Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].N1C=CN=C1.[Si:36](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([O:27][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 70 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
3β-Hydroxy-4,4-dimethylchol-5-en-24-oic acid methyl ester (19.1 g) is suspended in 390 ml of N,N-dimethylformamide (hereinafter designated DMF) and 39 g of imidazol and 34.6 g of tert-butyldimethylsilyl choride is added. The reaction mixture is stirred at 70° C. for 20 hours. After aqueous work-up, a crude product 23.9 g is isolated. Crystallization from tetrahydrofurane/methanol (hereinafter tetrahydrofurane and methanol are designated THF and MeOH, respectively) yields 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-chol-5-en-24-oic acid methyl ester (19.55 g). Melting point: 144-146° C. 1H-NMR (CDCl3, 300 MHz): δ=5.52 (1H, m); 3.66 (3H, s); 3.18 (1H, m); 0.89 (9H, s); 0.02 (6H, m).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])[C:10](=[O:22])[NH:11]2)[C:6]([OH:32])=[C:5]1[C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cc(F)ccc3OC)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1C1C=C2C(=CN(Cc3ccccc3)C(C(=O)NCCC(=O)O)=C2O)NC1=O
Temperature: 25 °C
Yield: 150.3 %

Procedure:
A mixture of 1-benzyl-3-(5-fluoro-2-methoxy-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.062 mmol), β-alanine (737 mg, 8.3 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a white solid. MS: (+) m/z 492.25 (M+1).
Reaction SMILES: [C:1]([CH:9]([N:11]1[CH2:16][CH2:15][C:14]([N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:24])[CH2:22][CH3:23])([CH2:17][O:18][CH3:19])[CH2:13][CH2:12]1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([N:11]1[CH2:16][CH2:15][C:14]([N:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:21](=[O:24])[CH2:22][CH3:23])([CH2:17][O:18][CH3:19])[CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)C(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)C(O)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 13.2 parts of N-[1-(1-benzoylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide in 164 parts of methanol are added portionwise 1.34 parts of sodium borohydride (slightly exothermic reaction). Upon completion, stirring is continued first for 2 hours at 35° C and further overnight at room temperature. The reaction mixture is evaporated. The residue is taken up in 50 parts of water and the whole is warmed for a while. After cooling, the product is extracted three times with 75 parts of trichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The oily residue is purified twice by column-chromatography over silica-gel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is triturated in petroleumether. The product is filtered off, crystallized from 2,2'-oxybispropane and a drop of 4-methyl-2-pentanone, filtered off again and dried at 110° C, yielding N-[1-(2-hydroxy-1 -methyl-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide; mp. 154.2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[N:5][S:6]([N+:9](CC)(CC)[CH2:10][CH3:11])(=[O:8])=[O:7])[O-:4].NCCO>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][NH:9][S:6]1(=[O:8])=[O:7])=[O:4]
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: NCCO
Product: COC(=O)N1CCNS1(=O)=O
Temperature: 25 °C

Procedure:
To a solution of 1-methoxy-N-triethylammoniosulfonylmethanimidate (Burgess reagent, 12.3 mmol) in THF (10 mL) at 0° C. was added 2-aminoethanol (4.91 mmol). The reaction was allowed to warm to rt and then heated to 90° C. for 8 h. After cooling to rt, the reaction was quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4) and concentrated to afford 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester as colorless oil that was used without further purification.
Reaction SMILES: [OH:1]O.[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([OH:23])=[C:11]([CH:22]=1)[C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:5])[CH3:4].[OH-].[Na+].Cl>C(O)C>[C:3]([NH:6][C:7]1[CH:22]=[C:11]2[C:10](=[CH:9][CH:8]=1)[O:23][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[C:13]([OH:1])[C:12]2=[O:21])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)c(C(=O)C=Cc2ccccc2)c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Aqueous hydrogen peroxide (30% w/v, 4 mL) was added to an ice-cold suspension of 5′-acetamido-2′-hydroxychalcone (5) (2.00 g, 7.11 mmol) and 1 M NaOH (20 mL) in ethanol (60 mL). The mixture was allowed to warm to room temperature and was vigorously stirred overnight. The mixture was acidified with 1 M HCl and the precipitate formed was collected by filtration to afford the flavonol (6) as a bright yellow powder (1.04 g, 50%), m.p. 241-242° C. 1H NMR (399.7 MHz, d6-DMSO) δ 2.10 (s, 3H, CH3); 7.48-7.59 (m, 3H, H3′,4′,5′); 7.73 (d, 1H, J7,8 9.2 Hz, H8); 7.89 (dd, 1H, J5,7 2.8, J7,8 9.2 Hz, H7); 8.21 (app. d, 2H, J=7.6 Hz, H2′,6′); 8.44 (d, 1H, J5,7 2.8 Hz, H5), 9.60 (br s, 1H, OH); 10.28 (s, 1H, NH).
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=2)[NH:6][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:3]1.CCO>Cl[Pd]Cl.C1COCC1>[CH3:19][CH2:18][CH:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([C:2]([OH:3])=[O:1])[NH2:6])[CH2:16][CH3:17]
Reactant: CCC(CC)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Agent: Cl[Pd]Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)c1cccc(C[C@H](N)C(=O)O)c1
Reaction time: 18 h
Yield: 84 %

Procedure:
To a 300 mL Parr bottle were added 0.41 g of PdCl2, 1.36 g of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)morpholine, 50 mL of EtOH, and 30 mL of THF. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated in vacuo to a volume of 15 mL. The solution was chilled in an ice bath and triturated with additional of 50 mL of hexane. A fine precipitate slowly formed. After storing at 5° C. overnight, the solid was collected by filtration and dried in vacuo to afford 0.65 g (72%) of 3-(3-pentyl)-L-phenylalanine.HCl as a white powder, m.p. 170° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:34][CH2:33][CH2:32][C@H:24]4C(OC(C)(C)C)=O)=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:34][CH2:33][CH2:32][CH2:24]4)=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(N3CCCC3)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
780 mg (1.54 mmol) of tert-butyl 1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40° C. for two days. The reaction mixture is then concentrated and stirred with ether and 2N aqueous sodium hydroxide solution. The aqueous phase is concentrated and stirred with ether and 2N hydrochloric acid. The organic phase of this extraction is dried over MgSO4, filtered and concentrated. The crude product is chromatographed over silica gel (CH2Cl2/EtOH/conc. aqu. NH3 sol.=100/1/0.1 to 20/1/0.1). This gives 280 mg (40% of theory) of the product.
Reaction SMILES: N1([C:10]([CH:12]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13]2)=[O:11])C2C(=CC=CC=2)CC1.[OH-:21].[Na+].[ClH:23]>O>[ClH:23].[N:16]1[C:15]2[CH2:19][CH2:20][CH:12]([C:10]([OH:11])=[O:21])[CH2:13][C:14]=2[NH:18][CH:17]=1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCc2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCc2nc[nH]c2C1

Procedure:
A 24 g portion of the above mentioned (-)-5-(2,3-dihydroindol-1-yl)carbonyl-4,5,6,7-tetrahydrobenzimidazole was dissolved in 120 ml of 6N hydrochloric acid and heated under reflux for 3 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue which was then dissolved in water, made alkaline with an aqueous sodium hydroxide solution, and washed with ethyl ether. Subsequent acidification of the aqueous layer with hydrochloric acid and concentration under reduced pressure yielded a white powder of (+)-4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride containing NaCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:22]
Reactant: CCOC(=O)CCN
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
m-Methoxybenzenesulfonyl chloride (3.53 g, 0.017 mol) and Et3N (4.76 mL, 0.034 mol) were dissolved in acetone (35 mL) at 0° C. β-Alanine ethyl ester hydrochloride (2.0 g, 0.017 mol) was added and stirring was continued at room temperature under N2 for 0.5 h. The reaction mixture was concentrated, partitioned between 0.1N HCl solution and EtOAc. The aqueous layer was washed with EtOAc, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without further purification.
Reaction SMILES: [C:1](/[C:4](=[CH:10]\[CH3:11])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[NH2:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:1]([CH3:2])[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[NH:12][C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: C/C=C(\C(C)=O)C(=O)OCC
Reactant: Nc1nc[nH]n1
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2ncnn2C1C
Temperature: 50 °C
Yield: 63.1 %

Procedure:
To 50 ml of ethanol are added 7.8 g of ethyl α-acetylcrotonate and 4.2 g of 3-amino-1,2,4-triazole, stirred at 50° C. for an hour and then heated under reflux for an hour. The ethanol is evaporated under reduced pressure, and the obtained crystals are recrystallized from ethanol to give 7 g of 6-ethoxycarbonyl-5,7-dimethyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 155°-157° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]#[C:9]Br.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]#[N:8])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C#N)CC1

Procedure:
In the manner given in Example 1, N-methylpiperazine is treated with cyanogen bromide and aqueous sodium hydroxide to give 4-methyl-1-piperazinecarbonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C1COCC1>[C:4]1([C:1]([OH:3])([CH2:12][CH:11]=[CH2:10])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC[Mg]Br
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: C=CCC(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of acetophenone (30 g, 0.25 mol) in dry THF (250 mL) at −78° C. was added dropwise 1M allylmagnesium bromide (1.25 L, 1.25 mol). After addition was complete, the mixture was allowed to stir at rt for 3 h. The reaction was quenched with satd aq NH4Cl solution (30 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give 2-phenylpent-4-en-2-ol (40.2 g), which was used for the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)[N:17]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: NCc1cccc(F)c1
Reactant: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Solvent: CS(C)=O
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 40 h

Procedure:
A mixture of N-(trans-4-(aminomethyl)cyclohexyl)-5′-chloro-6-fluoro-2,4′-bipyridin-2′-amine (15 mg, 0.045 mmol), DMSO (0.35 ml), TEA (0.012 ml, 0.090 mmol) and (3-fluorophenyl)methanamine (50.5 mg, 0.403 mmol) reaction mixture was flushed with argon and then stirred at about 105° C. for about 40 hours. The excess (3-fluorophenyl)methanamine was removed under reduced pressure to yield a crude material, which was mixed with 0.5 ml DMSO, filtered, purified by prep LC, and then lyapholized to yield 11.2 mg of the title compound, as a TFA salt. LCMS (m/z): 440.2 (MH+), retention time=0.62 min. 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.11-1.28 (m, 2H) 1.28-1.47 (m, 2H) 1.67 (ddd, J=10.92, 7.40, 3.66 Hz, 1H) 1.92 (d, J=11.72 Hz, 2H) 2.14 (d, J=10.55 Hz, 2H) 2.83 (d, J=6.74 Hz, 2H) 3.57-3.69 (m, 1H) 4.63 (s, 2H) 6.84 (d, J=8.79 Hz, 1H) 6.90 (s, 1H) 6.94 (d, J=7.03 Hz, 1H) 6.96-7.03 (m, 1H) 7.10 (d, J=9.96 Hz, 1H) 7.18 (d, J=7.62 Hz, 1H) 7.29-7.39 (m, 1H) 7.69-7.77 (m, 1H) 8.01 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(CCc2sccc2S(=O)(=O)Cl)cc1
Product: Cc1ccc(CCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 52 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide was prepared, as described in Example 2, using 2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride and 5-amino-4-bromo-3-methylisoxazole in 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C)C=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2 g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K2CO3 (14.2 g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4 equiv.). The mixture was stirred at 70° C. overnight, then filtered to remove the solids. The filtrate was removed under vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, 3.65 g (73%) as a light yellow solid, MS (ISP): m/e=235.1 (M+CH3CN+); δH (300 MHz; CDCl3) 7.36 (1H, dd, J=8.5, 2.0), 7.30 (1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43 (2H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH3:13]>>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: COCCCCl
Product: COCCCN1CCC(=O)CC1

Procedure:
1-(3-Methoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-methoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:18][O:19]C1CCCCO1)[CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][C:2]([CH3:26])([CH2:3][N:4]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[N:5]1)[CH2:18][OH:19]
Reactant: CC(C)(COC1CCCCO1)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
1-[2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 47C, 539 mg, 1.48 mmol) was dissolved in EtOH (2.64 mL) and p-TsOH.H2O (56.3 mg, 0.296 mmol) was added to the reaction mixture. The reaction was left to stir at rt for 16 hrs. Solid NaHCO3 (1.24 g, 14.8 mmol) was added to the reaction mixture and left to stir at rt for an additional 30 min. The reaction mixture was quenched with water and then extracted with EtOAc. The organic layer was washed with sat. NaHCO3 (1×), brine (2×), extracted, dried over sodium sulfate, filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0-30% Acetone/Heptanes] to afford 237 mg of the title compound (57%). MS (ESI): m/z=281.38 [M+H]+. UPLC: tR=1.12 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure E using 2,4-dichloro-3-methyl-1,7-naphthyridine (200 mg, 0.94 mmol), 2-tri-n-butylstannylpyridine (0.35 mL, 0.939 mmol), Pd(PPh3)4 (108 mg, 0.094 mmol) with heating in toluene (10 mL) for 14 h. After purification 4-chloro-3-methyl-2-(pyridin-2-yl)-1,7-naphthyridine was obtained as a white solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: c1ccc2c(c1)CCCC2
Product: c1ccc2ccccc2c1

Procedure:
In practice tetralin together with the catalyst to be tested is introduced into a small unstirred autoclave. No hydrogen is added to the autoclave. The autoclave is heated to an elevated temperature, and the tetralin dehydrogenates as the equilibrium shifts towards a new value characteristic of the elevated temperature used. The rate at which the system moves towards equilibrium and hence the quantity of naphthalene produced in a given time depends upon the activity of the catalyst. The quantity of naphthalene produced is determined by GLC or by 1H-nuclear magnetic resonance (1H-nmr). The quantity of naphthalene produced is then expressed as a percentage of that produced when using a fresh unused catalyst to obtain a measure of the catalyst activity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32]([OH:34])=O)=[O:15])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]([F:53])([F:52])[C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][NH2:48].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:42][C:43]([F:52])([F:53])[C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][NH:48][C:32]([C:31]1[CH:35]=[CH:36][N:37]=[C:29]([C:18]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]=2[NH:16][C:14]([C:13]2[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])=[O:15])[CH:30]=1)=[O:34]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (220 mg, 0.38 mmol, 1.00 equiv), 3-(trifluoromethyl)benzylamine (134 mg, 0.77 mmol, 2.00 equiv), EDC.HCl (124 mg, 0.63 mmol, 1.65 equiv), 4-dimethylaminopyridine (76 mg, 0.62 mmol, 1.63 equiv), and dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was washed with 5×30 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 360 mg (90%) of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as yellow oil.