Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([CH:19]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:21]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC(Oc1ccccc1C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
15.2 g of methyl salicylate and 18.0 g of potassium carbonate were introduced into 125 ml of acetonitrile in a 250 ml flask under an argon atmosphere and, at room temperature, 20.9 g of methyl 2-bromohexanoate were added. The colourless suspension was heated under reflux with stirring for 16 hours, and the progress of the reaction was checked by thin-layer chromatography. After cooling to room temperature, the suspension was filtered and the residue was washed with acetone. Concentration of the filtrate in vacuo resulted in 27.8 g (99% of theory) of methyl 2-(1-methoxycarbonylpentoxy)benzoate as yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:12]4[N:11]=[CH:10][N:9]=[C:8]5[C:13]=4[N:14]=[CH:15][N:7]5[CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:18][CH:19]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3ncn4C3CCCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of 4-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yloxy]-phenylamine (0.311 g, 1 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.334 g, 1.5 mmol) in DMF (5 mL) was added TEA (216 μL, 2 mmol) followed by HATU (0.76 g, 2 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water (25 mL) and extracted with EtOAc (2×). The combined organic extracts were washed with 10% LiCl(aq.) (4×), satd. NaHCO3(aq) (2×), water, (1×) and brine (1×), followed by drying over MgSO4 and concentration in vacuo. The crude solids were purified by flash chromatography (silica gel, 1:1 EtOAc:Hexanes containing 2% 7N NH3 in MeOH), affording N-(4-fluorophenyl)-N′-(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (0.430 g, 83% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 7.20 (m, 2H), 7.0 (m, 2H), 5.8 (m, 1H), 4.20 (m, 1H), 3.8 (m, 1H), 2.20 (m, 3H), 1.80 (m, 2H), 1.7 (m, 5H). MS (ESI) for C27H25FN6O4: 517 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)(OCC)OCC>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc2c1CN(CC)CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Yield: 94 %

Procedure:
0.5 ml of acetic anhydride was added to 3.8 g (14.9 mM [sic]) of 2-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 40 ml of triethyl orthoformate and refluxed under nitrogen for 1 h. The solution was decanted off from the insoluble black deposit on the walls of the flask and then completely evaporated in a rotary evaporator at 80° C. 3.5 g (94%) of crude product were isolated as a dark oil which is sufficiently pure for further reaction.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]([CH3:25])([CH3:17])[CH2:19][CH2:20]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CCC(=O)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
In a 250 mL round-bottomed flask was placed magnesium turnings (1.85 g, 76.1 mmol), which were stirred under vacuum without solvent overnight. To the turnings was added anhydrous THF (10 mL) and 4-benzyloxybromobenzene (10.0 g, 38.0 mmol) in anhydrous THF (40 ml) over 15 min. After the reaction was complete, the resulting gray slurry was stirred for 2 h at 60° C. To the slurry, cooled in an ice-water bath, was added 4,4-dimethyl-cyclohexanone (3.36 g, 26.6 mmol) in THF (15 mL). The reaction mixture was stirred for 1 hour at room temperature after which the solvent was removed under reduced pressure. The residue was partitioned between EtOAc/saturated NH4Cl. The mixture was extracted twice with EtOAc. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified via column chromatography on silica gel (eluting with 10-40% ethyl acetate/hexanes) to give 4.14 g (50%) of 1-(4-benzyloxy-phenyl)-4,4-dimethylcyclohexanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:20])[CH:15]=[CH:16][C:17](O)=[O:18])=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][C:44]([NH2:46])=[S:45]>CN(C)C=O.C(OCC)(=O)C>[NH2:46][C:44]1[S:45][CH:16]([CH2:15][C:14]([NH:13][C:7]2[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20])[C:17](=[O:18])[N:43]=1
Reactant: CCOC(=O)c1c(NC(=O)C=CC(=O)O)sc(C)c1C
Reactant: NC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(NC(=O)CC2SC(N)=NC2=O)sc(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To 2-(3-Carboxy-acryloylamino)-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (2.97 g, 10.0 mmol) in 50 mL of N,N-dimethyl-formamide was added N-hydroxy-benzotriazole (1.48 g, 11.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethyl-carbodiimide hydrochloride (2.88 g, 15.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes and thiourea (0.84 g, 11.0 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes and was heated at 60° C. for 12 hours. The reaction mixture was diluted with 250 mL of ethyl acetate and was washed with 100 mL of water and 100 mL of brine. The organic layer was collected, dried over sodium sulfate and concentrated. The residue was load on a 120 g silica gel column and purified by flash chromatography (eluted with a gradient of 0 to 10% ethyl acetate/hexanes). Ethyl 2-{[(2-amino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl) acetyl]amino}-4,5-dimethylthiophene-3-carboxylate (1.80 g, 51% yield) was produced.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][C:13](O)=O.[NH4+].[OH-]>CO>[CH3:10][O:11][CH2:12][C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9]
Reactant: Cc1ccnc(N)c1N
Reactant: COCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COCc1nc2nccc(C)c2[nH]1
Temperature: 165 °C

Procedure:
A mixture of 2,3-diamino-4-picoline (0.1 g, 0.81 mmol) and methoxyacetic acid (0.16 ml, 2 mmol) was heated in a sealed tube at 165° C. for 24 hours. The reaction was cooled and neutralized with NH4OH. The crude material was dissolved in methanol (2 ml) and silica-gel (10 g) was added. The dried silica-gel was then loaded on a silica-gel flash-column and eluted initially with EtOAc and then with 2% methanol in EtOAc. The pure desired compound was obtained as a cream colored solid (0.067 g, 47%). 1H-NMR (CDCl3): 8.27 (d, 1H, J=5 Hz), 7.07 (d, 1H, J=5 Hz), 4.86 (s, 2H), 3.57 (s, 3H), 2.7 (s, 3H). FAB-MS: m/e 178 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](=[S:25])[NH:22][C:21]4=[O:26])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:4])=[O:3].[CH3:33]I>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([S:25][CH3:33])=[N:22][C:21]4=[O:26])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(=S)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: CI
Product: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one was prepared from 5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and methyl iodide following General Procedure C.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:14].[OH-].[K+].Cl>C(O)C.CO>[O:7]([CH2:8][CH2:9][CH2:10][SH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCOc1ccccc1
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: SCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
160 g of 3-bromopropyl phenyl ether and 63 g of thiourea were dissolved in 300 ml of ethanol and the solution was refluxed with heating for 3 hours. A methanol solution containing 194 g of potassium hydroxide was added to the reaction solution and the mixture was stirred at 50° C. for 2 hours. The mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate followed by distillation under reduced pressure to obtain 76.5 g of 3-phenoxypropanethiol. A boiling point was 135° to 138° C. at 17 mm Hg.
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[C:7]=1[C:29]([NH2:31])=[O:30]>CO.C1COCC1.[Pd]>[NH2:5][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:7]=1[C:29]([NH2:31])=[O:30]
Reactant: CC(C)(C)n1nc(-c2ccc(OCc3ccccc3)cc2)c(C(N)=O)c1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(-c2ccc(O)cc2)c(C(N)=O)c1N
Temperature: 25 °C

Procedure:
Ammonium formate (160 mg, 2.5 mmol) and 10% Pd/C (50 mg) are added to a solution of 21 (2 mmol) from the preceding reaction in methanol (4 mL) and THF (2 mL). The mixture is stirred at room temperature. The reaction is monitored by tlc and after reaction occurs, the mixture is filtered through Celite and rinsed with ethyl acetate. The filtrate is diluted with ethyl acetate and is washed successively with aq. NaHCO3 and with half-saturated brine, then dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The desired 5-amino-1-(1,1-dimethylethyl)-3-(4-hydroxyphenyl)pyrazole-4-carboxamide 22 is obtained by purification of the crude product with HPLC.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:8](=[O:21])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[C:13]([NH2:20])[CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[C:8](=[O:21])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[C:13]([NH:20][C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: CC(=O)Cl
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)c2c(NC(C)=O)cccc2C1=O
Temperature: 0 °C

Procedure:
Acetyl chloride (1.5 ml, 20 mmol) is added dropwise, over 10 min, to an ice water cooled, stirred suspension of 12a from Example 5 (466 mg, 2 mmol) in chloroform (15 ml) containing pyridine (1.6 ml, 20 mmol). After a total reaction time of 30 min, the mixture is diluted with chloroform (50 ml) and then washed with water (2×25 ml). The chloroform phase is dried over MgSO4, concentrated to dryness and the residue recrystallized from iso-propanol affording 498 mg (85%) of 12b R1 =R2 =OCH3, with mp 162°-163°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[F:19])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][C@H:7]1[F:19])[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a suspension of tert-butyl 4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate (WO2010/056633) (2.17 g, 7.55 mmol) and Pd/C (10% Pd, 217 mg) in dry EtOH (7 mL) was stirred at rt under a H2 atmospheric pressure until completion of the reaction. The mixture was then filtered, washed with EA/EtOH, and the filtrate concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 6:1) to give cis-tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate as a pale yellow oil. LC-MS-conditions 08: tR=0.86 min; [M-CH3+H]+=275.32.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[O:3]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].Cl>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:17])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:18](=[O:19])[NH:16][C:11]=3[CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)c(N)c2)OC1(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (1.20 g, 5.1 mmol) in anhydrous THF (20 mL) was added 1,1′-carbonyldiimidazole (910 mg, 5.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 1 N HCl (10 mL) and extracted twice with 50 mL portions of Et2O. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.0 g (79%) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one. 1H NMR (400 MHz, CDCl3): δ 7.46 (dd, 1H), 7.40 (s, 1H), 7.35 (dd, 1H), 1.35 (s, 12H). MS (EI) for C13H17BN2O3: 261 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9](Cl)=[O:10])/[O:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:9](=[O:10])[CH:8]=[C:4]2[C:5](=[O:7])[O:6][C:2]([CH3:12])([CH3:1])[O:3]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Reactant: Cc1ccc(CNc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(CN(C(=O)C=C2OC(C)(C)OC2=O)c2ccc(Cl)cc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A solution of (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (0.553 g, 2.90 mmol) in dry dichloromethane (5 ml) was added dropwise to a cold (0-5° C.) solution of (4-chlorophenyl)-(4-methylbenzyl)-amine (0.545 g, 2.35 mmol) (Ballistreri et al., J. Org. Chem., 41, 1976, 3364), pyridine (0.35 ml) and a small crystal of 4-N,N-dimethylaminopyridine in dry dichloromethane (10 ml). After 30 min, the cooling bath was removed and the resulting clear solution was stirred at 22° C. for another 30 min. The reaction mixture was then diluted wih ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo, filtration of the residue on a short silica gel pad (elution-toluene ethyl acetate; 85:15) followed by crystallization from ethyl acetate-hexane gave 0.794 g (87%) of the title amide as white needles: mp 149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 2.31 (3H, s, CH3), 4.88 (2H, s, NCH2), 5.64 (1H, s, CH), 6.93 (2H, d, J=8.5 Hz, aromatics), 7.08 (4H, m, aromatics), 7.3 (2H, d, J=8.5 Hz, aromatics). Anal. Calcd for C21H20ClNO4: C, 65.37; H, 5.22; N, 3.63. Found: C, 65.22; H, 5.25; N, 3.52.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(#N)C.[F:20][C:21]1[CH:22]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:55][C:54]3[CH:56]=[CH:57][CH:58]=[CH:59][C:53]=3[NH:52]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](N3C(C)=CC(C)=N3)=[NH:43])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1>C(OCC)(=O)C>[F:27][C:25]1[CH:24]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:52][C:53]3[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=3[NH:55]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](=[NH:43])[N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:2][CH2:3]3)(=[O:39])=[O:40])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2cccc(C(=O)C(C(=O)c3cc(F)cc(F)c3)=C3Nc4ccccc4N3)c2)n1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 30.5 %

Procedure:
At 0° C., benzyl piperazine-1-carboxylate (1.37 g) was added to an acetonitrile (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-3,5-dimethyl-1H-pyrazole-1-carboximidamide (205 mg), and heated under reflux for 3 days. After cooling, ethyl acetate was added, then washed with aqueous saturated ammonium chloride solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/4) to obtain benzyl 4-[[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)methyl]piperazine-1-carboxylate (76 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[O:11][N:10]=[C:9]([CH3:20])[C:8]=2[NH2:7])=[CH:18][CH:17]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1N
Reaction time: 3 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester (0.38 g, 1.07 mmol) was treated with 50% trifluoroacetic acid in CH2Cl2 and stirred for 3 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1(=[O:25])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:17]1[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:14](=[O:25])[CH2:15][CH2:16]1)[NH:11][C:10]2=[O:12]
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-chloro-6-methylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (16.8 g, 103 mmol) in toluene (200 mL) was added triethylamine (16.1 mL, 116 mmol). After being refluxed overnight, the reaction mixture was cooled to room temperature. The formed solid was collected by filtration, washed with ethanol (50 mL) and ethyl acetate (100 mL), and then dried in vacuo to afford 21.0 g of the desired product as a white solid (yield was 80%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][N:20]1[C:25]2=[CH:26][N:27](COCC[Si](C)(C)C)[C:28]([C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[C:24]2[C:23](=[O:45])[N:22]([CH3:46])[C:21]1=[O:47]>C1COCC1>[CH3:19][N:20]1[C:25]2=[CH:26][NH:27][C:28]([C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[C:32]#[N:33])=[C:24]2[C:23](=[O:45])[N:22]([CH3:46])[C:21]1=[O:47]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
TBAF solution (20.3 mL, 20.3 mmol) was added to a suspension of 3-(1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 3) (832 mg, 2.0 mmol) in THF (6 mL), giving a solution which was stirred at 60° C. for 1 hour. Most of the organic solvent was removed from the reaction mixture, water (100 mL) was added and the mixture was stirred for 5 minutes The aqueous suspension was extracted with chloroform (4×100 mL). A large amount of the mixture remained as an emulsion. Sat brine (100 mL) was added to break up the emulsion, and the aqueous phase was extracted with more chloroform (4×100 mL). The combined organic extracts were dried with magnesium sulfate and the solvent was removed under vacuum to yield a red oil. The crude red oil was triturated with methanol to give a pink solid which was dried under vacuum at 50° C. The solid was triturated with methanol again and dried under vacuum at 50° C. to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][OH:10])[N:6]=[CH:5]1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Si:11]([O:10][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:3][O:2][CH3:1])[CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCn1cnc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
The compound (8.81 g) obtained in (2) was dissolved in dichloromethane (100 mL), followed by addition of tert-butyldiphenylsilyl chloride (hereinafter, also referred to as TBDPSCl) (24.3 mL), DIEA (21.6 mL) and DMAP (0.760 g) under stirring, and the stirring was continued for 1 day. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=50%→100%) using silica gel column (product name: Hi-Flash Column 4 L, manufactured by Yamazen Corporation) to afford the title compound (16.9 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][O:22][CH2:23][O:10][CH2:9][C:6]1[CH:7]2[CH2:8][CH:3]([CH2:4][CH:5]=1)[C:2]2([CH3:11])[CH3:1]
Reactant: COCCl
Reactant: CC1(C)C2CC=C(CO)C1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC1=CCC2CC1C2(C)C
Yield: 100 %

Procedure:
rac-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol (10.0 g, 65.7 mmol), diisopropylethylamine (17.0 mL, 97.6 mmol) and chloromethyl methyl ether (6.5 mL, 85.6 mmol) were stirred in dichloromethane (100 mL) at room temperature for 1 day. After completion of the reaction, the reaction solution was mixed with saturated sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=10/1) to give the desired product (100% yield).