Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)C.C(OCC)(=O)C>O>[F:16][C:13]1([F:17])[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]1
Reactant: O=C(OC1CCC(F)(F)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: OC1CCC(F)(F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 4,4-difluorocyclohexyl benzoate (2.0 g), 1M sodium hydroxide solution (10 mL) and ethanol (20 mL) was stirred at 70° C. for 3 hr. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (1.0 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](=[O:15])C(Cl)(Cl)Cl.C(N([CH2:21][CH3:22])CC)C.[OH2:23]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([O:15][CH2:21][CH3:22])=[O:23]
Reactant: O
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 g (1.84 mmol) of 1-methyl-4-nitro-2-trichloroacetyl-1H-pyrrole are initially charged in 5 ml of ethanol, 0.26 ml (1.84 mmol) of triethylamine are added and the mixture is stirred at RT for 2 h. 5 ml of water are added, the reaction mixture is stirred at 0° C. for 30 min and the precipitate is then filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH2:44][C:45]1[S:46][C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])=[N:48][N:49]=1>C(Cl)(Cl)Cl.O>[C:50]([C:47]1[S:46][C:45]([NH:44][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([CH3:24])[C:18]=2[CH3:23])=[O:42])=[N:49][N:48]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-tert-butyl-1,3,4-thiadiazole (65 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 28 mg of the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:26])[CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.Cl.C(O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[ClH:17].[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[O:9][CH2:8][CH2:7][NH:6][CH2:5][CH:4]2[CH2:3][C:2]([NH2:1])=[O:26])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC(N)=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)CC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in ethyl acetate (0.5 ml) was added 2 N hydrogen chloride-ethanol solution (1 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue was added 1 N hydrochloric acid. The solvent was evaporated under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]1[S:12][CH2:11][S:10](=[O:13])[CH2:9][S:8]1)=[O:4].C(OO)(=[O:16])C>>[CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]1[S:12][CH2:11][S:10](=[O:16])(=[O:13])[CH2:9][S:8]1)=[O:4]
Reactant: CNC(=O)ON=C1SCS(=O)CS1
Reactant: CC(=O)OO
Product: CNC(=O)ON=C1SCS(=O)(=O)CS1
Reaction time: 18 h

Procedure:
2-(Methylcarbamoyloximino)-1,3,5-trithiane-5-oxide prepared by the method of Example IV was further reacted with 5 ml of peracetic acid and left standing for 18 hours at room temperature. Concentrating under reduced pressure yielding 0.15g of a solid residue. Crystallization from acetonitrile yielded a solid, m.p. 174°-177° C (decomp.)
Reaction SMILES: C=O.[BH3-][C:4]#[N:5].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH:27]3[CH:22]([CH2:23][CH2:24][CH2:25][CH:26]3[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)N[CH2:20][CH2:19]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]([N:18]2[CH:27]3[CH:22]([CH2:23][CH2:24][CH2:25][CH:26]3[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:5]([CH3:4])[CH2:20][CH2:19]2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C1CCCC2N1CCCC1
Reaction time: 1.5 h

Procedure:
Formalin (37%, 223 mg, 2.7 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (17.2 mg, 0.27 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (109 mg, 0.27 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred for 1.5 hours. After addition of saturated Na2CO3 solution (12 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off and MeOH was evaporated off from the filtrate under 100 mbar. The aqueous phase was extracted by shaking five times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=16 cm, V=5 ml). A yellowish resin was isolated.
Reaction SMILES: O[C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([O:5][CH3:6])=O.[O-]S(C(F)(F)F)(=O)=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1[C:43](C)=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:45].C1([SH:52])C=CC=CC=1>>[CH3:6][O:5][C:3](=[S:52])[C@H:2]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:45]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC[C@@H](O)C(=O)OC
Reactant: Sc1ccccc1
Reactant: Cc1cccc(C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCCCCCCC[C@H](C(=S)OC)c1ccccc1

Procedure:
Following the procedure of Example 5, (R)-methyl 2-hydroxydecanoate (0.99 gm, 4.90 mmol) was converted to the triflate with triflic anhydride (0.95 ml, 5.65 mmol) and 2,6-lutidine (0.66 ml, 5.63 mmol). The triflate was displaced with thiophenol (0.62 ml, 5.88 mmol) in the presence of TEA (1.57 ml, 11.3 mmol). The desired (S)-methyl-2-phenylthiodecanoate (1.48 g) was purified by silica gel chromatography (1.00 gm, 3.39 mmol, 69%). [α]D =-101.2° (c=1, MeOH). 1H NMR δ7.41 (m, 2H), 7.25 (m, 3H), 3.63 (dd, 1H, J=6.8,8.3 Hz), 3.62 (s, 3H), 1.86 (m, 1H), 1.74 (m, 1H), 1.43-1.24 (m, 12H), 0.86 (t, 3H, J=6.8 Hz).
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[CH2:2][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1

Procedure:
30 g (0.09 mol) of 1-bromo-4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone, 12.4 g (0.18 mol) of 1,2,4-triazole and 24.8 g (0.18 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 6 hours. The mixture is then allowed to cool and is filtered with suction and the mother liquor is concentrated in vacuo. The residue is taken up in methylene chloride and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is recrystallized from diethyl ether. 12.8 g (45.6% of theory of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone of melting point 85° C. are obtained. ##STR10##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:17]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: O=C(Nc1ccc(F)cc1)N1CCNCC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(Cc2ccc3ccccc3n2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid (4-fluoro-phenyl)-amide and 2-quinolinecarbaldehyde. 1H NMR (400 MHz, CDCl3): 8.16 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.74-6.69 (m, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.56-7.52 (m, 1H), 7.32-7.25 (m, 2H), 6.99-6.94 (m, 2H), 6.38 (s, 1H), 3.88 (s, 2H), 3.52 (t, J=5.1 Hz, 4H), 2.60 (t, J=5.1 Hz, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[Br:14][CH2:15][C:16](O)=[O:17]>C(O)(C)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([OH:17])[N:13]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[BrH:14]
Reactant: O=C(O)CBr
Reactant: Nc1nccnc1N1CCOCC1
Solvent: CC(C)O
Product: Br
Product: Oc1cn2ccnc(N3CCOCC3)c2n1
Temperature: 25 °C

Procedure:
Compound 1b (6.0 g, 33 mmol) and bromoacetic acid (5.3 g, 38 mmol) in isopropanol (100 mL) were heated at 90° C. overnight. The reaction mixture was allowed to cool to rt and the solids formed were collected by suction filtration to obtain 8-morpholinoimidazo[1,2-a]pyrazin-2-ol as its HBr salt. This compound was used in next step without further purifications.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[Mn]([O-])(=O)(=O)=[O:20].[K+]>N1C=CC=CC=1>[CH3:18][Si:2]([CH3:1])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([OH:20])=[O:7]
Reactant: CCCCCCCCCC[Si](C)(C)CCCCO
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCCCCCCCCC[Si](C)(C)CCCC(=O)O
Reaction time: 30 h

Procedure:
To a solution of 25.0 g (91.7 mmol; 366.8 electron equivalents) of 5,5-dimethyl-5-sila-n-pentadecanol in 100 ml of pyridine, is added 21.5 g (136 mmol; 408 electron equivalents) of potassium permanganate in 320 ml of pyridine, at 20°-25° with stirring, and stirring is continued for 30 hr. A dark brown precipitate forms which is filtered off (leaving a colorless filtrate). The filter cake is thoroughly washed with methanol and ligroine. The washes and filtrate are combined and concentrated to near dryness. The residue is added to a mixture of water, ice, petroleum ether and dilute hydrochloric acid and the organic phase recovered. The aqueous phase is washed once with petroleum ether, which wash is then combined with the previously recovered organic phase, and the combined organic phases washed thrice with water, dried, and then concentrated to obtain crude title product, which is refined by distillation through a Vigreux column, b.p. 142°-132° at 0.145-0.115 mm Hg.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate (110 mg, 0.30 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (60 mg, 1.50 mmol, 5.00 equiv), and water (2 mL). The resulting solution was stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 50 mg (46%) of 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1.CO>[OH:25][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
At 0° C., sodium tetraborohydride (78 mg, 2 mmol) was added to a solution of ethyl (1-methyl-2-phenyl-1H-indol-3-yl)-oxo-acetate (8a) (630 mg, 2.05 mmol) in a mixture of tetrahydrofuran (10 mL) and methanol (15 mL). The mixture was stirred at room temperature for 2 hours and then hydrolyzed with water. Methanol and tetrahydrofuran were removed under reduced pressure and the residue was diluted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane) to afford the desired alcohol (8b) (440 mg, 1.42 mmol, 69%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1>C(OCC)C.CS(C)=O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1([CH2:14][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH2:4][O:16]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
Sodium hydride (3.78 g, 0.079 mole as 50% dispersion in oil) was suspended, with stirring, in 20 ml of dry diethyl ether. The ether was then removed by decantation, and the sodium hydride was dried in a stream of dry nitrogen. 100 ml of dry dimethylsulphoxide was added followed by 17.34 (0.079 mole) of dry powdered trimethylsulphoxonium iodide, in portions, over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20° C.). 2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloro acetophenone (18.33 g, 0.072 mole) as a solution in 50 ml of dry dimethylsulphoxide was then added. The mixture was heated at 60° C. for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was cooled and quenched in ice. The product was then extracted into ethyl acetate (600 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, and concentrated to give a red gum. Column chromatography of the gum on silica, eluting with ether, gave 6.62 g (34.4%) of the title compound as a gum.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:9][NH:8][N:7]=1.[F:24][C:25]([F:35])([F:34])[C:26](=O)[CH2:27][C:28](OCC)=[O:29]>CCOCC>[OH:29][C:28]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:26]([C:25]([F:35])([F:34])[F:24])[CH:27]=1
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1cc(C(F)(F)F)nc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In an 8 ml acetic acid solution of 1.07 g of 3-amino-4-(4phenylthiophenyl)pyrazole, 0.6 ml of ethyl 4,4,4-trifluoroacetoacetate was added and stirred for 2 hours at 100° C. After allowing to cool, ether was added, and the precipitate was filtered and dried, and the title compound was obtained (200 mg, 13%).
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C@H:20](CC(O)=O)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC([N:67]4CC5C(=CC=CC=5)N[C:68]4=[O:77])CC3)CC=2C=1>>[CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([NH:67][C:68]([N:27]2[CH2:28][CH2:29][CH:30]([CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:43])[CH2:31][CH2:32]2)=[O:77])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2CC1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=C(O)C[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccccc2)C1=O
Product: O=C1Nc2ccccc2CC1C1CCN(C(=O)N[C@@H]2Cc3ccc4[nH]ncc4c3CN(Cc3ccccc3)C2=O)CC1
Yield: 33 %

Procedure:
(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (80 mg, 0.24 mmol) and 3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.33 mmol) were reacted in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 33% yield. MS m/e (M+H)+=542.3. 1H NMR (500 MHz, DMSO-D6): δ=13.01 (s, 1H), 10.11 (s, 1H), 8.21 (s, 1H), 7.36 (d, J=7.93, 1H), 7.17 (m, 1H), 7.11 (m, 2H), 6.91 (m, 1H), 6.83 (d, J=7.63, 1H), 5.35 (d, J=17.09, 1H), 4.61 (d, J=17.40, 1H), 4.38 (m, 1H), 4.02 (m, 1H), 3.83 (s, 1H), 3.55 (t, J=12.36, 1H), 2.95(m, 6H), 2.79(m, 1H), 2.42(m, 1H), 2.31(m, 2H), 1.90(m, 1H), 1.63(m, 2H), 1.17(m, 1H), 0.72(d, J=9.77, 9H).
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([O-:46])=[O:5])[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:39])[CH3:40].[Li+:2]
Reactant: [Li]O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Product: [Li+]
Temperature: 40 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
LiOH.H2O (0.044 g, 1.06 mmol) was added to tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I6) (0.211 g, 0.352 mmol) in THF (10 mL), water (2.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir for 3 hours at 40° C. The volatiles were removed in vacuo and the residue was diluted with EtOAc (100 mL) and 2 M aq. NaOH (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the organic layers were combined, washed with brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (I7) (0.195 g, 96% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 8.61 (s, 1H), 7.64-7.55 (m, 2H), 7.26-7.14 (m, 4H), 6.97-6.91 (m, 2H), 3.65 (s, 2H), 3.50-3.41 (m, 4H), 3.10-2.93 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.32 min; m/z 586.3 [M+H]+.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([NH:9][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([NH:9][C:10]1[C:11]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCCCCCNc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCCCNc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.6 ml, 9.6 mmol) and 3-(4-hexylamino-1,2,5-thiadiazol-3-yl)pyridine (3.2 mmol) in acetone (5 ml) was stirred at room temperature for 18 h and evaporated.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN1CCOCC1.[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56](ON1C(=O)CCC1=O)=[O:57]>Cl.CCOC(C)=O>[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56]([NH:1][C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:57]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NCC(N)=O)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 1.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-Gly-NH2, 10 ml of 4 N HCl-AcOEt, 0.34 ml of NMM and 0.54 g of Z-Pro-OSu in the same manner as in Example 26-(4).