Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH2:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]2[N:28]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:30]=[C:23]2[N:22]=1.S(Cl)(Cl)(=O)=O.[OH-].[Na+]>C(Cl)CCl.C(#N)C>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]2[N:28]=[C:29]([S:31]([NH:13][C:7]3[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:32])=[O:33])[N:30]=[C:23]2[N:22]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: CC(=O)OCc1cccc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)OCc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 13.1 %

Procedure:
A solution of 1.30 gm (6.50 mmol) of 2-amino-3-chlorobenzyl acetate, 4.11 gm (52.0 mmol) of pyridine and 5.0 ml of acetonitrile was treated with 1.61 gm (6.50 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride and the resulting mixture stirred at 25° C. for 120 hours. An additional 0.53 gm (2.2 mmol) of the sulfonyl chloride was added and stirring at 25° C. continued for an additional 24 hours. The mixture was filtered and the filtrate evaporated to provide a brown oil. The oil was then dissolved in 40 ml of m ethylene chloride and stirred with 25 ml of 0.5M NaOH. After 5 minutes, the aqueous phase was separated, washed with ether and acidified with 3N HCl. A light brown solid was collected, washed with water, dried and recrystallized from acetonitrile to provide 0.35 gm (13%) of the desired product as a solid, m.p. 214°-217° C., containing approximately 10% of an impurity. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: COc1ccc(CC(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Yield: 14 %

Procedure:
Prepared as in Example 8 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(4-methoxyphenyl)acetyl chloride in 14% yield. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.15-1.29 (m, 1H), 1.44-1.65 (m, 4H), 1.70-1.78 (m, 1H), 3.01 (m, 1H), 3.66 (s, 2H), 3.70 (s, 3H), 3.90 (br s, 1H), 4.19 (br s, 1H), 4.43 (t, J=12 Hz, 1H), 5.03 (br s, 1H), 5.64 (d, J=8 Hz, 1H), 6.80 (t, J=8 Hz, 3H), 7.13 (d, J=8 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.81 (br s, 2H), 10.63 (s, 1H). M+H=459.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(CC)CC.ClC(OCC)=O.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>C1COCC1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cnccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (2.00 g, 16.1 mmol) and Et3N (2.50 ml, 17.7 mmol) in THF (40 mL) was added ethyl chloroformate (1.74 mL, 17.7 mmol) dropwise at 5° C. and the mixture was stirred at 5° C. for 1 hour. 4-Fluoro-3-nitroaniline (2.80 g, 17.7 mmol) was added to the mixture at 5° C. The mixture was warmed to room temperature, stirred at room temperature for 4 hours, and then evaporated. The residue was suspended in a mixture of H2O (100 ml) and i-Pr2O (100 ml) and stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration and washed with H2O and i-Pr2O to give the desired product as pale brown crystals (2.91 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:6][C:7](=[O:10])[O:8][CH3:9].C[O-].[Na+].[CH3:20][C:21](=[CH:23][CH2:24][CH2:25]/[C:26](=[CH:28]/CO)/[CH3:27])[CH3:22].CO>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:5]([CH2:4][C:3]([O:2][CH2:1]/[CH:28]=[C:26](/[CH2:25][CH2:24][CH:23]=[C:21]([CH3:20])[CH3:22])\[CH3:27])=[O:16])[CH2:6][C:7](=[O:10])[O:8][CH2:9]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])\[CH3:22]
Reactant: COC(=O)CN(CC(=O)OC)CC(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)=CCC/C(C)=C/COC(=O)CN(CC(=O)OC/C=C(\C)CCC=C(C)C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-bis(2-methoxy-2-oxoethyl)glycine methyl ester (7.0 g, 30 mmol, 1 eq) in toluene (80 ml) under argon was slowly added some sodium methoxide (0.49 g, 0.009 mol, 3*0.10 eq) and geraniol (14.57 g, 95 mmol, 3*1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over two hours after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-bis(2-geranyloxy-2-oxoethyl)glycine geranyl ester as a yellow oil (quantitative yield).
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:9]([OH:8])[C:10]=3[CH:11]=[CH:12]2)=[CH:19][CH:20]=1
Reactant: c1ccc(COc2ccc(-n3ccc4c(OCc5ccccc5)cccc43)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccc3c(O)cccc32)cc1
Yield: 69.2 %

Procedure:
4-[(phenylmethyl)oxy]-1-{4-[(phenylmethyl)oxy]phenyl}-1H-indole (D24) (143 mg, 0.352 mmoL) was dissolved in ethyl acetate (10 mL) and was hydrogenated at room temperature and atmospheric pressure in the presence of 10% palladium on charcoal (50% wet) (70 mg). After 28 hours the mixture was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage SP4) eluting with a gradient of 0 to 100% ethyl acetate in hexane to give the title compound (E14), (55 mg).
Reaction SMILES: [O:1]=[C:2]([NH:12][C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:15]=2[CH:14]=1)[CH2:3][NH:4]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:14]1[C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[O:17][C:16]=2[CH:25]=[CH:26][C:13]=1[NH:12][C:2](=[O:1])[CH2:3][NH2:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 72.2 %

Procedure:
A solution of tert-butyl [2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.10 g) in 1:1 trifluoroacetic acid:dichloromethane (5 mL) was stirred at room temperature for 30 min and then concentrated to provide N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (52 mg) as its trifluoroacetic acid salt. MS (ESI) m/z 259 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.C(Cl)Cl>CS(C)=O>[CH3:1][C:2]1([CH3:11])[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]=[O:10])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(CCO)CC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)CCC(CC=O)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 109.3 %

Procedure:
Under an argon atmosphere, to a mixture of 2-(4,4-dimethylcyclohexyl)ethanol (25.3 g) and DCM (200 mL) were added DMSO (50 mL) and TEA (100 mL), and a sulfur trioxide-pyridine complex (77.7 g) was added in small divided portions while maintaining the inner temperature to 10° C. or lower under ice-cooling. After stirring at room temperature for 2 hours, to the reaction mixture was added ice water, followed by concentration under reduced pressure and then extraction with chloroform. The organic layer was washed sequentially with 1 M hydrochloric acid and brine. To the organic layer was added MgSO4, followed by stirring. Then, the mixture was filtered and concentrated under reduced pressure to obtain (4,4-dimethylcyclohexyl)acetaldehyde (27.3 g).
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:47]=[CH:46][C:20]([O:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH:26]2[CH2:38][O:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:24])=[CH:46][CH:47]=1
Reactant: COc1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OCC(=O)N2CCNCC2COc2cccnc2)cc1
Reaction time: 12 h
Yield: 19 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(2-(4-methoxyphenoxy)acetyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (182 mg, ≦0.305 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were brought to pH ˜12 with 1 N NaOH and were extracted with EtOAc (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 20.9 mg (19%) of the desired product as a thick oil. LC-MS: RT=3.76 min, [M+H]+=358.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C@@H:10]3[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@@H:29]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@H:20]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:11]3[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56]Cl)=[CH:54][CH:53]=1.O>CN(C)C=O>[CH3:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C@@H:10]4[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[C@@H:29]([O:30][CH2:31][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[C@H:20]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C@H:11]4[O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=3)[CH:3]=[CH:2]2)=[CH:54][CH:53]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: c1ccc(COC[C@H]2O[C@@H](c3ccc4cc[nH]c4c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2ccc3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc32)cc1
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To a solution of 1-(1H-indol-6-yl)-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (0.13 g) in N,N-dimethylformamide (2 mL) was added sodium hydride (60%, 0.01 g) at 0° C., and the mixture was stirred for 10 minutes. To the mixture was added 4-methylbenzylchloride (0.032 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.12 g).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=1)=[O:7])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][C:5]=1[C:6]([NH:8][C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[N:10]=1)=[O:7]
Reactant: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (900 mg, 1.96 mmol, 1.00 equiv) in methanol (15 mL) and ethyl acetate (15 mL). The mixture was treated with Pd/C (500 mg) stirred under a hydrogen atmosphere for 1 h at room temperature in an oil bath. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 600 mg (71%) of product as a brown solid.
Reaction SMILES: [C:1](=[O:22])([O:3][C@@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=O)[NH2:2].C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>COCCOC>[C:1](=[O:22])([O:3][C@@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:29])[NH2:2]
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@H](OC(N)=O)C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(c1c[nH]c2ccccc12)[C@H](OC(N)=O)C(N)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-tert-butyl-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl carbamate (500 mg, 1.6 mmol) in anhydrous 1,2-dimethoxyethane (10 mL) was mixed in portions with sodium hydrogencarbonate (520 mg, 6.2 mmol) and diphosphorus pentasulphide (730 mg, 3.2 mmol) and stirred overnight at room temperature. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up in ethyl acetate (30 mL) and washed with water and saturated sodium hydrogencarbonate solution (3×20 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (600 mg) was taken up in diethyl ether/cyclohexane (10 mL each) and concentrated to low volume again. During this a white solid separated out.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:15]=[N:16][NH:17][CH:18]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Br)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)Cl>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:15]=[N:16][N:17]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2-c2c[nH]nn2)cc1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4'-Methyl-2-(1,2,3-triazol-4-yl)biphenyl (2.61 g, 11 mmol, 1.0 eq), triethylamine (1.69 mL, 12 mmol, 1 eq), tritylbromide (3.88 g, 12 mmol, 1 eq) and methylene chloride (30 mL) were mixed and stirred at 0° C. and then allowed to warm to room temperature. After 1 hour, ethyl acetate was added (200 mL) and the organic phase was washed with water (3×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield 5.15 g of a yellow solid. This product was recrystallized from methylcyclohexane to give 3.26 g of off-white crystals; m.p. 181.0°-182.5°. NMR (200 MHz, CDCl3) δ 8.18 (d, 1H, J=7Hz); 7.50-7.16 (m, 12H); 7.05-6.89 (m, 10 Hz); 6.47 (s, 1H); 2.54 (s, 3H). Anal. Calcd. for C34H27N3 : C, 85.50; H, 5.70; N, 8.80. Found: C, 86.60; H, 5.80; N, 8.94.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:2].[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[Cl:33])=[CH:15][CH:16]=1)[CH3:32]
Reactant: CCN(CC)CCCCCCOc1ccc(C(=Cc2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Combine (E and Z)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-ethylene (2.17 g, 5.07 mmol), N-chlorosuccinimide (0.745 g, 5.57 mmol), and chloroform (40 mL). Heat to reflux for 18 hours. Cool to ambient temperature. Add N-chlorosuccinimide (0.745 g, 5.57 mmol). Heat to reflux. After 2 hours evaporate in vacuo. Chromatograph on silica gel eluting with 10% methanol/dichloromethane. Combine product containing fractions and concentrate in vacuo to give the title compound. Separate the isomers by HPLC, 90 mg per injection, using a Waters and Associates μPorasil column (19 mm by 300 mm), eluting with 80/20/0.2 chloroform/hexane/triethylamine at 20 mL/minute to give (E)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene and (Z)-1-[4-(6-diethylaminohexoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH2:1]([S:8]([C:9]1[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[C:10]=1[Cl:17])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc(S(=O)Cc2ccccc2)c(Cl)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
16.0 g (60.0 millimoles) of 5-benzylthio-4-chloro-2-methylpyridazin-3(2H)-one from Method 4 were dissolved in 200 ml of dichloromethane, the solution was cooled to -20° C. and a solution of 11.4 g (66.1 millimoles) of m-chloroperbenzoic acid in dichloromethane was added dropwise. Stirring was continued for 1 hour at -10° C., and then overnight at room temperature. The reaction solution was washed three times with saturated NaHCO3 solution and once with water, dried and evaporated down, and the residue was triturated with diethyl ether and then filtered off under suction to give 13.1 g (77%) of a product of melting point 129°-131° C. (active ingredient no. 2 a).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:6](OCC)=[O:7])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Nc1ccc(C(CO)CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of 2-(4-amino-phenyl)-malonic acid diethyl ester (450 mg, 1.8 mmol) in anhydrous ether (20 ml), cooled at 0-10° C., was added lithium aluminum hydride (68 mg, 1.8 mmol). After stirring at room temperature for 2 hours, the reaction was cooled to 10° C. and quenched by the addition of hydrated sodium sulfate (2 g). The mixture was filtered and the solid was rinsed with tetrahydrofuran (10 ml). The combined filtrates were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% methanol-chloroform to provide 2-(4-amino-phenyl)-propane-1,3-diol (52 mg, 17% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: COc1ccccc1C(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1C(=O)Nc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester, from Example 173, Step A was treated with N-(4-Hydroxy-phenyl)-2-methoxy-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H29NO7 [+H]+: 480.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]>[Cu]>[CH3:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]
Reactant: Cc1c(I)cccc1[N+](=O)[O-]
Agent: [Cu]
Product: Cc1c(-c2cccc([N+](=O)[O-])c2C)cccc1[N+](=O)[O-]
Temperature: 230 °C
Yield: 46.9 %

Procedure:
A 20 mL round bottomed flask equipped with a reflux column under argon was charged with 7.05 g of 2-iodo-6-nitrotoluene and 6.55 of copper bronze. The reaction mixture was heated in an oil bath at 230° C. for 9 hours. The mixture was extracted with methylene chloride and the extract filtered. The extract was stripped of solvent and chromatographed on silica gel using carbon tetrachloride as the eluent. In this way 1.71 g (65% yield) of yellowish crystals were obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2]
Reactant: CCc1nc2cnc3cc(O)ccc3c2n1CCOc1ccccc1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2cnc3cc(OCC(=O)C(C)(C)C)ccc3c2n1CCOc1ccccc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
A suspension of 2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.0 g, 3.0 mmol) and cesium carbonate (1.49 g, 4.57 mmol) in DMF was stirred for 15 minutes; 1-bromopinacolone (0.6 mL, 4.5 mmol) was added dropwise. The reaction was heated at 65° C. and stirred for 20 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water (3×) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.3 g of 1-[2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one as an orange solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C:14]#[N:15])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24]Br>CS(C)=O>[CH2:1]([O:3][P:4]([C:13]1([C:14]#[N:15])[CH2:24][CH2:23]1)([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC#N)c1ccc(F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(c1ccc(F)cc1)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.470 g of ethyl(cyanomethyl)(4-fluorophenyl)phosphinate was initially charged in 20 ml of DMSO, and 0.572 g (4.138 mmol) of potassium carbonate and then 0.388 g of 1,2-dibromoethane were added. The mixture was stirred at room temperature for 4 h and then at 50° C. for 2 h. The reaction mixture was concentrated, taken up in dichloromethane and washed with H2O.