Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15](=O)[NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:32]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:32][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.4 mmol) and ammonia acetate (3.7 g, 20 eq.) in Xylene (2 mL) was heated in microwave at 110° C. for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, containing 15% starting material, yield 35%). LCMS-ESI−: calc'd for C19H21BrN4O2: 417.30. Found: 418.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]#[CH:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:42]#[C:41][CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: CC(C)(C)OC(=O)NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to N-(tert-butoxycarbonyl)propargylamine (Aldrich, St. Louis, Mo.) to afford tert-butyl (3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)carbamate after purification via column chromatography on silica gel (10 to 40% EtOAc in hexanes). 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.08 (dd, J=1.00, 5.09 Hz, 1H), 7.69 (dd, J=0.98, 3.72 Hz, 1H), 7.51-7.56 (m, 2H), 7.32 (dd, J=3.91, 4.89 Hz, 2H), 7.07 (d, J=9.39 Hz, 1H), 3.94 (d, J=5.48 Hz, 2H), 3.26-3.29 (m, 4H), 3.12-3.18 (m, 4H), 1.40 (s, 9H); m/z (ESI, +ve ion) 628.1 (M+H)+. GK-GKRP IC50 (Binding)=0.695 μM.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1 g of caffeic acid was dissolved in 25 mL of dimethylsulfoxide. 0.77 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 1.10 mL of phenethyl bromide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 75 mL of cold water and extracted with ethyl acetate (3×60 mL). The combined organic extract was washed with 50 mL of 5% HCl and water (60 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 760 mg and the purity was greater than 90%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:34]([C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[O:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[N:18]([S:34]([C:37]3[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)=[O:44])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)Nc2ccccn2)cc1
Yield: 71.7 %

Procedure:
2-[[ [3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) dissolved in 20 ml of dichloromethane and 0.2 ml of triethylamine was added to 170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized to give 237 mg of the titled product. M.P. 78-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22][CH2:23][C:24]([O:26]CC=C)=[O:25])=[O:21])=[C:9]2[CH3:30])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>[Pd].C1(C)C=CC=CC=1>[CH3:30][C:9]1[N:8]([C:6]([C:5]2[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[C:10]=1[CH2:19][C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: C=CCOC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
31.9 g of acemetacin allyl ester, 100 ml of toluene, 2.3 g of triphenylphosphine and 0.75 g of palladium on charcoal (5% strength) are taken as an initial charge, under nitrogen. 11.9 g of piperidine are added dropwise, with stirring, and the mixture is then stirred for a further 3 hours at 90° C. It is filtered hot and the catalyst is rinsed with hot toluene. The filtrate is evaporated, the residue is taken up in methylene chloride (about 300 ml) and this solution is washed with half-concentrated hydrochloric acid (100 ml) and then with water. After removal of the solvent in vacuo, the residue is recrystallized from toluene.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:26][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:15]2[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=2)=[O:18])[CH2:21][CH2:22]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Product: CN1CCC(NC(=O)c2cccc3nc(-c4ccccc4)oc23)CC1
Yield: 58 %

Procedure:
N-(1-Methylpiperidin-4-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 4-amino-1-methylpiperidine using the method outlined in Step C of Example 7. This compound was obtained in 58% yield and obtained as a white solid: mp 209-210° C.; 1H NMR (300 MHz, CDCl3) δ 8.22 (m, 1H), 8.21 (dd, J=5.7, 1.8 Hz, 1H), 8.10 (dd, J=8.1, 0.9 Hz, 1H), 7.91 (dd, J=9.9, 1.2 Hz, 1H), 7.64-7.54 (m, 3H), 7.48 (t, J=7.8, 1H), 4.26-4.17 (m, 1H), 2.93 (d, J=11.4 Hz, 2H), 2.46 (s, 3H), 2.30 (t, J=11.1 Hz, 2H), 2.22-2.17 (m, 2H), 1.85-1.73 (m, 2H); MS (ESI) m/z 336 [M+H]+
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Product: O=C(Nc1ccc(O)cc1C(F)(F)F)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-(trifluoromethyl)phenol (prepared according to the method described by Filler, R.; Novar, H. J. in Org. Chem. 1961, 26, 2707-2710″), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][N:29]=1>CN(C=O)C>[Br:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:24])[CH:14]=3)[C:19]2=[O:23])=[CH:32][CH:33]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(Br)nc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Example 11 (400 mg) in DMF (5 mL) was added sodium hydride (60 mg) and the reaction stirred at room temperature for 10 minutes before the addition of a solution of 2-bromo-5-(bromomethyl)pyridine (760 mg) in DMF (5 mL). The reaction mixture was stirred at room temperature for 30 min.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S([N:28]=[N+:29]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N+:28]=[N-:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)C2CC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Ethyl 2-(4-cyclopropylsulfonylphenyl)acetate [obtained as described in WO2004/072031 (40 g, 149.07 mmol)] was dissolved in dry acetonitrile (745 mL) under argon atmosphere. To the above solution para toluene sulfonyl azide (32.33 g, 163.97 mmol) was added, followed by DBU (33.40 mL, 223.6 mmol) in dropwise manner, and stirred for 30 min. Reaction mixture was poured in ice cold water (500 mL), solid obtained was filtered through buchner funnel and dried under vaccum which yielded ethyl 2-(4-cyclopropylsulfonylphenyl)-2-diazo-acetate (40 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCOC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of tert-butyl 4-(tetrahydrofuran-3-yl)benzoate (350 mg, 1.41 mmol) was added trifluoroacetic acid (2 mL) in dichloromethane (10 mL) and then stirred at room temperature for 0.5 hour. Solvent concentration gave final desired product 4-(tetrahydrofuran-3-yl)benzoic acid (200 mg, 74%) as a white solid. LRMS (M−H+) m/z: calcd 192.08. found 192.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH:13](OCC)=[O:14]>>[CH:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:14]
Reactant: CCOC=O
Reactant: C=CCCCCCCCCCN
Product: C=CCCCCCCCCCNC=O
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of commercially available 1-aminoundec-10-ene (1 g) dissolved in ethyl formate (3.5 mL) was kept at 50° during 3 h. Evaporation of the solvent yielded 1.18 g of N-formyl-1-aminoundec-10-ene (yield: 99%).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[C:26]2[C:31]=1[O:30][CH2:29][CH2:28][O:27]2)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[O:27]1[CH2:28][CH2:29][O:30][C:31]2=[C:23]([C:2]3[C:10]4[C:6](=[N:7][N:8]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)[N:9]=4)[C:5]([C:25]4[S:24][CH:23]=[C:31]5[C:26]=4[O:27][CH2:28][CH2:29][O:30]5)=[CH:4][CH:3]=3)[S:24][CH:25]=[C:26]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1cc(-n2nc3c(-c4scc5c4OCCO5)ccc(-c4scc5c4OCCO5)c3n2)ccn1
Temperature: 100 °C

Procedure:
A mixture of Intermediate A (0.71 g, 2.0 mmol), tributyl(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)stannane (2.27 g, 5.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.20 g, 0.28 mmol), and anhydrous dimethylformamide (20 mL) was stirred under argon and heated at 100° C. for 4 hours. The volatiles were removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, dichloromethane/ethyl acetate 75:25) and washing with ethanol (20 mL) to give 4,7-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 10) as orange crystals, 0.47 g (49%). 1H NMR (400 MHz, CDCl3): δ 8.82 (m, 2H, pyridine), 8.37 (m, 2H, pyridine), 8.20 (s, 2H, benzotriazole), 6.53 (s, 2H, thiophene), 4.39 (s, 4H, OCH2CH2O), 4.30 (s, 4H, OCH2CH2O). UV-vis spectrum (dichloromethane): λmax=448 nm. Fluorimetry (dichloromethane): λmax=559 nm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: NCCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Br)c(CNCCCO)c1
Reaction time: 4 h

Procedure:
To a stirring solution of 2-bromo-5-nitrobenzaldehyde (1 eq) in methylene chloride (0.1 M) at room temperature was added 3-amino-1-propanol (2 eq). After stirring for 4 hr, sodium triacetoxyborohydride (2 eq) and acetic acid (5 eq) was added. The reaction mixture was stirred for 3 hr and carefully quenched with methanol. The organic phase was washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/Hexane). EI-MS m/z 289 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-Chloro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O-:15][C:16]#[N:17].[K+].Cl[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[NH:17][C:10]([CH3:11])=[N:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC=NNc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)c([N+](=O)[O-])c2)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a stirred solution of 5.25 g (00246 mole) of acetaldehyde 4-chloro-3-nitrophenylhydrazone in 25 ml of acetic acid was added dropwise a solution of 2.0 g (0.0246 mole) of potassium cyanate in 5 ml of water. After complete addition, 50 ml of an aqueous 5% sodium hypochlorite solution was added dropwise, forming a precipitate. After about 1/2 hour, the solid was collected by filtration and dried to yield 5.4 g of 1-(4-chloro-3-nitrophenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: COc1ccc(OC)c(C(=O)Cl)c1
Yield: 96.3 %

Procedure:
A mixture of 2,5-dimethoxybenzoic acid (25 g, 137.2 mmol) and thionyl chloride (35 mL, 470.6 mmol) was heated at reflux under Ar for 4 h. The reaction solution was evaporated to dryness and the residue was purified by high vacuum distillation at 127° C./2 mm Hg to give compound 45 as a pale yellow oil (26.5 g, 96.7%). When standing at room temperature, this oil changed to yellow crystals, m.p. 36°-38° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:7]2[N:14]([CH3:15])[CH:13]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:8]2=[N:9][C:10]=1[CH3:11])=[O:4].[OH-].[Na+].Cl>CO.O>[CH2:27]([CH:26]([NH:25][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH3:11])[N:9]=[C:8]2[C:12]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])=[CH:13][N:14]([CH3:15])[C:7]=12)[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(CC)Nc1c(C(=O)OC)c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)Nc1c(C(=O)O)c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12

Procedure:
A mixture of 7-(1-ethyl-propylamino)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester and NaOH in a 1:1 mixture of MeOH/water was heated at reflux over night. The resulting mixture was acidified with 2N HCl to a pH of 4-5, and extracted with chloroform. The organic layer was dried and concentrated to give the title compound.
Reaction SMILES: [CH:1](/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3].[C:19]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[F:28])#[N:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1](/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[C:22]([F:28])[CH:23]=3)=[O:15])=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)=[CH:2]\[CH3:3]
Reactant: C/C=C/[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Reactant: N#Cc1ccc(O)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(C#N)c(F)c3)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 2.68 g of 4-[trans-4-(1E-propenyl)cyclohexyl]benzoic acid, 1.8 g of 4-cyano-3-fluorophenol and 187 mg of 4-(dimethylamino)pyridine in 25 ml of methylene chloride was cooled to 0° C. and treated while stirring with 3.17 g of N,N'-dicyclohexylcarbodiimide. After stirring at 0° C. for 5 minutes and at room temperature for 3 hours the suspension was filtered and the filtrate was concentrated. Chromatographic purification of the residue on 50 g of basic aluminium oxide with methylene chloride and subsequent crystallization from hexane/ethyl acetate gave 2.67 g of 4-cyano-3-fluorophenyl 4-[trans-4-(1E-propenyl)cyclohexyl]benzoate as colourless crystals; m.p. (C-N) 117.5° C., cl.p. (N--I) 233.1° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(C2C=CC=C(C[NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)C=2)=CC=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][CH2:16][C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reactant: O=Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Product: O=[N+]([O-])c1ccc(-c2cccc(CNCc3ccc(F)cc3)c2)cc1
Yield: 71 %

Procedure:
4′-Nitrobiphenyl-3-carbaldehyde (0.73 g, 3.2 mmol) was converted to the desired compound (0.82 g, 71%) in a manner similar to the preparation of 1-(4′-chlorobiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (Compound A of Example 207). 1H NMR (CDCl3) δ 8.34-8.30 (m, 2H), 7.80-7.74 (m, 2H), 7.64 (bs, 1H), 7.58-7.42 (m, 3H), 7.38-7.30 (m, 2H), 7.09-7.00 (m, 2H), 3.91 (s, 2H), 3.84 (s, 2H). MS (ESI): 337.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].Cl>O1CCCC1>[CH:22]1([C:20]([CH3:21])([CH3:19])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: Cc1ccccn1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(Cc1ccccn1)C1C=Cc2ccccc21
Yield: 85.8 %

Procedure:
A solution of α-Picoline (1.97 ml, 20 mmol) in 10 ml of tetrahydrofuran was cooled to −20° C. and 15% n-butyl-lithium in hexane (13 ml, 20 mmol) was added during 10 min with stirring. The cooling bath was removed and the solution allowed to stir for 1 h while the temperature rose to room temperature. The resulting mixture was treated with a solution of 1-(1-methylethylidene)-1H-indene (3.12 g, 20 mmol) in 5 ml of tetrahydrofuran (5 ml) with vigorous stirring. The resulting solution was stirred for 14 h and hydrolyzed with 60 ml of 15-% hydrochloric acid. The organic layer was isolated and the aqueous phase washed once with ethyl acetate, then neutralized with aqueous ammonia solution and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent removed to give 4.28 g (86%) of 2-[2-(1H-inden-1-yl)-2-methylpropyl]pyridine as an oil. The product was NMR-pure, so no further distillation was necessary.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:39])=[O:38]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.