Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@H](C)c2ccc(Cl)cc2)CC1

Procedure:
Example 167 was prepared from (2R)-2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=−9.3° (C=1.65, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1 H), 7.36–7.24 (m, 4 H), 7.22–7.12 (m, 2 H), 7.08 (d, 1 H, J=8.0 Hz), 6.92 (s, 1 H), 3.53 (q, 1 H, J=7.2 Hz), 3.42–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.73–2.59 (m, 1 H), 2.57–2.43 (m, 1 H), 2.42–2.33 (m, 2 H), 2.28 (s, 3 H), 2.08–1.92 (m, 2 H), 1.86–1.56 (m, 6 H), 1.51 (d, 3 H, J=7.2 Hz), 1.24 (d, 6 H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH2:63][C:64]1[CH:65]=[C:66]([F:76])[C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C>[F:76][C:66]1[C:67]2[C:71]([CH3:72])([CH3:73])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=[C:64]([CH2:63][NH:62][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:10][C:2]=2[CH3:1])[CH:65]=1
Reactant: CC1(C)OB(O)c2cc(CN)cc(F)c21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1cc(F)c2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of crude 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (0.45 g, 1 mmol) in DMF (5 mL) at rt under N2 was added HBTU (0.76 g, 2 mmol), followed by DIPEA (0.39 g, 3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was purified by chromatography over silica gel eluted with PE-DCM (1:1) to give an activated intermediate from acid, which was used directly to mix with 6-(aminomethyl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (0.3 g, 1.44 mmol) in 5 mL of DMF. The reaction mixture was stirred at rt overnight. The reaction was monitored by LC-MS. The reaction solution was purified by pre-HPLC to give the final title compound (260 mg, 40.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.97 (t, 1H), 7.86 (s, 2H), 7.63-7.62 (m, 2H), 7.53-7.51 (m, 2H), 7.24 (d, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.43-4.31 (m, 2H) 2.42 (s, 3H) 1.53 (s, 6H) ppm; HPLC purity: 97.9% at 220 nm and 99.6 at 254 nm; MS (ESI+): m/z=643 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]1[NH:38][C:37](=[O:39])[O:36][N:35]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][CH2:24][CH2:25]OS(C)(=O)=O.[NH:40]1[CH2:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:40]1([CH2:25][CH2:24][CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:31]=[CH:32][C:33]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Reactant: C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCN2CCC2)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 130 mg of methanesulfonic acid 3-[5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propyl ester in 7 mL of acetonitrile was added 25 μL of azetidine and 57 mg of diisopropylethyl amine. The resulting mixture was heated in a sealed tube to 60° C. under microwave irradiation for 30 minutes and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by a 2 g SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH and another column chromatography on silica gel (eluting with dichloromethane 90/methanol 10) to give 3.5 mg of 3-{4-[4-(3-azetidin-1-yl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7].COC1C=CC(O)=CC=1>>[C:5]([O:9][CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:8])[CH:6]=[CH2:7]
Reactant: C=CC(=O)O
Reactant: C=CCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OC(C)CC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.9 mol (51 g) of liquid 1-butene, one mole (72 g) of acrylic acid, 11 g (8.5 % by weight/charge) of ZrSA15 and 0.018 g (250 ppm relative to the acrylic acid) of hydroquinone methyl ether, which serves as a stabilizing agent, are charged at room temperature into a stainless steel reactor with a capacity of 200 ml, fitted with a thermometer and a manometer. The reactor is closed and is immersed in an oil bath at 150° C. The reaction medium is maintained at 100° C. with stirring for four hours. The pressure falls from 10 bar at the start of the reaction to 4 bar at the end of the reaction. At the end of the reaction, the reaction mixture is cooled to room temperature. The reactor is then opened so as to degas the unreacted butene.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14].C([O-])(O)=O.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Yield: 80.1 %

Procedure:
2-Chloro-4-fluorobenzonitrile (2.13 g, 13.8 mmol), (2S)-2-amino-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (2.6 g, 13.8 mmol) and NaHCO3 (3.5 g, 41.4 mmol) in DMSO (70 mL) and H2O (10 mL) were stirred at 95° C. for 15 h. After cooling, the reaction mixture was diluted with H2O (100 mL) and washed with Et2O (100 mL). The H2O layer was acidified to Congo Red midpoint and extracted with Et2O (2×). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to give the titled product (3.59 g, 80%) as a foam. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.89 (2H, m), 3.54 (1H, m), 4.42 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.70 (1H, s), 7.43 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 325.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34]CC4C=CC=CC=4)[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:43]=[CH:42][C:22]([C:23]([N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[OH:34])[CH3:26])=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc([N+](=O)[O-])cc3)cc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(N(C)C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(N)cc3)cc2)c(O)c1
Reaction time: 5 h
Yield: 103 %

Procedure:
A solution of 4-(4′-nitrobiphenyl-2-carboxamido)-N-(2-benzyloxy-4-methylphenyl)-N-methylbenzamide (430 mg), 20% palladium hydroxide (80 mg) in methanol (20 ml) and 1,4-dioxane (30 ml) was stirred under atmospheric pressure of hydrogen at 30° C. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 3% methanol in chloroform) to give 4-(4′-aminobiphenyl-2-carboxamido)-N-(2-hydroxy-4-methylphenyl)-N-methylbenzamide (350 mg) as amorphous.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:5]2[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 4-methoxyphenylboronic acid (5.0 g), copper acetate (6.0°g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.7 g, 66%) as a pale-yellow oil.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([C:18]1[N:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)=[O:17])[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[N:20]=[N:19][C:18]([C:16]([N:11]4[CH2:10][CH:9]5[NH:8][CH:13]([CH2:14][CH2:15]5)[CH2:12]4)=[O:17])=[CH:23][CH:22]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)nn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.187 mmol) in DCM (1 ml) at −78° C. was added TFA (1 mL, 13.0 mmol). After warming to room temperature and stirring for 1 h, the reaction was concentrated under reduced pressure. The resulting oily residue was dissolved in 2 mL MeOH, flushed through a PL-HCO3 MP-Resin cartridge to remove TFA, then purified by HPLC which gave a white solid (55 mg, 0.112 mmol). 1H NMR (400 MHz, DMSO): δ, 10.71 (s, 1H), 8.88 (s, 1H), 8.60 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 6.68 (s, 1H), 4.81-4.72 (m, 1H), 4.22 (d, J=12 Hz, 1H), 3.53 (d, J=12 Hz, 1H), 3.48 (br s, 1H), 3.29 (br s, 1H), 3.27 (d, J=12 Hz, 1H), 3.06 (s, 3H), 3.05 (s, 3H) 2.93 (d, J=12 Hz, 1H), 2.42-2.33 (m, 2H), 2.01-1.96 (m, 4H), 1.72-1.58 (m, 6H); HRMS calcd for C25H31N9O2.H+ (M+H)+ 490.2679. found 490.2676 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@:4]3([O:30][C@H:5]3[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 47115.7 %

Procedure:
To a stirred solution of 3β-hydroxyandrost-5-en-17-one (0.81 g) in CH2Cl2 (7.4 mL) cooled at 0° C., a solution of mCPBA (0.77 mg) in CH2Cl2 (13.6 mL) was added dropwise. After 0.5 h at 0° C. and 0.5 h at room temperature, a 10% aqueous solution of Na2SO3 was added. The mixture was neutralized by addition of 5% NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give 3β-hydroxy-5α,6α-epoxyandrostan-17-one (0.64 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.62 (d, 1H), 3.52 (m, 1H), 2.87 (d, 1H), 2.44-0.56 (m, 19H), 1.00 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([NH:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)C(=CN)C(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=CNC(=O)C(Cl)(Cl)Cl)C(C)=O

Procedure:
Methyl 2-aminomethylene-3-oxobutanoate (1.4 g) in methylene chloride (20 ml) was treated with triethylamine (2.0 ml) and trichloroacetyl chloride (2.0 ml) while stirring at 20°-25° C. The mixture was stirred for 4 hours at 20° C. to give a solution of the title compound, which was used immediately to prepare the dihydropyran of Example 15 without isolation.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:28][C:30]2[CH:35]=[CH:34][N:33]=[C:32]3[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=23)[CH:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)[C@@H](N)C(=O)NC1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (R)-2-amino-N-cyclopentyl-3-methylbutanamide (68.1 mg, 0.370 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (105 mg, 90%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([CH3:22])[CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:10]1.CN([CH:26]=[O:27])C>O1CCCC1>[CH3:6][CH:7]([CH3:22])[CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 45.5 mL, 1.15 equivalents) was added dropwise to a stirred, −78° C. solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Example 32 of U.S. Pat. No. 4,689,338, 25.64 g) in tetrahydrofuran (450 mL). The solution was stirred for 10 minutes, then DMF (20.1 mL, 2.3 equivalents) was added. The reaction mixture was allowed to warm to room temperature over 1 hour. The volatiles were removed under reduced pressure and the residue was portioned between ethyl acetate (400 mL) and brine (400 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown solid that was purified by flash chromatography (silica gel, gradient elution with 0.5-1% methanol in dichloromethane) to provide 10.5 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2ccccc2)CC1
Yield: 48.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound, potassium carbonate (2.1 g) and 7-bromo-1-phenyl-1-heptanone (0.92 g) were reacted and treated in the same manner as in Example 172 to give 0.80 g of 4-amino-5-chloro-2-methoxy-N-((1-(7-oxo-7-phenylheptyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:8])[NH:7][CH2:6][CH2:5][S:4]1.C(N(CC)CC)C.[C:16](=[S:18])=[S:17].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>C(O)(C)C>[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[Zn+2:23]
Reactant: CC1(C)NCCS1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C)SCCN1C(=S)[S-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
While cooling and stirring at 10°C, 76.8 g. (0.50 mole) 2,2-dimethylthiazolidine hydrochloride [preparation described by B. Sweetman et al, J. Med. Chem. 12, 888 (1969)] was added to a mixture of 30 ml isopropanol and 101 g. (1.00 mole) triethylamine. Likewise, 38.0 g. (0.50 mole) of carbon disulfide was gradually added, followed by 45.8 g. (0.25 mole) of anhydrous zinc acetate. After standing overnight at room temperature, the precipitate was filtered, twice water-washed with 1 liter portions of water and air-dried to give 80.5 g. of the yellow product melting at 148° - 153°C (decomp.) and having the following analysis: Found: C, 31.51; H, 4.70%. Calcd for C12H20N2S6Zn: C, 32.04; H, 4.45%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]>C(O)(=O)C.ClCCl>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:6]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc(OC)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of fuming nitric acid (12.1 ml; s.g. 1.5) in glacial acetic acid (120 ml) was added in one portion to a stirred solution of 4-ethyl-2-methoxyphenol (41.7 g) in dry dichloromethane (800 ml). After 1 minute the solution was washed with water (3×300 ml), and the organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give an orange crystalline residue. This was recrystallised from a mixture of methanol and water to give 4-ethyl-2-methoxy-6-nitrophenol (31.3 g), m.p. 59°-61° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC(S(=O)=O)=CC=1.C(Cl)(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCO
Agent: Cc1ccc([SH](=O)=O)cc1
Solvent: ClC(Cl)Cl
Product: OCCCCCOC1CCCCO1
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
To 31.2 g of 1.5-pentanediol was added 380 mg of p-toluenesulfonic acid monohydride and dropwise 8.4 g of dihydropyran with ice-cooling and stirring over 20 minutes, and the mixture was stirred at a room temperature for 3.5 hours. After adding 300 ml of chloroform, the mixture was washed with 2% sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with hexane/ethyl acetate (3:1) to obtain 6.0 g of 2-(5-hydroxypentyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]1[C:14]([O:16][C:17](=[O:18])[CH:8]21)=[O:15])[CH:5]=[CH2:6].[OH-].[Na+]>O>[OH:3][N:2]=[C:17]([CH:8]1[CH:9]([C:14]([OH:16])=[O:15])[CH:10]2[CH2:13][C:7]1([CH2:4][CH:5]=[CH2:6])[CH:12]=[CH:11]2)[OH:18]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NO
Yield: 84.8 %

Procedure:
139 g (2 mol) of hydroxylamine hydrochloride are dissolved in 200 ml of water, 408 g (2 mol) of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride (prepared according to Example 1 of U.S. Pat. No. 3,105,839) are added to the solution and, with vigorous stirring, 160 g of 50% aqueous NaOH solution are then added dropwise. The mixture is subsequently heated for 1 hour under reflux, the water and traces of oily components are distilled off and the residue is taken up in toluene. The toluene phase is filtered in order to remove the sodium chloride, and the toluene is subsequently removed by rotary evaporation at 150° C. and 2000 Pa, affording 402.6 g of the product (91.5% of theory) as a pale brown viscous liquid with a viscosity of 1.28 Pa.s at 80° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-t-butoxycarbonylamino-1-hexanol (2.17 g, prepared in (1)) in dichloromethane (20 ml) were added triethylamine (1.67 ml) and methanesulfonyl chloride (0.93 ml) under ice cooling. After being stirred at the same temperature for 1 h, the mixture was washed with water, 10% aq. citric acid, sat. aq NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (Merck, Kieselgel 60) with hexane/ethyl acetate=2/1 for elution to give the product (1.32 g).