Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=4)[C:21]3=[O:35])[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1>N1C=CC=CC=1.CS(C)=O>[Cl:14][C:12]1[CH:11]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:21]3=[O:35])[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: Nc1nccs1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 12, Method A: To a solution of 2-aminothiazole (15.9 mg, 0.16 mmol) in pyridine (0.4 mL) was added 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride (25 mg, 0.05 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford the desired product.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][C:21]=1[Cl:34])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[Cl:34][C:21]1[CH:22]=[C:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][C:20]=1[CH2:19][OH:1]
Reactant: CC(C)(C)[Si](OCc1ccc(COc2ccccc2)cc1Cl)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(COc2ccccc2)cc1Cl
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of 1-((tert-butyldiphenylsiloxy)methyl)-2-chloro-4-(phenoxymethyl)benzene (2.84 g) in tetrahydrofuran (14 ml) was added tetrabutyl ammonium fluoride/tetrahydrofuran solution (1.0 M, 7.0 ml) under ice-cooling and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture and the resulting product was extracted twice with ethyl acetate. The organic layers were combined, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give 2-chloro-4-(phenoxymethyl)benzyl alcohol (1.38 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.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.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:14]3)=[C:2]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)[CH:7]=1
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
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: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3-c3ccncc3)cccc2c1
Temperature: 100 °C
Yield: 6 %

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (80 mg, 0.166 mmol), potassium carbonate (115 mg, 0.832 mmol), pyridin-4-ylboronic acid (30.7 mg, 0.250 mmol), tetrakis(triphenylphosphine)palladium(0) (19.23 mg, 0.017 mmol), dioxane (1109 μl) and water (555 μl). The reaction mixture was heated in a microwave at 100° C. for 30 min. The mixture was then cooled to room temperature and the organic layer was separated from the aqueous layer by pipet. The resulting organic layer was then injected as is onto a reverse phase HPLC for purification (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were dried under a vacuum to provide 5-(4-chloro-2-(pyridin-4-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (5 mg, 0.01 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (s, 2H) 7.04 (d, J=5.98 Hz, 2H) 7.36-7.41 (m, 1H) 7.46 (d, J=8.76 Hz, 1H) 7.51-7.60 (m, 2H) 7.63-7.70 (m, 3H) 8.09 (d, J=8.33 Hz, 1H) 8.16 (s, 1H) 8.26 (d, J=5.56 Hz, 2H) 8.39 (d, J=1.71 Hz, 1H); m/z (ESI) 479.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5].NC(N)=[S:20].Cl.[OH-].[Na+]>O.C(O)(=O)C>[SH:20][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=S
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73.9 g (0.24 mol) of 2-bromo-4-(4-clorophenyl)nicotinic acid and 22.0 g (0.29 mol) of thiourea were weighed, and 100 ml of 5% HCl aqueous solution and 150 ml of acetic acid were added thereto. The resultant mixture was stirred at 100° C. for 2 hours, and was poured into water. Thereafter, 400 ml of 50% sodium hydroxide aqueous solution was added to the resultant mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then acidified with 20% HCl aqueous solution, and the crystal thus precipitated was filtrated out and was washed with water. The washed crystal was then dried to obtain a crude crystal of 2-mercapto-4-(4-chlorophenyl)nicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)c1
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 76%). MS (ESI) m/z 442 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH:20]([O:22][CH3:23])=O.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11](/[C:12](=[CH:20]\[O:22][CH3:23])/[C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC=O
Reactant: COC(=O)Cc1cccnc1Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(O)c1
Yield: 31 %

Procedure:
A solution containing methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (1 g; prepared as described in Example 2) and methyl formate (4.68 ml) in DMF (5 ml) was added dropwise to a stirred suspension of sodium hydride (0.55 g, 50% dispersion in oil, pre-washed with petroleum ether) in DMF (10 ml). On completion of the reaction, the reaction mixture was worked up as before to afford crude methyl 2-[2-(3-(3-hydroxyphenoxy)pyridin-3-yl]-3-hydroxypropenoate. The product was treated with potassium carbonate (0.31 g) and dimethyl sulphate (0.27 g) in DMF (10 ml) under the conditions described in Example 2 to give after standard work-up an oil. Chromatography on silica gel (eluent petroleum ether - ether, 50:50) gave (E)-methyl 2-[2-(3-hydroxyphenoxy)pyridin-3-yl]-3-methoxypropenoate as a white solid (0.35 g, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[CH3:2].N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37](Cl)=[O:38].Cl>C(O)C.[C].[Pd]>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])=[N:12][CH:13]=1)=[O:38]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(OCC)c1
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:3]1=[O:19].C(Cl)Cl>C(O)=O>[F:20][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=[O:13])[C:3]1=[O:19]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(F)(F)c2ccccc21
Solvent: ClCCl
Solvent: O=CO
Product: O=C(O)CN1C(=O)C(F)(F)c2ccccc21
Reaction time: 16 h

Procedure:
A 30 mL reaction vial was charged with tert-butyl 2-(3,3-difluoro-2-oxoindolin-1-yl)acetate (275 mg, 1 mmol) as a yellow oil. DCM (3 mL) was added, followed by an equal volume of formic acid. The reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid as a yellow solid. The desired M+H (228) was observed in the LCMS using the method [1] with a retention time of 1.652 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:11]([C:4]1[CH:3]=[C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][OH:14])=[CH:17][CH:18]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)cc1[N+](=O)[O-]
Reaction time: 22 h
Yield: 45.2 %

Procedure:
4-fluoro-1,2-dinitrobenzene (20.0 g, 107.5 mmol), 4-(hydroxymethyl)phenol (14.7 g, 118.2 mmol) and potassium carbonate (17.8 g, 129.0 mmol) were stirred in 250 ml of dimethylformamide at room temperature for approximately 17 hours. The reaction was heated at 35 degree Centigrade for 1.5 hours. Cesium carbonate (2 g, 6.14 mmol) was added and the reaction was heated at 45 deg. C. for approximately 22 hours. The solids were filtered away and washed with ethyl acetate. The filtrate was diluted with water and extracted 4 times with ethyl acetate. The ethyl acetate layers were washed with a water/brine mixture 5 times. The aqueous wash layers were back extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexane) to give 14.1 g of {4-[(3,4-dinitrophenyl)oxy]phenyl}methanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
A mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}methanol (3.80 g), activated manganese dioxide (12.0 g) and tetrahydrofuran (150 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (3.64 g, yield 97%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 155-156° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccnc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(=Nc3cccnc3)CC2)cc1

Procedure:
A mixture of 19 parts of 1-(phenylmethyl)-4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylbenzene and a small volume of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (The reaction vessel is provided with reflux-condensor and water-separator). After the calculated amount of water is separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2°-oxybispropane and evaporated again, yielding 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine as a yellow-brown oil.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1OC)=O.C1(CCC(Cl)=O)C=CC=CC=1>>[C:7]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:3][CH:4]=[C:5]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:6]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1ccccc1
Agent: O=C(Cl)CCc1ccccc1
Product: NS(=O)(=O)c1cccc(-c2ccccc2)c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenyl-propanoyl chloride, gave 5-formyl-6-methoxy-N-3-phenyl-propanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][NH:25][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:23]
Reactant: COCCCC(=O)NN
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COCCCC(=O)NNC(=O)c1ccc(-c2ccccc2)nc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 65.3 %

Procedure:
6-Phenylnicotinic acid (5.90 g) was dissolved in pyridine (150 ml), followed by addition of 4-methoxybutyric acid hydrazide hydrochloride salt (5.99 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (8.51 g), and stirred at 60° C. for 10 hours. After the reaction solution was cooled to ambient temperature, the solvent was evaporated under reduced pressure. The resulting residue was washed with water, to afford 6-phenylnicotinic acid N′-(4-methoxybutyryl)hydrazide as pale yellow solid (6.06 g, 65%). The physico-chemical values are as follows.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1(C(=O)N)C(CCC2C=CC=CC=2)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:8]2[C:6]([OH:7])=[O:5])(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)CCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(CCc3ccccc3)C2(C(N)=O)C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)CCc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(3-phenylpropionyl amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (22 mg, 0.04 mmol) is reacted in the same manner as 1-(4-Methoxybenzenesulfonyl)-3-phenethyl carbamoyl-azepane-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1) to afford the acid: Cal. 457.5 found (M-H)+ 456.6; 1H NMR (DMSO, 400 MHz), ppm: 7.78 (d, 2H), 7.28 (m, 2H), 7.20 (m, 3H), 7.01 (d, 2H), 5.6 (m, 1H), 5.5 (m, 1H), 4.3 (m, 3H), 4.0 (m, 1H), 3.82 (s, 3H), 2.8 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C@@H:25]1[O:27][CH2:26]1)[Cl:24]>ClCCCl>[Cl:24][CH2:23][C@H:25]([OH:27])[CH2:26][N:14]1[CH:15]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:13]1[CH2:12][CH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[N:8]=1
Reactant: ClC[C@H]1CO1
Reactant: Cc1cccc2nc(CCc3nc(-c4cccs4)c[nH]3)nn12
Solvent: ClCCCl
Product: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CCl)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 5-Methyl-2-[2-(4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (48 mg, 0.16 mmol) in 1,2-dichloroethane (1.5 mL) was added (R)-(−)-epichlorohydrin (80 μL, 1.00 mmol), the reaction vessel was capped and stirred at 100° C. for 16 hours. The volatiles were removed in vacuo and the residue purified by preparative LC-MS to yield the title compound. 6% yield, LC-MS: m/z=402.1 (MH+), tR=0.49 minutes, method B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[C:12]([Cl:24])[CH:11]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
80 mg of the t-butyl{(1S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate [107-1] was dissolved in 3 mL of chloroform, then 70 mg of N-chlorosuccinimide was added thereto, and stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and thus obtained residue was purified by preparative thin-layer chromatography, to obtain 80 mg of t-butyl{(1S)-1-[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate [139-1] as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19](F)[CH:18]=2)[N:3]=1.O.[NH2:27][NH2:28]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:18]=[C:19]3[C:20]([C:23]([NH2:24])=[N:27][NH:28]3)=[CH:21][CH:22]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOCC3C(N)=O)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: NC(=O)C1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-morpholinecarboxamide (360 mg, 1.05 mmol) and hydrazine monohydrate (2.58 mL, 52.6 mmol) in ethanol (10 mL) was stirred at 90° C. in a sealed tube for 16 hours. The mixture was cooled and diluted with water. Attempts to extract the product from the water using 90/10 CH2Cl2/IPA were unsuccessful, so the aqueous phase was combined with the residue from the concentrated CH2Cl2/IPA extractions and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (68 g SiO2, CHCl3 to 80/20/2 CHCl3/CH3OH/NH4OH gradient with a 10 minute hold at 90/10/1 CHCl3/CH3OH/NH4OH) to give the title compound (40 mg) as an off-white solid. LC-MS (ES) m/z=355 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.29-3.41 (m, 1H), 3.41-3.50 (m, 1H), 3.61 (dd, J=11.6, 3.5 Hz, 1H), 3.85-3.93 (m, 1H), 3.99-4.18 (bs, 1H), 4.35 (d, J=11.6 Hz, 1H), 4.82-5.08 (bs, 1H), 5.39 (s, 2H), 6.12 (s, 2H), 6.55 (s, 1H), 7.19 (s, 1H), 7.35 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][C:17]3[S:18][CH:19]([CH3:23])[CH:20](O)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCOCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:24]#[C:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:16][C:17]3[S:18][C:19]([CH3:23])=[CH:20][N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC2=NC(O)C(C)S2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(C#Cc2ccccc2)Cc2ncc(C)s2)cc1OC1CCCC1
Yield: 22.8 %

Procedure:
A solution of (+/-)-2-[2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl]-4-hydroxy-5-methyl-4,5-dihydrothiazole (70 mg, 0.2 mmol) in CDCl3 (4 ml) was treated with HCl (0.2 ml of a 1N solution in Et2O) and heated to 50° for 3 hr. The solvent was evaporated, the residue taken up in Et2O, washed with aqueous NaHCO3, H2O, dried and the solvent evaporated. Purification by flash chromatography (silica gel, 2% Et2O in CH2Cl2) gave the titled compound (19 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.36 (s, 1 H), 7.30 (m, 3 H), 7.00 (m, 1 H), 6.92 (d, 1 H), 6.84 (d, 1 H), 4.74 (m, 1 H), 4.28 (t, 1 H), 3.82 (s, 3 H), 3.40 (d, 2 H), 2.42 (s, 3 H), 1.78-1.98 (m, 6 H), 1.60 (m, 2 H).