Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].[C:26]([OH:31])([OH:30])=[CH:27][CH2:28][CH3:29]>CN1CCCC1=O.[Pd](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:28]1[CH2:29][O:30][CH:26]([OH:31])[CH2:27]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1C
Reactant: CCC=C(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(O)C4)cc3c2c1C
Yield: 27.2 %

Procedure:
Under argon, 720 mg (2 mmol) of 6-iodo-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated in a pressure vessel with 202 mg (2.4 mmol) of sodium bicarbonate, 75 mg (0.42 mmol) of palladium dichloride, and 705 mg (8 mmol) of butenediol in 10 ml of N-methylpyrrolidone for 2 hours to 150° C. After filtration and concentration, the mixture is distributed in ethyl acetate/water. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried, filtered, and concentrated. The residue is chromatographed over silica gel with toluene:ethanol=80:40 as the eluent. Recrystallization of the corresponding fractions from ethyl acetate/diisopropyl ether yields 185 mg (26% of theory) of 6-(2-hydroxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 177°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][CH2:9]2
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 7-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (prepared according to the procedures published in Journal of Medicinal Chemistry 1995, 38, 4764-7) (525 mg, 2.08 mmol) in 5 mL of trifluoroacetic acid (TFA) was added triethylsilane (2.41 g, 20.80 mmol). The mixture was then heated at reflux for 8 h. After cooling to room temperature, the reaction was quenched with 20 mL of ice-water mixture, extracted with diethyl ether (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) afforded the title compound (445 mg, 90% yield) as a light yellow oil:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Product: N[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 59.3 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.166 g) and (3S)-3-pyrrolidinamine (0.127 g) to afford the title compound (0.113 g).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH3:24])[CH2:20][N:21]([CH3:23])[CH3:22].[ClH:25]>Cl.C(O)C.CCOCC>[ClH:25].[CH3:22][N:21]([CH3:23])[CH2:20][CH:19]([N:18]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2)[CH3:24]
Reactant: CC(N)CN(C)C
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(CN(C)C)n1c(-c2ccc(Br)cc2)cc2c1CCSC2
Temperature: 5 °C

Procedure:
A solution of 5.5 g (0.017 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 2 (a)], 1.6 g of 2-amino-1-dimethylaminopropane, 16 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux for 3 hours, cooled to 5°C, and filtered to provide a solid product. The resulting product is dissolved in ethanol, the solution is acidified with ethereal hydrogen chloride and diluted to the cloud point with ether. Upon standing, a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(1-dimethylamino-2-propyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 237° to 238°C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH3:28]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][C:21]([O:23][CH2:27][CH3:28])=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1
Reactant: CCBr
Reactant: Oc1ccc2c(c1)CN(c1cc(Cl)c3ccccc3n1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CN(c1cc(Cl)c3ccccc3n1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol (36 mg, 0.11 mmol) in 5 mL of dry N,N-dimethylformamide was added sodium hydride (8 mg, 0.17 mmol), then bromoethane (18.5 mg, 0.17 mmol) was added dropwise under nitrogen. After the addition, the reaction was stirred at room temperature for further 1 hour. The resulting mixture was diluted with dichloromethane (10 mL), washed with brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 28 mg of product. MS obsd. (ESI+) [(M+H)+] 353.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[O:12])=[CH:7][CH:6]=1.C[O:15][C:16](=O)[C:17]([F:20])([F:19])[F:18].Cl>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[C:16](=[O:15])[CH2:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Sodium methoxide (25.6 g) and toluene (105 ml) were taken in a flask. A solution of 4-methylacetophenone (50 g) in toluene (52 ml) was added at 20-25° C. in 30 minutes. The resultant reaction mixture was stirred further at 20-25° C. for 30 minutes. A solution of methyltrifluoroacetate (56.8 g) in toluene (52 ml) was added slowly at 20-25° C. for about 1 hour and the reaction mixture was heated to about 110° C. for 24 hours. The reaction mixture was cooled to 30° C. and poured into a flask containing aqueous hydrochloric acid (210 ml, 3N). The layers were separated and the aqueous layer was extracted with toluene (2×50 ml). The organic layers were combined and washed with water (2×50 ml). The solvent was removed completely under vacuum to afford the title compound (Yield: 79 g).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([N:22]3[CH2:29][CH2:28][C@:27]4([CH3:32])[C@H:30]([CH3:31])[C@H:23]3[CH2:24][C:25]3[CH:36]=[CH:35][C:34]([C:37]([NH:39][OH:40])=[NH:38])=[CH:33][C:26]=34)=[O:21])=[CH:19][C:14]=2[N:13]=[CH:12]1>>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([N:22]3[CH2:29][CH2:28][C@:27]4([CH3:32])[C@H:30]([CH3:31])[C@H:23]3[CH2:24][C:25]3[CH:36]=[CH:35][C:34]([C:37]5[N:38]=[CH:1][O:40][N:39]=5)=[CH:33][C:26]=34)=[O:21])=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: CCOC(OCC)OCC
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=N)NO)cc3[C@]1(C)CCN2C(=O)c1ccc2[nH]cnc2c1
Product: C[C@@H]1[C@H]2Cc3ccc(-c4ncon4)cc3[C@]1(C)CCN2C(=O)c1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of triethyl orthoformate (4 mL) and (2R,6R,11S)-3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxamidine (0.25 g) is stirred at 100° C. for 6 h. After cooling to room temperature, the mixture is concentrated and the residue is purified by HPLC on reversed phase (water/MeCN/NH3) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1cc(OC)c(-c2cccnc2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC)c(-c2cccnc2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 51 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyridin-3-yl-benzaldehyde (Ex-104A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 51% yield, mp 253–255° C. 1H-NMR (DMSO-d6) δ 8.69 (d, J=1 Hz, 1H), 8.50 (d, J=4 Hz, 1H), 8.25 (d, J=9 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 8.02 (s, 1H), 7.84–7.94 (m, 4H), 7.51 (s, 2H), 7.40–7.44 (m, 1H), 6.82 (s, 1H), 3.98 (s, 3H), 3.88 (s, 3H). MS m/z=424([M]+, 45%), 393 (100%). HMRS (EI) calcd. for C22H20N2O5S: 424.1093; found 424.1100.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:10])[S:8][C:4]=2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:26]=[CH:25][C:5]4[N:6]=[C:7]([C:9]([NH:11][CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]5)=[O:10])[S:8][C:4]=4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3s2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a stirred solution of tert-butyl 4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate (0.20 g, 0.54 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.13 g, 0.64 mmol), 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.13 g, 0.54 mmol), and triphenylphosphine (0.17 g, 0.64 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=3/7) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate (compound 14) as a white solid (0.28 g, 86%). 1H-NMR (CDCl3, 300 MHz): δ 7.95 (m, 1H), 7.48 (m, 3H), 7.27 (m, 1H), 7.17 (m, 1H), 6.97 (m, 2H), 4.62 (m, 1H), 4.12 (m, 3H), 3.61 (m, 2H), 3.29 (m, 2H), 2.95 (m, 2H), 2.06 (m, 6H), 1.56 (m, 2H), 1.41 (s, 9H) ppm; MS (ESI): 605.5 (M+1).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)[CH:9]=O.[C:20]([CH2:22]P(=O)(OCC)OCC)#[N:21].C(OCC)(=O)C>C1COCC1.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:22]/[C:20]#[N:21])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C#N)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A lithium hydroxide monohydrate powder (2.23 g) was added to a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) and diethyl cyanomethylphosphonate (8.2 g) in THF (50 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for one hour. Ethyl acetate (200 mL) and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered through a silica gel pad (carrier: Chromatorex™ NH). The filtrate was concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate and hexane, and the crystals were collected by filtration. The resulting crystals were dried under reduced pressure to obtain 7.49 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=[O:31])[C:25]=2[CH:24]=[CH:23][N:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:26]3([OH:31])[CH2:27][CH2:28][CH2:29][C:30]4[CH:21]=[N:22][CH:23]=[CH:24][C:25]3=4)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nccs2)cc1
Reactant: O=C1CCCc2cnccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cnc(-c3ccc(F)cc3)s2)CCCc2cnccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of DIPA (0.424 g, 4.2 mmol) in dry THF at −78° C. was added n-BuLi (0.268 g, 4.2 mmol) dropwise at −78° C., and the mixture was stirred for 30 min to produce LDA. A solution of 2-(4-fluorophenyl)thiazole (0.510 g, 2.8 mmol) in dry THF at −78° C. was then added to the above LDA solution. 7,8-Dihydroisoquinolin-5(6H)-one (0.419 g, 2.8 mmol) [prepared as described in Vanotti, International Patent Publication No. WO-2008/065054] was added dropwise to the reaction mixture, which was then stirred for 20 min at −78° C. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (3×30 mL), washed with water followed by brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude solid was purified by washing with the mixture of MeOH and ether, followed by filtering resulted in 5-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol (0.42 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.67 (m, 1H), 1.97 (m, 1H), 2.16 (t, 2H), 2.80 (t, 2H), 6.50 (s, 1H), 7.26 (s, 1H), 7.29 (m, 3H), 7.92 (m, 2H), 8.36 (m, 1H), 8.41 (s, 1H); LC-MS m/z calculated for [M+H]+ 327.09. found 327.1.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH2:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH3:27])[CH:26]=[C:18]([CH3:17])[CH:19]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CC(=O)OC1CCN([C@H]2CCCC[C@H]2N)C1
Product: CC(=O)OC1CCN([C@H]2CCCC[C@H]2NC(=O)c2cc(C)cc(C)c2)C1

Procedure:
Following the procedure of Example 1b, using cis-N-[2-(3-acetyloxy-1-pyrrolidinyl)cyclohexyl]amine and 3,5-dimethylbenzoyl chloride there is obtained as product cis-N-[2-(3acetyloxy-1-pyrrolidinyl)cyclohexyl]-3,5-dimethylbenzamide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[N:3]1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:12].[K+]>O>[CH3:1][N:2]1[C:6]([C:7]([OH:12])=[O:8])=[CH:5][N:4]=[N:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cn1nncc1C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nncc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (Preparation 33, 5 g, 45 mmol) and sodium hydroxide (8.59 g, 215 mmol) in water (120 ml) at 15° C. was added dropwise a solution of potassium permanganate (5.83 g, 36.9 mmol) in water (120 ml). The reaction was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction was filtered and the filtrate acidified to pH 3 with concentrated HCl before extracting with ethyl acetate (3×100 ml). The combined organic extracts were washed with saturated aqueous brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[C:8]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:6][CH:7]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].CS(C)=O>C(OCC)(=O)C>[O:11]=[C:9]1[NH:10][C:4]2[C:5](=[N:6][CH:7]=[C:2]([B:17]([OH:21])[OH:18])[CH:3]=2)[C:8]21[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: O=C1Nc2cc(Br)cnc2C12CCOCC2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Nc2cc(B(O)O)cnc2C12CCOCC2
Reaction time: 16 h

Procedure:
An oven dried resealable Schlenk tube was charged with 6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one (preparation 16, 0.350 g, 1.24 mmol), bis(pinacolato)diboron (0.470 g, 1.85 mmol), potassium acetate (0.240 g, 2.48 mmol) and dimethylsulphoxide (4 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.06 g, 0.07 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 110° C. After 16 hours, the mixture was cooled and ethyl acetate was added and the organic layer was extracted with 2M aqueous hydrochloric acid solution. The aqueous phase was washed with ethyl acetate and then the pH of the solution was adjusted to 6 with 6M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give the title compound in quantitative yield as a brown oily residue, which was used without further purification.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cc(F)cc(F)c2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cc(F)cc(F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3,5-difluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: N#Cc1cnc(Cl)s1
Product: N#Cc1cnc(N2CCNCC2)s1
Yield: 86 %

Procedure:
Prepared in analogy to example 2 (b) from 2-chloro-1,3-thiazole-5-carbonitrile and piperazine. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 86%). MS (m/e): 194.9 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.O>O1CCOCC1.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>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2cc(N3CCCCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60 %

Procedure:
To a solution of (6′-chloro-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-2′-yl)-(4-trifluoromethoxyphenyl)-amine (200 mg, 0.53 mmol) in 1,4-dioxane (8 mL) were added potassium carbonate (148 mg, 1.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.053 mmol), followed by 4-fluorophenyl boronic acid (150 mg, 1.6 mmol). This reaction mixture was refluxed for 8 hours, after which time water was added (10 mL) to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (15% ethyl acetate in petroleum ether) to afford the desired compound as colorless gummy mass (130 mg, yield 60% ).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:26][N:27]1[C:31]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])=[CH:30][N:29]=[C:28]1[CH3:39]>ClCCl.N1C=CC=CC=1>[CH3:39][C:28]1[N:27]([CH3:26])[C:31]([C:32]2[CH:33]=[C:34]([NH:35][C:12]([C:10]3[S:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])[CH:36]=[CH:37][CH:38]=2)=[CH:30][N:29]=1
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: O=C(O)c1ccc(-c2ccccc2)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3ccc(-c4ccccc4)s3)c2)n1C
Yield: 83.1 %

Procedure:
To a suspension of 5-phenylthiophene-2-carboxylic acid (102 mg) and oxalyl chloride (0.2 ml) in dichloromethane (2 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for an hour. The resultant solution was evaporated under reduced pressure to give a crude acid chloride. To a suspension of 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and pyridine (0.12 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane (2 ml) followed by stirring for 12 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-imidazol4-yl)-phenyl]-5-phenyl-thiophene-2-carboxamide (155 mg, 82.9%).
Reaction SMILES: [Na].[C:2]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:28])[CH:21]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]
Reactant: CCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 2.1 g of sodium in 180 ml of absolute ethanol are added with stirring 15.0 g of p-(1-cyclooctenyl)-phenol. After stirring has continued for a further 30 minutes, 28.5 g of 2-bromo-heptanoic acid ethyl ester are slowly added dropwise to this solution and the mixture is maintained at 50° C for 24 hours. Upon removal of the solvent in vacuo, the residue is partitioned at 0° C between ether and 2N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo, to yield the oily α-[p-(1-cyclooctenyl)-phenoxy]-heptanoic acid ethyl ester of the formula ##STR7##