Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:24]=[CH:23][N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=1.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O.O>C1COCC1.CN(C1C=CN=CC=1)C>[C:39]([O:38][C:36]([N:22]1[CH:23]=[CH:24][C:20]([Br:19])=[CH:21]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of TBAF (1.0 M in THF, 3.6 mL) was added to a solution of 3-bromo-1-triisopropylsilanyl-1H-pyrrole (1.0 g, 3.308 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 30 minutes. (BOC)2O (0.866 g, 3.965 mmol) and DMAP (40 mg, 0.3308 mmol) were added to the reaction and the resulting mixture was stirred for 2 additional hours. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and with brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc) to give 0.197 g (24% yield) of 3-bromo-pyrrole-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH3:10])[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a stirred mixture of 5-bromo-3-methylthiophene-2-carboxylic acid (1.70 g, 7.69 mmol), 1-hydroxybenzotriazole (1.56 g, 11.54 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.21 g, 11.54 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added N,N-diisopropylethylamine (4.10 mL, 23.54 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.78 mL, 7.69 mmol). The resulting reaction mixture was stirred at ambient temperature for 16 h, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 7% methanol in dichloromethane to afford 5-bromo-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide as an off-white solid (1.92 g, 80%): MS (ES+) m/z 311.1 (M+1), 313.1 (M+1).
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CC(=O)O
Product: Ic1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Over a period of 15 minutes samples of iodine (8.62 grams, 0.034 mol) and silver benzoate (7.78 grams, 0.034 mol) were added in portions to a magnetically stirred solution of 5 grams of 1-phenylpiperazine in 80 mL acetic acid. The mixture stirred for 1hour. The solvent was evaporated and the residue partioned between 150 mL diethyl ether and 150 mL 2N sodium hydroxide. The organic layer was washed with 100 mL water, 100 mL brine, then dried over potassium carbonate and concentrated in vacuo to yield 1.0 gram (11%) of 1-(4-iodophenyl)-piperzine (110°-115° C.). the material obtained was used without further purification. 1H NMR (CDCl3, dTMS) 7.51 (2H, d, 3JHH =9 Hz, m-ArH), 6.69 (2H, d, 3JHH =9 Hz, o-ArH), 3.17 (4H, m), 3.04 (4H, m), 13C NMR (CDCl3) 151.36, 137.73, 118.05, 81,35, 49.92, 45.95.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C([Sn](CCCC)(CCCC)[C:13](=[CH2:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Cl>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:13](=[CH2:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:3]1
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1ccc(I)n1
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)c1ccn(C)n1
Temperature: 55 °C
Yield: 67.8 %

Procedure:
To a solution of 0.30 g (1.4 mmol) of 3-iodo-1-methyl-1H-pyrazole in 3 mL of anhydrous THF was added a solution of 0.82 g (1.8 mmol) of benzyl 2-(tributylstannyl)acrylate from step B above in 1 mL of anhydrous THF, 0.18 g (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.14 g (1.4 mmol) of copper (I) chloride. The reaction mixture was heated to 55° C. for 12 h, cooled and evaporated to dryness under reduced pressure. The residue was dissolved in 10 mL of a 1:1 mixture of hexane and EtOAc then filtered through a pad of Celite®. The pad was washed with 15 mL of a 1:1 mixture of hexane and EtOAc and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-80% EtOAc in hexanes gradient to afford the title compound as a colorless oil (0.23 g, 66%). LC-MS: m/z (ES) 265 (M+Na)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(OCC)C>[N:17]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCN3CCOCC3)cccc21

Procedure:
4-Bromobutylphthalimide (564 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([C@@H:24]([C:33](=[O:36])[NH:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C@@H:24]([N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:33](=[O:36])[NH:34][CH3:35]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
N-((1R)1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (0.85 g; 1.63 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 15 min at room temperature. Methylene chloride (25 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.669 g of (2R)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][NH:24][CH2:23][C:22]=3[C:18]=2[CH:17]=1.O>N1C=CC=CC=1>[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][N:24]([S:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])(=[O:13])=[O:12])[CH2:23][C:22]=3[C:18]=2[CH:17]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(OC)c(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,5-Dimethoxybenzenesulfonyl chloride (63 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 36 (94 mg, 96% yield) as a yellow solid. LC-MS (M+H=408, obsd.=408).
Reaction SMILES: O[CH:2]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])[CH2:3][CH2:4][CH3:5]>CCCCCC.C(OCC)(=O)C>[CH2:2]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:29])([CH3:31])[CH3:30])[C:7]=1[CH3:33])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 33 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Examples 90 and 91, the title compound was synthesized in the same manner as in Example 23. Yield: 33%. Melting point: 149-151° C. (hexane-ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:15][CH2:14][CH2:13][NH:12][C:4]1[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: OCCNc1nc(Cl)nc2c1SCCC2
Product: CN1CCN(c2nc3c(c(NCCO)n2)SCCC3)CC1
Yield: 95.3 %

Procedure:
In the same manner as described in Example 20, 6 g of 2-chloro-4-(2-hydroxyethyl)amino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was reacted with 15 g of N-methylpiperazine to obtain 7.2 g of 4-(2-hydroxyethyl)amino-2-(N-methylpiperazino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine which was then recrystallized from methanol-diethyl ether. Colorless prisms. Melting point: 162°-164° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17][CH3:18])=[O:16]>CC(O)=O.[Pd]>[CH2:6]1[C:5]2[C:10](=[CH:1][C:2]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][CH:4]=2)[CH2:9][CH2:8][CH:7]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCC(C(=O)OC)C2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of dimethyl naphthalene-2,6-dicarboxylate (25.0 g, 102 mmol) and 5% Pd—C (5.0 g) in AcOH (75 mL) was shaken under an atmosphere of hydrogen (ca. 150 p.s.i.) at 80° C. for 6 h. The reaction mixture was cooled, purged with argon, and filtered through a pad of Celite, washing with AcOH. The filtrate was concentrated under reduced pressure to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:19][C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:10](/[CH:11]=[N:12]/[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][C:21]1[C:20]([CH3:19])=[N:24][O:23][N:22]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(C=NOCC2CC2)c1Cl
Reactant: Cc1nonc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1ccc(Cl)c(/C=N/OCC2CC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
400 mg (1.39 mmol) of 2,4-dichloro-3-{[(cyclopropylmethoxy)imino]methyl}benzoic acid and 14418 mg (1.39 mmol) of 4-methyl-1,2,5-oxadiazole-3-amine were dissolved in 10 ml of CH2Cl2, 1.33 g (2.08 mmol) of propanephosphonic anhydride were added at 10-20° C. and the mixture was stirred at RT for 1 h. 700 mg of triethylamine and 34.6 mg (0.278 mmol) of DMAP were then added, and the mixture was stirred at RT for 2 days.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][OH:11]>N1C=CC=CC=1.O>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CCCC(CO)CCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(CCOS(C)(=O)=O)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride (16.95 g) was added dropwise to a stirred solution of 3-hydroxymethylhexan-1-ol (8.94 g) in pyridine (39.5 g), maintaining the temperature at less than 5° C. Following the addition, the reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with water and extracted with dichloromethane. The extracts were washed successively with water, dilute hydrochloric acid (X 2), water, aqueous sodium bicarbonate, and water, then dried over magnesium sulphate and concentrated to give 3-methanesulphonyloxymethylhex-1-yl methanesulphonate. (16.13 g, 83%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([NH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=2)[C:19]([NH2:21])=[O:20])=[O:12])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To solution of (4-nitro-phenoxy)-acetic acid (50 mg, 0.25 mmol), 2-amino isonicotinamide (52 mg, 0.37 mmol) and DMAP (62 mg, 0.5 mmol) in DMF 6 ml was added PyBOP (684 mg, 1.31 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtOAc:n-Hexane:MeOH=1:2:1˜1:2:2) to afford 2-[2-(4-nitro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.04 g, 50% yield).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[C:45]([OH:49])=[C:44]([Br:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1.C(O)=O>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[C:45]([OH:49])=[C:44]([Br:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: O=C(O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.4 mg (0.06 mmol) LiOH in 1 mL water was added to a solution of 30 mg (0.04 mmol) of (R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 138) in 3 mL THF and the reaction solution was stirred overnight at RT. The solvent was eliminated in the nitrogen current, the residue was taken up in 1 mL water, acidified with formic acid, the precipitate formed was removed by suction filtering and dried in vacuo.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[F:26]>CC(C)=O>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(NCCN2CCCCC2)c(F)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-(piperidin-1-yl)ethanamine (0.90 g, 7.02 mmol) and K2CO3 (0.97 g, 7.02 mmol) in acetone (30 mL) was added 1,2-difluoro-4-nitrobenzene (1.11 g, 6.98 mmol) in one portion in an ice bath and the mixture was refluxed overnight, cooled to rt and filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: Fc1cncc(Br)c1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-bromopyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=374.3 (M+H+).
Reaction SMILES: [Br-:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:15][CH2:14][N+:13]3([CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]=4[N+:24]([O-])=O)[CH2:16]3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl-].[Ca+2].[Cl-]>[Zn].C(O)C.O>[Br-:1].[NH2:24][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH2:23][N+:13]1([CH2:16]2)[CH2:12][CH2:11][CH:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc2c1C[N+]1(CCC(Cc3ccc(F)cc3)CC1)C2
Agent: [Br-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1C[N+]1(CCC(Cc3ccc(F)cc3)CC1)C2
Reaction time: 5 h
Yield: 84.1 %

Procedure:
1,3-Dihydro-4′-[4-fluorophenylmethyl]-4-nitro-spiro[2H-isoindole-2,1′-piperidinium] bromide (1.03 g, 2.46 mmol, 1.0 eq), zinc (5.32 g, 81.5 mmol, 33.0 eq), and calcium chloride (0.18 g, 1.60 mmol, 0.65 eq) were refluxed under N2 in 25 ml of a 78% ethanol/water solution. The reaction was worked up after 5 hours by filtering through Celite® and rinsing the cake with methanol. The filtrate was concentrated in vacuo to a mixture of water and an amber oil. The mixture was dissolved in 50 ml of 2-propanol, and concentrated in vacuo to remove excess water. The resulting yellow foam was dissolved in methanol and applied to a 3.5 cm×5 cm quartz column via silica plug. The product was eluted with 20% MeOH/CHCl3 to yield 0.81 g of a yellow foam. NMR (300 MHz, DMSO) δ7.27-7.05 (m, 5H), 6.61-6.53 (m, 2H), 5.43-5.41 (m, 2H), 4.80 (bs, 1H), 4.74 (bs, 2H), 4.63 (bs, 1H), 3.62-3.43 (m, 4H), 2.60 (bd, 2H, J=7 Hz), 1.98-1.59 (m, 5H).
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]#[C:14][Si](C)(C)C)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]#[CH:14])[CH:7]=2)[CH3:19])[CH2:3][CH2:2]1
Reactant: Cc1ccc(CN(C)C2CC2)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CN(C)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of cyclopropyl-methyl-(4-methyl-3-trimethylsilanylethynyl-benzyl)amine (Intermediate 98, 0.95 g, 3.5 mmol) in methanol (10 mL) was treated with potassium carbonate (2.3 g, 16.6 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.67 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:23])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:33](=[O:35])[CH3:34])=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}methanamine (0.2 g) and triethylamine (0.08 g) in tetrahydrofuran (5 mL), acetyl chloride (0.05 g) was added dropwise and the mixture was stirred for one hour at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide (0.05 g).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[OH-].[K+].Cl[CH:18]([F:20])[F:19].O>CC(O)C>[F:19][CH:18]([F:20])[O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: FC(F)Cl
Reactant: Cc1c(C(F)(F)F)nn(C(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C(C)C)c1OC(F)F
Reaction time: 2 h
Yield: 75 %

Procedure:
Into 17.1 g (82.1 mmol) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole in 100 ml of 2-propanol was added 23.0 g (410.7 mmol) of powdery potassium hydroxide at room temperature, followed stirring. Furthermore, stirring was continued while an excess amount of chlorodifluoromethane was introduced into the reaction solution. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 15.9 g (yield: 75.0%) of 5-difluoromethoxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.