Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[K+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11](=[O:19])[C@H:10]([CH3:26])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10 g of (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1-a, R1=pivaloyl) were dissolved in 150 ml toluene. The mixture was cooled to about 0° C. and 71.5 ml potassium bis(trimethylsilyl)amide solution (0.5 M in toluene) were added. After 15 min, 11 ml dimethyl sulphate were added and the mixture was stirred for a further hour. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were concentrated to dryness to obtain 15.3 g of crude (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one. According to HNMR analysis, on the crude, the ratio of diastereoisomers is 83:17 [(3R,5S):(3S,5S)]. Spectroscopic data for (2-a, R1=Pivaloyl) is reported in Example 5-1, Method 1. Spectroscopic data for (2-b, R1=Pivaloyl) is reported in Example 5-2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[CH3:13].[H-].[Na+].[CH:17]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C.CC(=O)OCC>[CH:17]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH2:12][CH3:13])[CH:7]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCCCC1
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(OCC2CCCCC2)cc(C(C)=O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-(3,5-Dihydroxyphenyl)ethanone (1.0 g) and ethyl bromide (0.531 ml) were dissolved at RT in DMF (20 ml), and sodium hydride (189 mg) was added. After stirring at 50° C. for 2 h, cyclohexylmethyl bromide (1.36 ml) was added, followed by further sodium hydride (315 mg). After stirring at 50° C. for another 2 h, the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-20% within 60 min). 378 mg of the title compound were obtained. LC-MS rt: 2.07 min [M+H]+: 277.2 (met. a)
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])O.[OH:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[S:1]([O:4][CH:13]([CH3:15])[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1)=[O:16])([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:3])=[O:2]
Reactant: OCCn1cccn1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC(C)C(=O)OCCn2cccn2)cc1

Procedure:
5.25 g (0.02 mol) of the S-enantiomer of lactyl chloride tosylate were added to a mixture of 2.24 g (0.02 mol) of 1-(2-hydroxyethyl)-pyrazole, 2 g (0.02 mol) of triethylamine and 50 ml of toluene at 20° C., while stirring. The reaction mixture was stirred at 20° C. for a further 14 hours and then worked up by adding water, extracting the mixture several times with toluene, drying the combined organic phases and concentrating them by stripping off the solvent under reduced pressure. 4.7 g (69.5% of theory) of the S-enantiomer of 2-(pyrazol-1-yl)-ethyl 2-tosyloxy-propionate were obtained in this manner.
Reaction SMILES: [H-].[Na+].[CH2:3](I)[CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[NH:12][C:13](=[O:15])[CH3:14])([O-:8])=[O:7].O>CN(C)C=O>[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[N:12]([CH2:3][CH3:4])[C:13](=[O:15])[CH3:14])([O-:8])=[O:7]
Reactant: CCI
Reactant: CC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Sodium hydride (50% in mineral oil; 1.44 g.), followed by ethyl iodide (3.6 ml.), were added, in small portions during 2 minutes, to a warm stirred solution of 3',5'-dinitroacetanilide (6.75 g.) in dimethylformamide (20 ml.). The mixture was heated on the steam bath for 150 minutes, then cooled, poured into water (400 ml.) and extracted with ethyl acetate (3 × 100 ml.). The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on alumina (150 g.) using benzene as the eluant. The fractions containing the required product were combined, evaporated to dryness and the residue crystallised from ethanol, to give 3',5'-dinitro-N-ethylacetanilide (4.2 g.), m.p. 126°-127°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][OH:21])=[O:13]
Reactant: O=C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Product: O=C(NO)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 67.2 %

Procedure:
According to the procedure of Example 1, 2-[(2,6-dichlorophenyl)amino]benzoic acid (J. S. Kaltenbronn, et al., Arzneimittel-Forschung/ Drug Research, 33(1), 4a, 621-627 (1983)) (4.1 g) is reacted with hydroxylamine hydrochloride (4.04 g) to provide 2-[(2,6-dichlorophenyl)amino]-N-hydroxybenzamide (2.9 g, 67%); mp 171-173° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].O>CN(C)C=O>[ClH:1].[CH3:31][S:32]([O:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1)=[O:33]
Reactant: CS(=O)[O-]
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)OCc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nccs2)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
5-(4-Chloromethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (700 mg) obtained in Example 94 and sodium methanesulfinate (325 mg) were dissolved in dimethylformamide (30 ml) and the mixture was stirred at 80° C. for 1 hr. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and, after drying, the solvent was evaporated. The obtained residue was suspended in acetone (30 ml) and 1 M hydrochloric acid—ether solution (3 ml) was added. The solvent was evaporated and the obtained residue was recrystallized from acetone to give 5-(4-methanesulfinyloxymethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl) imidazole-4-carboxamide hydrochloride (736 mg), melting point 278-282° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(OCC)(=O)C.CCCCCC>[Si:26]([O:33][CH2:34][CH2:35][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[N:10])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: N#CCCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Combine 3-phenylpropionitrile (2.0 g, 15.25 mmol) and tetrahydrofuran (15 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (16.0 mL, 1 M in THF, 16.0 mmol). After 1 hour, add 2-(t-butyldimethylsilyloxy)ethyl iodide (4.58 g, 16.0 mmol). After the addition of 2-(t-butyldimethylsilyloxy)ethyl iodide is complete, warm slowly to ambient temperature over about 7 hours. Add water and extract twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound: Rf=0.50 (silica gel, 10% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].CCN(CC)CC.[C:20](Cl)(Cl)=[O:21].C1(C)C=CC=CC=1>C1COCC1>[CH3:11][C:9]1([CH3:10])[O:12][C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2
Reactant: Cc1ccc(N)c(C(C)(C)O)c1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 14A (11.8 mmol, 1.95 g) in 200 mL THF was added Et3N (29.6 mmol, 4.06 mL) at 0° C. followed by a dropwise addition of a solution of phosgene in toluene (20% solution, 12.19 mmol, 7.9 mL). The reaction mixture was stirred at r.t. overnight It was extracted with Et2O, washed with water and brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo to the desired product (2.14 g, expected wt.=2.25 g) which was used in the next step without further purification. MS (electrospray): mass calculated for C11H13NO2, 191.09, m/z found 192 (100%), [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27](Cl)=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.CO>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:4]4[N:5]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:7](=[O:9])[NH:8][C:3]4=[N:1][N:2]=3)[CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Reactant: NNc1nnc(-c2ccccc2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C2(c3nnc4[nH]c(=O)c(-c5ccccc5)nn34)CC2)cc1
Yield: 70.6 %

Procedure:
To a solution of 3-hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one (40.0 mg, 0.197 mmol) in pyridine (0.5 mL) was added 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (0.062 g, 0.30 mmol) and the resulting mixture was irradiated under microwave at 150° C. for 15 min. The reaction mixture was diluted with methanol and purified by RP-HPLC to afford the desired product (50 mg, 70%). Analytical LCMS: (M+H)+=360.2.
Reaction SMILES: S(Cl)(Cl)=O.CN(C1C=CC=CN=1)C.[F:14][C:15]([F:24])([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:16]=[N:17]O.CC1C=CN=C(N)C=1C>ClCCl>[F:14][C:15]([F:24])([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:16]#[N:17]
Reactant: COCCCC(F)(F)C=NO
Agent: CN(C)c1ccccn1
Agent: Cc1ccnc(N)c1C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCCC(F)(F)C#N
Temperature: -15 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Thionyl chloride (809 mg, 6.8 mmoles) in ice cold dry dichloromethane (7 ml) is added to a solution of dimethylamino pyridine (903 mg, 7.4 mmoles) in dichloromethane (15 ml) kept under nitrogen and cooled at -15° C. The oxime 34 (1.04 g, 6.2 mmoles), dissolved in dichloromethane (20 ml) is added, followed by addition of dimethyl aminopyridine as a solid (903 mg, 7.4 mmoles). The reaction mixture is then allowed to rise to room temperature, kept at 25° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, and finally with water. Concentration of the organic phase, previously dried over sodium sulfate, (30° C., 100 mm Hg) affords the title compound (620 mg) which is purified by bulb to bulb distillation (50° C., 30 mm Hg): 485 mg (52%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1C(O)=O.C1C=CC(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[NH2:35][C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (5.00 g, 17.6 mmol), DPPA (5.67 mL, 26.4 mmol) and Et3N (3.65 mL, 26.4 mmol) in toluene (35 mL) was heated to 100° C. for 2 h. To the mixture was added 8 M NaOH aqueous solution (22 mL) at 0° C. The mixture was stirred at room temperature for 2 h, diluted with brine, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc/i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and washed with EtOAc/hexane to yield the title compound (2.50 g, 56% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): 8 ppm 6.17 (1H, d, J=7.5 Hz), 6.52 (2H, brs), 7.67-7.81 (2H, m), 8.04 (1H, d, J=7.5 Hz), 8.10 (1H, s), 8.75 (1H, d, J=7.5 Hz).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12.CO.O.O[Li].O>C1COCC1>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nsnc3c2)c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nsnc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.22 g, 0.479 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (60.3 mg, 1.438 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methyl pentanoic acid (105 mg, 50.0%) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 8.18 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 3.68 (t, 1H), 3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([O:31][CH2:32][C:33]([O:35]C)=[O:34])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:37](=[O:39])[NH2:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([O:31][CH2:32][C:33]([OH:35])=[O:34])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:37](=[O:39])[NH2:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cc(-c2ccc(C(F)(F)F)cc2)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of the {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (101 mg, 0.19 mM) and 0.95 mL (1.9 mM) of 2 N NaOH in 9.5 mL of ethanol was stirred for 30 minutes at 25° C. The reaction was acidified with 1N HCl to pH=2. After stirring 30 minutes, the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 73 mg (75%) {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ11.0 (bs, 1H), 8.0 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.8 (bs, 1H), 7.7 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.4 (m, 2H), 7.3-7.1 (m, 6H), 7.0 (s, 1H), 5.8 (s, 2H), 5.0 (s, 2H). MS (ES) m/e 502,519.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:27]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30]>CN(C=O)C.CCOC(C)=O>[N:27]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:30]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
Next, 1.34 g (2.5 m moles) of H-Phe-Arg(NO2)-CHA was dissolved in 10 ml of 0.75N-NEM/DMF, to this solution was added 0.84 g (2.5 m moles) of BOC-D-Pro-SDP at 0° to 5° C. and reacted at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with 150 ml of AcOEt, and washed 4 times with 50 ml of cold 5% hydrochloric acid, and washed twice with 50 ml of an aqueous solution saturated with sodium chloride, then decolored and dried with activated carbon and anhydrous magnesium sulfate. After drying, magnesium sulfate and activated carbon were removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure to obtain crude product of BOC-D-Pro-Phe-Arg(NO2)-CHA, recrystallized from AcOEt to obtain 1.2 g (85.9%) of BOC-D-Pro-Phe-Arg(NO2)-CHA.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[C:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O:25]CC)=[O:24]>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][C:23]([OH:25])=[O:24])=[CH:31][CH:32]=3)=[CH:17][C:6]([C:7](=[O:8])[NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: O=C(O)CCc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)cnc2OCC2CC2)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-bromo-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and 4-(2-carbethoxyethyl)benzene-boronic acid (commercially available) as starting materials to give the product as white solid, MS (ISP): 437.2 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])/[CH:26]=[CH:27]/[CH2:28][CH3:29]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:12]1[CH2:17][CH2:16][N:15]([C:25](=[O:30])/[CH:26]=[CH:27]/[CH2:28][CH3:29])[CH2:14][CH2:13]1
Reactant: CC/C=C/C(=O)Cl
Reactant: Cc1cccc2c(N3CCNCC3)ccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2ccnc3c(C)cccc23)CC1
Yield: 9 %

Procedure:
8-Methyl-4-piperazin-1-yl-quinoline (22.7 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (1 ml of a 0.12 M solution in dichloromethane) followed by a solution of (E)-pent-2-enoyl chloride (1 ml, 0.12 M in dichloromethane). The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 2.8 mg of a solid (0.009 mmol, 9%).
Reaction SMILES: [OH-:1].[Na+].O=[C:4]1[CH2:11][C:8]([CH3:10])([CH3:9])[CH2:7][C:6]([CH3:12])=[CH:5]1.C([O-])([O-])=O.[K+].[K+].[CH:19]#[N:20]>[OH-].[Na+].C([O-])([O-])=O.[K+].[K+].CN(C)C=O>[CH3:9][C:8]1([CH3:10])[CH2:7][C:6]([C:19]#[N:20])([CH3:12])[CH2:5][C:4](=[O:1])[CH2:11]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C#N
Reactant: [OH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)CC(C)(C#N)C1
Yield: 53.7 %

Procedure:
The applicant of published Japanese application JP-A 57-116038 attempted to improve the method cited referring to the previously evaluated DE-AS 10 85 871 and DE-PS 12 40 854. According to the comparison tests disclosed in the Japanese document, a yield of 53.7% was obtained using a methanolic NaOH solution as catalyst (0.9 ml 15% NaOH per 204 g isophorone) after a total reaction time of 4.5 hours and a yield of 71.1% was obtained using K2CO3 as catalyst (4.9 g K2CO3 per 192.2 g isophorone) and also using dimethylformamide. In contrast published Japanese application JP-A-116038 teaches the reaction of hydrogen cyanide in the presence of basic catalysts such as e.g. alkali-metal cyanides, -carbonates, -oxides, -hydroxides and -alcoholates, and glycols with isophorone. The glycols are added in an amount 1 to 50 times greater than the catalyst. High yields of isophorone nitrile are disclosed in the examples, but the reaction times using sodium and potassium carbonate or sodium cyanide are in the range of the methods already previously known at the time. The space-time yield thus continued to remain unsatisfactory. As a result of the use of glycols, the workup becomes more expensive and the economy is reduced.