Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][CH2:25][CH2:26][O:27][C:28]1[C:29]([CH3:61])=[C:30](/[CH:34]=[CH:35]/[S:36]([N:39]2[CH2:60][CH2:59][C:42]3([N:46]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:57])([F:56])[F:55])[CH:48]=4)[NH:44][C:43]3=[O:58])[CH2:41][CH2:40]2)(=[O:38])=[O:37])[CH:31]=[CH:32][CH:33]=1)(C)(C)C>C1COCC1>[OH:24][CH2:25][CH2:26][O:27][C:28]1[C:29]([CH3:61])=[C:30](/[CH:34]=[CH:35]/[S:36]([N:39]2[CH2:40][CH2:41][C:42]3([N:46]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:56])([F:57])[F:55])[CH:48]=4)[NH:44][C:43]3=[O:58])[CH2:59][CH2:60]2)(=[O:37])=[O:38])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)cccc1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)cccc1OCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Tetrabutylammonium fluoride (0.11 ml, 0.11 mmol, 1 M in THF) was added to a solution of 8-((E)-2-{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-2-methyl-phenyl}-ethenesulfonyl)-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one obtained above in anhydrous THF (1 ml) at room temperature in an Ar atmosphere. The mixture was stirred at room temperature for two hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc=1:1) to give 8-{(E)-2-[3-(2-hydroxy-ethoxy)-2-methyl-phenyl]-ethenesulfonyl}-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (3.2 mg, yield in two steps: 48%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[S:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[C:24]([O:23][C:21]([CH2:20][CH:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH3:8])=[S:6])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCCC(=S)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC(C)(C)C)C(=S)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a −78° C. solution of methyl 4-methylthiobutyrate (1.48 g, 10.0 mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11 mL). After 30 min, tert-butyl bromoacetate (2.34 g, 12.0 mmol) was added to the reaction, and the reaction mixture was gradually warmed to the room temperature over 6 hours. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (2×20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 5% ethyl acetate in hexane to give the title compound (1.21 g, 46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[F:18])[CH:12]=[CH:11]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: CC(C)(C)OC(=O)Nc1ccc2c(ccn2-c2ccc([N+](=O)[O-])cc2F)c1

Procedure:
The title compound can be synthesized from (1H-indol-5-yl)carbamic acid tert-butyl ester and 3,4-difluoronitrobenzene in the same manner as in Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([F:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[N:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([F:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH:5]=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[OH:20]
Reactant: O=S(=O)(F)c1ccc(N=Nc2ccc(O)c(Cl)c2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(N=Nc2ccc(S(=O)(=O)F)cc2)cc(Cl)c1O
Temperature: -30 °C
Reaction time: 0.22 h

Procedure:
Solid 2-Chloro-4-(4-fluorosulfonylphenylazo)phenol (7.5 g. 23 mmol) was added rapidly to a vigorously stirred mixture of 15 ml concentrated nitric acid and 15 ml concentrated sulfuric acid, cooled to -30° C. After 13 minutes of stirring, the reaction mixture was poured into 400 ml ice water with vigorous stirring. The resulting precipitate was filtered off and washed with water. During drying on the funnel the solid softened and became tarry. When the tar was dissolved in acetic acid and then carefully and slowly diluted with water, a fine precipitate separated and was filtered off. This process was repeated with the filtrate until the resulting precipitate no longer separated as a solid. The collected solids were combined and air dried. Yield: 3.1 g, (37%) m.p. 129°-133° C.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([P:7](=[O:16])([O:12]CC=C)[O:8][CH2:9][CH:10]=[CH2:11])(OC)=[O:4]>>[C:3]([P:7](=[O:16])([O-:12])[O:8][CH2:9][CH:10]=[CH2:11])(=[O:4])[NH2:2].[NH4+:2]
Reactant: C=CCOP(=O)(OCC=C)C(=O)OC
Agent: [NH4+]
Agent: [OH-]
Product: C=CCOP(=O)([O-])C(N)=O
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A solution of 48.5 parts of 29% aqueous ammonium hydroxide is stirred and cooled with an external ice bath to 15°C. To the cooled solution 22 parts of diallyl carbomethoxyphosphonate is slowly added over a ten-minute period. The mixture turns cloudy, but clears up after about 15 minutes. During this time, the mixture is allowed to warm spontaneously to about 30°C. and stirring is continued for two hours. The clear solution is stripped under reduced pressure (15 mm of Hg) at a water-bath temperature or 70°C. The residue is a white crystalline solid which is recrystallized from absolute ethyl alcohol, giving 12.3 parts of ammonium allyl carbamoylphosphonate, m.p. 160°-162.5°C. Nonaqueous titration either as an acid or a base gives a molecular weight of 182±1.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]2[S:27][C:26]3[C:28]4[C:19]([CH:20]=[N:21][C:22]=4[N:23]=[CH:24][CH:25]=3)=[CH:18]2)=[O:16])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C.C(=O)([O-])O.[Na+]>[CH2:29]([N:7]1[CH2:8][CH2:9][CH2:10][N:4]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[S:27][C:24]3[N:23]4[C:19](=[CH:20][N:21]=[C:22]4[CH:28]=[CH:26][CH:25]=3)[CH:18]=2)=[O:16])[CH2:5][CH2:6]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NCCCN1CCCNCC1)C1C=C2C=Nc3nccc(c32)S1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1CCCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Yield: 55 %

Procedure:
In 10 ml of ethanol were suspended 606.9 mg (1.3 mM) of N-[3-(hexahydro-1,4-diazepin-1-yl)propan-1-yl]-5-thia-1,8-diazaacenaphthylene-4-carboxamide trihydrochloride and 342.1 mg (2.0 mM) of benzyl bromide, followed by addition of 0.91 ml (6.5 mM) of triethylamine, and the mixture was refluxed overnight. This reaction mixture was diluted with 5% aqueous solution of sodium hydrogen carbonate and and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over Na2SO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=2/3) to provide the title compound as deep-red liquid (320.0 mg, 55.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E431) in pyridine was added was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E432).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 39.6 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (36 mg, 0.35 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.114 g, 0.35 mmol) and N,N-diisopropylethylamine (208 mg, 1.6 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (50 mg, 40%) as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[C:12]1=[O:13].[H][H]>[Ni].COCCOC.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]2[C:12](=[O:13])[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:20]2=[O:21])[CH:4]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Agent: [Ni]
Solvent: COCCOC
Solvent: CCO
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 94.9 %

Procedure:
Wet Raney Nickel (0.9 g) is added to a solution of N-(2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (1.0 g, 3.4 mmol) in a 4:1 ethylene glycol dimethyl ether/ethanol solution. The reaction mixture is hydrogenated over 45 psi of hydrogen until the reaction mixture takes up 9 psi. The reaction mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a yellow residue. Chromatography of the residue gives the title product as a yellow-orange solid (0.84 g, mp 134°-136° C.) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4](Cl)[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.[Al]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 55 %

Procedure:
A microwave vessel was charged with a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.165 g, 0.88 mmol) in ethanol (3 mL). p-Toluenesulfonic acid (0.167 g, 0.88 mmol) and ethyl 2-(4-aminophenyl)acetate (0.157 g, 0.88 mmol) were added and the vessel was sealed with an aluminum cap. The mixture was heated to 120° C. for 2 d, cooled, diluted with satd. aq. sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.160 g, 55%) as an orange oil. MW=330.81. 1H NMR (CDCl3, 500 MHz) δ 7.33-7.28 (m, 2H) 7.16-7.12 (m, 2H), 6.74 (s, 1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 331 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[F:17][CH:18]([F:25])[CH2:19]OS(C)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:19][CH:18]([F:25])[F:17]
Reactant: CS(=O)(=O)OCC(F)F
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)COc1c(Cl)cc(Cl)cc1Br

Procedure:
To a solution of 2-bromo-4,6-dichloro-phenol (14.6 g, 60.3 mmol, Step A compound) in DMF (10 ml) were added K2CO3 (16.53 g, 120.6 mmol) and methanesulfonic acid 2,2-difluoro-ethyl ester (10.7 g, 66.4 mmol, Step B compound) and the mixture was heated to reflux for 16 h. The DMF was then evaporated in vacuo and the resulting residue was dissolved in EtOAc (300 ml). This solution was washed two times with water, with brine, dried with Na2SO4 and evaporated. The remaining crude product was purified by chromatography (silica gel; hexane) and the title compound was obtained as white solid (14.5 g, 79%). MS: m/z=304 [M]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[OH-].[Na+:29]>CO.O1CCCC1>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[CH:12][C:11]([C:7]3[O:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([O-:27])=[O:2])[N:6]=3)=[CH:16][CH:15]=2)=[CH:22][CH:21]=1)(=[O:24])=[O:25].[Na+:29]
Reactant: COC(=O)Cc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CC(=O)[O-]

Procedure:
To a stirring solution of {2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-acetic acid methyl ester (See Intermediate 19) (1.0 mmol) in 1:1 methanol/tetrahydrofuran (0.10M), add 2N sodium hydroxide (1.2 mmol) and heat to reflux for 1 hour. After this time, concentrate the reaction in vacuo. Wash the resulting solid twice with dichloromethane to rinse away any impurities. MS (nme): 373.3 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:40]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[O:45][C:42]1[CH:43]=[CH:44][C:39]([F:38])=[C:40]([C:46]([F:49])([F:47])[F:48])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccccc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1ccc(F)c(C(F)(F)F)c1)n2Cc1ccccc1
Temperature: 90 °C
Yield: 90.4 %

Procedure:
Step 1 7-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.272 g, 1.97 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.19 g, 1.03 mmol) were combined in DMF (5 mL). The reaction was heated at 90° C. After 6 h the reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. This solid was purified using a 25 g silica column eluted with 20% ethyl acetate/hexanes to give 7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.54 g, 90% yield) as a white solid. LCMS retention time=5.342 min and 97% purity, LCMS MH+=607.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[C:13](=[O:20])[C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(-c2n[nH]c3c2Cc2sccc2-3)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2sccc2-c2[nH]nc(-c3cccc(Cl)c3)c21
Temperature: 25 °C
Yield: 960 %

Procedure:
A mixture of 6-(3-Chloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.27 g, 1.0 mmol) and Cs2CO3 (3.26 g, 10 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. After poured into ice water, aqueous wash, and evaporation of the solvent provided the corresponding 6-(3-Chloro-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one (2.75 g, 9.6 mmol) as orange solid in 96% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[C:23]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:23]3[C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:32][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 71 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](CBr)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of N-tert-butoxycarbonyl-1-bromo-2-(S)-amino-4-methylpentane 1.76 g, 6.3 mmol) and triethylamine (0.96 ml, 6.9 mmol) in THF (50 ml) at room temperature was added morpholine (0.60 ml, 6.9 mmol). The mixture was stirred overnight and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous ammonium chloride (50 ml) and ethyl acetate (2×100 ml). The crude N-tert-butoxycarbonyl-1-morpholino-2-(S)-amino-4-methylpentane was then used directly in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[N:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CS(C)=O>C(O)C>[N:17]1([CH:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCO
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCC(N4CCCCC4)CC3)cc2)[nH]c1=O

Procedure:
A mixture of 10.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile [J. Med. Chem. 14, 342 (1971)] and 16.8 g. of 4-piperidinopiperidine in 140 ml. of dimethyl sulfoxide is stirred and heated at 95°-100° for 50 hours. The mixture is cooled and diluted with 450 ml. of 95% ethanol. The resulting precipitate of 6-[p-(4-piperidinopiperidino)phenyl]-1,2-dihydro-2-oxonicotinonitrile is collected by filtration, washed with 95% ethanol and dried; m.p. 288°-293° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[C:6]2=[O:25].[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:7]1[C:6](=[O:25])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][C:8]1([CH3:13])[CH3:14]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)C(C)(C)O2
Yield: 99 %

Procedure:
A mixture of 7.3 g (0.0125) of the product of Example 110 and 700 mg 5% palladium on carbon in 200 mL ethyl acetate and 50 mL tetrahydrofuran was shaken in a Parr hydrogenator under 30 psi hydrogen for 3 hours. The mixture was filtered through Celite and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes yielded 6.8 g (99%) of the title product as an oil. NMR (CDCl3): δ1.38 (s, 3H); 1.47 (s, 3H); 2.20 (dd, 1H); 2.90 (m, 1H); 3.00 (dd, 1H); 3.60 (s, br, 2H); 3.78 (s, 3H). MS (Cl, NH3) m/e: 329 (M+ +18), 312 (M+ +1,2 100).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(Cl)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Cl)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.23 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylthio)imidazole in 100 ml of dichloromethane. The reaction mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.90 g of 4,5-bis(4-methoxyphenyl)-2-(4-chlorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[OH:25]>C(O)(C)C>[ClH:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:20][C:19]=1[OH:25]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Cl)c(O)c3)c2cc1OC
Yield: 85.8 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (500 mg, 1.916 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-3-hydroxyaniline (300 mg, 2.09 mmol), (as described in UK patent 1427658), in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-3-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (605 mg, 86%). m.p. >250° C.