Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=1
Reactant: CCOC(COc1ccc(C(F)(F)F)cc1)OCC
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc2occc2c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a mixture of benzene (100 mL) containing polyphosphoric acid (19.45 g, 57.54 mmol) was added 1-(2,2-diethoxyethoxy)-4-(trifluoromethyl)benzene (8.0 g, 28.75 mmol). The mixture was stirred vigorously while being heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 5-(trifluoromethyl)-1-benzofuran (5.0 g, crude) as colorless oil.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Br:14][C:15]1[C:16]([F:26])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2.[N+]([O-])(O)=O>>[Br:14][C:15]1[C:16]([F:26])=[CH:17][C:18]([N+:10]([O-:13])=[O:11])=[C:19]2[C:24]=1[N:23]=[C:22]([Cl:25])[CH:21]=[CH:20]2
Reactant: Fc1ccc2ccc(Cl)nc2c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(F)c(Br)c2nc(Cl)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene, the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=O.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cccc(-c2nccn2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cn1ccnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(1-methyl-1H-imidazol-2-yl)benzoate [CAS-No. 168422-44-4] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light yellow liquid (1.26 g).
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][C:4]#[CH:5].Cl[CH2:38][CH:39]=[N:40][OH:41]>>[CH3:38][C:39]1[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][C:6]2[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]3[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]3[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:41][N:40]=1
Reactant: ON=CCCl
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(C)no1)CCCC3
Yield: 34.8 %

Procedure:
Using the method of Example 595 Part B, di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, was reacted with α-chloroacetaldoxime (1.13 g, 12.1 mmol). The crude product was purified by chromatography (silica gel, elution with a gradient of 20-40% ethyl acetate in hexanes) to provide 1.55 g of di(tert-butyl) 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a glassy solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH3:15][N:16]1[CH:20]2[CH2:21][C:22]([CH2:24][CH:17]1[CH2:18][CH2:19]2)=[O:23].O>C(OCC)C>[OH:23][C:22]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:21][CH:20]2[N:16]([CH3:15])[CH:17]([CH2:18][CH2:19]2)[CH2:24]1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1C1(O)CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-bromoanisole (9.25 ml, 0.074 mol) in dry diethyl ether (110 ml) under argon was cooled to 0° C. and was treated with n-butyllithium (1.6M) (45.6 ml, 0.073 mol) slowly. The reaction mixture was then allowed to warm to room temp. After 0.5 h, a solution of tropinone (10.14 g, 0.073 mol) in dry diethyl ether (60 ml) was added causing the reaction mixture to reflux. Reflux was maintained for a further 0.5 h, before the reaction mixture was allowed to cool. Water (40 ml) was then added and the reaction mixture was stirred for 0.25 h. The organic layer was then separated, dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oily solid, which was triturated with petroleum ether (60-80). The resultant suspension was then filtered to give the title compound as a white solid, which was dried in vacuo (9.04 g, 50%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 97.5 °C
Yield: 90.2 %

Procedure:
p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g) were suspended in N,N-dimethylformamide (250 mL). To the suspension was added dropwise benzyl chloride (20.2 g) at room temperature. After heating at 95 to 100° C. for one hour, the reaction mixture was cooled to room temperature and water (400 mL) was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (34.3 g) as milk-white crystals in a yield of 90%.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:7]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccc(-c3cnco3)c2)cc1
Yield: 58.8 %

Procedure:
A solution of 3-oxazol-5-yl-phenylamine (0.5 g, 3.1 mmol) and 4-nitro-benzenesulfonyl chloride (0.91 g, 4.1 mmol) in pyridine (20 ml) was stirred over weekend at room temperature. The residue was partitioned between EtOAc and H2O. The organic layer was separated, washed twice with H2O and once with saturated aqueous sodium chloride solution, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (5%-15% EtOAc-hexane) to afford 0.63 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][C:14]#[N:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:14]([CH2:13][S:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:18])[CH3:17])#[N:15]
Reactant: N#CCSc1ccc(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N

Procedure:
(2-Amino-4-trifluoromethylphenylsulfanyl)acetonitrile (0.66 g) was stirred on an ice bath at 0° C. Acetic acid anhydride (2.5 ml) was added, and the resulting solution was allowed to reach room temperature. After 1 h the mixture was concentrated in vacuo and the solid residue was triturated with petroleum ether (2×2 ml), filtered off and and dried to give the title compound as a white solid. Yield 0.75 g (96%), mp 103-103.3° C.; 1H-NMR(CDCl3) δ (ppm): 8.79 (br, 1H), 8.36 (br, 1H), 7.78 (d, 1H), 7.38 (dd, 1H, J: 8 Hz/2 Hz), 3.50 (s, 2H) 2.29 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 169.2 (C═O), 137.1, 134.3, 129.6, 127.7 (q, J=32 Hz), 122.7 (m, 2C), 123.9 (CF3, J=272), 117.6 (CN), 23.2 (H3), 17.6 (CH2); IR (KBr) ν (cm−1): 3249, 2244 (C≡N), 1660, 1530, 1483, 1335, 1170, 1116, 1095.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1>CCCCCC.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([OH:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)CCN2CCCC2)cc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(C(O)(CCN2CCCC2)c2ccccn2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
400 ml of toluene is charged into a round-bottom flask, which is cooled to −40° C. and then solution of n-butyllithium (76.6 g) in hexane is added and the temperature of the reaction mixture is maintained at −40° to −50° C. 2-Bromopyridine (189.2 g) is then added to the reaction mixture and the temperature is maintained at −65° to −55° C. for 35 to 45 minutes. 200 g of 4′-methyl-3-pyrrolidinopropiophenone in 200 ml of toluene is added to the reaction mixture in the R.B. flask. The reaction mass is stirred at −65° to −55° C. for 2 hours and it is further stirred for 1 hour at −40° to −50° C. The reaction mass is quenched in ice water and HCl is added slowly at 10° to 20° C. to get a clear solution. The aqueous layer is separated and it is added slowly to NaOH in the R.B. flask at 15° C.-20° C. The reaction mass is stirred for half an hour and the precipitated solid is filtered off. The solid is transferred into a round-bottom flask and then 500 ml of methanol is added. The reaction mass is refluxed at 60° C. for half an hour and the mass is cooled to 10°-20° C. The solid mass is filtered and dried under suction for one hour. On drying the solid compound at 70°-80° C. for 4 hours, 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol (220 g, 80.5% yield) with 99.3% HPLC purity is obtained whose melting point is in the range of 115°-119° C.
Reaction SMILES: C([O:3][CH2:4][CH3:5])=C.Cl[Si:7]([CH3:36])([CH3:35])[CH2:8][CH2:9][C:10]([F:34])([F:33])[C:11]([F:32])([F:31])[C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]>>[C:4]([Si:7]([CH3:35])([CH3:36])[CH2:8][CH2:9][C:10]([F:33])([F:34])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:3])[CH3:5]
Reactant: C=COCC
Reactant: C[Si](C)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CC(=O)[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Acetyidimethyl-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsilane was synthesized from ethyl vinyl ether and chlorodimethyl-3,3,4,4,5,5,6,6,7,7,8,8, 9,9,10,10,10-heptadecafluorodecylsilane after the procedure of Cunico and Kuan (J. Org. Chem. 1985, 50, 5410-5413).
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O>C(O)C>[O:2]=[C:3]1[NH:7][C:6](=[O:8])[C:5](=[CH:17][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:4]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
Sodium (4.92 g, 0.21 g atom) was dissolved in absolute ethanol (600 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (50.5 g, 0.21 mole) added. After 10 minutes, a solution of ethyl 4-(3-formyl-4-nitrophenoxy)butanoate (50.0 g, 0.18 mole) in ethanol (100 mL) was added in one portion. The mixture was stirred for 2 hours, concentrated in vacuo to about 250 mL and diluted with water. After 20 minutes the precipitate was filtered off. Two further crops were subsequently collected from mother liquors. Combined solids were dried in vacuo over P2O5 to afford ethyl 4-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]butanoate (61.3 g, 95%) which by NMR was a 4:1 mixture of geometrical isomers. An analytical sample of the major isomer was obtained by crystallization from aqueous ethanol and had m.p. 131°-134° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.B(Cl)(Cl)Cl.O>ClCCl>[OH:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 28.8 g (0.1 mole) of 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine was added 200 ml of 1 N boron trichloride in dichloromethane. The mixture was then stirred at room temperature overnight, after which 500 ml of water was added. After three hours, the resultant precipitate was collected by filtration. The aqueous phase of the filtrate was separated and neutralized with aqueous sodium carbonate, giving a second precipitate. The combined solids were purified by column chromatography, giving the title compound, m.p. 194°-195°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.[C:21]([NH:24][CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:75]=[CH:74][C:35]([O:36][CH2:37][C:38]3([O:44][C:45](=[O:73])[CH:46]([NH:62][C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:53])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[C:34]([F:76])[CH:33]=2)[CH2:27]1)(=[O:23])[CH3:22].C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:21]([NH:24][CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:75]=[CH:74][C:35]([O:36][CH2:37][C:38]3([O:44][C:45](=[O:73])[CH:46]([NH:62][C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:53])[CH2:39][CH2:40][N:41]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:42][CH2:43]3)=[C:34]([F:76])[CH:33]=2)[CH2:27]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 62 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 178 mg 2,6-bis-benzyloxycarbonylamino-hexanoic acid 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester hydrochloride (MW: 814.31, 0.22 mmol), 90 mg triethylamine (MW: 101.19, 0.88 mmol) and 48 mg trimethylchlorsilan (MW: 108.64, 0.44 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 94 mg, 42%. MS: 1025.3 (M+H)+, Method ESI+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CN(C)C=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc(CN2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)c1
Yield: 79.6 %

Procedure:
The product is prepared according to the procedure described in Example 22, but using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 57 mg of 1-(chloro-methyl)-3-methoxybenzene and 214 mg of caesium carbonate in 2 ml of dimethylformamide. After treatment, the residue is stirred into acetonitrile. The solid is spin-filter-dried, rinsed with diethyl ether and then dried under a vacuum bell jar. 111 mg of (8S)-9-(3-methoxybenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=N2)CCCCC>>[CH2:11]([S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=[N:1]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Reactant: CCCCCCSCCSc1nc(N)n[nH]1
Product: CCCCCCSCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 13 was prepared from Compound 6, using a procedure analogous to that described previously for Compound 20. The crude product was recrystallized from ethyl acetate to give a white solid, m.p. 125.5°-126° C. Analysis: Calculated for C14H22N4OS2 : C, 51.50; H, 6.79; N, 17.16. Found: C, 50.87; H, 6.62; N, 17.04.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13](Cl)[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3
Reactant: Clc1nc2ccc(Br)c3c2n1CCC3
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc3ccc(Br)c4c3n2CCC4)CC1
Yield: 57 %

Procedure:
A solution of 7-bromo-2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in N-methylpiperazine (20 ml) was stirred under reflux, under nitrogen, for two hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 7:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate-ether to give 2.1 g (57%) of product, mp 132°-133° C.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[C:8](Cl)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=1>C1COCC1>[N+:11]([C:7]1[C:8]([NH2:1])=[CH:9][C:4]([C:3]([F:15])([F:14])[F:2])=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: N
Reactant: O=[N+]([O-])c1cnc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ncc1[N+](=O)[O-]
Yield: 96 %

Procedure:
Ammonia gas is bubbled through a solution of 2-trifluoromethyl-4-chloro-5-nitro-pyridine (4.12 g, 18.23 mmol) in anhydrous THF at room temperature for 3 h. Removal of solvent under reduced pressure affords 5-nitro-2-trifluoromethyl-pyridin-4-ylamine (3.6 g, 96%); 1H NMR (300 MHz, CDCl3) δ 7.15 (s, 1H), 9.15 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:15](Cl)=[O:16]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:9])[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:11]([F:26])([F:25])[F:10])[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: CNc1cnccc1I
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I

Procedure:
The title compound was prepared in analogy to example 25, intermediate a, from (4-iodo-pyridin-3-yl)-methyl-amine and 3,5-bis-trifluoromethyl-benzoyl chloride (CAS RN 785-56-8). Pale yellow liquid (15%). MS (ESI): m/z=475 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Temperature: 75 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylate (112 mg, 0.30 mmol) in methanol (3 mL) and water (3 mL) was added sodium hydroxide (36 mg, 0.94 mmol). The reaction mixture was heated at 75° C. and stirred for 48 hours. The mixture was acidified to pH=4 using 1 N hydrochloric acid and concentrated to give a brown solid. It was purified by reverse phase HPLC to give the title compound (40 mg, 37% yield) as a pale solid. MS (ES+) 355.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.11 (br. s, 1 H), 11.95 (br. s, 1 H), 8.07 (s, 1 H), 7.95 (s, 1 H), 7.75 (d, 2 H), 7.62 (s, 1 H), 7.43 (d, 2 H), 3.89 (t, 2 H), 2.53 (m, 2 H), 2.09 (m, 2 H).