Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](=[O:36])[N:18]([CH2:37][CH2:38][CH3:39])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](=[O:36])[N:18]([CH2:37][CH2:38][CH3:39])[C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(OCc4ccccc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2c(nc(-c3ccc(O)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 8-(4-benzyloxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.500 g, 0.91 mmol) in methanol (10 ml), 10% Pd/C (0.150 g) was added and stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered, solvent was removed and the residue was washed with hexane to obtain 8-(4-hydroxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione as a white solid (0.398 g, 95%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1COCC1.O>[OH:13][C:11]([C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH2:16][CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: c1cscn1
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](C(C)=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of thiazole (800 mg, 9.40 mmol) in THF (94 mL) was cooled to −78° C. nBuLi (2.5 M in THF, 3759 μl, 9.40 mmol) was added and the solution was stirred for 30 minutes at −78° C. Butyl cis-4-acetylcyclohexanecarboxylate (2552 mg, 11.28 mmol) in THF (5 mL) was added in one portion and the solution was stirred for one hour at −78° C. The reaction was diluted with water and then warmed to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5-30% ethyl acetate/hexanes) to afford cis-butyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calc'd. for C16H25NO3S [M+H+] 312. found 312.
Reaction SMILES: [C:1]1([C:15](OCC)=[O:16])[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[C:1]1([CH2:15][OH:16])[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccc2c1CCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1cccc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Under a dry nitrogen atmosphere a solution of ethyl 9,10-dihydrophenanthrene-1-carboxylate (5.15 grams, 0.02 mole) in anhydrous diethyl ether (50 ml) was added to a slurry of lithium aluminum hydride (0.5 grams, 0.013 mole) in anhydrous diethyl ether (100 ml). The rate was such that a reflux was maintained throughout the addition. After complete addition, the mixture was stirred at room temperature for two hours. Water (1 ml) was cautiously added to the reaction mixture, followed by 10% aqueous sodium hydroxide (1 ml) and water (3 ml). Diatomaceous earth was added to the mixture and the resultant mixture filtered. The filter cake was washed with diethyl ether and the filtrates combined and evaporated under reduced pressure to give a green solid. This solid was chromatographed on silica gel using methylene chloride as eluant to give a brown solid. Recrystallization from n-hexane gave 9,10-dihydrophenanthrene-1-methanol (1.5 grams) as tan crystals (mp 108°-110°).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([CH2:9][CH2:10]F)([F:8])([F:7])[F:6].Cl.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:6][C:5]([F:8])([F:7])[CH2:9][CH2:10][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: FCCC(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: FC(F)(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 9.4 g AlCl3 in 90 mL benzene cooled in an ice bath, was added (over 18 minutes) a solution of 14.2 g of CF3CH2CH2F in 10 mL benzene. The mixture was stirred for an additional 0.5 hour at ice-bath temperature and 1 hour at room temperature. It was then poured into 50 g ice and 25 mL concentrated HCl, and the resulting solution stirred until the color disappeared. The benzene layer was separated, washed with 25 mL saturated NaCl and dried (Na2SO4). Distillation provided 1,1,1-trifluoro-3-phenylpropane (CH3CH2CH2Ph), bp 77-79° C. at 32 mm Hg. 1H NMR: 7.1(5H), 2.8(m) ppm. 19F NMR: -67.2 (t, J=9.7 Hz) ppm. This example shows the utility of CF3CH2CH2F. It illustrates that it can be used in a Friedel-Crafts reaction to make the same product as would be obtained if CF3CH=CH2 had been used.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17](=[S:19])[NH:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CCO.O>[C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:10][C:9]([C:12]2[C:21]([Cl:22])=[CH:20][C:15]3[NH:16][C:17]([S:19][CH2:2][C:3]([OH:5])=[O:4])=[N:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)CBr
Reactant: S=c1[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetic acid (43.4 mg, 0.312 mmol) in EtOH (1 mL) was added dropwise to a 20 mL scintillation vial equipped with a stirring bar and a septum cap containing a solution of compound 2-3 (52.6 mg, 0.156 mmol) in EtOH (0.5 mL). To this solution, 1M KOH (1.5 mL) was added dropwise, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with water (4 mL) and acidified with 10% aqueous HCl. The solution was extracted with EtOAc (3 mL, then three times 1 mL). Extracts were combined and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1 mL), filtered and purified by reverse-phase HPLC with to give the title compound as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.70-7.76 (4H, m), 7.64 (1H, s), 7.46-7.55 (4H, m), 7.45 (1H, s), 7.36-7.40 (1H, m), 4.12 (2H, s); LRMS (API-ES): calculated for C21H15ClN2O2S 394.1, observed m/e 395.0 (M+H)+ (Rt 3.14 min).
Reaction SMILES: S([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)(=O)=O.[OH-:14].[Na+]>>[OH:14][C:13]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Agent: [Na+]
Product: O=C(O)c1cccc(O)c1

Procedure:
The sulphobenzoic acid melt is pumped or injected under pressure, for example into previously taken molten 60 to 90% strength sodium hydroxide solution, in the course of which, merely by utilizing the heat thus liberated, the reaction temperature of, for example, 260° to 370° C. is reached, which is advantageous for the subsequent reaction to give 3-hydroxybenzoic acid. If it is intended to achieve, in this process variant, a limitation of the simultaneous increase in pressure, this can be effected by blowing off steam.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]1[CH2:20][CH2:19]1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH:18]1[CH2:20][CH2:19]1)[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 58.5 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole (367 mg, 1.1 mmol) was alkylated by treating with 0.1 mL (1.1 mmol) of methyl bromoacetate and 43 mg (1.1 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane to give 265 mg (59% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Br[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:30])[C:8]1=[O:21]
Reactant: CC(Br)c1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: CC(c1ccccc1)n1c(=O)n(O)c(=O)c2sc3ccccc3c21

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with (1-Bromoethyl)-benzene and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.16 (d, J=7 Hz, 3H); 6.49 (q, J=7 Hz, 1H); 7.30-7.65 (m, 6H); 7.73 (dd, J=8 Hz, 1H); 8.10 (d, J=8 Hz, 1H); 8.31 (d, J=8 Hz, 1H); 10.80 (br s, 1H); Retention time=2.70 min., m/z=339.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=[O:15])[CH3:14]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13](=[O:15])[CH3:14])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2pc[nH]c12
Reactant: CC(=O)OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a suspension of 7-amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.3 g, 2 mmol) in dry DMF (20 mL) was added sodium hydride (96 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at ambient temperature for 30 min and 4-bromobutyl acetate (0.35 mL, 2.4 mmol) was added. After stirring for 3 h, DMF was evaporated and the residue was purified by chromatography over a silica gel column (2×15 cm). The column was flash eluted with dichloromethane containing 0-5% methanol. The homogeneous fractions containing the desired product were collected and evaporated under reduced pressure to yield 0.34 g (64%) of the title compound, mp 168-170° C. 31 p nmr (DMSO-d6): δ 62.34. 1H nmr (DMSO-d6): δ 1.56 (m, 2 H, CH2), 1.90 (m, 5 H, CH2, CH3), 4.00 (t, 2 H, NCH2), 4.30 (t, 2 H, CH2), 8.27 and 8.38 (2s, 2 H, NH2), 8.50 (d, 1 H, C5H), and 8.92 (d, 1 H, J =56.4 Hz, C2H ). Anal. Calcd. for C11H15N4O2P: C, 46.99; H, 5.43; N, 19.49. Found: C, 46.69; H, 5.44; N, 19.37.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:18])([CH:14]([CH3:17])[CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.Cl[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:18]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:15][CH:14]2[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)C1(N)CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of an optically-active compound of 3-amino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylic acid tert-butyl ester (258 mg), triphenylphosphine (472 mg) and triethylamine (502 μl) in dichloromethane (7.7 ml) cooled to 0° C. was added carbon tetrabromide (596 mg). The reaction mixture was stirred at room temperature for 2.5 hours and cooled to 4° C. Then, thereto were added triethylamine (279 μl) and benzyl chloroformate (267 μl), and the mixture was stirred for 40 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1 to 2/1) to give the titled compound (85 mg).
Reaction SMILES: C(OC([N:8]1[CH:13]([C@@H:14]([OH:29])[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH2:9]1)=O)(C)(C)C.[ClH:37].O1CCOCC1>>[ClH:37].[C:26]([NH:25][C@@H:15]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[C@@H:14]([C@@H:13]1[NH:8][CH2:9][C@H:10]([CH2:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[O:11][CH2:12]1)[OH:29])(=[O:28])[CH3:27]
Reactant: CCCC(=O)OC[C@H]1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(=O)OC[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)CO1
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To (R)-5-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-butyryloxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.022 g, 0.043 mmol) add 4 M hydrogen chloride in 1,4-dioxane (0.500 mL, 2.00 mmol) and stir for 45 minutes. Concentrate under reduced pressure to give the title compound as an off-white solid (20.0 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:27])[C:5]=2[NH:4][N:3]=1.O.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:27])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
(S)-Methyl 2-(1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (230 mg, 0.542 mmol) was dissolved in a mixture of tetrahydrofuran (5.0 mL) and methanol (5.0 mL). Water (5.0 mL) was added to the mixture followed by lithium hydroxide hydrate (66 mg, 1.573 mmol). Reaction was warmed to 50° C. and held with stirring for 4.5 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was neutralized with 1.6 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 94% yield. MS (M−H)−=407.9, 409.9.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:21])=[O:20])[CH:16]=[N:17][CH:18]=1>>[CH3:11][C:3]1[N:4]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[S:6][C:2]=1[C:13]1[CH:18]=[N:17][CH:16]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:21])=[O:20])[CH:14]=1
Reactant: O=S(=O)(NCCN1CCOCC1)c1cncc(Br)c1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Product: CC(=O)Nc1nc(C)c(-c2cncc(S(=O)(=O)NCCN3CCOCC3)c2)s1
Yield: 7 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-N-(2-morpholinoethyl)pyridine-3-sulfonamide to give the title compound (Method A HPLC: retention time 3.7 minutes; 8 mg, 7%); 1H NMR Spectrum: (DMSOd6) 12.27 (1H, br s); 8.91 (1H, d); 8.87 (1H, d); 8.17 (1H, br t); 7.96 (1H, br s); 3.42 (4H, br t); 3.00 (2H, t); 2.40 (3H, s); 2.29 (2H, t); 2.22 (4H, br t); 2.16 (3H, s); Mass Spectrum: M+H+ 426.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH2:12]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14].O>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)Cc1cccc([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
To a solution of 5.13 g of m-nitro-benzyl chloride in 100 ml benzene at 10° C. was added in small portions 6.2 g of dipropylamine over a period of 15 minutes. The reaction mixture was stirred and allowed to come to room temperature for 1.5 hours, and was then refluxed for 4 hours. Water was added to the solution and the organic layer was separated and collected. The organic layer was washed with water (3×100 ml), dried (MgSO4) and stripped to leave a dark-red oil. The product (Compound No. 1) was chromatographed over silica gel (hexane: CH2Cl2 ; 1.0:0; 4:1), to yield the title product as a yellow-amber oil. Analysis: C: calculated, 66.08; found, 65.38. H: calculated, 8.53; found 8.55. N: calculated, 11.85; found, 11.73.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.Cl>C(O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@H](O)CO)cc1
Temperature: 25 °C

Procedure:
An amount of 127.1 g (221.4 mmol) of the compound from example 6A were suspended in 800 ml of ethanol and admixed with 800 ml of 37% strength hydrochloric acid. The mixture was stirred under reflux overnight. After cooling to room temperature, the precipitate formed was isolated by suction filtration, washed with ethanol and dried under reduced pressure at 50° C. overnight. This gave 108.3 g (92% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][CH2:13][CH2:12][C:11]2=[O:24])=[CH:6][CH:5]=1)([O-])=O.O.N>CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][CH2:13][CH2:12][C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccc([N+](=O)[O-])cc1
Agent: [Ti+3]
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
A solution of 6.5 g of 1-(4-nitrophenyl)-6-(3,4-dichlorophenyl)-2-piperidone in 180 ml of methanol was cooled to 4° C., and then 110 g of 25% titanium trichloride was added dropwise to the solution. After stirring at 18° to 20° C. for 40 minutes, the reaction mixture was poured into cold ammonia water and the precipitates were filtered off. The filtrate was extracted with chloroform. On the other hand, the precipitate obtained above was throughly washed with chloroform. The chloroform layer was combined with the former, washed with water, dried, and concentrated. The residue was recrystallized from ethanol to give 4.59 g of 1-(4-aminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C([Li])CCC.[CH3:32][CH:33]([CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O>[CH3:48][C:47]([CH2:46][CH2:45][CH2:44][CH:43]([CH3:50])[CH2:42][CH2:41][CH2:40][CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:2])[CH3:38])=[CH2:49]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A flask, equipped with a mechanical stirrer and placed under argon, was charged with 1.80 mol (642.6 g) of triphenylmethylphosphonium bromide and 2 L of THF. To this suspension 1.88 mol (1.175 L) of a solution of butyllithium (1.6 mol/L in hexane) were added dropwise during 3 hours at 0° C. The resulting mixture was stirred at 0° C. for an additional hour. Then 1.50 mol (402.7 g) of 6,10,14-trimethyl-2-pentadecanone were added dropwise at 0° C. during 1 hour and the mixture was allowed to warm up to 22 to 23° C. After 2 hours, 150 mL of water were added dropwise and the resulting white suspension was filtered off over decalite. The filtrate was washed thrice with 300 mL of water and dried over Na2SO4. After filtration and evaporation of the solvent in vacuo, the mixture was filtered off over decalite to remove white cristals and the filtrate was evaporated in vacuo. The resulting crude oil was purified by distillation under vacuum (145° C., 0.2 mbar) to give 1.20 mol (319.2 g) of 2,6,10,14-tetramethylpentadecene as a colorless oil (yield: 80% based on 6,10,14-trimethyl-2-pentadecanone; purity: 96.2%-GC area).
Reaction SMILES: O=[C:2]([CH3:28])[C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:40][C@@H:41]([CH2:46][C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:45][O:44][C:42]([C@@H:41]([NH:40][C@H:2]([CH3:28])[C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])[CH2:46][C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:49][CH:48]=1)=[O:43]
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)N[C@H](C)[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.3 %

Procedure:
To a mixture of methyl (2S)-3-oxo-2-tritylaminobutyrate (2.00 g) and methyl (2S)-2-amino-3-(3-indolyl)propionate mono-p-toluenesulfonate (3.13 g) in methanol (30 ml) was added sodium cyanoborohydride (360 mg) and the mixture was stirred for 1 day at room temperature. The mixture was diluted with chloroform and washed successively with water and brine. The organic phase was separated and dried over magnesium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel (50 g) column and the elution was carried out with a mixture of n-hexane and ethyl acetate (4:1). The object fractions were collected and evaporated in vacuo to give methyl (2S,3R)-3-[[(1S)-1-methoxycarbonyl-2-(3-indolyl)ethyl]amino]-2-tritylaminobutyrate (625 mg) as a pale yellow oil.