Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[CH:5]([C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1N)([CH3:7])[CH3:6].[BrH:18]>O>[CH:5]([C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1[Br:18])([CH3:7])[CH3:6]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.5 g of sodium nitrite in 20 ml of water was added at -20° C. to 0° C. over 20 minutes to a suspension of 18.5 g of the product of Step C, 120 ml of a 48% hydrobromic acid solution and 80 ml of water and the mixture was stirred at 0° C. for 15 minutes and kept thereafter at 0° C. A solution of 22 g of cuprous bromide in 80 ml of 48% hydrobromic acid solution was heated with stirring to 50°-55° C. and the previous solution was then added thereto. The mixture was stirred at 55°-60° C. for one hour, was cooled and poured into water. The mixture was extracted with methylene chloride and the combined organic phases were washed with N sodium hydroxide solution, with water, dried and evaporated to dryness under reduced pressure at 50° C. The residue was rectified under reduced pressure to obtain 20.4 g of 3-isopropyl-4-bromo-nitrobenzene with a boiling point of 150°-152° C. at 8 mm Hg and having a refractive index of nD22 =1.5775.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[C:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=2)[C:8](=[O:11])[O:9][CH3:10])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)=O)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-(1-hydroxyethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 140, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 2:3 EtOAc:hexane. 1HNMR (CDCl3, 600 MHz) δ 8.02 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.32-7.55 (m, 4H), 6.99 (m, 1H), 4.18-4.58 (m, 4H), 3.79 (s, 3H), 3.69-3.76 (m, 3H), 2.57 (s, 3H). LC-MS (M+1) 608.3 (4.19 min).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=2)[C@H:10]1[CH3:27])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=2)[C@H:10]1[CH3:27]
Reactant: COc1cc(N2C(=O)C3(CC3)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)C3(CC3)[C@@H](O)[C@@H]2C)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-methoxybenzonitrile (320 mg) in tetrahydrofuran (8 mL)-methanol (8 mL) was added 6 mol/L hydrochloric acid (6 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 49.7 mg, 22%).
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23]([C:25]4[NH:26][C:27]([C:30]5[O:31][C@@H:32]([CH3:35])[CH2:33][N:34]=5)=[CH:28][CH:29]=4)[CH:22]=[C:21]([O:36][C@@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[CH:20]=3)=[CH:14][N:13]=2)(=[O:11])=[O:10])=CC=1>FC(F)(F)C(O)=O>[CH3:40][O:39][CH2:38][C@H:37]([CH3:41])[O:36][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]2[NH:26][C:27]([C:30]3[O:31][C@@H:32]([CH3:35])[CH2:33][N:34]=3)=[CH:28][CH:29]=2)[CH:22]=1)[O:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH3:7])(=[O:11])=[O:10])=[N:13][CH:14]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
N-(4-Methoxybenzyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridine-2-sulfonamide (292 mg, 0.47 mmol) synthesized in Example (121c) was dissolved in trifluoroacetic acid (2 mL), and stirring was carried out at 45° C. for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride and triethylamine were added in small portions to the residue, and the solvent was distilled off again under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (208 mg, yield 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26].[CH2:27]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH3:30])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: CCCCNCCCC
Reactant: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 36.1 %

Procedure:
1 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 0.98 g (7.5 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.44 g (36%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[C:3]=1[C:22]1([OH:26])[CH2:25][O:24][CH2:23]1.[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][C@@H:51]3[CH3:60])=[CH:46][N:45]=2)[C:29]1=[O:61].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:26][C:22]1([C:3]2[C:4]([N:8]3[CH2:20][CH2:19][N:11]4[C:12]5[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=5[CH:18]=[C:10]4[C:9]3=[O:21])=[N:5][CH:6]=[CH:7][C:2]=2[C:32]2[CH:31]=[C:30]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([N:50]4[CH2:55][CH2:54][N:53]([CH:56]5[CH2:57][O:58][CH2:59]5)[CH2:52][C@@H:51]4[CH3:60])=[CH:46][N:45]=3)[C:29](=[O:61])[N:28]([CH3:27])[CH:33]=2)[CH2:23][O:24][CH2:25]1
Reactant: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1C1(O)COC1)CCCC3
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3C3(O)COC3)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 14.4 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 148b (100 mg, 0.3 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 130f (173 mg, 0.36 mmol), Pd(dppf)Cl2 (15 mg, 0.015 mmol), K3PO4 (130 mg, 0.6 mmol), and NaOAc.3H2O (90 mg, 0.6 mmol) in CH3CN (30 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 25:1 DCM/MeOH to afford 148 (30 mg, 20%) as a pale yellow solid. MS: [M+H]+ 693.3. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=2, 1H), 8.50 (d, J=5, 1H), 8.01 (d, J=2.5, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.38-7.32 (m, 2H), 6.89 (s, 1H), 6.83 (d, J=8.5, 1H), 6.67 (s, 1H), 4.93 (d, J=6, 1H), 4.71-4.63 (m, 6H), 4.46 (d, J=7.5, 1H), 4.24-4.18 (m, 2H), 4.10-4.05 (m, 1H), 3.90 (d, J=12.5, 1H), 3.70 (s, 3H), 3.55-3.46 (m, 2H), 3.10 (t, J=4.5, 2H), 2.63-2.48 (m, 7H), 2.22 (t, J=7.5, 1H), 1.92-1.88 (m, 2H), 1.82-1.77 (m, 2H), 1.02-1.00 (m, 3H)
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1cnc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc(Br)ncc1=O
Reaction time: 0.25 h

Procedure:
5-Bromopyrazin-2-ol (1.209 g, 6.91 mmol) was dissolved in DMF (10.0 mL) and sodium hydride (60% in mineral, 530 mg, 13.25 mmol) was added. The reaction flask was put in a water bath and stirred under argon for 15 minutes, and then (2-bromoethoxy)(tert-butyl)dimethylsilane (1.69 mL, 7.93 mmol) was added as a solution in DMF (4.7 mL total volume), followed by a ˜0.5 mL rinse with DMF. The reaction was stirred under argon at room temperature for 2 days. It was then quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The organic extracts were combined, washed with water (4×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The material was taken on crude to the next step.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].[N:5]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1.[OH-].[Na+]>O.C(O)(=O)C>[N:5]1([CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:3]([NH2:4])=[O:1])=[CH:18][CH:19]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: N#CO[K]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(c1ccc(NC(N)=O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A solution of KOCN (2.25 g) in water was added dropwise at RT to a mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0278 mol) in acetic acid (4 ml) and water (50 ml) and the mixture was stirred at RT for 1 hour. The mixture was neutralized with NaOH 3N and extracted with CH2Cl2 and CH3OH. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.3). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone, yielding 2.7 g (51.4%) (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenylurea (compound 266).
Reaction SMILES: [CH:1]1([C:4]2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11]C)=O)[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:13]=[C:8]([CH2:9][OH:11])[C:7]([O:14][CH2:15][CH3:16])=[CH:6][C:5]=2[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)[CH2:2][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C2CC2)cc1C(=O)OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2cccc(F)c2)c(C2CC2)cc1CO
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of methyl 5-cyclopropyl-2-ethoxy-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.50 g), (3-fluorophenyl)boronic acid (1.90 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.418 g), a 2 M aqueous sodium carbonate solution (10.2 mL), tris(dibenzylideneacetone)dipalladium(0) (435 mg), and toluene (20 mL) was stirred overnight at 100° C. in an argon atmosphere. Water was added to the reaction mixture, and then, the mixture was filtered through celite, followed by extraction with ethyl acetate. The organic layer was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). A THF (10 mL) solution of the obtained purified product was added to a THF (20 mL) suspension of lithium aluminum hydride (500 mg) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (0.5 mL) and a 15% aqueous sodium hydroxide solution (0.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (1.5 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.80 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:17])[NH:11]2)[OH:5].C(N(CC)CC)C.[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53][NH:2][CH2:3][C@H:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]([OH:16])=[C:12]5[C:7]=4[CH:8]=[CH:9][C:10](=[O:17])[NH:11]5)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(C=O)ccc1OCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)ccc1OCCOC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a suspension of (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (0.211 g, 0.83 mmol) in methanol (6 mL) was added triethylamine (0.229 mL, 1.65 mmol). The mixture was stirred for 10 minutes and then a solution of 2-(4-formyl-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.445 g, 0.69 mmol) in methanol (2 mL) was added. The mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (0.292 g, 1.38 mmol) followed by acetic acid (0.188 mL, 3.28 mmol) added and the reaction continued for a further 18 hours. The reaction mixture was quenched with water and evaporated at reduced pressure. The residue dissolved in iso-butanol and washed with water. The organic phase was evaporated at reduced pressure and the crude material was purified by reverse phase preparative HPLC to afford the title compound (0.065 g, 11%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15]OCC.C(OC(=O)C)(=O)C>>[CH3:11][O:12][C:13](=[O:22])[C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CCOC=C(C(=O)OC)[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 45 h
Yield: 51 %

Procedure:
A 4-l. battery jar was charged with 641 g (4.23 moles) of 6-chloroindole, 926 g (5.3 moles) of crude (ca. 85% pure) alpha-nitro-beta-ethoxy acrylic acid methylester and 475 g (4.65 moles) of acetic anhydride. The mixture was well stirred at room temperature for 45 hours to give a highly viscous suspension of an orange precipitate. 1.5 l of a mixture of benzene-ether-hexane 1:1:3 was added and the mixture stirred vigorously for 30 minutes. The product was collected by filtration, washed with 1.0 l of the same solvent mixture and dried at room temperature and 16 mmHg to constant weight to afford 600 g (51%) of product as orange crystals, m.p. 159°160°.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Pb+2].[F:31][C:32]([F:39])([F:38])[CH2:33][S:34]([OH:37])(=[O:36])=[O:35]>CO>[F:31][C:32]([F:39])([F:38])[CH2:33][S:34]([O-:37])(=[O:36])=[O:35].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S(=O)(O)CC(F)(F)F
Agent: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: O=S(=O)([O-])CC(F)(F)F
Temperature: 40 °C

Procedure:
In 36 g of methanol was dissolved 3.3 g (0.009 mol) of (4-tert-butoxyphenyl)diphenylsulfonium chloride. 1.7 g (0.0063 mol) of lead carbonate and 1.6 g (0.010 mol) of 2,2,2-trifluoroethanesulfonic acid were added to the solution, which was heated at 40° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. 100 g of chloroform was added to the residue, the solution was washed with 100 g of water, and evaporated again, obtaining 3.1 g (two-steps yield 50%) of (4-tert-butoxyphenyl)diphenylsulfonium 2,2,2-trifluoroethanesulfonate with 98% purity.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.[ClH:17].O1CCOCC1>C(O)C.[C].[Pd]>[ClH:17].[CH3:16][O:15][CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC[C@@H]1CNCCO1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
(2S)-4-Benzyl-2-methoxymethylmorpholine (3 g) is dissolved in ethanol (50 ml) and thereto are added 4N hydrogen chloride/dioxane (3.4 ml) and 10% palladium-carbon (0.3 g), and the mixture is stirred under hydrogen pressure of 5 kg/cm2 at 40° C. for 6 hours. After removing palladium-carbon, the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-methanol to give the title compound (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:29]([N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:30][CH2:29][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)CCCl
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Temperature: 100 °C

Procedure:
The title compound was prepared by reacting the compound of Preparation 4a supra, 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with an equimolar amount of 2-(N,N-diethylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol). The mixture was heated to 100° C. and was maintained at that temperature for about two hours. The reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:16]C(=O)OC(C)(C)C)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[NH2:16][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-benzyl-2-oxoazocan-3-ylcarbamate (9.0 mg, 0.027 mmol) in DCM (0.2 mL) at rt was added TFA (0.2 mL). The clear solution was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-Amino-1-benzylazocan-2-one trifluoroacetate (6.3 mg, 0.027 mmol, 100% yield) as a colorless oil. Anal. Calcd. for C14H20N2O m/z 232.3. found: 233.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].O.Cl>C1COCC1>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:8]2[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Reaction time: 1 h

Procedure:
2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid ethyl ester (1.64 g, 5.2 mmol) is dissolved in THF (20 ml), treated with aq. NaOH (1N, 10.5 ml, 10.5 mmol) and stirred for 1 h at reflux temperature. After cooling water is added and the mixture acidified with aq. HCl (3N). The mixture is extracted with ethyl acetate (3×50 ml), the extract washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid as a colorless solid. Yield 1.36 g (92%)