Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:9]=2[CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)cccc2-c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 199A (1.5 g) in N,N-dimethylformamide (20 ml) was added 60% sodium hydride (0.596 g). The mixture was stirred at room temperature for 30 minutes and dimethylaminoethyl chloride hydrochloride salt (1.073 g) was added. After the resulting mixture was stirred overnight, additional 60% sodium hydride (0.596 g) and dimethylaminoethyl chloride hydrochloride salt (1.073 g) were added. The reaction mixture was further stirred overnight, diluted with ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].Cl.Cl.[NH2:36][C@@H:37]([CH3:45])[CH2:38][CH2:39][NH:40][CH2:41][CH2:42][O:43][CH3:44]>CO.ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([OH:11])=[C:5]3[C:3](=[O:4])[N:36]4[C@@H:37]([CH3:45])[CH2:38][CH2:39][N:40]([CH2:41][CH2:42][O:43][CH3:44])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COCCNCC[C@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 57.7 %

Procedure:
In a manner similar to that described in example Z-36, from 16 (15 mg, 0.034 mmol) and [(3S)-3-Aminobutyl][2(methyloxy)ethyl]amine bis hydrochloride (19 mg, 0.087 mmol), (4S,12aS)-N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,8,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid after silica gel chromatography (1-12% methanol/dichloromethane). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a yellow solid (9 mg, 60%, 2 steps). 1H NMR (CDCl3) δ 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.98 (m, 2H), 5.08 (m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 8H), 3.08 (m, 1H), 2.04-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES+MS: 459 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(F)cc2[nH]1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2ccc(F)cc21
Yield: 47.7 %

Procedure:
To a suspension of 7-fluoro-2(1H)-quinolinone (1.53 g, 9.39 mmol) in DMF at 0° C. was added sodium hydride (0.83 g of a 60% w:w dispersion in oil, 20.65 mmol) and the reaction was allowed warm to rt over 0.5 h before addition of allyl iodide (1.91 ml, 20.65 mmol). The reaction was stirred at rt for a further 0.25 h before addition of water (100 ml). The aqueous phase was then extracted with 10% MeOH in DCM (3×200 ml) and the combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 10% MeOH in DCM gradient to provide the desired compound (0.91 g, 48%). This material contained approximately 10% of the isomeric 5-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[C:8]([O:18]C3CCCCO3)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[C:8]([OH:18])=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(OC2CCCCO2)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(O)cc1F
Temperature: 50 °C
Reaction time: 19 h
Yield: 81 %

Procedure:
To a stirred mixture of T22.4 (5.65 g, 16.2 mmol) in MeOH (60 mL) was added PPTS (0.42 g, 1.69 mmol). The mixture was heated to 50° C. and monitored with TLC and LCMS. After 19 hours, the organic solvent was removed under reduced pressure, and the residue was then purified on silica gel (0-15% EtOAc in hexanes) to yield T22.5 as a white solid (3.47 g, 81% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (1H, d, J=8.3 Hz), 6.71 (1H, d, J=12.0 Hz), 5.93 (1H, d, J=1.7 Hz), 5.80 (1H, t, J=2.4 Hz), 3.90 (3H, s), 2.54 (2H, m), 1.93 (2H, t, J=7.1 Hz), 1.11 (6H, s).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:35]=[CH:34][C:26]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:26]3[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(NC2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCC(Nc5ccc(F)cc5)CC4)cc3nc21
Yield: 68.1 %

Procedure:
7-Fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.7 g of 4-(4-fluoroanilino)-piperidine in 16 cm3 of pyridine. After recrystallizing from 10 cm3 of dimethylformamide, 1.65 g of 7-fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 280° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxy-2-methylindole (46 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline (30 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere, 45.0 g (0.209 mole) of 2-amino-3'-fluorobenzophenone was added in four portions at 15 min intervals to a stirred melt (120°-125° C.) of 38.2 g (0.241 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 120°-125° C. for one hr. and then at 145°-150° C. for 45 min. The mixture was cooled to 130° C. and 100 ml of toluene was added. The cooled mixture (room temperature) was diluted with 100 ml of ethyl acetate and extracted with 100 ml of 10% potassium hydroxide. The organic layer was extracted with three 100 ml portions of 3N hydrochloric acid, 100 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 35.5 g (50%) solid. The solid was dissolved in 200 ml of methylene chloride and the solution stirred with 50 g of fluorisil for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo. A 5 g portion of the residue was recrystallized from ethyl acetate-isopropyl ether to give 4.1 g of yellow-orange solid, m.p. 98°-101° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>ClCCl>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of aluminum chloride (6.67 g) in dichloromethane (70 ml) was added hexanoyl chloride (7.0 ml) at 0° C. After the mixture was stirred at 0° C. for 15 minutes, isobutylbenzene (7.9 ml) was added to the mixture. The mixture was stirred at 0° C. for 30 minutes and poured into ice water. The organic layer was washed with water, aqueous sodium bicarbonate and brine. The solution was dried over magnesium sulfate and evaporated to give 4'-isobutylhexanophenone (10.52 g) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3]Br.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>O1CCOCC1>[O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3][N:26]1[CH2:25][CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCc2cc(C(=O)CBr)ccc2N1
Solvent: C1COCCO1
Product: O=C1CCc2cc(C(=O)CN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3.0 of 6-(1-oxo-2-bromoethyl)-3,4-dihydrocarbostyril and 5.5 g of 4-(3-chlorophenyl)piperazine were dispersed in 50 ml of dioxane and the dispersion was stirred at 50° C. for 5 hours. Then the reaction mixture was cooled and the insoluble matters formed in the reaction mixture were removed and the dioxane mother liquor was concentrated under a reduced pressure to dryness. 80 Milliliter of ether was added to the dried matter to effect the crystallization. Crude crystals thus obtained were recrystallized from dioxane-water to obtain 3.1 g of 6-{1-oxo-2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3,4-dihydrocarbostyril in light yellow needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH2:3]1>[Cl-].[NH4+].C(O)C.[Fe]>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Temperature: 25 °C
Yield: 91 %

Procedure:
To a suspension of 4,4,6-trimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (12.3 g, 40 mmol) in saturated aqueous ammonium chloride and ethanol (100 mL) was added powder iron (9.3 g, 160 mmol) at room temperature. After addition, the resulting mixture was stirred at reflux under nitrogen for 3 h. The reaction mixture was cooled to room temperature; and filtered through a pad of celite. The solvent of ethanol in filtrate was removed under reduced pressure and the water phase was extracted with ethyl acetate. The combined organic phase was dried, concentrated to give 2-(4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (9.7 g). The product was used in the next step without further purification. LC/MS m/e obsd. (ESI+) [(M+H)+] 267.1.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.[H][H]>[Ni]>[CH3:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: [H][H]
Agent: [Ni]
Product: CCCCCCCCCCCCCCC
Temperature: 240 °C
Reaction time: 12 h

Procedure:
1000 g of 1-hexadecanol (Lorol C 16 from Cognis) were initially charged in a stirrable pressure vessel with 10 g of a nickel catalyst (Ni-5249 P from Engelhard; Ni content=63% by weight) and heated to 240° C. Subsequently, over a period of 12 h, hydrogen was added through a sparging tube at a pressure of 20 bar and the reaction gases were simultaneously discharged through a valve in the reactor lid. Thereafter, the product was cooled, discharged and filtered. This reaction product was fractionated in a distillation to give pure pentadecane and then deodorized with nitrogen. This gives a colorless, liquid and low-odor product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][N:11]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-((benzyloxycarbonyl)(methyl)amino)piperidine-1-carboxylate (0.3 g, 0.682 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (2.5 ml) was added at 0° C. and stirring was carried out for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].CO>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8](=[O:13])[C:9]([F:12])([F:10])[F:11]
Reactant: Cc1ccncc1N1CCN(c2ccc(C(O)C(F)(F)F)c(F)c2)C1=O
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc(C(=O)C(F)(F)F)c(F)c2)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
MnO2 (536 mg, 6.165 mmol) was added to 1-[3-fluoro-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-197a: 325 mg, 0.880 mmol) in DCM (20 mL) under nitrogen atmosphere. The resulting suspension was stirred at 50° C. overnight. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was cooled to room temperature and filtered through celite pad. The filtrate was washed with CHCl3, dried over Na2SO4 and concentrated. The concentrate was washed with hexane and dried to afford 240 mg of the product (74.53% yield).
Reaction SMILES: [CH2:1]([C:8]1([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][CH2:11][O:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C1COCC1>[NH2:14][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: O=C1OCCC1(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NC1(Cc2ccccc2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-benzyl-3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one (5.67 g, 15.95 mmol) in MeOH (50 mL) and THF (50 mL) was added 6N HCl (5.3 mL, 32 mmol). After 5 min stirring at RT, the reaction mixture was concentrated in vacuo, diluted with water and benzophenone was extracted with diethyl ether (3×). The aqueous layer was basified to pH 10 with 6N NaOH, extracted with DCM (×2), dried over sodium sulfate and concentrated in vacuo to give 3-amino-3-benzyldihydrofuran-2(3H)-one as a colorless oil, which was carried as is in the next step.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:23](O)(=[O:26])[CH2:24][CH3:25]>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:23](=[O:26])[CH2:24][CH3:25])=[O:7])#[N:3]
Reactant: CCC(=O)O
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: CCC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with propionic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-propionyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 384.1 [M+H]+.
Reaction SMILES: [NH3:1].S(O[CH2:13][CH:14]1[CH2:22][CH2:21][C:17]2[N:18]=[CH:19][S:20][C:16]=2[CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O>CO>[NH2:1][CH2:13][CH:14]1[CH2:22][CH2:21][C:17]2[N:18]=[CH:19][S:20][C:16]=2[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ncsc3C2)cc1
Reactant: N
Solvent: CO
Product: NCC1CCc2ncsc2C1
Yield: 42 %

Procedure:
The compound is prepared by action of ammonia on the above tosylate (V), in methanol, in a autoclave at 100° C. B.p.0.5 =100°-106° C. Yield: 42%.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]1[O:20][CH:15](OC(=O)C)[C@H:14]([O:21][C:22](=[O:24])[CH3:23])[C@@H:13]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:41]1[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]1=[O:43].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:22]([O:21][C@@H:14]1[C@H:13]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:12]([C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:20][C@H:15]1[N:41]1[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]1=[O:43])(=[O:24])[CH3:23]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OC1O[C@H]([C@@H](COC(=O)c2ccccc2)OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H]([C@@H](COC(=O)c2ccccc2)OCc2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of the anomeric mixture 14 (4.50 g, 8.21 mmol) and thymine (1.55 g, 12.31 mmol) in anhydrous acetonitrile (50 cm3) was added N,O-bis(trimethylsilyl)-acetamide (12.2 cm3, 49.3 mmol). The reaction mixture was stirred at 60° C. for 1 h and then cooled to 0° C. Trimethylsilyl triflate (2.97 cm3, 16.4 mmol) was added dropwise during 10 min and the mixture was heated for 2 h under reflux. The reaction mixture was allowed to cool to room temperature and the volume was reduced by 50% under reduced pressure. After cooling to 0° C., a saturated aqueous solution of sodium hydrogen carbonate (100 cm3) was added and extraction was performed with dichloromethane (2×50 cm3). The combined organic phase was washed with brine (50 cm3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 15 as white solid material (4.06 g, 81%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [CH:1]12[C:7](=[O:8])O[C:4](=[O:5])[CH:2]1[CH2:3]2.[CH2:9]([NH:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([N:16]1[NH:17][C:7](=[O:8])[CH:1]2[CH:2]([CH2:3]2)[C:4]1=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNCc1ccccc1
Reactant: O=C1OC(=O)C2CC12
Solvent: CC#N
Product: O=C1NN(Cc2ccccc2)C(=O)C2CC12
Yield: 29.8 %

Procedure:
In 150 ml of acetonitrile was dissolved 42 g (374 mmol) of 1,2-cyclopropanedicarboxylic acid anhydride, and to the solution was added dropwise a solution of 45.8 g (374 mmol) of benzylhydrazine in 50 ml of acetonitrile, and the mixture was heated under reflux for 15 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Crystallization from ethyl acetate gave 24.1 g (29.7%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH2:29]Br)[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH2:29][N:11]1[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Fc1cc(Br)cc(CBr)c1
Product: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
219 mg (0.71 mmol) of the compound from Example 5A and 191 mg (0.71 mmol) of 1-bromo-3-(bromomethyl)-5-fluorobenzene were reacted analogously to the preparation of Example 101A. This gave 181 mg (51% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][NH2:26].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[N:26][O:25][CH3:24])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of the Compound of Example 83 (0.14 g, 0.44 mmol) in 1.5 mL of pyridine was added O-methylhydroxylamine (0.04 g, 0.48 mmol). After 4 hours stirring at r.t., the reaction was checked by TLC and considered to completion. It was diluted with water, acidified by 1N HCl and extracted with EtOAc. After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a colorless oil. Yield: 75.4%