Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
5-Formylindole (500 mg, 3.44 mmol) was dissolved in acetonitrile (10 mL), and the solution was added with 1-(tert-butoxycarbonyl)piperazine (961 mg, 5.16 mmol), acetic acid (3.90 mL, 68.1 mmol) and sodium triacetoxyborohydride (3.65 g, 17.2 mmol) little by little, followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and sodium carbonate to adjust the pH to 9, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=19/1, 7/3, 1/1) to obtain 5-[4-(tert-butoxycarbonyl)piperazin-1-ylmethyl]indole (505 mg, yield 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:45]1[CH2:50][CH2:49][CH2:48][CH:47](O)[CH2:46]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:47]2[CH2:48][CH2:49][CH2:50][O:45][CH2:46]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: OC1CCCOC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCOC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg (0.691 mmol) rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 257 mg (0.864 mmol) triphenylphosphine and 84.7 mg (0.829 mmol) tetrahydro-pyran-3-ol in 8.5 ml tetrahydrofuran were added 191 mg (0.829 mmol) di-tert-butyl azodicarboxylate and the reaction mixture stirred at ambient temperature for 2 hours. Then the reaction mixture was evaporated and purified by flash chromatography on silica gel with a heptane/ethyl acetate gradient of 0-30% ethyl acetate. The title compound was obtained as colorless solid: MS (ISN): 444.2 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CO.C(OCC)C>[CH3:15][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(I)cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C=Cc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 4-iodo-cinnamic Acid in methanol was treated with a solution of diazomethane in diethyl ether. The reaction mixture was allowed to warm to ambient temperature, the volatiles were-evaporated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C[Si]([C:43]#[N:44])(C)C.CN(C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:43]([C:34]1[CH:35]=[C:30]([CH:3]([O:4][C:5]2[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:31]=[CH:32][N:33]=1)#[N:44]
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccnc(C#N)c1)C(F)(F)F
Yield: 102.1 %

Procedure:
Compound B4 (210 mg, 0.367 mmol) obtained in Step 1 was dissolved in dichloromethane (4 mL). To the solution were added trimethylsilyl cyanide (0.25 mL, 1.8 mmol) and dimethylcarbamoyl chloride (0.17 mL, 1.8 mmol), and the mixture was refluxed for 24 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound B5 (218 mg, 100% yield).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9].[Br-:16]>>[Br:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9]
Reactant: CCCCCNC(=O)NCCCCCO
Reactant: [Br-]
Product: CCCCCNC(=O)NCCCCCBr

Procedure:
Following the protocol described above, 1-(5-hydroxypentyl)-3-n-pentylurea (1.30 g, 6.02 mmol) was converted into the corresponding bromide (1.45 g, 87%), obtained as a colorless oil. TLC: EtOAc/hexanes (2:3), Rf˜0.40; 1H NMR (300 MHz) δ 4.44 (br s, —NH, 2H), 3.40 (t, J=6.7 Hz, 2H), 3.10-3.20 (m, 4H), 1.82-1.92 (m, 2H), 1.40-1.58 (m, 6H), 1.24-1.38 (m, 4H), 0.89 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 159.46, 40.02, 33.88, 33.02, 30.29, 29.92, 29.36, 25.83, 22.12, 14.02. HRMS calcd for C11H24BrN2O [M+1]+ 279.1072. found 279.1073.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([OH:19])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:25][CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=3)=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Reactant: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a mixture containing 5,6-diphenyl-2-pyrazinol (2.45 g), 4-[2-(methanesulfonyloxy)ethoxy]benzaldehyde (2.44 g), and potassium carbonate (1.8 g), dimethylformamide (100 mL) was added. The resultant mixture was heated at 100° C. on an oil bath for two hours under stirring, and the reaction mixture was poured into an ice-water mixture. The thus-formed organic matter was separated through extraction by use of ethyl acetate, followed by washing sequentially with water and saturated saline. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column and crystallized from n-hexane, to thereby yield 3.34 g of the title compound (yield 85.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1cncc(Br)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-bromo-5-methylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Product: COc1ccc(NC(C)=O)cc1Br

Procedure:
By the reaction in the same manner as in Example 33-(i) using 2-bromo-4-nitroanisole (5.41 g), iron powder (6.49 g) and acetic anhydride (4.4 ml), the title compound (4.87 g) was obtained as a colorless powder crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3].[C:24]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)(=[O:28])[C:25]([CH3:27])=[CH2:26].[F:34][CH:35]=[C:36]([CH3:40])[C:37]([O-:39])=[O:38].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:34][CH:35]=[C:36]([CH3:40])[C:37]([OH:39])=[O:38].[CH2:30]([O:29][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[CH:31]1[O:33][CH2:32]1.[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=CF)C(=O)[O-]
Agent: C=C(C)C(=O)OCC1CO1
Agent: C=CC(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC(=CF)C(=O)O

Procedure:
To the above solvent, a mixture of 200 g of stearyl acrylate, 20 g of glycidyl methacrylate, 5 g of fluoromethacrylate having the following formula and 3 g of azobisisobutyronitrile was added dropwise at a constant speed over a period of 5 hours at 90° C. to complete the polymerization reaction. Thus, stearyl acrylate - glycidyl methacrylate - fluoromethacrylate copolymer was obtained. ##STR14##
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[S:9]1[CH2:14][CH2:13][CH:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1>C1COCC1>[O:16]=[C:15]([CH:12]1[CH2:13][CH2:14][S:9][CH2:10][CH2:11]1)[CH2:1][C:2]#[N:3]
Reactant: COC(=O)C1CCSCC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCSCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A solution of CH3CN (48.7 mmol, 2.54 mL) in 10 mL of THF was added dropwise to a solution of nBuLi (48.7 mmol) in 15 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of methyl tetrahydro-2H-thiopyran-4-carboxylate (24.3 mmol, 3.90 g) in 10 mL of THF was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, and then slowly warmed to −40° C. in 2 h. The reaction was quench with 1 N HCl (pH<1). THF was removed and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes) to afford 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (3.60 g, 87.5%) as a light brownish oil. LCMS tR=1.29 Min. Mass calculated for, M+ 1694.1, observed LC/MS m/z 170.1 (M+H)
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([O-:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[NH2:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12>>[O:1]([CH:8]([CH3:12])[C:9]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Oc1ccccc1)C(=O)[O-]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: [Li+]
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)Oc3ccccc3)[C@H]2SC1

Procedure:
The procedure of Example 1 was repeated using 1.9 g of lithium α-phenoxypropionate and 2.14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid. 7-(α-Phenoxypropionamido)-3-methyl-3-cephem-4-carboxylic acid was obtained as a colorless crystalline product in a yield of 3.22 g (95%, mp. 145° C (dec.). This product showed the infra-red and ultra-violet absorption spectra which were entirely coincident with those of the authentic sample.
Reaction SMILES: [Br-:1].[K+].C1OCCOCCOCCOCCOCCOC1.ClC1C=C(C=CC=1)C(OO)=O.[CH:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])([CH3:34])[CH3:33]>C(Cl)Cl>[Br:1][C:39]1[CH:38]=[CH:37][C:36]([O:41][CH3:42])=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:40]=1
Reactant: [Br-]
Reactant: COc1ccccc1C(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a suspension of potassium bromide (18.8 g, 157.7 mmol) in 400 mL of methylene chloride at 0° C. were added 18-Crown-6 (2.08 g, 7.88 mmol), 3-chloroperoxy benzoic acid (27.2 g, 157.7 mmol) and 2-isopropylanisole (12.0 g, 78.8 mmol). After stirring for 3 hours at 0° C., the reaction mixture was poured into ice water (500 mL), and stirred for 30 minutes. The organic layer was separated, washed with saturated NaHCO3 solution (400 mL), followed by water (300 mL), and dried (MgSO4). The solvent was evaporated to give an oil, which was purified by flash column chromatography (silica gel, 98:2 hexane/ethylacetate) to give 13 g (56.7 mmol, 72%) of 4-bromo-2-isopropylanisole (3) as an oil; 1HNMR (CDCl3) δ 1.2 (d, 6H), 3.3 (heptet, 1H), 6.7 (d, 1H), 6.84 (d, 1H), 7.29 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Cl:11])=[C:9]([Cl:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2-thiophenecarboxylic acid ethyl ester (5.27 g). 5-Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4,5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60° C. for 15 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17]Cl.C(OCC)C>CN1CCCC1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][O:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: ClCCOCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(Cl)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a solution of the NaH (60% by weight, 4 g, 98 mmol) and 1-methylpyrrolidin-2-one (82.5 mL) at −20° C., was added dropwise a mixture of 2-(4-chlorophenyl)acetonitrile (5 g, 33 mmol) and 2-chloroethyl chloromethyl ether (4 mL, 33 mmol) in diethyl ether (16.5 mL, 33 mmol). The mixture was allowed to warm to room temperature over 24 hours. The reaction was then slowly quenched with ice water and extracted with ether (3×). The organic layers were combined, washed with H2O (3×) and brine, dried over Na2SO4, concentrated in vacuo, and purified by silica flash chromatography (13% EtOAc/hexane) to give the desired compound as a yellow oil. MS m/e=208.0 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>O1CCCC1>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CC(O)CN
Reactant: O=C(O)c1cccnc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)CNC(=O)c1cccnc1
Temperature: -4 °C
Reaction time: 2 h

Procedure:
To 4.29 g (0.039 mol) of nicotinic acid suspended in 120 mL of dry tetrahydrofuran, 4.04 g (0.039 mol) of freshly distilled triethylamine was added in one portion. The resultant clear solution was cooled to -4° C. in an ice bath under argon. Ethyl chloroformate (4.33 g, 0.039 mol) in 25 mL of tetrahydrofuran was added at such a rate that the temperature of the solution did not exceed 0° C. Then, 3 g (0.039 mol) of 1-amino-2-propanol were added directly to the cold reaction mixture. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The oily residue was washed several times with anhydrous ether and allowed to stand. The title compound was obtained as a white, hygroscopic, low-melting, waxy solid melting at 40° C. (6.11 g, 85%) and having the formula ##STR116##
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:29]=1
Reactant: O=C(O)c1nc(C2CCCCC2)oc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nc(C3CCCCC3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H25F3N4O3 (m/e) 426, obsd 427 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1ccccc1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and phenylboronic acid (Aldrich, Buchs, Switzerland, 16.5 mg, 0.135 mmol) to give the title compound as a white solid. (HPLC: tR 2.70 min (Method A); M+H=370 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.16 (s, 1H), 8.11-8.06 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.53 (m, 1H), 7.50-7.44 (m, 4H), 7.42-7.34 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1F)([O-:14])=[O:13]>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:16]1[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
15.7 Grams (0.1 mole) of 1-methyl-2-hydroxymethyl-5-nitro-imidazole and 21.0 g (0.1 mole) of 2-nitro-4-trifluoromethylfluoro-benzene dissolved in 100 ml of butanone-2 were mixed with 15 g of triethylamine and were heated for 2 hours on a steam bath. The crystals obtained when the solution had been cooled were suction-filtered, were washed with water and were recrystallized from a little isopropanol, while adding charcoal. As a result, 25 g (= 72% of the theory) of 1-methyl-2-(4-trifluoromethyl-2-nitrophenoxymethyl)-5-nitro-imidazole were obtained in the form of yellowish crystals having a melting point of 126° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C@@H:12]([CH:36]([CH3:39])[CH2:37][CH3:38])[C:13]([NH:15][C:16]1([C:33]([OH:35])=O)[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:14])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:73][O:74][NH:75][C:76](=[O:83])[C@@H:77]([NH2:82])[CH:78]([CH3:81])[CH2:79][CH3:80]>CN(C=O)C>[CH3:73][O:74][NH:75][C:76]([C@@H:77]([NH:82][C:33]([C@:16]1([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:36]([CH3:39])[CH2:37][CH3:38])[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:35])[CH:78]([CH3:81])[CH2:79][CH3:80])=[O:83]
Reactant: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)NC1(C(=O)O)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Reactant: CCC(C)[C@H](N)C(=O)NOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](C(=O)NOC)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.500 g (0.91 mmol) of (R/S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (synthesized in according to WO 2006/005484), 0.521 g (1.37 mmol) of HATU and 2.0 mL (11.76 mmol) of DIPEA were dissolved in DMF and stirred for 30 min at room temperature. 0.220 g (1.37 mmol) of (S)-2-Amino-3-methyl-pentanoic acid methoxy-amide were added and the reaction mixture and heated at 110° C. for 3 h. The solvent was removed under vacuum and the residue was purified by high performance liquid chromatography.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:9][N:8]=1.C1COCC1.[NH3:30].C1COCC1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:30])=[O:2])=[N:8][N:9]=[C:10]2[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: COC(=O)CCCc1nnc(-c2nccs2)c2cc(OC)ccc12
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc2c(CCCC(N)=O)nnc(-c3nccs3)c2c1
Temperature: 85 °C
Yield: 73.1 %

Procedure:
A suspension of 4-(6-methoxy-4-thiazol-2-yl-phthalazin-1-yl)-butyric acid methyl ester (1.2 g, 3.5 mmoles), prepared as described in example 115, in NH3/THF (10 ml) was added with THF (15 ml), then placed in autoclave at 85° C. After 1 night the mixture was dried, taken up in CH3OH (30 ml) and saturated with NH3 at 0° C., then heated at 85° C. for 44 hours. The mixture was cooled and dried to give a residue which was chromatographed (eluent: CH2Cl2/CH3OH 95:5 to 90:10). The solid was triturated in CH2Cl2 to give 840 mg of the title compound (yield: 73.1%)