Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][NH:32][CH2:33][C@@H:26]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:32]3[CH2:31][C@H:27]4[C@H:26]([NH:25][CH2:30][CH2:29][CH2:28]4)[CH2:33]3)[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1C[C@@H]2CCCN[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D) (0.331 g, 1 mmol) and (4aS,7aS)-tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (Example 50B) (0.226 g, 1 mmol) in methylene chloride (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.45 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel chromatography eluting with ethyl acetate to yield the t-butoxycarbonyl-protected title compound. That material was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL) for 1 hour at room temperature. The reaction mixture was concentrated and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.35 (m, 4H), 7.00 (m, 4H), 4.25 (dd, 1H), 3.96 (t, J=16.78 Hz, 1H), 3.47 (m, 7H), 3.00 (m, 1H), 2.78 (m, 2H), 2.63 (m, 1H), 2.27 (m, 1H), 1.72 (m, 2H) 1.45 (m, 2H); MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:17]1[CH:18]=[CH:19][C:14]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Nc2ccncc2)CC1
Yield: 41.1 %

Procedure:
A solution of ethyl 4-aminopiperidine-1-carboxylate (2.20 g, 12.7 mmol), 4-bromopyridine (3.47 g, 17.8 mmol), sodium t-butoxide (4.54 g, 47.2 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.398 g, 0.639 mmol) and palladium acetate (0.143 g, 0.639 mmol) in toluene (40 mL) was heated at 60° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The aqueous layer was washed 3 times with methylene chloride, and the combined organic layers dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 0 to 10% {5% ammonium hydroxide in methanol}in methylene chloride gradient elution), which gave the title compound (1.3 g, 41% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:30]1[N:35]=[CH:34][C:33]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:32][N:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)nc1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg) in 1,2-dimethoxyethane (10 mL) was added 2-methyl-5-tributylstannanyl-pyrimidine (176 mg) and copper(I)bromide-dimethyl sulfide (94 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (13 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 306. NMR: (CDCl3) 2.69-2.72 (4H, m), 2.83 (3H, s, Me), 2.84 (3H, s, Me), 3.31-3.34 (4H, m), 3.90-3.93 (6H, m), 4.06-4.08 (4H, m), 7.37 (1H, Ar) and 9.58 (1H, Ar). MS: (ESI+): MH+=490.15
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl>ClCCl.O1CCOCC1>[CH3:13][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C)CC2CCCCN2)cc1
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 2-(((4-(methoxycarbonyl)phenylmethyl)(methyl)amino)methyl)piperidine-1-carboxylate in dichloromethane (6 mL) was treated with a solution of 4 N hydrochloric acid in dioxane (6 mL). The reaction was stirred overnight. Solvent was removed under reduced pressure and the product, methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate, was isolated as the hydrochloride salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]([NH:15][C:16]([NH2:18])=[NH:17])(=[O:14])[CH3:13]>CN(C=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[NH:18][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[N:17][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-bromo-1-(4-bromophenyl)ethanone (2.00 g, 7.20 mmol) and acetylguanidine (2.18 g, 21.6 mmol) in DMF (40 mL) was stirred at rt for 48 h. The solution was concentrated to dryness in vacuo and the resulting brown solid was of sufficient purity for use in the next step. LCMS: Anal. Calcd. for C11H10BrN3O: 279, 281; found: 280, 282 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18]([O:20]CC)=O.[CH3:23][CH:24]([SH:26])[CH3:25]>>[CH:24]([S:26][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[S:5][C:4]=1[CH2:18][OH:20])([CH3:25])[CH3:23]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: CC(C)S
Product: CC(C)SCc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO

Procedure:
Prepared from intermediate 43 and isopropylthiol
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O>[CH3:13][C:6]1[C:11]2[O:12][C:2](=[O:3])[S:4][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)SCl
Reactant: Cc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccc2sc(=O)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
Chlorocarbonylsulfenyl chloride (30.5 mmol, 2.58 ml) was added to a solution of o-cresol (Compound 101) (27.7 mmol, 3.00 g) and tributylamine (30.5 mmol, 7.35 ml) in dichloroethane (48 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. Aluminum chloride (66.6 mmol, 8.88 g) was then added to the reaction mixture at 0° C., and the mixture was stirred at room temperature overnight. Water (10 ml) was then added to the reaction mixture at 0° C., after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution=100/0→30/70) to afford 7-methylbenzo[d][1,3]oxathiol-2-one (Compound 102) (2.46 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=O.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH3:20][N:21]1[C:5]([C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=2)=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:24][C:22]1=[O:23]
Reactant: O=C(CC(=O)c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CNC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Cn1c(-c2cccc(Cl)c2)cc(-c2cccc(Cl)c2)nc1=O

Procedure:
To a solution of 38 g. di(m-chlorobenzoyl)methane in 400 ml. glacial acetic acid is added 23 g. N-methylurea and 57 g. p-toluene sulfonic acid. This mixture is refluxed for 24 hours and acetic acid removed by evaporation in vacuo. The residue is treated with 2N. sodium hydroxide till basic, extracted several times with methylene chloride. The combined methylene chloride extracts are then exhaustively extracted with water, dried and evaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether and then twice from benzene to obtain 1-methyl-4,6-di(m-chlorophenyl)-pyrimidine-2(1H)-one, m.p. 178°-181°C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35](P(=O)(OCC)OCC)[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:35]/[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.37 g), tetraethyl methylenediphosphonate (0.26 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.31 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: O1CCCC1.C([NH:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[NH2:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(NCc2ccccc2)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Yield: 72.1 %

Procedure:
Palladium hydroxide (0.29 g) was added to a solution of tetrahydrofuran (7.2 ml) and methanol (14.3 ml) containing tert-butyl cis-2-(6-benzylamino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (1.43 g), followed by stirring at room temperature for 1 hour in a hydrogen atmosphere. Insoluble matter was removed by filtration, and filter cake was washed with ethyl acetate. The filtrate was mixed with the washing solution, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-amino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (870 mg) was thus obtained.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1.CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([N:1]6[CH2:8][CH2:7][CH2:6][C@H:2]6[C:3]([OH:5])=[O:4])(=[O:49])=[O:50])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 1 h

Procedure:
L-Proline (57 mg, 0.50 mmol) was treated with N,O-bis(trimethylsilyl)acetamide (250 μl, 1.0 mmol) in 1 mL dioxane overnight at 50° C. To this mixture was added 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-sulfonyl chloride (˜35 μmol, 400 μl solution in chloroform) followed by DIEA (100 μL). The reaction mixture was kept at room temperature for 1 h, evaporated, and diluted with DMSO (400 μl). The resulting solution was subjected to preparative HPLC purification. Fractions containing the desired material were combined and concentrated in vacuum centrifuge at 40° C. to provide the trifluoroacetic salt of (S)-1-{5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic acid. ESI-MS m/z calc. 548.1, found 549.1 (M+1), retention time 3.40 min; 1H NMR (250 MHz, DMSO-d6) δ 1.04 (m. 2H), δ 1.38 (m, 2H), δ 1.60 (m, 1H), δ 1.80-1.97 (m, 3H) δ 2.16 (s, 3H), δ 3.21 (m, 1H), 3.39 (m, 1H), 4.15 (dd, 1H, J=4.1 Hz, J=7.8 Hz), δ 6.01 (s, 2H), δ 6.89 (s, 2H), δ 6.98 (s, 1H), δ 7.21 (d, 1H, J=8.3 Hz), δ 7.45 (d, 1H, J=2 Hz), δ 7.52 (dd, 1H, J=2 Hz, J=8.3 Hz), δ 7.55 (d, 2H, J=8.3 Hz), δ 7.88 (d, 2H, J=8.3 Hz), δ 8.80 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:18][N:19]=[CH:1][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[C:16]1[CH:5]=[CH:4][CH:3]=[CH:1][CH:17]=1
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Reactant: C=CCON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/c1ccc(C=NOCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
a solution of trans 4-formyl-cinnamic acid A (Y═CH═CH, R1, ═H, R3═H, 0.346 g, 1.96 mmol.) and B O-Allylhydroxylamine hydrochloride (0.258 g, 2.37 mmol.) dissolved in 2 mL of DMF was warmed at 50° C. and stirred for 5 h. Then the solution was diluted with AcOEt and washed with water. Organic layer was dried on Na2SO4 and then concentrated under reduced pressure to give 0.421 g of the intermediate C (2E)-3-(4-{[(benzyloxy)imino]methyl}phenyl)acrylic acid (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8]([NH2:10])=O)=[O:4]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[C:7]([C:8]#[N:10])[CH:6]=1
Reactant: COC(=O)c1cc(I)cc(C(N)=O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc(C#N)c1
Temperature: 90 °C
Yield: 28.5 %

Procedure:
A mixture of 3-methoxycarbonyl-5-iodobenzamide (2.5 g, 8.2 mmol) in thionyl chloride (2 mL) was heated for 2 hours at 90° C. The reaction mixture was cooled and concentrated in vacuo. Silica gel chromatography afforded 670 mg (29%) of methyl-3-cyano-5-iodobenzoate, as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1.C1COCC1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cnccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cnccn1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a mixture of 6-chloronicotinoyl chloride (160 mg, 0.91 mmol), aminopyrazine (87 mg, 0.91 mmol) and THF (10 ml) was added triethylamine (0.25 ml, 1.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (100 ml), wash with water (50 ml), saturated aqueous NaCl (50 ml), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (3:2) to give 8 mg (4% yield) of the title compound as yellow solid. 1H NMR (CDCl3): 9.68 (d, J=1.2 Hz, 1H), 8.95 (d, J=2.7 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.4 (bs, 1H), 8.33-8.32 (m, 1H), 8.23 (dd, J=2.4, 8.1 Hz, 1H), 7.53 (dd, J=0.6, 8.4 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:22][CH2:21][CH2:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=2[CH:27]=1)[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([N:22]1[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:6][CH2:7][CH3:8])=[CH:27][C:17]=2[CH:18]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2C(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Propionyl chloride (1.0 ml) was added dropwise to a suspension of methyl 7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) and potassium carbonate (2.2 g) in DMF (10 ml) under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere, and poured into water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].N[CH2:34][C@@H](O)C>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:34])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: C[C@H](O)CN
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 53 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using (S)-(+)-1-amino-2-propanol (0.98 mL, 12.45 mmol) as the amine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.13 g, 53%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.93 (dd, 1H, J=1.6 Hz), 7.69 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.94 (m, 1H), 3.39 (m, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.9 (d, 3H, J=6.4 Hz); ES-HRMS m/z 478.1308 (M+H C23H23ClF2N3O4 requires 478.1340). Both (+) and (−) atropomers will be resolved and characterized.
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C@@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C@H:37]1[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=2)[N:12]=3)[CH2:42]1
Reactant: C[C@@H]1CNCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
An N-methyl-2-pyrrolidone suspension (24 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (2.42 g, 5.82 mmol) and (2R)-2-methylpiperazine (2.92 g, 29.1 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 6 hours. The resulting mixture was left standing to cool, then poured into methylene chloride-methanol (10:1), and washed with water. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (2.51 g, 90%) as a pale yellow solid.