Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](=[O:29])[NH:2][C@H:3]([C:4](=[O:5])[N:6]([CH3:8])[CH3:7])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](OC(=O)N[C@H](C(=O)N(C)C)C(C)(C)C)C(=O)OCc1ccccc1
Yield: 85.6 %

Procedure:
(2S)-2-Amino-3,3-dimethyl-N,N-dimethylbutyramide hydrochloride (0.25 g), (2S)-2-chlorocarbonyloxy-4-methylvaleric acid benzyl ester (0.36 g) and TEA (0.31 g) were reacted in ethyl acetate (10 ml) in a similar manner to that of Example 4-1) to give (2S)-2-[N-[(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvaleric acid benzyl ester (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Al]>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[O:18][C:17]([CH3:19])=[N:16][C:15]=3[CH3:20])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,4-dimethyloxazol-5-yl)methanol (960 mg, 2.01 mmol, Intermediate 51: step a) was added 1,4-dioxane (50 mL) and activated MnO2 (900 mg, 10.3 mmol) at room temperature. The mixture was heated to 85° C. in an aluminum heating mantle under a nitrogen atmosphere. After 60 minutes, the contents were filtered through Celite® while the solution is still warm and rinsed with THF, and concentrated to give an off white solid. The crude material was triturated with Et2O to give a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:18][CH2:17]1.[OH-].[Na+]>C(O)CCC.O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:20][CH2:21]1
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCNc2ccccc2OC(F)(F)F)CC1

Procedure:
A solution of 2.09 g of 2-trifluoromethoxyaniline and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 20 mL of n-butanol was stirred at 100° C. for 2 hrs. The mixture was then cooled, diluted with H2O alkalinized with 2 N NaOH and extracted with CHCl3. The organic phase was dried on anhydrous Na2SO4, evaporated until dry and the crude purified via flash chromatography (EtOAc-petrolium ether 3:7) and subsequently crystallized from EtOH giving 0.55 g (12%) of the title compound. Melting point: 69.5-71° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:4](=[O:3])[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CN
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Product: CNC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 48 h

Procedure:
2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are left to stand for 48 hours at room temperature. The reaction mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate. The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.24; m.p. 190-191° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:28][C@@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[C:13]([CH3:27])[CH:12]=1)(=[O:3])[NH2:2].[Cl:41]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([Cl:41])[C:7]([NH:28][C@@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:21][CH2:22][CH2:23][O:24]3)[CH2:19][CH2:18]2)=[C:13]([CH3:27])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (1.16 g) and chloroform (35 mL) was added N-chlorosuccinimide (294 mg), followed by stirring at room temperature for 4 hours, and then N-chlorosuccinimide (84 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reactant was added silica gel, and then the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl (3R)-3-[(5-carbamoyl-3-chloro-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (851 mg) as a yellow solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]([F:19])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:22])=O>>[ClH:22].[F:2][C:3]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]([F:19])=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(c2cc(F)c(C(=O)O)cc2F)CC1
Agent: Cl
Product: CN1CCC(c2cc(F)c(C(=O)Cl)cc2F)CC1

Procedure:
2.91 g (10 mmoles) of 2,5-difluoro-4-(1-methyl-4-piperidinyl)benzoic acid hydrochloride was refluxed with thionyl chloride and evaporated to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:15][O:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 mL) was added CH2BrCl (34.4 g, 0.27 mol) and K2CO3 (75 g, 0.54 mol) at 80° C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (Petroleum Ether/Ethyl Acetate=10:1) to afford methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (12.6 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.21 (s, 1H), 6.05 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][N:5]2[C:6](=[O:14])[C:7]([C:10](OC)=[O:11])=[CH:8][N:9]=[C:4]2[CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][N:5]2[C:6](=[O:14])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn2c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=c1c(CO)cnc2cc(Br)ccn12
Reaction time: 1 h
Yield: 16.2 %

Procedure:
To a solution of methyl 8-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1 g, 3.5 mmol, 1 equiv) in anhydrous THF (25 mL) was added DIBAL-H (5 mL) at 0° C. dropwise. After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl. The solution was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude was purified by column chromatography to give 145 mg of the desired product. MS (ESI): 255, 257 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:14][S:15]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: O[C@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
(S)-Tetrahydrofuran-3-ol 2a (300 mg, 3.40 mmol) and triethylamine (687 mg, 6.80 mmol) were dissolved in 20 mL of dichloromethane in an ice bath, followed by addition of methanesulfonyl chloride (908 mg, 7.93 mmol). The reaction solution was warmed up to room temperature and stirred for 2 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with water (30 mL×2), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-tetrahydrofuran-3-yl methanesulfonate 2b as a yellow oil (522 mg, yield 92.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][Cl:33])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCCBr
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (20.00 g), K2CO3 (10.37 g), KI (1.04 g), 1-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.01 (m, 2H), 3.68 (t, J=4.2 Hz, 2H), 4.00 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H), 7.30 (s, 1H), 7.47 (s, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[CH:14][N:10]=[C:8]([OH:9])[C:6]=2[N:7]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Product: Oc1ncnc2ccc(Cl)nc12
Yield: 82 %

Procedure:
A suspension of 6-chloro-3-nitropicolinamide (12 g, 70 mmol) in triethyl orthoformate (490 ml) was refluxed for 3 hours. A yellow suspension was formed which was cooled to room temperate. The precipitate was collected by filtration, and dried under vacuum to obtain 6-chloropyrido[3,2-d]pyrimidin-4-ol (10.44 g, 82% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].C(#N)C.C(N(CC)CC)C.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](OC2C=CC=CC=2)=[N:46][C:47]#[N:48])=[CH:40][CH:39]=1>>[C:47](/[N:46]=[C:45](\[O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)/[N:20]1[CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:27])[CH2:10][CH2:11]2)=[O:16])[C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]1)#[N:48]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 85 °C

Procedure:
To a stirred solution of methyl (3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (386.500 mg, 1.04334E-3 mol) in anhydrous acetonitrile (6.000 mL, 0.1149 mol) at rt was added triethylamine (0.2923 mL, 0.002087 mol) and diphenyl cyanocarbonimidate (384.4 mg, 0.001565 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product (60% in yield). MS (ESI): (M+H)+=515.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of 90.6 g of 3-(trifluoromethyl)phenol, 55.2 g of 4-fluoroacetophenone and 400 ml of dry dimethylacetamide was treated under argon with 71.9 g of anhydrous potassium carbonate in portions. The mixture was stirred and refluxed at 155°-160° C. on an oil bath for 18 hours. The mixture was cooled, poured into 1.5 Kg of ice and extracted with three portions of ether. The extracts were combined, washed successively with water, three 100 ml. portions of cold 1N sodium hydroxide, water and then brine, dried and evaporated to an oil. This oil was distilled at 105°-120° C., 0.15-0.20 mm Hg, giving the desired intermediate as an oil, bp 130°-142° C. (0.2 mm).
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[C:27]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC>[I:25][C:26]1[CH:31]=[CH:30][N:29]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[C:28](=[O:32])[C:27]=1[CH3:33]
Reactant: Cc1c(I)cc[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1c(I)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 22 h
Yield: 80.7 %

Procedure:
Tert-butyl 4-(((4-methylphenyl)sulfonyl)oxy)piperidine-1-carboxylate (21.7 g) was added to a mixture of 4-iodo-3-methylpyridin-2(1H)-one (8.98 g) and potassium carbonate (21.1 g) in 1-methoxy-2-(2-methoxyethoxyl)ethane (160 mL) at room temperature. The mixture was stirred at 100 C under nitrogen atmosphere for 22 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Toluene was added to the residue. The mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=4[C:29](=[O:30])[NH:31][CH3:32])[C:23]([Cl:37])=[CH:22][N:21]=3)[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1C2CCC1c1cc(N)ccc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)N1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 140 °C
Yield: 49.3 %

Procedure:
4-Amino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester (J. Med. Chem. 1988, 31, 433-444)(30 mg, 0.12 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36 mg, 0.12 mmol) were combined with 4 N HCl (0.030 mL, 0.12 mmol) in isopropanol (1 mL). The resulting mixture was heated in a microwave at 140° C. for 30 min. The resulting mixture was then made basic with saturated aqueous NaHCO3, extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 4-[5-Chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester as a yellow solid (30 mg, 49%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.4 (s, 1H), 8.8 (d, 1H, J=4.6 Hz), 8.7 (d, 1H, J=8.1 Hz), 8.2 (s, 1H), 7.8 (d, 1H, J=7.1 Hz), 7.7-7.5 (m, 2H), 7.4 (m, 1H), 7.1 (t, 1H, J=7.1 Hz), 7.0 (d, 1H, J=8.3 Hz), 4.7 (m, 1H), 4.4 (m, 1H), 4.1-3.9 (m, 2H), 3.2 (d, 1H, J=14.1 Hz), 2.8 (d, 3H, J=4.6 Hz), 2.2-2.0 (m, 2H), 1.7 (t, 1H, J=9.4 Hz), 1.6 (m, 1H), 1.2 (m, 1H), 1.2-1.0 (m, 3H); MS (m/e) 507 (M+1); mp 140-144° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]3[CH2:28][CH2:29][CH2:30][O:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNOC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCO3)ccc2n1CC1CCOCC1
Yield: 34.6 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), isoxazolidine hydrochloride (44 mg, 0.40 mmol), DIPEA (0.2 mL, 149 mg, 1.15 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 24 mg (36%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.61 (m, 4 H), 1.63 (s, 9 H), 2.02-2.19 (m, 2 H), 2.25-2.42 (m, 1 H), 3.29-3.38 (m, 2 H), 3.64-3.73 (m, 2 H), 3.86 (t, J=7.13 Hz, 2 H), 3.88-3.96 (m, 2 H), 4.49 (d, J=7.42 Hz, 2 H), 7.98 (d, J=1.56 Hz, 1 H), 7.99 (s, 1 H), 8.24 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C20H29N3O4S+1.20 TFA+0.20 EtOAc (561.99): C, 49.58; H, 5.70; N, 7.48. Found: C, 49.74; H, 5.53; N, 7.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1cccc([C@@H](C)N)c1
Product: COc1cccc([C@@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)c1
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 76%). MS(ESI) m/z 442 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-nitroaniline (4-7) (13.8 g, 100 mmol) and phenylsulfonyl chloride (14 mL, 100 mmol) in pyridine (50 mL) was heated at 100° C. for 2 h. The resultant solution was concentrated, and the residue dissolved in ethyl acetate. The organic extract was washed successively with 2M hydrochloric acid, sat. aq. sodium bicarbonate brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was dissolved in a minimum amount of ethyl acetate with warning, and hexane added until the solution turned cloudy. The mixture was allowed to cool slowly to RT and then chilled at 0° C. The yellow solid precipitated was obtained by filtration. Further drying under vacuum overnight provide N-phenylsulfonyl-4-nitroaniline.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6]1)=[C:2]=[S:3].[NH2:17][NH2:18]>C(O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:2](=[S:3])[NH:17][NH2:18])[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: S=C=NCC1CC(c2ccc(Cl)cc2)=NO1
Reactant: NN
Solvent: CCO
Product: NNC(=S)NCC1CC(c2ccc(Cl)cc2)=NO1

Procedure:
A 25 g. portion of the product of Example 1 was reacted with excess hydrazine in 200 ml. of ethanol for 2 hours, allowing the reaction to heat to reflux temperature. The solids which precipitated upon cooling were separated by filtration and identified as 27 g. of product, m.p. 115°-117°, NMR singlets at 4.48, 7.4, 7.63, 7.97 and 8.73 ppm., and multiplets at 3.05-4.12 and 4.67-5.28 ppm.