Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2OC=1)#[N:2].Cl.N[OH:28].O.C[N:31](C)[CH:32]=[O:33]>C(O)C>[NH2:31][C:32]1[O:33][C:6]2[CH:13]=[C:12]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][C:7]=2[C:8](=[O:9])[C:3]=1[C:1](=[O:28])[NH2:2]
Reactant: CN(C)C=O
Reactant: NO
Reactant: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc2oc(N)c(C(N)=O)c(=O)c2cc1Oc1ccccc1
Yield: 72 %

Procedure:
3.56 g of 3-cyano-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, 970 mg of hydroxylamine hydrochloride, 1.5 ml of water, 7 ml of N,N-dimethylformamide and 150 ml of ethanol were mixed, and subjected to refluxing for 3 hours. The reaction mixture was cooled, and thereafter, the precipitated crystals were collected by filtration and then recrystallized from acetonitrile to obtain 2.8 g (yield: 72%) of 2-amino-3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([NH:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CN)OC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+. 1H NMR (CD3OD 300 MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7](Cl)=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)=O.[O:24]1C2C=CC=CC=2C(C2C(Cl)=C(Cl)C3OC(C(O)=O)CC=3C=2)=[N:25]1.S(=O)(=O)(O)O>C(O)C>[Cl:18][C:8]1[C:7]2[O:24][N:25]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[C:6]=2[CH:17]=[C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=12
Reactant: O=C(c1ccccc1Cl)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: O=C(O)C1Cc2cc(-c3noc4ccccc34)c(Cl)c(Cl)c2O1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)C1Cc2cc3c(-c4ccccc4Cl)noc3c(Cl)c2O1

Procedure:
8-Chloro-3-(o-chlorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acid (4d) was prepared from (3d) using the procedure above; the product contained a significant impurity, presumably the countercyclized 5-(3-benzisoxazolyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid. The mixture was dissolved in 200 ml. absolute ethanol and treated with 0.5 ml. concentrated sulfuric acid overnight. The solution was then evaporated to dryness, redissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and re-evaporated. Chromatography of the ester on silica gel with chloroform and n-hexane in a 3:1 ratio gave a solid, m.p. 136° C., which was determined by detailed mass spectral analysis to be the desired isomer. Hydrolysis at 60° C. in 25 ml. absolute ethanol and 200 ml. aqueous 1M sodium hydroxide for 20 minutes furnished a white precipitate which was distributed between ethyl acetate and 4.0 M aqueous hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization from ethyl acetate with n-hexane gave (4 d), m.p. 224°-225° C., in 8.1% yield. Analysis (C16H9Cl2NO4) C,H,N,Cl.
Reaction SMILES: [C:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:11]2[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:7][CH:8]=[CH:9][CH:10]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CC(C)(C)Sc1ncccc1CCl
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SC(C)(C)C)c(F)c1
Yield: 86 %

Procedure:
2-t-Butylsulfanyl-3-chloromethyl-pyridine (0.08 g, 0.37 mmol) obtained in Step C of Preparation Example 17 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.13 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][N:17]([CH3:19])[CH2:16][C:15]3[N:14]=[C:13]([OH:20])[CH:12]=[CH:11][C:10]2=3)=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC([N+](C(OC(C)(C)C)=O)=[N-])=O)(C)(C)C.[N:56]1([CH2:62][CH2:63][CH2:64]O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:18][N:17]([CH3:19])[CH2:16][C:15]3[N:14]=[C:13]([O:20][CH2:64][CH2:63][CH2:62][N:56]4[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:12]=[CH:11][C:10]2=3)=[CH:7][CH:8]=1
Reactant: OCCCN1CCCCC1
Reactant: COc1ccc(C2CN(C)Cc3nc(O)ccc32)cc1
Agent: CC(C)(C)OC(=O)[N+](=[N-])C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CN(C)Cc3nc(OCCCN4CCCCC4)ccc32)cc1
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a mixture of 5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-2-ol (0.10 g, 0.37 mmol) and PPh3 (0.097 g, 0.37 mmol) in THF (5 mL) was added a solution of di-tert-butyldiazodicarboxylate (0.085 g, 0.37 mmol) in THF (5 mL). After 30 min, a solution of 3-piperidin-1-yl-propan-1-ol (0.053 g, 0.37 mmol) in THF (5 mL) was added slowly. After 18 h, the mixture was concentrated, and the resulting solid was purified (SiO2; 0-8% 2 M NH3 in MeOH/DCM) to give the title compound (30 mg, 20%). MS (ESI): mass calcd. for C24H33N3O2, 395.26; m/z found, 396.6 [M+H]+. 1H NMR (CDCl3): 7.10-7.04 (m, 3H), 6.83 (d, J=8.6, 2H), 6.45 (d, J=8.4, 1H), 4.33-4.25 (m, 2H), 4.15-4.10 (m, 1H), 3.79 (s, 3H), 3.76-3.70 (m, 1H), 3.57-3.50 (m, 1H), 3.02-2.97 (m, 1H), 2.53-2.45 (m, 3H), 2.44 (s, 3H), 2.42-2.38 (m, 3H), 2.00-1.92 (m, 2H), 1.66-1.54 (m, 7H).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:27])[NH:15][C:16](=[O:26])[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg]>CO.C(OCC)(=O)C>[C:1]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:16](=[O:26])[NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1cccc(C2=C(c3cn4c5c(cccc35)CCC4)C(=O)NC2=O)c1
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc([C@@H]2C(=O)NC(=O)[C@H]2c2cn3c4c(cccc24)CCC3)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)-1H-pyrrole-2,5-dione (0.73 g, 2.04 mmol), magnesium (0.89 g, 36.7 mmol) in anhydrous methanol was heated to reflux for 1.5 h. After cooling to room temperature, the light yellow solution was diluted with ethyl acetate (200 mL), washed with 1.0 M hydrochloric acid (2×50 mL), water (100 mL), dried over sodium sulfate and concentrated to provide a light brown solid. The residue was purified by column chromatography on silica gel eluting with 40-50% ethyl acetate in hexane to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)pyrrolidine-2,5-dione as a light yellow solid. Mp 87-91° C.; 1H NMR (CDCl3) 400 MHz δ: 8.73 (s. I H), 7.25-7.30 (m, 1H), 7.14 (d, J-J=7.6 Hz, 1H), 6.93-7.01 (m, 3H), 6.77-6.86 (m, 3H), 4.36 (d, J=6.4 Hz, 1H), 4.24 (d, J=6.4 Hz, I H), 4.18 (t J=5.5 Hz, 2H), 3.78 (s, 3H), 2.97 (t, J=5.6 Hz, 2H), 2.19-2.24 (m, 2H).
Reaction SMILES: [I:1][CH3:2].[CH3:3][C:4]1[N:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:12][C:11]=2[F:20])[N:5]=1>C(O)C>[IH:1].[CH3:3][C:4]1[N:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([S:18][CH3:2])=[NH:19])=[CH:12][C:11]=2[F:20])[N:5]=1
Reactant: Cc1nc(C)n(-c2ccc(NC(N)=S)cc2F)n1
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1ccc(-n2nc(C)nc2C)c(F)c1
Product: I
Temperature: 70 °C
Yield: 100.5 %

Procedure:
Step T (4) [80456-011]: Iodomethane (0.281 mL, 4.51 mmol) was added to a solution of 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)thiourea (1.14 g, 4.30 mmol) in absolute ethanol (50 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed under high vacuum to afford methyl 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenylcarbamimidothioate, hydroiodide (1.76 g, 4.32 mmol, 101% yield) as a grey solid. LC-MS (M+H)+ 280.1.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([CH3:34])[CH2:21][Si:22]([CH3:33])([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[O:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C1CCCCC=1>[Pd].C(O)C>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([CH3:34])[CH2:21][Si:22]([CH3:33])([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[O:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(COc1ccc(C(=O)O)c(O)c1)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
A mixture of 12 g of benzyl 2-hydroxy-4-(2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)-oxy]disiloxanyl]propyloxy]benzoate (0.023 mol), ethanol (40 ml), cyclohexene (12 ml) and 10% palladium-on-charcoal (1.2 g) was maintained at reflux for 1 hour. The mixture was cooled and was rinsed with ethanol. The fluids were concentrated and the resulting product was recrystallized from a 50/50 water/ethanol mixture to give the 2-hydroxy-4-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyloxy]benzoic acid in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH3:20][S:21]SC.Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[S:21][CH3:20])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c(S(=O)(=O)NC(C)(C)C)ccn1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 6.48 g (30 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 150 mL THF under nitrogen atmosphere cooled to -78° C. was added dropwise at such a rate as to keep the temperature below -65° C. 25.52 mL (61.5 mmol) 2.41M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 2.97 mL (33 mmol) of dimethyldisulfide in one portion and the resulting reaction mixture was allowed to warm to room temperature and stir for ca. 1.5 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (20% ethyl acetate/80% hexanes) affording 4.63 g of the title compound as an off white solid, m.p. 116°-119° C.
Reaction SMILES: ON1[C:6](=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(OOC(C)(C)C)(C)(C)C.[CH2:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:3]1([OH:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6]1.[C:3]1(=[O:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6]1.[CH2:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)OOC(C)(C)C
Solvent: C1CCCCCCC1
Product: O=C1CCCCCCC1
Product: OC1CCCCCCC1
Reaction time: 8 h

Procedure:
2 mmol of N-hydroxyphthalimide and 4 mmol of di-tert-butyl peroxide are added at a temperature of 130° C. to 200 mmol of cyclooctane in a round-bottomed flask having an attached reflux condenser. Air at approximately 15 l/h is passed through the reaction mixture for 8 hours at said temperature. Cyclooctanol is obtained at a selectivity of 15% and cyclooctanone at a selectivity of 43%, at a cyclooctane conversion rate of 51%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:18])[N:9]2[CH:12]2[CH2:13][CH2:14][N:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[CH:29][C:21]=3[O:20][CH3:19])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc2N1C1CCNCC1
Reactant: CCOc1ccc(C(=O)O)c(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccc(F)cc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
7-Fluoro-1-(4-piperidinyl)-3,4-dihydrocarbostyril (2.37 g), 2-methoxy-4-ethoxybenzoic acid (2.43 g) and bis(2-oxo-oxazolydinyl)phosphinyl chloride (3.65 g) are dissolved in dichloromethane (50 ml) and thereto is added dropwise triethylamine (4 ml). The mixture is stirred at room temperature overnight and poured into water. The mixture is extracted with dichloromethane, dried with sodium carbonate and then purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1). The resultant is recrystallized from ethanol/water to give 7-fluoro-1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2.5 g) as white powder, m.p. 159°-161° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[NH2:35])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([NH:35][S:2]([CH3:1])(=[O:4])=[O:3])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (12 μL, 0.16 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (49 mg, 0.08 mmol) and triethylamine (24 μL, 0.17 mmol) in dichloromethane (4 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methanesulfonamide which was used without further purification.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)#[CH:9].Cl.CN(C)[CH:23]=[O:24]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]#[C:9][C:9]2[CH:8]=[C:10]3[C:15](=[CH:6][CH:7]=2)[C:23](=[O:24])[CH2:13][CH2:12][CH2:11]3)=[CH:11][CH:12]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(CC(C)C)cc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Cc1ccc(C#Cc2ccc3c(c2)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To cuprous iodide (48 mg), a solution of the compound (353 mg) prepared in Reference Example 06 in N,N-dimethylformamide (3 mL), triethylamine (279 μl) and a solution of 1-ethynyl-4-isobutylbenzene (158 mg) in N,N-dimethylformamide (5 mL) were added, followed by stirring at room temperature for 5 minutes. Next, tetrakis(triphenylphosphine) palladium (0) (58 mg) was added thereto, followed by stirring for 19 hours. After adding 1 N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was successively washed with 1 N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to thereby give the title compound (209 mg) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[N:6][CH:7]=1.O1CCCC1.[OH-].[Li+].Cl>O>[ClH:1].[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:31])=[C:11]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)[CH:12]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NCC2CCN(C(C)C)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(CNc2cc(C(=O)O)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 17 h
Yield: 60.9 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)-4-methoxycarbonylbenzamide (100 mg, 0.225 mmol) in 4:1 tetrahydrofuran:water (2.5 mL) was treated with lithium hydroxide (20 mg, 0.90 mmol). After 17 h, the pH of the mixture was adjusted to 2-3 by addition of 1 N HCl. The mixture was then concentrated and the residue purified by RPHPLC affording 32 mg (30%) of the title compound as a hydrochloride salt.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[C@H:13]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH2:23])[CH2:12][CH2:11]1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>CO>[OH:8][CH2:9][C@@H:10]1[C@H:13]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH2:23])[CH2:12][CH2:11]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1CC[C@@H]1COCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: Nc1ncnc2c1ncn2[C@@H]1CC[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 mL flask with 9-[cis-4-(benzyloxymethyl)-cyclobutyl]adenine (63.2 mg, 0.2 mmol) inside, dry anisole 5 mL was added to give a light yellow solution under argon. In another 10 mL flask with AlCl3 inside, dry anisole 2 mL was added under argon to give a totally clear red solution. This solution was added drop by drop to the first flask to give a red solution. After stirring at ambient temperature for 1 hr, TLC showed no starting material. The reaction mixture was cooled to 0° C. and dry MeOH was added drop by drop until the red color disappeared. The solvents were removed by rotovap to give an off-white solid and this was purified by silica gel flash chromatography (CH2Cl2:MeOH=15:1) to yield a white solid (33 mg, 72.4%, Rf=0.15 (CH2Cl2:MeOH=15:1)).
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C>C(O)=O.CCN(CC)CC>[CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NCc1ccccc1)c1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(NCc1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 23 %

Procedure:
The catalyst of formula 1.3 (10 μmol) was added to N-benzyl acetophenone imine (1 mmol) and tBuOK (5.6 mg, 50 μmol) was added too. Now 0.5 ml of a HCO2H/Et3N (3:2) mixture was added and the solution was stirred under nitrogen at 400 C for 24 h. After 36 h at ambient temperature 23% N-benzyl-1-phenylethylamine had formed.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[CH:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:14][N:13]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)[nH]n1

Procedure:
Benzoyl acetonitrile from part A hereinabove (10.0 g, 68.9 mmole) and hydrazine monohydrate (4.34 mL, 89.6 mmole) were combined in 95% ethanol (90 mL) and refluxed for 1.5 hours. The solvent was evaporated under vacuum and the crystalline subtitled compound, residue was crystallized from chloroform (three crops, 9.49 g, 86%, m.p. 125°-126.5°, lit., m.p. 123°-125°, Taylor, E. C. et al., J. Org. Chem., (1966), 31, page 1818.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH3:10]>Cl.C(Cl)Cl>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8])[CH3:10]
Reactant: CCN1CC2OC2C1
Reactant: CCOc1ccccc1O
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CN(CC)C[C@H]1O

Procedure:
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 22.1 g. (0.16 mole) of o-ethoxyphenol and 3 drops of concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.1 g. (21%) of an oil which crystallized on standing. The solid was recrystallized from cyclohexane to yield a tan solid, m.p. 73°-75° C.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH:15]([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
In an argon atmosphere, 5.70 g (24.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 40 mL of hexane and after adding 2.90 g (49.1 mmol) of isopropylamine, the mixture was stirred at room temperature for 5 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.7×102 Pa) to obtain 1,3-di-tert-butyl-2-isopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHiPr) as a pale yellow liquid (yielded amount: 5.65 g, yield: 90%).