Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C@H:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Cl:26])C(=O)C1>C1COCC1>[Cl:26][N:15]1[CH2:16][CH2:17][C@H:12]([C:9]2[S:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)[CH2:13][C@@H:14]1[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc2sc([C@H]3CCN[C@@H](C)C3)cc12
Solvent: C1CCOC1
Product: COc1cccc2sc([C@H]3CCN(Cl)[C@@H](C)C3)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of cis-(±)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine in THF (35 mL) was cooled to 0° C. (ice-water bath), then treated with NCS (2.26 g, 16.94 mol). After stirring 15 minutes, the ice-water bath was removed and the mixture was stirred at room temperature for 45 minutes. The mixture was then concentrated under reduced pressure and diluted with Et2O (100 mL), saturated aqueous NaHCO3 (50 mL) and H2O (50 mL). The mixture was shaken and partitioned in a separatory funnel. The aqueous layer was separated and extracted once with Et2O. The combined organic layers were washed once with H2O (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the cis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine as a yellow oil (4.78 g, 99%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C1C=CC2N(O)N=NC=2C=1.[NH:19]([C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[NH2:20].CCOP(O)N(C(C)C)C(C)C>C(Cl)Cl.C1(N=C=NC2CCCCC2)CCCCC1.CCN=C=NCCCN(C)C.Cl.CO.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([NH:20][NH:19][C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: NNc1ccc(-c2ccc(Oc3ccccc3)cc2)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CCOP(O)N(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(CC(F)(F)F)NNc1ccc(-c2ccc(Oc3ccccc3)cc2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3,3-trifluoropropionic acid (2.07 mmole) in DCM (10 mL), was added EDCI HCl (3.02 mmole) and HOBt (2.07 mmole). The solution was stirred at RT for 0.5 hour followed by addition of 3-hydrazinyl-6-(4-phenoxyphenyl)pyridazine A, prepared as disclosed in Example 3, (2.07 mmole) in 30 mL of DCM and EDIPA ((7.24 mmole). The coupling reaction will also work with 1,3-dicyclohexylcarbodiimide and DCM as a solvent or EDCI HCl and methanol as a solvent. The resulting reaction mixture was stirred at RT overnight. The mixture was diluted with saturated aqueous NaHCO3. The organic extract was washed with H2O and dried over Na2SO4 and then evaporated in vacuo. The crude product was purified with prep TLC eluting with 5% methanol and dichloromethane mixture to give B.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc([N+](=O)[O-])cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride. Add excess trifluoracetic acid and stir overnight at room temperture. Concentrate the reaction in vacuo, dilute with ethyl acetate and rinse with saturated sodium bicarbonate, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-nitroindole.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[C:24](Cl)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(=O)NCc1ccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide as an off-white solid (349 mg, 58% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.12 min (96.3%); mp, 223-225° C.; 1HNMR (DMSO-d6) 0.84 (t, J=6 Hz, 3H, CH; of long chain), 1.24-2.20 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.36 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.56-7.88 (m, 3H, Ar), 8.41 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.86, 20.92, 21.95, 23.39, 25.23, 28.31, 30.61, 30.99, 35.33, 41.57, 56.51, 119.99, 123.79, 126.51, 133.96, 138.38, 145.74, 154.53, 160.40, 169.47, 172.25, 172.60. LCMS MH=413; Anal Calcd For C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 63.76; H, 6.68; N, 13.42.
Reaction SMILES: C1(=O)N(C(C(O)=O)CCCC([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=O)C(=O)C2=CC=CC=C12.C[Si](C)(C)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(N(CC)CC)C.C(O)=O.CO.N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[NH2:12][CH:13]1[C:28](=[O:29])[N:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]12
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(C(=O)O)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O=CO
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred slurry of 3.0 grams of 7-(5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 50 milliliters of absolute methylene chloride were added 2.9 milliliters of absolute pyridine and 4.5 milliliters of trimethylchlorosilane, to protect both of the carboxyl groups. The resulting reaction mixture was stirred for two and one-half hours, then cooled to -12° C. in a carbon tetrachloride: dry ice bath. To this were added 5.6 milliliters of absolute pyridine in one lot, and then 36.2 milliliters of a 10 percent solution of phosphorus pentachloride in absolute methylene chloride, dropwise, maintaining the temperature at -12° C. The reaction mixture was stirred for two and one-half hours, 40 milliliters of absolute methanol was added dropwise at -12° C. and stirred for thirty minutes, and for another thirty minutes at room temperature. Then 10 milliliters of 50 percent formic acid was added dropwise, the pH adjusted to 2 by addition of triethylamine, and the reaction mixture stirred for forty-five minutes. The solution became cloudy. Then the pH was adjusted to 3.4, and the reaction mixture was refrigerated overnight and filtered, yielding 600 milligrams of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 40 percent yield. This was taken up in 5 milliliters of water, stirred and filtered. The solid was washed with about 2 milliliters of water and 10 milliliters of acetone, yielding 450 milligrams of purified 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 30 percent yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28]O[CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=CC=C[CH:31]=1.C(OC(C)(C)C)(=O)C=C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[C:24]1(=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:11][CH:10]=2)[CH2:29][CH2:28][CH2:35][CH2:30][CH2:31][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: C=CC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Yield: 49 %

Procedure:
Following the procedure described for compound 47, 4-[(4-bromophenyl)cyclooctylidene)methyl]phenol (49) (0.105 g, 0.283 mmole), tert-butyl acrylate (0.084 mL, 0.573 mmole), P(o-tolyl)3 (0.0097 g, 0.0319 mmole), Et3N (0.125 mL, 0.897 mmole), Pd(OAc)2 (0.0042 g, 0.0187 mmole) and DMF (1.5 mL) yielded 0.059 g (49%) of compound 50 as a white solid. 1H NMR (CDCl3): δ 7.54 (d, J=15.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.30 (d, J=15.9 Hz, 1H), 4.73 (s, 1H), 2.27 (m, 4H), 1.64 (m, 2H), 1.57 (m, 8H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 82.5 °C
Yield: 75 %

Procedure:
Into the same device as used in Example 1 were placed 77.3 g (0.28 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate, 27.3 g (0.42 mole) of sodium azide, 57.7 g (0.42 mole) of triethylamine hydrochloride and 280 ml of toluene. Thereafter, the mixture was heated to a temperature of 82 to 83° C. to undergo a reaction for 24 hours. Subsequently the same procedure as in Example 1 was repeated, and crystals were collected by filtration. Further, the crystals were recrystallized from methanol and water, filtered and dried, giving 67.7 g (0.21 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate (yield 75.8% based on methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate). The reaction is illustrated below with chemical formulas: ##STR27##
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH:1]1[N:2]=[C:3]([CH:17]=[O:18])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccn2cncc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc2ccccn12
Temperature: -40 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
To imidazo[1,5-a]pyridine (2.337 g, 19.78 mmol) in tetrahydrofuran (40 mL) was added n-butyl lithium (2.5 M in hexane, 15.76 mL, 39.4 mmol) at −40° C. The mixture was stirred at −40° C. for 3.5 hours, followed by the addition of dimethylformamide (3.1 mL, 40 mmol). The reaction mixture was stirred at 25° C. overnight and quenched with water. The mixture was then partitioned between dichloromethane (80 mL) and water (15 mL). The organic phase layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-50% ethyl acetate/dichloromethane to give the title compound (1.78 g, 62% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:29].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:29])=[O:20])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Temperature: -15 °C
Reaction time: 3.5 h

Procedure:
100 mg of 3-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]propan-1-ol was introduced into 2.5 ml of acetone and mixed at −15° C. with 0.15 ml of a solution of Jones reagent (produced from 0.27 g of chromium(VI) oxide, 1 ml of water and 0.23 ml of concentrated sulfuric acid). After 3.5 hours of stirring at −15° C., it was quenched with the addition of isopropanol. It was diluted with water, extracted three times with dichloromethane, the combined organic phases were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:43])[CH:11]([NH:23][C:24](=[O:42])[C@@H:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][SH:51])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([NH:9][C:10](=[O:43])[CH:11]([NH:23][C:24](=[O:42])[C@@H:25]([S:51][CH2:50][C:49]1[CH:52]=[CH:53][C:46]([O:45][CH3:44])=[CH:47][CH:48]=1)[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=C(NCCc1ccccc1)C(NC(=O)[C@@H](Br)CCCCN1C(=O)c2ccccc2C1=O)C(=O)NCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@@H](CCCCN2C(=O)c3ccccc3C2=O)C(=O)NC(C(=O)NCCc2ccccc2)C(=O)NCCc2ccccc2)cc1
Reaction time: 15 h

Procedure:
Combine N,N′-diphenethyl-2-((S)-2-bromo-6-phthalimidohexanoylamino)malonamide (10 mmol), 4-methyoxybenzylmercaptan (3.48 mL, 25 mmol), and tetrabutylammonium iodide (about 50 mg) in dimethylformamide (10 mL). Degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add cesium carbonate (4.10 g, 12.5 mmol). After 15 hours, partition the reaction mixture between water and methyl t-butyl ether, saturate the aqueous layer with sodium chloride. Extract the aqueous layer with brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:19]([C:18](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:17]1[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=1)#[N:20]
Reactant: CCOC1(OCC)CCCN1C
Reactant: N#CCc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CN1CCCC1=C(C#N)c1ccc(Cl)cc1

Procedure:
Boil 22.7 g of 2,2-diethoxy-1-methylpyrrolidine, 19.8 g of 4-chlorobenzylcyanide and 90 ml of benzene for 1 hour under reflux and with stirring. Distil off the volatile constituents under a vacuum. After trituration with a little diethyl ether, filter off the residue to obtain 20.8 g (68% of theory) and the title compound (m.p. 71° to 72° from isopropanol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(=O)OCC>CN(C=O)C>[CH2:21]([O:28][CH2:29][CH2:30][O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) in DMF (50 mL) was added K2CO3 (6.61 g, 47.8 mmol) and 2-(benzyloxy)ethanol (4.00 g, 26.3 mmol) at rt. The mixture was stirred at 110° C. for 12 h. LCMS and TLC (PE/EA=5:1, Rf=0.4) showed the reaction was finished. The mixture was filtrated, and the filtrate was concentrated to give crude product, which was purified by silica gel column to obtain 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (7.1 g, 18.18 mmol, 76.0% yield): 1H NMR (400 MHz, CDCl3) 8.49 (d, J=2.4 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 7.54-7.28 (m, 5H), 7.13 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J=4.8 Hz, 2H), 3.89 (t, J=3.6 Hz, 2H); ES-LCMS m/z 342 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][CH:28]([SH:30])[CH3:29].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:30][CH:28]([CH3:29])[CH3:27])[CH:7]=1)[CH3:2]
Reactant: CC(C)S
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3-(2-Bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.94 mmol), 2-propanethiol (0.11 mL, 1.13 mmol), and sodium hydride (60% in mineral oil; 0.05 g, 1.13 mmol) were combined in 1,4-dioxane and stirred at room temperature for 30 minutes. The mixture was worked-up to give [3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was then reduced to the amine as described in Example 3, Step 5 to provide [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester The amine was then treated with pivaloyl chloride according to Example 3, Step 6 to provide {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester according to the procedure described in Example 3, Step 7 provided the acid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 21.8 %

Procedure:
The title compound (45.2 mg) was prepared as in Example 177, Steps C and D, using 269.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 359.2 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C19H22F3N3, 349.49. found, m/z 350.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.87 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 4.48 (m, 1H), 3.43-3.40 (m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.07-1.86 (m, 6H), 1.66-1.57 (m, 2H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.4 min, 97.7% purity.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Cc2nc3ccccc3n2C)cc1
Temperature: 0 °C
Yield: 28 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (0.2 g, 0.75 mmol) in acetone was treated with potassium carbonate (0.31 g, 2.2 mmol), cooled to 0° C., treated dropwise with and methyl iodide (0.070 mL, 1.1 mmol), heated at 40° C. for 12 h, cooled to room temperature, and filtered. The filtrate was evaporated under reduced pressure. Purification of the resultant residue by column chromatography (silica, chloroform) afforded the title product (28%). 1H NMR (400 MHz, CDCl3): 7.98 (d, J=8.4 Hz, 2H), 7.7 (m, 1H), 7.37 (m,5H), 4.38 (s, 2H), 3.9 (s, 3H), 3.5 (s, 3H). [M+H] 281.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C@H:10]2[C@@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC[C@@H]2CNCC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.37 mmol, 0.2 g) in DCM (2 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring for 1 h at room temperature. The volatiles were removed under reduced pressure; residue was dissolved in DCM, added hexanes to precipitate the desired HCl salt. Solvent was removed under reduced pressure and the solid was dried under high vacuum to provide (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol.