Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35]C(=O)OC(C)(C)C)=[N:4][C:5]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)=[C:6]([C:8]([NH:10]C(C2C=CC=CC=2)(C)C)=[O:9])[CH:7]=1.C(O)(C(F)(F)F)=O>>[NH2:35][C@H:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]1[NH:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[N:4]=1.[ClH:1]
Reactant: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(Cl)cc2C(=O)NC(C)(C)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)c(Cl)cc2C(N)=O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.3 %

Procedure:
A mixture of tert-butyl cis-2-(3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)-6-(5-methylpyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate (12 mg) and TFA (0.5 ml) was stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure (at 40° C. or less), ethyl acetate and 4N hydrogen chloride/1,4-dioxane (25 μl) were added, and the resultant was left at rest overnight at room temperature. Solid matter was collected by filtration, and a white solid of 6-(cis-2-aminocyclohexylamino)-5-chloro-2-(5-methylpyridin-3-ylamino)nicotinamide•hydrochloride (8 mg) was thus obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]([C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:35]([N:37]1[C:49]2[CH:48]=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36]>>[C:14]([CH:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[C:29]2[CH:28]=[CH:27][C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:34][CH:33]=2)[C@H:9]([C:16]([NH:50][C:46]2[CH:47]=[CH:48][C:49]3[N:37]([CH2:35][CH3:36])[C:38]4[C:43]([C:44]=3[CH:45]=2)=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:18])[CH2:10]1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3C(=O)c3ccc(Oc4ccccc4)cc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 37% purity by LC/MS. MS(ESI+): m/z=541.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:24])[CH:3]=1.IC.[C:27](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[C:4]([F:24])[CH:3]=1
Reactant: O=C(CC(c1ccc(Br)cc1F)C1CCCC1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2F)C2CCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=406.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=O)=[C:4]2[CH2:3]1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:23][NH2:24])=[O:19])=[C:4]2[CH2:3]1
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O

Procedure:
50 g (187.3 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 400 ml of ethanol are heated to boiling under reflux for 2 hours together with 150 ml of hydrazine hydrate. The precipitated material is filtered off under suction and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of melting point 312°-313°.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A mixture of 2-bromo-3-methyl-5-nitropyridine (10.0 g), cesium carbonate (42 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1.88 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (15 g) in 1,4-dioxane (150 ml) and water (50 ml) was stirred at 110° C. for 2.5 hours. To the reaction solution was added water, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give 4-(3-methyl-5-nitropyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (13.25 g) as a red solid.
Reaction SMILES: BrCC1C=CC(C(OC)=O)=CC=1.CN1C=NN=C1S.CN1C=NN=C1SCC1C=CC(C(OC)=O)=CC=1.[CH3:38][N:39]1[CH:43]=[N:42][N:41]=[C:40]1[S:44]([CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53]C)=[O:52])=[CH:49][CH:48]=1)=[O:45].[CH3:57][N:58]1[CH:62]=[N:61][N:60]=[C:59]1[S:63]([CH2:66][C:67]1[CH:76]=[CH:75][C:70]([C:71]([O:73]C)=[O:72])=[CH:69][CH:68]=1)(=[O:65])=[O:64]>>[CH3:38][N:39]1[CH:43]=[N:42][N:41]=[C:40]1[S:44]([CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([OH:53])=[O:52])=[CH:49][CH:48]=1)=[O:45].[CH3:57][N:58]1[CH:62]=[N:61][N:60]=[C:59]1[S:63]([CH2:66][C:67]1[CH:76]=[CH:75][C:70]([C:71]([OH:73])=[O:72])=[CH:69][CH:68]=1)(=[O:64])=[O:65]
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2nncn2C)cc1
Reactant: COC(=O)c1ccc(CS(=O)c2nncn2C)cc1
Agent: COC(=O)c1ccc(CBr)cc1
Agent: COC(=O)c1ccc(CSc2nncn2C)cc1
Agent: Cn1cnnc1S
Product: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 740 mg was hydrolyzed via Procedure M to give 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzamide. MS (Q1) 452.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.C(Cl)(Cl)(Cl)[Cl:24].C1C(=O)N(Cl)C(=O)C1>CN1C(=O)CCC1>[Br:1][C:2]1[C:14]([Cl:24])=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Temperature: 45 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (90 g, 249 mmol), CCl4 (2900 mL), and NMP (600 mL) was added NCS (36.1 g, 271 mmol). The reaction mixture was stirred at 45° C. for 2 h. After cooling to room temperature, the solid was collected by vacuum filtration. The solid was stirred in methanol (1 L) at 60° C. for 2 h and then cooled to room temperature. The solid was collected and dried to give ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (69.5 g, 167 mmol, 67% yield) (95% purity).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[C:9](/[NH:16][CH2:17][CH2:18][OH:19])=[CH:10]/[C:11]([O:13]CC)=O)=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1.C[Si]([N:26]=[C:27]=[S:28])(C)C>CC1OCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[N:16]([CH2:17][CH2:18][OH:19])[C:27](=[S:28])[NH:26][C:11](=[O:13])[CH:10]=2)=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: CCOC(=O)/C=C(\NCCO)c1ccc(OC)nc1OC
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCO)c(OC)n1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
To a solution of (Z)-ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-((2-hydroxyethyl)amino)acrylate (100 mg, 0.34 mmol) in 2-MeTHF (1.0 mL) was added (trimethylsilyl)isothiocyanate (0.30 mL, 2.0 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The cooled reaction mixture was diluted with EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was concentrated in vacuo. The residue was triturated with MeOH and the resulting solids were collected by vacuum filtration to give the title compound (16 mg, 16%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl>[OH:20][CH:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10](=[O:13])[O:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(O)c2ccc([N+](=O)[O-])cc21

Procedure:
A mixture of 6-nitro-1(3H)-isobenzofuranone (8.99 g, 50.0 mmol) and N-bromosuccinimide (8.9 g, 50.0 mmol) in carbon tetrachloride (135 mL) was stirred and heated under reflux for one hour during which time the reaction mixture was exposed to the light from a 275 Watt, 125 Volt Hanovia sunlamp that was situated 8 inches from the flask. After cooling, the succinimide was removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was mixed with water (200 mL), and the mixture was refluxed for one hour to give a clear, colorless solution. On cooling, the Compound 3a crystallized from solution. An analytical sample was prepared by recrystallization from water; m.p. 157°-160° C.; IR 3390 cm-1 (OH), 1770 cm-1 (C=0), 1H NMR (CDCl3 -Me2SO-d6 -D2O)δ6.78 (s, br, 1H, H3), 7.88 (d, 1H, H4, J 4,5 =9 Hz), 8.56 (d, 1H, H5, J=9 Hz), 8.62 (s, 1H, H6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>O1CCCC1.CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=4)[NH2:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Yield: 77.4 %

Procedure:
5-(4-Fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine (250 mg, 0.588 mmol) was dissolved in tetrahydrofuran (15 mL) and added (under an atmosphere of argon) to a suspension of 25 mg of 10% palladium/carbon in methanol (30 mL) and acetic acid (5 mL). The mixture was then shaken under 40 psi of hydrogen overnight. The palladium/carbon was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2×30 mL). The organic layer was separated, concentrated, and purified by column chromatography over silica gel using 33% ethyl acetate in hexanes as eluant to give 180 mg (76%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline as a colorless gum. MS [M+H] 396.1, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.45-7.40 (m, 2H), 7.21 (s, 1H), 7.09-7.00 (m, 3H), 6.30 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.8 Hz, 1H), 6.11 (s, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.69 (t, J=6.0 Hz, 3H), 3.68 (b, 2H), 2.05 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[H-].[Na+].CS(C)=O.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>O1CCCC1>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][CH2:27][CH:29]2[O:31][CH2:30]2)[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ClCC1CO1
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Temperature: 25 °C
Yield: 16.3 %

Procedure:
A mixture of 20.0 grams (70 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5), 1.68 gram (70 mmol) of sodium hydride, 2 ml of dimethyl sulfoxide, and 150 ml of tetrahydrofuran is heated at reflux for three hours. The reaction mixture is cooled to room temperature, and a solution of 6.5 grams (70 mmol) of epichlorohydrin in 50 ml of tetrahydrofuran is added over a 5-minute period. The reaction mixture is stirred sixteen hours at room temperature and then partitioned between ether and water. The aqueous layer is extracted with ether and the combined ether solutions are dried over anhydrous magnesium sulfate before concentrating to yield an oil. Purification by flash chromatography (4:1 hexane:ethyl acetate) affords 3.9 grams (16% yield) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2C=[CH:15][C@H:14](C)[C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@H:12]([CH3:26])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])[CH2:33][CH2:32][O:31]CC1.[O-:35]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.O.C(OCC)(=O)C.O=[Os](=O)(=O)=O>[C:1]1([S:7]([C:10]2[C@@H:32]([OH:31])[C@@H:33]([OH:35])[C@H:14]([CH3:15])[C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@@H:12]([CH3:26])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=S([O-])([O-])=S
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@H]1[C@H](O)[C@H](O)C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 83 %

Procedure:
A mixture of dienyl sulfone 33 (45 mg, 0.11 mmol), OsO4 (2 mg, 0.0078 mmol), 4-methylmorpholine N-oxide (27 mg, 0.23 mmol) in acetone (0.5 mL) and H2O (0.5 mL) as co-solvent was stirred at room temperature for 36 h, then saturated aqueous Na2S2O3 (5 mL) was added, and stirred for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL), separated, and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexanes; 1:1) to afford 40 mg (83%) of diol 39 as a colorless solid. mp 117.0-119.0° C.; [α]20D=−72.7 (c=1.09, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.86-7.90 (m, 2H), 7.52-7.67 (m, 3H), 7.31 (d, J=7.5 Hz, 1H), 4.55 (d, J=2.7 Hz, 1H), 3.79 (dd, J=5.4 Hz, 1.5 Hz, 1H), 3.47 (dd, J=9.9 Hz, 2.4 Hz, 1H), 2.82 (m, 2H), 2.35 (m, 1H), 2.06 (br s, 1H), 1.26 (d J=7.5 Hz, 3H), 1.13 (d, J=6.9 Hz, 3H), 0.88 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 147.9, 140.1, 138.9, 133.4, 129.2, 127.7, 77.5, 71.8, 69.8, 40.1, 35.9, 25.8, 18.0, 17.4, 16.8, −4.5, −4.8; Analytical. Calculated for C21H34O5SSi: C, 59.12; H, 8.03. Found: C, 59.07; H, 7.89.
Reaction SMILES: C1(C2CC(=O)NN=2)CC1.ClC1C2C(=CC=C(OC)C=2)[N+]([O-])=CC=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[NH:28]/[C:27](=[C:37]2/[C:38]([CH:43]3[CH2:45][CH2:44]3)=[N:39][NH:40][C:41]/2=[O:42])/[CH:26]=1.[C:46]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1)(=[O:48])[CH3:47]>C(OC(=O)C)(=O)C.C(O)C>[CH:43]1([C:38]2=[N:39][NH:40][C:41](=[O:42])/[C:37]/2=[C:27]2\[NH:28][C:29]3[C:34]([C:25]([S:56][C:53]4[CH:52]=[CH:51][C:50]([NH:49][C:46](=[O:48])[CH3:47])=[CH:55][CH:54]=4)=[CH:26]\2)=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:45][CH2:44]1
Reactant: COc1ccc2c(c1)C(Cl)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: COc1ccc2c(c1)c(Cl)cc[n+]2[O-]
Agent: O=C1CC(C2CC2)=NN1
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(Sc1ccc(NC(C)=O)cc1)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Temperature: 180 °C

Procedure:
3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.2 mmol) and 4-chloro-6-methoxyquinoline 1-oxide (0.025 g, 0.2 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one (0.04 g, 0.11 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.019 g, 0.11 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether to give Example 47. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (d, J=6.57 Hz, 2H) 0.65-0.71 (m, 2H) 1.43-1.54 (m, 1H) 2.11 (s, 3H) 3.98 (s, 3H) 7.18 (s, 1H) 7.45 (d, J=2.53 Hz, 1H) 7.63 (dd, J=9.09, 2.27 Hz, 1H) 7.70 (d, J=8.59 Hz, 2H) 7.82 (d, J=8.59 Hz, 2H) 8.07 (d, J=9.09 Hz, 1H) 10.39 (s, 1H); ESI-MS: m/z calc'd for C24H22N4O3S 446.52. found 447.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35]CC)=O)=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+:2]=[N-:3].[NH2:42][C:43]([NH2:45])=[NH:44].NCCOCCOCCOCCNS(C1C=CC(OC2C(F)=CC(/C=C(\C)/C(N=C(N)N)=O)=CC=2F)=CC=1)(=O)=O>O>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:41]=[CH:40][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:38])/[C:33]([N:42]=[C:43]([NH2:45])[NH2:44])=[O:35])=[CH:26][C:25]=2[F:39])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+:2]=[N-:3]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Reactant: N=C(N)N
Agent: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1)C(=O)N=C(N)N
Solvent: O
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1)C(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (250 mg, 0.42 mmol) was added 4.4 M guanidine in in methanol (as prepared in example 45) (1.0 mL, 4.4 mmol) and the reaction was stirred at RT. After 30 minutes, water (10 mL) was added, and the mixture was extracted with DCM (4×25 mL). The aqueous phase was adjusted to pH 7, and extracted with DCM (2×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (245 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]([CH3:32])([CH3:31])[CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][O:28][CH2:29][CH3:30])=[O:9].C(N(CC)CC)C.C1C(=O)N([O:47][C:48]([CH2:50][CH2:51][S:52][S:53][C:54]2[N:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=O)C(=O)C1>O1CCCC1.CN(C=O)C>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][O:28][CH2:29][CH3:30])[N:13]([CH2:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:48](=[O:47])[CH2:50][CH2:51][S:52][S:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][N:59]=3)([CH3:31])[CH3:32])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1.[C:8]([NH2:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(N)=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)CCSSc1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Alternatively, N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-6-{[3-(pyridin-2-yldithio)propanoyl]amino}hexanamide was synthesized from 6-amino-N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}hexanamide hydrochloride in one step. A mixture of 6-amino-N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}hexanamide hydrochloride (68 mg, 0.16 mmol), triethylamine (0.046 mL, 0.32 mmol), and N-succinimidyl 3-(2-pyridyldithio)propionate in tetrahydrofuran (1.6 mL) and DMF (0.5 mL) was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to provide 36 mg of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-6-{[3-pyridin-2-yldithio)propanoyl]amino}hexanamide as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)NC(C(O)=O)=C2.[CH2:14]([O:16][C:17](=[O:31])[CH2:18]N1C2C=C(N)C=CC=2OCCC1)[CH3:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[CH3:15][CH2:14][O:16][C:17]([CH3:18])=[O:31].[CH3:4][CH2:3][CH2:2][CH2:10][CH2:9][CH3:8]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)CN1CCCOc2ccc(N)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 122.5 %

Procedure:
5-Chloroindole-2-carboxylic acid (73 mg, 0.37 mmol, 1 eq.), (2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetic acid ethyl ester (93 mg, 0.37 mmol, 1 eq.), and BOP (163 mg, 0.37 mmol, 1 eq.) were dissolved in 5 mL of anhydrous THF in a round bottom flask. Triethylamine was added in a single portion (0.103 mL, 74 mmol, 2 eq.) and reaction mixture stirred at room temperature for 5 hours. The reaction mixture was then concentrated and the residue purified by preparative TLC in 50% AcOEt/hexane affording 79 mg (50% yield) of the product an off-white crystalline solid. LC MS: AP+ 428/430, AP− 426/428.
Reaction SMILES: [C:1]([S:9][S:10]Cl)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:12][NH:13][C:14]([F:16])=[O:15]>>[CH3:12][N:13]([S:10][S:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[C:14]([F:16])=[O:15]
Reactant: CC(C)(C)CC(C)(C)SSCl
Reactant: CNC(=O)F
Product: CN(SSC(C)(C)CC(C)(C)C)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting t-octylthiosulfenylchloride with methylcarbamoyl fluoride. b.p. 112° C/0.5 Torr ND23 1.4960.