Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(N(CC)CC)C.C(O)(=O)C(C)(C)C.CC(O[CH2:26][C:27]1[CH2:36][S:35][C@@H:30]2[C@H:31]([NH2:34])[C:32](=[O:33])[N:29]2[C:28]=1[C:37]([OH:39])=[O:38])=O>O>[NH2:34][CH:31]1[C:32](=[O:33])[N:29]2[C:28]([C:37]([OH:39])=[O:38])=[C:27]([CH2:26][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:36][S:35][C@H:30]12
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 30 g of 5-methyl-2-mercapto,1,3,4-thiadiazole, 32 ml of triethylamine and 5 g of pivalic acid in 2 liters of water was heated to 82° C. Thereafter there was added in one shot 40 g of 7-aminocephalosporanic acid (92%) and 5 g of pivalic acid were added in one shot to the resulting solution. Precipitation started after a few minutes and increased with time. After 30 minutes of vigorous stirring at the same temperature, the mixture was cooled to 65° C. The solid was isolated by filtering, washed with water and acetone to give 35 g of the compound of the title. The liquors were cooled to 20° C. and filtered and gave a further 5 g fraction, with an overall yield of 87%. The infrared and proton magnetic resonance spectra are consistent with the technically pure product.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=[O:14].[Na+]>O>[C:1]1([N:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:13]=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: CC(C)(C)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N(N=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl-t-butylamine (6 g, 0.04 mol) was treated with conc.HCl (5 ml) and a solution of NaNO2(6.4 g, 2.4 eq.) in 20 ml of water was added slowly. The resulting mixture was stirred for 2 hr at r.t. to produce an oily layer which was extracted with EtOAc, washed with brine, and dried over Na2SO4.Yield 6 g (85%). This nitrosoamine was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH2:19](I)[CH3:20].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH2:19]([O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: CCI
Reactant: CC(=O)NC1CCc2c([nH]c3cc(O)ccc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3

Procedure:
A mixture of 0.02 mol of N-(1,3,4,9-tetrahydro-7-hydroxy-2H-carbazol-2-yl)acetamide, 0.022 mol of ethyl iodide, 0.022 mol of anhydrous K2CO3, and 50 ml of Me2CO was stirred and refluxed for 48 hr. Sufficient CHCl3 and H2O were added to the cooled reaction mixture to give two clear layers. The CHCl3 layer was washed with 1 N NaOH, H2O, dried, evaporated, and the resulting solid residue was recrystallized from i-PrOH to give the title compound, mp 184°-186°.
Reaction SMILES: [CH:1]([C:3]1[C:4]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[CH:13][C:7]1[C:8](=[O:12])[O:9][CH:10]([OH:11])[C:6]=1[CH:5]=2)=[O:2].[CH3:18][C:19](OC(C)=O)=[O:20]>[Cl-].[Na+].O>[C:19]([O:11][CH:10]1[O:9][C:8](=[O:12])[C:7]2[CH:13]=[C:14]3[C:4](=[CH:5][C:6]1=2)[C:3]([CH:1]=[O:2])=[CH:17][CH:16]=[CH:15]3)(=[O:20])[CH3:18]
Reactant: O=Cc1cccc2cc3c(cc12)C(O)OC3=O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OC1OC(=O)c2cc3cccc(C=O)c3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
To a solution of 5-formyl-3-hydroxynaphtho[2,3-c]furan-1(3H)-one (190 mg, 0.83 mmol) pyridine (1.66 mL) at rt was added Ac2O (126 mg, 0.117 mL, 1.25 mmol). The solution was stirred at rt for 18 hours and then poured into brine and extracted with EtOAc. The extract was dried over MgSO4 and concentrated The crude material was chromatographed on silica get (3:1 hexanes:EtOAc) to give the title compound (100 mg, 44%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:9][C:7]2[C:6]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[CH:5][N:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 2-(hydroxymethyl)-5-(4-methoxybenzyloxy)pyridin-4(1H)-one (Intermediate 62, 3.48 g, 13.32 mmol) in DMF (100 mL) at room temperature was added 4-methoxybenzyl chloride (1.987 mL, 14.65 mmol) followed by potassium carbonate (2.273 mL, 39.96 mmol). The reaction mixture was stirred for 1 hour at room temperature then heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine. The ethyl acetate layer was concentrated to afford an oil. To the oil was added 1N HCl and a light brown solid crashed out. This was collected by filtration. The solid was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a brown solid (2.62 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CN(C)C(=N)N(C)C.[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([CH:47]=O)=[CH:44][CH:45]=2)[CH:40]=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([CH:47]=[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[C:3]([O:2][CH3:1])=[O:4])=[CH:44][CH:45]=2)[CH:40]=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)n1ncc2cc(C=O)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.50 g, 16.6 mmol) and tetramethylguanidine (1.99 mL, 15.9 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at −78° C. for 20 min. To this was added a solution of 5-formyl-indazole-1-carboxylic acid tert-butyl ester (3.72 g, 15.1 mmol) in tetrahydrofuran (25 mL) slowly via syringe over 10 min. The reaction mixture was stirred at −78° C. for 4 h and then allowed to warm to room temperature overnight. The solvent was evaporated and the resulting residue subjected to flash column chromatography on silica gel (1:2 ethyl acetate/hexane) giving the title compound as a white foam (5.77 g, 85%). 1H-NMR (CDCl3, 500 MHz) δ 8.09 (d, J=9.0 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.47 (s, 1H), 7.30 (br s, 5H), 6.43 (br s, 1H), 5.09 (s, 2H), 3.84 (s, 3H), 1.72 (s, 9H). Mass spec.: 452 (MH)+.
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1)C1C=CC=CC=1.[ClH:18].[H][H]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[ClH:18].[NH:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][OH:17])[CH2:11]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: OCC1CNCCO1

Procedure:
In an autoclave under an argon atmosphere at ambient temperature (20° C.), 215 ml of methanol, 1.7 g of palladium hydroxide (12135-22-7), 12.4 g of (4-benzylmorpholin-2-yl)methanol and 15 ml of 4M HCl are successively placed in dioxane. After the autoclave has been closed, the reaction medium is placed under 6 bar of hydrogen at 25° C. for 24 h. The reaction medium is filtered through Clarcel, rinsed several times with methanol; the filtrate is concentrated under reduced pressure. Morpholin-2-ylmethanol hydrochloride (9.65 g) is isolated in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]12CCCN=C1C[CH2:30][CH2:29][CH2:28][CH2:27]2>C(#N)C=CC>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:29]([CH3:30])[CH2:28][C:27]#[N:26])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC=CC#N
Solvent: CC#N
Product: CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 55 °C
Reaction time: 17.5 h
Yield: 247.3 %

Procedure:
Into a 250 mL three-neck round bottom flask equipped with a stir bar, condenser, thermocouple and nitrogen inlet was charged 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (5, 10.3 g, 0.033 mol), 2-butenenitrile (36, 3.0 mL, 0.037 mmol, 1.12 equiv) and acetonitrile (100 mL, 2.0 mol) at room temperature. The resulting mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.0 mL, 0.013 mol, 0.4 equiv) and was subsequently warmed to 55° C. The reaction mixture was stirred at 55° C. for 15-20 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to yield an orange oil. The crude product was then purified by flash column chromatography (SiO2, 40-80% ethyl acetate/hexane gradient elution) to afford 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (37, 12.3 g, 12.62 g theoretical, 97.5% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For 37: 1H NMR (CDCl3, 400 MHz) δ ppm 8.84 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.39 (d, 1H, J=3.8 Hz), 6.79 (d, 1H, J=3.8 Hz), 5.67 (s, 2H), 4.77 (m, 1H), 3.53 (t, 2H, J=8.2 Hz), 3.05 (dd, 1H, J=16.8, 6.2 Hz), 2.98 (dd, 1H, J=16.8, 6.3 Hz), 1.79 (d, 3H, J=6.5 Hz), 0.91 (t, 2H, J=8.3 Hz), −0.068 (s, 9H); C19H26N6OSi (MW, 382.53), LCMS (EI) m/e 383 (M++H).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CCO>CC#N>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH3:2])[CH3:20]
Reactant: C[C@@H]1CCCN1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].C([O-])(O)=O.[Na+]>CC#N>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([S:25][CH3:24])[CH:27]=2)[N:11]=1
Reactant: CSc1cccc(N)c1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(SC)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
A mixture of methyl 2,6-dichloro-4-cyanonicotinate (340.8 mg, 1.475 mmol), DIPEA (0.3 mL, 1.718 mmol) and 3-(methylthio)aniline (234.8 mg, 1.687 mmol) in CH3CN (5 mL) was stirred at 60° C. for 2 days. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE and filtered to give the title compound as a yellow solid (157.8 mg). The filtrate was purified by column chromatography (SiO2, hexanes/EtOAc=8/1) to give another crop (135.5 mg) of the title compound as a yellow oil of (total 293 mg, 60%). 1H-NMR (CDCl3) δ ppm 2.52 (s, 3H), 4.05 (s, 3H), 7.00 (s, 1H), 7.03-7.05 (m, 1H), 7.25-7.32 (m, 2H), 7.66-7.67 (m, 1H), 10.51 (br s, 1H). [M+H] calc'd for C15H13ClN3O2S, 334. found, 334.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(O)C>[C:3]([CH:4]([CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[NH:2])[NH2:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(C(=N)N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-amino-3-iminopropionoate hydrochloride (10 g) and triethylamine (18.4 mL) in ethanol (100 mL) was added ethyl acrylate (7.15 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCOCC1>CO>[N:21]1([CH2:27][CH2:28][NH:29][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: NCCN1CCOCC1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN3CCOCC3)cc2s1
Yield: 44.2 %

Procedure:
the title compound (56 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-morpholin-4-ylethylamine (80 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 423.5 (M+1, 100%). Yield=43%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:16](=[O:17])[C:15]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:13]2)=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16](=[O:17])[C:15]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:14]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:13]2)=[CH:36][CH:37]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(N)cc1)CN2c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(NS(C)(=O)=O)cc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Methanesulfonyl chloride (0.39 mL, 5.02 mmol) was added dropwise at 0° C. to tert-butyl 3-(4-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.19 g, 5.02 mmol) and pyridine (0.61 mL, 7.53 mmol) in dichloromethane (10 mL). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with dichloromethane, washed with 2M aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as an oil (2.38 g, 92%); 1H NMR (DMSO-d6); δ1.45 (s, 9H); 1.63 (d, J=14 Hz, 2H); 2.18-2.23 (m, 2H); 2.98 (s, 3H); 3.30-3.55 (m, 2H); 3.80-3.95 (m, 2H); 4.52 (s, 2H); 4.59 (s, 2H); 6.67 (d, J=8 Hz, 2H); 6.76 (t, J=7.2 Hz, 2H); 7.15-7.21 (m, 4H); 7.26-7.28 (m, 2H); MS for C26H34N4O5S m/z 515 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][OH:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>CN(C)C=O>[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][O:21][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cc1cc(N2CCCCCC2)c2ccc(CO)cc2n1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCCCC2)c2ccc(COc3ccc(C#N)cc3)cc2n1
Temperature: 50 °C
Yield: 88.1 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 22 mg, 0.55 mmol) was added to a mixture of (4-azepan-1-yl-2-methyl-quinolin-7-yl)-methanol (example 3, 120 mg, 0.44 mmol) and 4-fluorobenzonitrile (54 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL). After heating 2 h at 50° C., the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded the title compound (144 mg, 87%). Light yellow solid, ISP-MS: m/e=372.3 ([M+H]+).
Reaction SMILES: C(C1N(C)C2C=C(N3C=CC(OCC4C=C([F:26])SC=4)=CC3=O)C=CC=2N=1)C.[CH2:28]([C:30]1[N:34]([CH3:35])[C:33]2[CH:36]=[C:37]([N:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:52]=[CH:51][S:50][CH:49]=4)=[CH:42][C:41]3=[O:53])[CH:38]=[CH:39][C:32]=2[N:31]=1)[CH3:29]>>[CH2:28]([C:30]1[N:34]([CH3:35])[C:33]2[CH:36]=[C:37]([N:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:52]=[CH:51][S:50][C:49]=4[F:26])=[CH:42][C:41]3=[O:53])[CH:38]=[CH:39][C:32]=2[N:31]=1)[CH3:29]
Reactant: CCc1nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cc2n1C
Reactant: CCc1nc2ccc(-n3ccc(OCc4csc(F)c4)cc3=O)cc2n1C
Product: CCc1nc2ccc(-n3ccc(OCc4ccsc4F)cc3=O)cc2n1C

Procedure:
A mixture of the title compound, 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one obtained in step B in example 231 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (1.8 mg) as a white solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:17]=[C:16]([C:30]3[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](NC(=O)c2cc(-c3cc(F)c(F)c(F)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the intermediate from step E (isomer A, 0.3 g, 0.56 mmol) in 10 ml of THF/MeOH was added 5 N NaOH (1 mL). The reaction was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was acidified with 1N HCl (10 ml). The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. This material was used in the next step without any further purification. 1H NMR (CD3OD, 500 MHz): 8.26 (d, J=2.1 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.59 (dd, J=6.6, 8.9 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 5.83 (s, 2H), 3.7 (m, 1H), 1.95 (d, J=10.1 Hz, 1H), 1.86 (d, J=10.3 Hz, 1H), 1.3 (m, 2H), 1.15 (m, 2H), 1.0 (m, 1H), 0.88 (s, 9H). LC-MS: 4.25 min; (M+H)=514.2.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27]>C(O)C1C=CC=CC=1>[OH:30][CH2:29][CH2:28][N:24]([CH2:25][CH2:26][OH:27])[CH2:23][CH2:22][CH2:21][NH:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: NCCCN(CCO)CCO
Solvent: OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNCCCN(CCO)CCO

Procedure:
A solution of octadecyl bromide (26.65 g., 80 mM.), N-(3-aminopropyl)diethanolamine (105 g., 640 mM.) and benzyl alcohol (120 ml.) is heated at 130° C. for twenty-three hours. The benzyl alcohol is removed in vacuo (0.1 mm. Hg, and 75° C.) and the residue taken up in methylene chloride (250 ml.). The methylene chloride solution is washed with aqueous sodium hydroxide (1 N) then with brine. It is dried (Na2SO4), concentrated, and distilled; b.p. 242°-246° C. at 0.1 mm Hg. The product is a waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4-bromophenol (0.173 g) in 4 mL of 1-methyl-2-pyrrolidone under argon atmosphere was treated with 4-(trifluoromethoxy)iodobenzene (0.313 mL), 2,2,6,6-tetramethylheptane-3,5-dione (0.046 mL) and caesium carbonate (0.652 g). The slurry was degassed by bubbling argon for 15 min and copper(I) chloride (0.099 g) was added. The reaction mixture was degassed by bubbling argon for 15 min, then heated to 100° C. under argon for 5 h. The reaction mixture was cooled to room temperature and added dropwise to 30 mL of tert-butyl-methyl-ether. The slurry was filtered and the solids washed with tert-butyl-methyl-ether (3×20 mL). The combined filtrates were washed subsequently with 1N NaOH (50 mL), water (50 mL), 2N HCl (50 mL), 1N HCl (50 mL), water (50 mL) and brine (50 mL). The resulting organic layer was dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography on silica gel eluting with hexane to afford 0.15 g of the title compound as a colourless liquid.