Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22]N)[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:19]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[NH:22][C:11]=2[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)CSc1ccc(F)c(Br)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(F)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 1-(3-Bromo-4-fluoro-phenylsulfanyl)-propan-2-one and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([F:15])([F:14])[F:13])=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH:20][C:21]1[CH:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1>>[N:27]1([C:24]2[N:23]=[CH:22][C:21]([NH:20][C:16]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][C:10]=3[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:26][CH:25]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(O)c1cc(-c2ccccc2)oc1C(F)(F)F
Reactant: CNc1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1cc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1 above, 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid and methyl-(6-morpholin-4-yl-pyridin-3-yl)-amine. LCMS calcd for C21H18F3N3O3 (m/e) 417, obsd 418 (M+H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\CC>C(Cl)Cl.C(OCC)C>[C:5]([O:4][CH2:1][CH2:2][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][CH3:14])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC/C=C\CCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC/C=C\CCCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Acetic anhydride (0.17 mL, 1.8 mmol), then pyridine (90 μL, 1.1 mmol), were added sequentially to alcohol 7 (0.17 g, 0.93 mmol) in CH2Cl2 (1.8 mL), and stirred at room temperature for 17 hours. The mixture was diluted with diethyl ether, washed with saturated aqueous NaHCO3, then brine, dried with Na2SO4, and concentrated. Flash chromatography of the residue (SiO2, 5% EtOAc in hexanes) provided 8 (0.18 g, 87% yield, 74% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.28-5.43 (2H, m), 4.05 (2H, t, J=6.8 Hz), 2.04 (7H, m), 1.61 (2H, td, J=9.8, 8.7, 4.6 Hz), 1.29 (10H, m), 0.95 (3H, m); 13C NMR (CDCl3): δ 171.3, 131.6, 129.3, 64.7, 32.6, 29.8, 29.5, 29.3, 29.2, 28.7, 26.0, 21.1, 20.6, 14.5; HRMS (FAB): 227.2045, [C14H26O2+H]+ requires 227.2006.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2.I[C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:30])([CH3:29])[C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[CH3:29][C:19]1([CH3:30])[C:20]2[CH:21]=[C:22]([N:11]3[C:12]4[C:8](=[CH:7][C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:14][CH:13]=4)[CH2:9][CH2:10]3)[CH:23]=[CH:24][C:25]=2[C:26]2[C:18]1=[CH:17][CH:16]=[CH:28][CH:27]=2
Reactant: c1csc(-c2ccc3c(c2)CCN3)c1
Reactant: CC1(C)c2ccccc2-c2ccc(I)cc21
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2ccc(N3CCc4cc(-c5cccs5)ccc43)cc21

Procedure:
Under the atmosphere of nitrogen, a mixed solution made of 2 parts of 2-thiopheneboric acid, 3 mL of ethanol and 10 mL of 2M sodium carbonate was dropwise added to a mixed solution of 2 parts of 5-bromoindoline and 20 parts of toluene, and the reactive components were caused to react for 1 hour. Thereafter, thereto was added 0.3 part of tetra-triphenylphosphine palladium (0), and the reactive components were caused to react at 80° C. for 12 hours. After the reaction, the reaction solution was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography (hexane/ethyl acetate) to yield 2 parts of a precursor of the compound (311), 5-(thiophene-2-yl)indoline as a colorless crystal. Next, under the atmosphere of nitrogen, 2 parts of this 5-(thiophene-2-yl)indoline, 6 parts of 2-iodo-9,9-dimethyl-9H-fluorene, 30 parts of dimethylformamide (DMF), 10 parts of potassium carbonate, and 1 part of copper powder (200 mesh) were stirred at 160° C. for 10 hours. After the reaction, the resultant was extracted with water/ethyl acetate, and the ethyl acetate phase was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was separated and purified by column chromatography to yield 2 parts of 1-(9,9-dimethyl-9H-fluorene-2-yl)-5-(thiophene-2-yl)indoline, which is a precursor of the compound (311) in the same manner, as a colorless crystal. Next, 1.7 parts of phosphorus oxychloride were dropwise added to 10 parts of DMF, the temperature of which was adjusted to 5° C., while the temperature of the reaction solution was kept at 10° C. or lower. The reaction solution was then stirred at 5° C. for 1 hour. Thereafter, 2 parts of 1-(9,9-dimethyl-9H-fluorene-2-yl)-5-(thiophene-2-yl)indoline described above were added thereto, and then the reactive components were caused to react at 25° C. for 1 hour. The reaction solution was then stirred at 70° C. for 1 hour. Thereafter, a 20% solution of sodium hydroxide in water was added to the reaction solution until the pH turned to 12. The precipitated crystal was filtrated, and the resultant crystal was washed with water. The crystal was then separated by column chromatography (hexane/ethyl acetate), and recrystallized from ethanol to yield 2 parts of the compound (311) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11].[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34]O)[CH2:30][CH2:29]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23][CH2:34][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11]
Reactant: OCC1CCOCC1
Reactant: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OCC1CCOCC1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-hydroxybenzoate (100 mg, 0.255 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (29.7 mg, 0.255 mmol) in toluene (1.5 mL) stirred in air at room temperature was added a solution of 2-(tributylphosphoranylidene)acetonitrile (61.7 mg, 0.255 mmol) in toluene (0.5 mL). The reaction mixture was then stirred at 20° C. for 24 hours. After this time, additional 2-(tributylphosphoranylidene)acetonitrile (61.7 mg, 0.255 mmol) was added and the reaction stirred for a further 2 hours. The solvent was evaporated and the purification attempted by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give a mixture of two products. Further purification was carried out by mass directed autoprep (Method O), to provide the desired product, 25 mg. LCMS [LCMS2] Rt 1.44 min, m/z (ES+) 490 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:24][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 8.8 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.768 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.218 g, 0.922 mmol) to give 0.04 g (9%) of the title compound as a tan solid, mp 142-143° C.; 1H NMR (DMSO-d6) δ 1.04 (d, 12 H), 1.81 (s, 3 H), 2.19 (s, 3 H), 3.07 (septet, 2 H), 3.81 (s, 2 H), 6.95-6.97 (m, 2 H), 7.14-7.20 (m, 3 H), 7.40-7.46 (m, 2 H), 7.47 (s, 2 H), 8.03 (d, 1 H). IR (KBr) 3400, 2950, 1675, 1375, 1180 cm-1. mass spectrum (EI), m/z 590 (M+). Anal. Calcd. for C33H34O8S.1.1H2O: C, 64.92; H, 5.98; N, 0.00. Found: C, 64.92; H, 5.76; N, -0.03.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]#[N:13])=[CH:9][C:4]=2[O:3][CH2:2]1.I[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.CC([O-])=O.[K+].CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].CCCCCC.CCOCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:12]#[N:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CC=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1
Reaction time: 1 h
Yield: 32.4 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-acrylonitrile (9:1 (E):(Z) mixture) (0.3 g, 1.73 mmol), 4-iodo-anisole (0.57 g, 2.43 mmol), Pd(OAc)2 (0.039 g, 0.17 mmol), KOAc (0.5 g, 5.2 mmol) and tetrabutylammonium bromide (0.6 g, 1.9 mmol) were combined in a microwave vial and DMF (3 mL) added, the reaction mixture was then degassed. The reaction vessel was placed in the microwave oven (Emrys Optimizer) at 150° C. for 1 hour. The contents were poured into water, EtOAc mixture (40 mL, 1:1) and filtered through Celite washing with more EtOAc. The organic layer was separated and the crude product isolated by CC (silica gel, hexanes:EtOAc, 3:1 to 1:1). Sonication of the purified compound with an ether:hexane mixture yielded (Z) 3-benzo[1,3]dioxol-5-yl-3-(4-methoxy-phenyl)-acrylonitrile (0.16 g, 0.56 mmol) in 32% yield: m.p 80-81° C.; 1H NMR (CDCl3) δ 7.25(d, 2H, Ar), 6.98(dd, 1H, Ar), 6.89-6.86(m, 4H, Ar), 6.03(s, 2H, CH2), 5.56(s, 1H, CH), 3.84 (s, 3H, OCH3); Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02 Found: C, 73.02; H, 4.90; N, 4.82.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][C:21](Cl)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CCCCO>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][C:21]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCO
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To the solution of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide (5.1 g, 9.62 mmol) in 80 mL of n-BuOH was added N-methylpiperazine (7.41 g, 74.1 mmol) under N2 atmosphere. Then the solution was stirred at 80° C. overnight. Concentrated and purified by flash chromatography to afford 4.98 g 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine 1-oxide as a white solid (Yield: 87.2%). 1HNMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.93 (s, 1H), 7.78 (s, 2H), 7.38 (m, 2H), 7.28 (m, 1H), 7.17 (m, 1H), 7.07 (s, 1H), 5.50 (s, 3H), 2.72 (d, J=4.4 Hz, 4H), 2.57 (m, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 1.45-1.20 (m, 6H).
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O.CN(C)C1C=CN=CC=1>[CH2:25]([S:32][CH2:1][CH:2]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: SCc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: O=C(CCC(CSCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 90.4 %

Procedure:
To a solution of dibenzyl 2-methylenepentanedioate (12.16 g, 37.5 mmol) in acetone (100 ml), was added benzylmercaptan (9.31 g, 75.0 mmol) and 4-dimethylaminopyridine (0.46 g, 3.75 mmol) with stirring. The reaction mixture was refluxed for 16 hours. The cooled solution was concentrated under reduced pressure and purified by column chromatography to yield 15.2 g (90%) of clear oil. 1H NMR (CDCl3): δ 2.0 (m, 2H), 2.3 (m, 2H), 2.5 (m, 1H), 2.6 (m 2H), 3.6 (s, 2H), 4.9 (s, 2H), 5.0 (m, 2H), 7.2-7.5 (m, 15H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[C:37]([O:40][CH2:41][C:42](Cl)=[O:43])(=[O:39])[CH3:38]>C1COCC1>[C:37]([O:40][CH2:41][C:42]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1)=[O:43])(=[O:39])[CH3:38]
Reactant: CC(=O)OCC(=O)Cl
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a mixture of 5-(4-aminobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.15 g, 0.37 mmol) and Et3N (0.3 mL, 2.33 mmol) in THF (20 mL) was added acetoxyacetyl chloride (0.12 mL, 1.11 mmol) at 0° C. The mixture was stirred overnight at rt. The solvent was evaporated, and the residue was purified by silica gel column chromatography eluted with 50% EtOAc in hexane to give 0.15 g (80% yield) of the titled compound.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([OH:28])[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)=[O:22].N1C=CN=C1.O>CN(C=O)C>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=1)=[O:22]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
TBDPSCl (1.73 g, 6.3 mmol) was dropped into a solution of (2S,4R)-4-Hydroxy-1-(4-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 2.9 mmol) and imidazole (0.98 g, 14.4 mmol) in DMF (20 mL), the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (50 mL), extracted with ethyl acetate (3×30 mL). The organic layers was combined, washed with water (2×30 mL), brine (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give compound 1.48 g (88%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.67-7.62 (m, 4H), 7.47-7.37 (m, 8H), 7.13 (d, 2H, J=8.7 Hz), 6.37 (s, 1H), 4.68-4.55 (m, 2H), 3.71 (s, 3H), 3.54-3.42 (m, 2H), 2.33-2.25 (m, 1H), 2.05-1.97 (m, 1H), 1.06 (s, 9H); LC-MS: 587.2 [M+1]+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:29]([NH2:31])=[O:30])[C:18]2[CH:28]=[CH:27][C:21]([C:22](OCC)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:29]([NH2:31])=[O:30])[C:18]2[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:27][CH:28]=2)[CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5.0 gm (11.83 m mol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 75 ml of absolute tetrahydrofuran was added dropwise, at an internal temperature of 0° C., to a stirred suspension of 0.68 gm (17.95 m mol) of lithium aluminium hydride in 25 ml of absolute tetrahydrofuran. The mixture was stirred for 20 hours at ambient temperature and then cooled to 0° C., and 4N sodium hydroxide solution was slowly added dropwise thereto until a filterable precipitate formed. The mixture was filtered, and the precipitate was decocted several times with ether. The combined organic solutions were concentrated by evaporation in vacuo. The evaporation residue was distributed between water and ether. The ether phase was dried, filtered, and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (5:1)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccccn1

Procedure:
150 mg (0.591 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 199.40 mg (0.709 mmol) of 2-bromo-1-pyrid-2-ylethanone hydrobromide and 10 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 15 min 50% B, t 25 min 70% B), 218 mg of (8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:28]([O:30][CH2:31]Cl)[CH3:29]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:31][O:30][CH2:28][CH3:29])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)n(COCC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.71 g (12.0 mmol) of potassium carbonate were added to a hot solution of 2.2 g (7.7 mmol) of 7-benzyl-3-propylxanthine from stage a) in 60 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for 1 hour. 0.93 ml (10.0 mmol) of ethoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 4.5 hours. A further 0.5 ml (5.3 mmol) of ethoxymethyl chloride was then added and the mixture was again stirred for 6 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was allowed to stand overnight, 60 ml of water were added again and the mixture was extracted three times using methyl tert-butyl ether. The combined organic phases were washed twice with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH2:17]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:16]=[CH2:15]
Reactant: CCOC(=O)NCC(OC)OC
Reactant: C=CCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCN(CC(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 g (2.82 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate, 625 g of powdered potassium hydroxide and 10 g of triethylbenzylammonium chloride are initially introduced into 2.7 l of toluene and 345 g (2.85 mol) of allyl bromide are added dropwise at room temperature. The mixture is stirred overnight at room temperature, the salts are filtered off with suction, and the filtrate is washed once with saturated sodium chloride solution, dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][N:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH3:32][NH:33][CH3:34]>C(Cl)Cl.C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:11]([CH2:10][C:9]2[CH:30]=[CH:31][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]([CH3:34])[CH3:32])=[CH:7][CH:8]=2)[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2R)-2-[[4-(2-bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoic acid amide (41 mg, 0.77 mmol) in CH2Cl2 (2 mL) was added excess 2.0 M dimethylamine in THF. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (24 mg) in 63% yield. MS (ESI), (M+H)+495.14, 1H NMR (CDCl3, 400 MHz) δ8.85 (s, 1H), 8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4.62 (m, 4H), 3.25 (t, 1H, J=6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)