21])[C:6]2[CH2:7][O:8][C:9](=[O:10])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1=C(O)COC1=O
Reactant: CNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCCC#N
Solvent: O
Product: CN(Cc1ccc(Cl)nc1)C1=CC(=O)OC1
Temperature: 115 °C
Reaction time: 5 h
Yield: 105 %

Procedure:
To a suspension of 18 g of 4-(methoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-ol and 15 g of N-[(6-chloropyridin-3-yl)methyl]methylamine in 210 ml of butyronitrile are added, at room temperature, 16 g of potassium hydrogensulphate. The mixture is stirred at a temperature of 115° C. for 5 hours. Subsequently, the mixture is cooled to room temperature and admixed with 150 ml of water and 70 ml of dichloromethane. The organic phase is removed and the aqueous phase is extracted twice with 70 ml each time of methylene chloride. The combined organic phases are concentrated to dryness. 24 g of 4-[[(6-chloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one are obtained in a purity of 88% (this corresponds to 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC)(=[O:26])[CH:24]=[CH2:25].[K].C(O)(=O)C>C(O)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[CH2:25][CH2:24][C:23]([OH:26])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCO
Product: OC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)CC1
Reaction time: 2 h

Procedure:
To a mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (7.82 g, 0.025 mol) and Methyl acrylate (2.58 g, 0.030 mol) in tert BuOH (80 ml) is added Potassium tert-butoxyde (5.6 g, 0.05 mol) in portions at 25° C. After stirring for two hours the resulting brown solution is poured in water (500 ml), acidified with acetic acid and partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by crystallizing from acetone. The resulting precipitate is filtered with suction to yield the title compound. (1.55 g, 16.9%) m.p. 222–226° C.
Reaction SMILES: [OH:1][CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[CH3:10]O>>[CH3:10][O:1][CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3]
Reactant: CO
Reactant: CC(O)N1CCCC1=O
Product: COC(C)N1CCCC1=O
Temperature: 20 °C

Procedure:
To 70 g of N-(α-hydroxyethyl)pyrrolidone (0.54 mol), 70 g of methanol (2.2 mol) was added and the mixture was stirred at 20° C. to make a solution. 2 g of dried Diaion PK 208H (cross-linked polystyrenesulfonic acid resin, made by Mitsubishi Chemical Industries Co.) was added to the solution and after 30 minutes of reaction, the reaction mixture was analyzed with a liquid chromatography. The reaction ratio of N-(α-hydroxyethyl)pyrrolidone was 98.6 mol % and the selectivity in forming N-(α-methoxyethyl)pyrrolidone based on N-(α-hydroxyethyl)pyrrolidone was 99.6 mol %.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[C:37]1([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:34])[CH3:35])[CH:27]=3)[CH2:21]2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)Oc1cccc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3cccc4ccccc34)C2)c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: CC(C)Oc1cccc(C(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3cccc4ccccc34)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(1-naphthyl)-1-(3-isopropoxybenzoyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[C:10]1([CH2:16][O:17][CH2:18][C:19](OC)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:10]1([CH2:16][O:17][CH2:18][C:19](=[O:20])[CH2:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: CCCCC(C)=O
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)CC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.22 h
Yield: 108.2 %

Procedure:
2-Hexanone (26.7 g) was added dropwise over 5 min at room temperature to a stirred suspension of sodium amide (10.4 g) in dry ether (290 ml) under nitrogen. The reaction mixture was stirred for 13 min. and a solution of methyl phenylmethoxyacetate (24.0 g) in dry ether (40 ml) was added dropwise over 12 min. The mixture was then heated at reflux for 3 h, cooled, and then poured into ice (400 g) and 2N HC1 (200 ml). The aqueous phase was extracted with ether (2×350 ml) and the combined etheral solution washed with 8% sodium bicarbonate solution (2×250 ml), water (200 ml) and brine (200 ml), then dried and evaporated to leave a yellow liquid (35.8 g). This was purified by column chromatography on silica gel eluting with System A (2:98) to give the title compound as a yellow oil (10.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (2.20 g, 6.17 mmol) in tetrahydrofuran (28.0 mL) was added trimethyl(trifluoromethyl)silane (2.73 mL, 18.50 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.617 mL, 0.617 mmol) at 0° C. After 30 min, to the mixture was added 1N hydrochloric acid (9.0 mL) and the reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (2.49 g, 5.82 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1([N:13]=[C:14]=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[OH:4][CH2:3][C:2]([NH:1][C:14]([NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:15])([CH3:6])[CH3:5]
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)(N)CO
Solvent: ClC(Cl)Cl
Product: CC(C)(CO)NC(=S)Nc1ccccc1
Yield: 59.2 %

Procedure:
In 500 g of chloroform was dissolved 2-amino-2-methyl-1-propanol (61.6 g, 0.69 moL). Then, 300 g of chloroform solution containing phenyl isothiocyanate (81.6 g, 0.6 moL) was slowly added dropwise to the mixture over one hour, while stirring. Upon completion of the addition, the resulting mixture was stirred for 12 hours at room temperature. The precipitated crystals were refluxed with heat to be dissolved and then recrystallized. The crystals thus obtained were collected by filtration, washed with 20 mL of diethyl ether three times, and then dried under reduced pressure at room temperature to give 80.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-N′-phenylthiourea (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.Br[CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15]([C:16]2[CH:17]=[C:18]([S:26][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)=[O:27])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.1 g, 229 μmol, example 216, intermediate a) in acetonitrile (2 mL) were added tert-butyl 2-bromoethylcarbamate (56.5 mg, 252 μmol) and DIPEA (59.2 mg, 80.0 μL, 458 μmol). After the addition of DIPEA the white suspension turned to a yellow solution, which was stirred at room temperature for 3 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.111 g; 83%). MS (ESI): m/z=580.19 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30]Cl)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]>CN(C)C=O>[CH2:10]([C:14]1[N:15]([CH2:28][CH2:29][CH2:30][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:26])[C:17]=2[N:27]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Sc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, benzenethiol (0.68 g, 6.21 mmol), sodium hydride (0.25 g, 60% dispersion, 6.21 mmol), and anhydrous dimethyl formamide (28 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 30 minutes, 2-butyl-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.64 g, 5.18 mmol) was added and the resulting cloudy solution was heated to 80° C. and maintained at 80° C. for 2.5 hours at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (200 mL). The resulting mixture was extracted with chloroform (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide 2-butyl-1-[3-(phenylthio)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.38 g, 3.53 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18](Cl)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([O:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 33 mmol), pyridin-4-yl-methanol (6.9 g, 63 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (60.0 mL, 60 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product is purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 7.1 g (57%) of 4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.65 (d, 2H), 7.32 (d, 2H), 5.49 (s, 2H), 3.55 (m, 8H) 1.48 (s, 9H) ppm. LC-MS (MH+)=378.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:8][C:7]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)(C)(C)C>C(O)=O>[C:26]([C:7]1[CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[NH:5][N:6]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(Nc2ccc(S(=O)(=O)Nc3nccs3)cc2)n(C(C)(C)C)n1
Solvent: O=CO
Product: CC(C)(C)c1cc(Nc2ccc(S(=O)(=O)Nc3nccs3)cc2)[nH]n1
Reaction time: 16 h
Yield: 59.6 %

Procedure:
A solution of 4-(2,5-di-tert-butyl-2H-pyrazol-3-ylamino)-N-thiazol-2-yl-benzenesulfonamide (20 mg, 0.04 mmol, 1.0 equiv) was heated in 1.0 mL of formic acid at 95° C. After 16 h, the reaction mixture was concentrated in vacuo. The residue was purified via automated flash chromatography (4 g SiO2, gradient from chloroform to 12% methanol in chloroform) to afford the product as an off-white solid (9 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[C:7](=[O:21])[CH:8](C(OC)=O)[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.CS(C)=O.O>>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:21])[CH2:8][CH:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)C1C(=O)c2sc(Br)cc2C1c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1CC(c2ccc(Cl)cc2)c2cc(Br)sc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a 500 mL round bottom flask was added a solution of methyl 2-bromo-4-(4-chlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (3.96 g, 10.3 mmol) in dimethyl sulfoxide (88.393 mL, 1245.6 mmol). Water (4.420 mL, 245.3 mmol) was added and the reaction mixture was heated to 150° C. and allowed to stir for 3 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (500 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (2.91 g, 82%) as a brown oil. LC/MS (AA) ES− 327, 329, 331. 1H NMR (dmso-d6, 400 MHz): δ 7.40-7.38 (m, 2H), 7.31 (s, 1H). 7.24-7.22 (m, 2H), 4.67 (dd, 1H), 3.40 (dd, 1H), 2.72 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])=S)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[S]>C(O)C>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNC(=S)Nc1ccccc1N)c1cccnc1
Agent: [S]
Solvent: CCO
Product: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNc1nc2ccccc2[nH]1)c1cccnc1

Procedure:
An ethanol mixture(20 ml) of 24-7 (89 mg, 0.18 mmol), mercuric oxide (78.8 mg, 0.36 mmol) and sulfur (1.8 mg, 0.056 mmol) was refluxed for 2 hr. After cooling, the mixture was filtered and the filtrate concentrated to a semi-solid which was purified by flash chromatography (20% MeOH/CH2Cl2) to provide 24-8 as a solid.