Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH:18]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.00 g, 4.11 mmol) is dissolved in THF (10 mL) and cooled to −78° C. 2.0 M Lithium diisopropyl amide in THF is added dropwise, then stirred for 1 hour. Iodomethane (0.563 mL, 9.04 mmol) is added and the mixture is stirred for 1 hour. The cold bath is removed and the reaction stirred for an additional 0.5 hour. The reaction mixture is quenched with saturated ammonium chloride (3 mL), concentrated, taken up in dichloromethane, and chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-5%, to give the title compound as a slightly yellow oil. (680 mg, 64% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(OC(=O)NCC(=O)[NH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)(C)(C)C.CCN(C(C)C)C(C)C.O.NN>C1COCC1.CN(C=O)C>[CH2:5]([O:4][C:2](=[O:3])[NH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)[CH3:6]
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(Oc2ccc(NC)c([N+](=O)[O-])c2)ccn1
Temperature: 25 °C

Procedure:
Ethyl chloroformate (2 eq.) was added to a stirring solution of aniline 1 (1 eq.) and iPr2NEt (2 eq.) in dry THF (14 mL) at 0° C. The reaction was allowed to warm to rt over 2 h. The reaction concentrated and the resulting residue dissolved in EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (3×) and the combined aqueous portions were extracted with EtOAc. The combined organic portions were concentrated to give an orange residue as 2. The residue was dissolved in DMF (20 mL), hydrazine monohydrate (1 eq.) added and the resulting reaction maintained at rt for 14 h. The reaction volume was reduced and the remaining solution was partitioned between EtOAc and water. The layers were separated and the aqueous phase extracted with EtOAc (3×). The combined organic layers were concentrated to give an orange solid as 3 which was carried forward without further purification: LCMS m/z 333.3 (MH+), tR=2.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[N:7]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:6]=2[CH:28]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:7]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:6]=2[CH:28]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCNC2)nc2ccc(Cl)cc21

Procedure:
((R)-tert-Butyl 3-(6-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (32C) (0.135 mmol, 0.055 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-6-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (32D) as a tan oil that was used directly in the next step without further purification. ESI-MS: m/z 308.3 (M+H)+.
Reaction SMILES: [CH2:1]([S:9][S:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:12][NH:13][C:14]([F:16])=[O:15]>C(N(CC)CC)C>[CH3:12][N:13]([S:10][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]([F:16])=[O:15]
Reactant: CCCCCCCCSSCl
Reactant: CNC(=O)F
Solvent: CCN(CC)CC
Product: CCCCCCCCSSN(C)C(=O)F

Procedure:
Prepared as above by adding 25.2 g triethylamine to a solution of 48.0 g. n-octylthiosulfenylchloride and 19.26 g N-methylcarbamoyl fluoride. b.p. 110-118° C/0.2 Torr. ND21 1.4900.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:15]=[C:16]1[CH:23]2[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([O:6][C:16]1([CH3:15])[CH:17]2[CH2:25][CH:21]3[CH2:20][CH:19]([CH2:24][CH:23]1[CH2:22]3)[CH2:18]2)=[O:5]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: C=C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC1(C)C2CC3CC(C2)CC1C3)C(F)(F)F
Temperature: 5 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 70.0 g (0.50 mol) of α-trifluoromethylacrylic acid (supplied from Tosoh F-tech Inc.), 1.0 g (10 mmol) of sulfuric acid and 100 g of toluene. Separately 88.8 g (0.60 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 5° C. Then the content was stirred for 15 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 133.9 g (yield: 93.0%) of the object 2-methyl-2-adamantyl α-trifluoromethylacrylate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH2:50]([O:49][C:47]([C:39]1[CH:40]=[C:41]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:12])([F:13])[F:11])=[C:2]([Cl:1])[CH:3]=2)[CH:42]=[CH:43][C:38]=1[F:37])=[O:48])[CH3:51]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(CC)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 64, step 7, trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 64, step 6) was reacted with 4-fluoro-3-(ethoxycarbonyl)phenylboronic acid (70° C., 5 h) to give title compound as a white solid. MS (m/e)=580.3 [M+H+].
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: ClCCOc1cccc2ccoc12
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4ccoc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(benzofuran-7-yloxy)ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (1.4 g, 7.4 mmol) and triethylaniine (0.74 g, 7.4 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride) afforded 0.31 g (30%) of product as a light-brown oil.
Reaction SMILES: C(N)CN.ClC1C=CC([N+]([O-])=O)=CC=1C.Cl.[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([NH:24][CH2:25][CH2:26][NH2:27])=[C:22]([CH3:30])[CH:21]=1)([O-:19])=[O:18].[N-:31]=[C:32]=[O:33].[K+]>>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([NH:24][CH2:25][CH2:26][NH:27][C:32]([NH2:31])=[O:33])=[C:22]([CH3:30])[CH:21]=1)([O-:19])=[O:18]
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCN
Reactant: [N-]=C=O
Agent: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [K+]
Solvent: NCCN
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(N)=O

Procedure:
4-nitro-2-methyl-N-(β-aminoethyl) aniline monohydrochloride is obtained by reacting ethylene diamine with 2-chloro-5-nitro-toluene. This monohydrochloride is then reacted with potassium isocyanate to produce 4-nitro-2-methyl-N-(β-ureidoethyl) aniline, which is reduced with hydrazine and Raney's nickel to 4-amino-2-methyl-N-(β-ureidoethyl) aniline.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[NH:6]3.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:27]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2C
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To 1.45 g (4.7 mmol) of the compound (155) obtained in Example 33, 10 ml (109 mmol) of dimethyl sulfate was added, and the solution was heated 3.5 hours at 120° C. After air-cooling, to 90 ml of ice/water containing 15 g (109 mmol) of anhydrous potassium carbonate, the solution was added, and the solution was stirred overnight. The solution was extracted with 50 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel 8 g, eluent solvent; chloroform:methanol=100:1) to obtain 830 mg of the subject compound (156) in a 57% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CO
Product: COC(=O)Cc1cccc(N)c1
Yield: 77 %

Procedure:
3-Aminophenylacetic acid (5 g, 33.1 mmol) was esterified with MeOH using Method B to give the title compound Yield: 4.22 g, 77%; LC/MS tr 0.70 min; MS(ES+) m/z 166 (M+H)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=2)=[CH:34][N:33]=1
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)N(C)C)CC4)cc3n2)c(OC)n1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide (Example 28) was reacted with 2,4-dimethoxypyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 113. NMR (CDCl3): 2.50-2.53 (4H, m, CH2), 2.75 (6H, s, Me), 3.21-3.24 (4H, m, CH2), 3.68-3.71 (6H, m, CH2), 3.94-3.98 (4H, m, CH2), 4.01 (3H, s, Me), 4.04 (3H, s, Me), 7.20 (1H, s, Ar) and 8.87 (1H, s, Ar). MS: (ESI+): MH+=565.44
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[NH:4][C:5](=[NH:13])[S:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]([N:4]=[C:5]([S:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:13][C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[O:14]
Reactant: CN(C)C(=O)NC(=N)SC1CCCCC1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CN(C)C(=O)N=C(NC(=O)NC(C)(C)C)SC1CCCCC1

Procedure:
A mixture of 5 parts of cyclohexyl 4,4-dimethylthioallophanimidate and 4 parts t-butylisocyanate in 70 parts of methylene chloride is refluxed for 2 hours. After evaporation of the solvent, the oily residue is triturated with petroleum-ether to give solids, which are recrystallized from cyclohexane to give pure cyclohexyl N-dimethylcarbamoyl-4-t-butylthioallophanimidate (a compound of formula I).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:13]3)=[O:7])=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonylnaphthalene (0.3 g, 0.63 mmol), [prepared as described in step 1 above], formic acid (0.096 ml, 2.5 mmol), triethylamine(0.36 ml, 2.5 mmol), palladium acetate (14 mg, 0.06 mmol), and 1,3-bis(diphenylphosphino)propane (0.10 g, 0.03 mmol) in DMF (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was poured into brine and extracted into ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution 10-30% ethyl acetate/hexanes) and then recrystallized from ethyl acetate-hexanes to give 0.1 g of 5-(4-fluoro-benzoyl)-2-methylsulfonylnaphthalene as a solid (48% yield).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:18][C:19](=[O:25])[NH:20][C@@H:21]([CH3:24])[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19](=[O:25])[NH:20][C@@H:21]([CH3:24])[CH:22]=[CH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyltriphenylphosphonium bromide (16.92 g, 47.30 mmol) was taken up in toluene (350 mL). The heterogeneous solution was cooled to 0° C. then KHMDS 0.5M in toluene (90 mL, 45 mmol) was added. The reaction was stirred at 0° C. for 30 min, then cooled to −78° C. and (1-(S)-methyl-2-oxo-ethyl)-carbamic acid benzyl ester (6.11 g, 29.56 mmol) that was dissolved in toluene (45 mL) was added. The solution was warm to rt, stirred at it for 30 min, then quenched with sat NH4Cl(aq) (150 mL). The layers were separated and the aqueous was washed with EtOAc. The organics were combined and dried over Na2SO4. Solids were removed by filtration and solvent removed under reduced pressure. (1-(S)-methyl-allyl)-carbamic acid benzyl ester (4.90 g, 81%) was isolated by silica gel chromatography as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH:23]=1
Reactant: ClCc1cccnc1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccnc2)c1
Yield: 40.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (152 mg, yield: 40.3%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.2 g, 3.07 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (640 mg, 3.37 mmol) and 4 Å powdered molecular sieves (2.5 g) in DCE (65 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (1.3 g, 6.13 mmol). The reaction mixture was stirred for 18 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%). A mixture of the resulting yellow powder and 3-mercaptopropyl ethyl sulphide silica (250 mg) was stirred in a mixture of EtOH and DCM at 50° C. for 3 h. The mixture was filtered and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with EtOH and the product eluted with 2M NH3/EtOH. The resulting oil was triturated with Et2O and dried in vacuo at 60° C. affording 354 as a pale yellow solid (1.26 g, 73%). LCMS (Method I): RT 2.43 min [M+H]+ 566.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.22 (m, 2 H); 4.34 (m, 4 H); 3.89-3.80 (m, 9 H); 3.59 (m, 2 H); 3.39-3.23 (m, 3 H); 3.12-3.04 (m, 6 H); 2.85 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21].C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[F:29][C:30]([F:37])([F:36])[CH2:31][S:32]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21])(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCCCCn1c(=O)c2cccc3ncc(c1=O)n32
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c2cccc3ncc(c(=O)n1CCCCNS(=O)(=O)CC(F)(F)F)n32
Yield: 38.7 %

Procedure:
To a suspension of 994 mg (3.0 mmol) of 4,5-dihydro-4-[4-(amino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloride in 50 ml of methylene chloride was added, while stirring under ice-cooling, 1.47 ml (10.5 mmol) of triethylamine. The mixture was stirred for 5 minutes, to which was added dropwise 0.66 g (3.6 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The reaction mixture was cooled with ice for one hour, which was stirred for 19 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), followed by washing with ether and dried to give 470 mg of the desired compound (38.7%, colorless solid), m.p.154.0-155.0° C. NMR(200 MHz,CDCl3 -DMSO-d6) δ: 1.58-1.90(4H,m), 3.17(2H,m), 3.84(2H,q,J=9.2 Hz), 4.19(2H,t,J=7.0 Hz), 7.45(1H,br), 7.83(1H,dd,J=8.6,7.6 Hz), 8.17(1H,d,J=7.6 Hz), 8.18(1H,d,J=8.6 Hz), 8.61(1H,s).
Reaction SMILES: C([O:4][C@@H:5]([CH3:37])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:25])[C:19]=3[N:18]=[C:17]2[S:26][C:27]2[C:35]([Br:36])=[CH:34][C:30]3[O:31][CH2:32][O:33][C:29]=3[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:25][C:20]1[C:19]2[N:18]=[C:17]([S:26][C:27]3[C:35]([Br:36])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[N:16]([CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C@@H:5]([OH:4])[CH3:37])[CH2:9][CH2:10]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](O)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S)-1-[4-(2-{4-amino-2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-1-yl}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (300 mg, 0.50 mmol) in MeOH (5 mL) was added K2CO3 (140 mg, 0.01 mmol) and the resulting mixture was stirred for 6 h at room temperature. After the completion of reaction, solids were collected by filtration, washed with water and dried to give the title product. 1H NMR (DMSO-d6) δ; 7.71 (d, J=5.8 Hz, 1H), 7.37 (s, 1H), 6.79 (d, J=5.8 Hz, 1H), 6.67 (s, 1H), 6.39 (s, 2H), 6.07 (s, 2H), 5.30-5.40 (m, 1H), 4.15-4.3 (m, 3H), 3.74 (brd, J=13.2 Hz, 1H), 2.88-3.0 (m, 1H), 2.40-2.55 (m, 1H), 1.62-1.76 (m, 2H), 1.45-1.58 (m, 3H), 1.26 (t, J=8.2 Hz, 3H), 0.87-1.18 (m, 2H); TOF-MS [M+H]+ 550.0915.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17]>C(OCC)(=O)C>[C:5]([C:4](=[C:3]([NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=1)[S:9][CH3:10])[C:7]#[N:8])#[N:6]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: COc1cccc(CN)c1
Solvent: CCOC(C)=O
Product: COc1cccc(CNC(SC)=C(C#N)C#N)c1

Procedure:
A mixture of 17.03 g (0.1 mol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 12.78 ml (0.1 mol) of 3-methoxy-benzylamine and 60 ml of ethyl acetate is heated under reflux for 2 hours and then concentrated by evaporation in vacuo, yielding the oily title compound; TLC-Rf 32 0.28 (toluene/isopropanol [9:1]).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Cl[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CC1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mol) in dimethylformamide (400 mL) was heated under an argon atmosphere at 80° C. for 9 h. The mixture was allowed to cool and was filtered through Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and was dried (sodium sulfate). The solvent was removed in vacuo to provide an off-white solid (21.2 g, 78%): m.p. 67°-69° C.