Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:48]1[CH2:47][CH2:46][N:45]([CH:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH2:50][CH2:49]1)=[O:16]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)CC1
Yield: 101.4 %

Procedure:
To a solution of Boc-D-tert-leucine (0.46 g) and HOBt (0.46 g) in acetonitrile (20 ml) was added WSC (0.58 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 1-(1-methyl-4-piperidyl)piperazine (0.70 g) and triethylamine (0.61 g) were added, and the reaction mixture was mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.80 g, quantitative).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:9](=[S:11])[NH2:10])=[C:6]([NH2:8])[N:7]=1.S(=O)(=O)(O)O.BrBr>>[NH2:10][C:9]1[S:11][N:8]=[C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=12
Reactant: CSc1nc(N)c(C(N)=S)s1
Agent: BrBr
Agent: O=S(=O)(O)O
Product: CSc1nc2nsc(N)c2s1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
15 parts of 2-methylmercapto-4-amino-5-thiocarbamoylthiazole are introduced, at 30° C., into 100 parts of sulfuric acid (of 98 percent strength by weight), containing 0.5 part of bromine. When the evolution of gas has subsided (after 10 minutes), the mixture is stirred for 10 minutes at 45° C. and is then poured on to 300 parts of ice, the batch is filtered and the filter residue is stirred with 100 parts of aqueous 30 percent by weight ammonia solution and filtered off. 12.5 parts of 3-amino-5-methylmercapto-thiazolo-(4,5-c)-isothiazole (84% of theory) of melting point 160°-166° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:19])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[NH:9][CH3:10].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[NH:9][CH3:10])[CH:13]([OH:19])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC

Procedure:
A suspension of 31 g. of 3',5'-dimethoxy-4'-(methylamino)-2-(methylsulfonyl)-acetophenone and 16.3 g. of sodium borohydride in 600 ml. of ethanol was stirred at room temperature for 16 hours. The solution was diluted with 600 ml. of water and the alcohol was removed by distillation under vacuum. The crystals formed were filtered with suction, washed with water and dried, whereby there was obtained 3,5-dimethoxy-4-(methylamino)-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 141°-142° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2)=[C:6]=[S:7]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:6](=[S:7])[NH:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2
Reactant: O=C1Cc2c(N=C=S)cccc2N1
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 110.8 %

Procedure:
Ethylenediamine (0.828 mL, 12.38 mmol) is added to a solution of 4-isothiocyanatooxindole (0.471 g, 2.48 mmol) in methylene chloride (20 mL). The resulting solution is stirred at room temperature for 2.5 hours. The reaction mixture is concentrated by rotary evaporation to yield 0.688 g of crude 4-[N'-(2-aminoethyl)thioureido]oxindole as a green solid. This material is carried on directly to the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:6][C:5]=1[CH2:18][OH:19].[Br:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:19][CH2:18][C:5]2[CH:6]=[CH:7][C:8]([C:14]([F:15])([F:16])[F:17])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=2[CH:3]([O:2][CH3:1])[O:20][CH3:21])=[CH:25][CH:24]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(Br)cc2)c1C(OC)OC
Yield: 77 %

Procedure:
According to a method similar to Example (6-7), from [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.00 g, 9.66 mmol) obtained in Example (6-6) and 4-bromophenol (2.00 g, 11.6 mmol), 1-[(4-bromophenoxy)methyl]-2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzene was obtained (3.46 g, yield: 77%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[CH:9][CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:9][CH:8]=2)[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2cccc(OCc3ccccc3)c2C(=O)O)=C(C)C1=O
Yield: 62.6 %

Procedure:
6-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (106 mg, 0.2345 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (321 mg, 0.5857 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (62 mg, 0.1469 mmol, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([C:24]#[N:25])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1>CO.[Pd]>[NH2:21][C:20]1[C:2]([Cl:1])=[C:3]([CH:17]=[C:18]([C:24]#[N:25])[CH:19]=1)[O:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc([N+](=O)[O-])c2Cl)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc(N)c2Cl)C1
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A mixture of (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (278 mg, 0.756 mmol) and Pd/C (80 mg, 0.038 mmol) in Methanol (20 mL) was hydrogenated at 20 psi for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 5-60% ethyl acetate/hexanes) to give (+/−)-tert-butyl 3-(3-amino-2-chloro-5-cyanophenoxy)pyrrolidine-1-carboxylate (48 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]([C:19]3[C:24]([F:25])=[CH:23][C:22]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][C:20]=3[F:30])=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:31][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[F:25][C:24]1[CH:23]=[C:22]([C:26]([OH:29])([CH3:27])[CH3:28])[CH:21]=[C:20]([F:30])[C:19]=1[C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:31])[CH3:2])=[CH:9][CH:8]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: CC(=O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-[(4-acetylphenyl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (50 mg, 0.116 mmol) was taken up in THF (1 mL) and cooled to 0° C. Methylmagnesium chloride (0.136 mL, 0.407 mmol) was added and stirring continued at 0° C. for 2.5 hours. After this time, additional THF (1 mL) was added to aid solubility, the mixture was allowed to warm to room temperature and stirring continued for 2.5 hours. Saturated NH4Cl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-10% MeOH—CHCl3) followed by MPLC (12-100% EtAOc-hexanes) gave 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(1-hydroxy-1-methylethyl)phenyl]amino}thiophene-3-carboxamide as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N=C=NCCCN(C)C)C.CCOCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[F:38])[O:28][CH:29]1[CH2:34][CH2:33][N:32]([C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(OC2CCNCC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(Oc2ccc(F)c(F)c2)CC1
Reaction time: 18 h

Procedure:
To a mixture of the product of Example 68E (225 mg, 0.73 mmol), 4-(3,4-difluorophenoxy)piperidine (155 mg, 0.73 mmol), and 4-(dimethylamino)pyridine (8.9 mg, 0.07 mmol) in CH2Cl2 (3 mL) at ambient temperature was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.129 mL, 0.727 mmol) via syringe. The reaction was stirred for 18 hours, then diluted with 50 mL CH2Cl2 and washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes). Hexanes (20 mL) were added and the flask was placed in an ultrasonic bath for 10 minutes resulting in a milky mixture. Ether (6 mL) was added to help precipitate the solid, which was collected by vacuum filtration and air-dried to give the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 10H), 7.06 (dd, J=19.1, 9.1, 1H), 6.72 (ddd, J=11.9, 6.6, 3.0, 1H), 6.64-6.55 (m, 1H), 4.49-4.32 (m, 2H), 4.11 (d, J=15.6, 1H), 3.80-3.33 (m, 6H), 2.73-2.56 (m, 2H), 2.01-1.72 (m, 6H); MS (ESI+) m/z 505 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13](B1OC(C)(C)C(C)(C)O1)=[CH:12][CH:11]=2.[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][C:33]1=[O:39].O>O1CCOCC1.[Pd]>[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([CH3:7])=[CH:16]3)=[CH:34][C:33]1=[O:39]
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2cc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)ccc2[nH]1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
Pd EnCat™ (93 mg, 0.03 mmol) was added to a mixture of potassium carbonate (115 mg, 0.83 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (86 mg, 0.33 mmol), and (2R)-N-hydroxy-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (115 mg, 0.28 mmol) in dioxane:water (2.5 mL, 5:1 mixture). The reaction mixture was heated overnight at 80° C. The reaction was cooled to ambient temperature, filtered through a nylon filter and concentrated. The material was dissolved in a minimal amount of DMSO and loaded onto a 13g c18 column. The gradient was run from 25-45% acetonitrile in water. The desired material was concentrated yielding 25 mg (22%) of a light brown solid. LCMS m/z 418.5 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 2.13-2.24 (m, 1 H) 2.32-2.46 (m, 1 H) 2.39 (s, 3 H) 3.12 (s, 3 H) 3.69-3.78 (m, 1 H) 4.06-4.16 (m, 1 H) 6.20 (s, 1 H) 6.65 (d, J=1.95 Hz, 1 H) 6.70 (dd, J=7.22, 1.95 Hz, 1 H) 7.31-7.39 (m, 2 H) 7.70 (d, J=7.22 Hz, 1 H) 7.79 (s, 1 H) 9.25 (br. s., 1 H) 11.11 (br. s., 1 H) 11.23 (br. s., 1 H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 5-hydroxy-2-methylaniline (34 mg, 0.231 mmol) similar to Example 190 and was isolated as a solid (3 mg). 1H NMR (CDCl3): 9.74 (d, J=1.2 Hz, 1H), 8.76–8.71 (m, 2H), 7.30 (brs, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.87 (brd, 1H), 6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.73 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][N:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)nc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (2.5 g, 67 mmol) was added in small portions to a solution of 6-(2-oxoethyl)pyridine-3-carbonitrile (5.0 g, crude) in 80 mL of MeOH at 0° C. The mixture was stirred at room temperature for 30 minutes and poured to 50 mL of water. The mixture was extracted with EtOAc (100 mL×5) and the combined organic layer was condensed. The residue was purified by flash chromatography to afford 6-(2-hydroxyethyl)pyridine-3-carbonitrile. TEA (2.1 g, 21 mmol) was added drop wise to a solution of 6-(2-hydroxyethyl)pyridine-3-carbonitrile (3.0 g, 20 mmol) and MsCl (2.3 g, 20 mmol) in 200 mL of DCM at 0° C. The mixture was stirred at RT for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum below 30° C. to afford the title compound which was used immediately without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH:42][CH2:41][CH2:40][CH2:39][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CCCCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(C=CCCCc1ncccn1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To the 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (902 mg, 2.0 mmol) suspended in anhydrous THF (15 ml), under Nitrogen, cooled to between −20 and −30° C. was added sequentially Lithium bis(trimethylsilyl)amide (1.0M in THF, 4.0 ml), Chlorotrimethylsilane (217 mg, 2.0 mmol, 253 μl) and 4-pyrimidin-2-ylbutanal (300 mg, 2.0 mmol). The mixture was stirred at −20° C. for 1 hour, quenched with saturated ammonium chloride solution and allowed to stand at ambient temperature overnight. The solvents were removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (5 ml), the organics separated and chromatogrammed (50 g Silica Bond Elute, eluted with 0→100% Ethyl Acetate/Hexane gradient) to give the 2-(5-[4-(4-bromophenyl)piperazino]sulfonylpent-4-enyl)pyrimidine as a white crystalline material (759 mg, 84% Yield)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:24][O:25][CH2:26][CH3:27])([OH:23])[CH:6]([N+:20]([O-])=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1)[CH3:2].[H][H]>[Ni].C(O)(C)C>[CH2:26]([O:25][CH2:24][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:23])[CH:6]([NH2:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=1)[CH3:27]
Reactant: CCCCCCc1ccc(CC([N+](=O)[O-])C(O)(COCC)COCC)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: CCCCCCc1ccc(CC(N)C(O)(COCC)COCC)cc1
Yield: 85.5 %

Procedure:
A mixture of α, α-diethoxymethyl-β-nitro-4-hexylbenzenepropanol (2.31 g) and Raney nickel (0.6 g) in isopropanol (70 ml) was stirred under hydrogen at atmospheric pressure until the hydrogen absorption was complete. The mixture was degased in vacuo for 15 minutes and filtered through celite. Evaporation of solvent gave α, α-diethoxymethyl-β-amino-4-hexylbenzenepropanol (1.82 g) as an oil. This oil was reacted with di-tert-butyl-dicarbonate (1.19 g) in methanol (40 ml). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by chromatography [silica gel 290 g, elution with ethyl acetate: cyclohexane, 2:8 (2 1)]. Two isomers of the title compound were isolated. Isomer A (0.90 g) and isomer B (0.90 g) were obtained as oils, Rf isomer A=0.30, Rf isomer B=0.19 (silica gel, ethyl acetate: cyclohexane, 1:4)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([OH:30])=[C:28]([O:31][CH3:32])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1[CH3:35].[O:36]=O>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29](=[O:30])[C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26](=[O:36])[C:25]=1[CH3:35]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: O=O
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Reaction time: 168 h

Procedure:
In dimethylformamide (200 ml) are suspended 6-(22-hydroxydocosyl)-2,3-dimethoxy-5-methyl phenol (300 mg) and bis(4-hydroxysalicylidene)ethylenediiminocobalt(II) (50 mg). The suspension is stirred in an oxygen gas stream at ambient temperature and atmospheric pressure for 7 days. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is diluted with water and extracted with ethyl acetate. The extract is treated in a conventional manner and the product is chromatographed on a silica gel column. The fractions obtained by elution with chloroform are pooled and recrystallized from ethanol to give orange-yellow needles of 6-(22-hydroxydocosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I, n=22). m.p. 89°-90.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]([C:15]#[N:16])([CH3:18])[CH3:19])[CH:21]=2)=[CH:7][C:6]=1[OH:8]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(O)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a two-layer solution of 5-amino-2-chlorophenol (3.19 g, 22.2 mmol) in tetrahydrofuran (50 mL)/1N aqueous sodium hydrogen carbonate solution (66 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (16 mL), and the mixture was stirred at room temperature for 6 hr. The aqueous layer was separated, and extracted with ethyl acetate (66 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was triturated with ethyl acetate/hexane to give the title compound (6.65 g, 95%) as a colorless powder.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=[O:21])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:12](=[O:21])[CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)Nc2ccccc2-1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)N(CCN(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.1 M) of methyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Step 4) in DMF was treated with sodium hydride (1.5 eq., 60% suspension in mineral oil) at 0° C. and then stirred at RT for 30 min. 2-Chloro-N,N-dimethylethylamine (2.0 eq.) was added and the solution stirred at 45° C. for 2 h. After cooling to RT, the suspension was diluted with EtOAc and washed with water, and brine. The organic phase was dried over sodium sulfate and the solvent evaporated in vacuo to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 8.14 (s, 1H), 7.74-7.45 (m, 4H), 5.04-5.01 (d, J 12, 1H), 4.43-4.40 (d, J 12, 1H), 4.18-4.15 (m, 1H), 3.83 (s, 3H), 3.65-3.61 (m, 1H), 2.90-2.82 (m, 1H), 2.15-2.06 (m, 2H), 1.81-1.23 (m, 10H). MS (ES+) m/z: 466 [M+H]+.