Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[F:11][C:12]([F:17])([F:16])S([O-])=O.[Na+].C(OO)(C)(C)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:12]([F:17])([F:16])[F:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=S([O-])C(F)(F)F
Reactant: Clc1cc2[nH]ncc2cn1
Agent: CC(C)(C)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1n[nH]c2cc(Cl)ncc12
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Ref: PCT Int. Appl., 2010086251, 2010. To a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (1a, 1 g, 6.51 mmol), sodium trifluoromethanesulfinate (3.05 g, 19.54 mmol) in 10 mL of DCM and 4 mL of H2O, 70% tert-butyl hydroperoxide (4.19 g, 32.6 mmol) aqueous solution was added. The heterogeneous reaction mixture was stirred vigorously at r.t. After 28 hr, LCMS analysis showed partial conversion. Additional sodium trifluoromethanesulfinate (3.05 g, 19.54 mmol) and tert-butyl hydroperoxide (4.19 g, 32.6 mmol) was added and the reaction mixture was stirred over the weekend. Water, DCM and aqueous Na2S2O3 was added. A yellow solid was filtered off and the filtrate was extracted with DCM. The organic layer was concentrated and purified (50 g silica gel, eluting with 1:30 MeOH/DCM) to give 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine as a yellow solid, which was further purified by recrystallization from MeOH/DCM/Hexane (200 mg, 13%). MS ESI calc'd. for C7H3ClF3N3[M+1]+ 222, found 222.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[NH2:19]C(N)=O>>[NH2:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18]
Reactant: NC(N)=O
Reactant: CC(C)N1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Product: CC(C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C

Procedure:
5-Chloro-2-isopropyl-6-nitroisoindoline-1,3-dione (14.40 g, 59.85 mmol) and urea (35.95 g, 599 mmol) were mixed together under argon. The mixture was stirred and heated to 150° C. for 3 h and cooled to rt. The solid was washed with 200 mL of hot water (90° C.) and filtered to remove the remaining urea. The isolated yellow solid was washed twice with hot water, dried under vacuum and purified by column chromatography (silica-gel CH2Cl2/acetone=19/1 v/v) to give a solid product.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][C:12](=[CH2:14])[C:11]([CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:10]1)(C(C)(C)C)(C)C.CCOCC>O1CCCC1>[CH3:18][CH:15]([C:11]1[C:12](=[CH2:14])[CH2:13][CH:9]([OH:8])[CH:10]=1)[CH:16]=[CH2:17]
Reactant: C=CC(C)C1=CC(O[Si](C)(C)C(C)(C)C)CC1=C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(C)C1=CC(O)CC1=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
2.02 Grams of (RS)-3-(1-methyl-2-propenyl)-4-methylidenecyclopent-2-en-1-yl t-butyldimethylsilyl ether was dissolved in 20 ml of tetrahydrofuran. Under ice-water cooling, 7.7 ml of a tetrahydrofuran solution of 1M n-tetrabutylammonium fluoride was added to the ether solution, and then stirred at an ambient temperature for six hours. The reaction solution was poured into ice-water and extracted with ether. The ether layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the oily substance obtained was subjected to silica gel column chromatography to yield 1.05 g of (RS)-3-(1-methyl-2-propenyl)-4-methylidenecyclopent-2-en-1-ol.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)[CH3:4].[CH2:22]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[C:32]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)=[O:26])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:22]([NH:24][C:25](=[O:26])[NH:27][C:28]1[N:29]=[CH:30][C:31]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:5]([C@@H:3]([CH3:4])[CH2:2][OH:1])[CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]3=[O:16])=[C:32]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:33]=1)[CH3:23]
Reactant: CCOC(=O)c1cn([C@@H](C)CO)c2ccc(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H](C)CO)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of palladium (II) acetate (28.0 mg, 0.12 mmol, 0.1 equiv.) and 1,1′-bis(di-t-butylphosphino)ferrocene (59.1 mg, 0.12 mmol, 0.1 equiv.) in acetonitrile (3 mL) was added (S)-ethyl 1-(1-hydroxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 49, 500 mg, 1.25 mmol), followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (Intermediate 17, 453 mg, 1.26 mmol) and a solution of potassium carbonate (258 mg, 1.87 mmol, 1.5 equiv.) in water (1 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to room temperature, and diluted with water (2 mL). The precipitate that formed was collected by filtration, washed with water and hexanes and dried to provide (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxypropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a grey solid (583 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13][Br:14])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(Br)cc1CBr
Yield: 92 %

Procedure:
A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.0 g, 4.0 mmol) (Ellanoval Laboratories Cat. No. 38-0304), N-bromosuccinimide (900. mg, 5.06 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (50 mL) was refluxed under a nitrogen atmosphere for 4 h. After cooling the mixture was diluted with methylene chloride. The organic solution was washed with brine, then dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (1.2 g).
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5]([CH2:9]O)([CH2:7]O)[CH2:4][C:3]=1[Br:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH2:6][C:5]([CH2:9][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])([CH2:7][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH2:4][C:3]=1[Br:11]
Reactant: OCC1(CO)CC(Br)=C(Br)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(Br)=C(Br)C2)cc1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Under nitrogen, a stirred solution of 5.7 g (19.9 mmol) of 1,2-dibromo-4,4-di(hydroxymethyl)cyclopentene (Step 5) in 50 mL of pyridine at ambient temperature was treated with 19 g (99.7 mmol) of p-toluenesulfonyl chloride. The reaction was allowed to stir overnight and was concentrated in vacuo. The residue was dissolved ethyl acetate and washed twice with 3% hydrochloric acid followed by brine. The solution was dried (Na2SO4) and concentrated in vacuo to give 5.2 g (44%) of 1,2-dibromo-4,4-di(tosylmethyl)cyclopentene (14 in Synthetic Scheme V) as a colorless semisolid: NMR (CDCl3) d 2.42 (s, 4H) , 2.47 (s, 6H), 3.90 (s, 4H), 7.37 (d, J=8 Hz, 4H), 7.74 (d, J=8 Hz, 4H) .
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>ClCCl>[C:25]1([CH3:33])[CH:30]=[CH:29][C:28](/[CH:31]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:27][CH:26]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(C)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
2.0 g of methyl (triphenylphosphoranylidene)acetate and 720 mg of p-toluenealdehyde are dissolved in 10 ml of dichloromethane and stirred at room temperature for twelve hours. Then, 4 g of kieselguhr are added, and the solvent is removed in vacuo. The resulting residue is purified on silica gel with n-heptane:ethyl acetate=4:1 as eluent. 850 mg of methyl trans-3-p-tolylacrylate are obtained as an oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 100 %

Procedure:
(2S,3R,4S)-2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (10.00 g, 29.11 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) was stirred for 1 h in 4M HCl/dioxane. The solvent was evaporated and the residue was dissolved in water which was washed with ether and then made basic with solid K2CO3. The mixture was saturated with solid NaCl and extracted into chloroform which was dried over Na2SO4 and evaporated to afford 7.09 g (100%) of a white solid, m.p. 110°-111° C.
Reaction SMILES: [Se]=O.[CH:3]([NH:5][C:6]1[N:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][N:7]=1)=[O:4].C(OCC)(=[O:19])C>O1CCOCC1>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][N:7]=1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)Cc1ccnc(NC=O)n1
Agent: O=[Se]
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccnc(NC=O)n1

Procedure:
Selenium oxide (9.92 g.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.52 g.) in dioxane (200 ml.) at 90° to 95° C. over 20 minutes, and stirred at the same temperature for an hour. After cooling the resultant solution, the solution was filtered through a column packed with silica gel (20 g.), washed with dioxane and concentrated under reduced pressure. The residue was dissolved in acetone and filtered, and then the filtrate was concentrated under reduced pressure. The residue was triturated with chloroform to give a crude product (8.2 g.). The product was added to ethyl acetate, heated and an insoluble material was filtered out. The filtrate was cooled, and the precipitates were collected by filtration to give methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate (5.55 g.). The product was recrystallized from ethyl acetate (saturated with water) to give mono hydrate thereof, mp 143° to 144° C.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]3[CH:8]=[N:9][N:10]([C:14]4[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=4)[C:11]=3[CH2:12][CH2:13][C:5]=2[CH:4]=1>ClCCl>[CH2:20]([C:17]1[CH:16]=[CH:15][C:14]([N:10]2[C:11]3[CH2:12][CH2:13][C:5]4[CH:4]=[C:3]([OH:2])[CH:24]=[CH:23][C:6]=4[C:7]=3[CH:8]=[N:9]2)=[CH:19][CH:18]=1)[CH2:21][CH3:22]
Reactant: CCCc1ccc(-n2ncc3c2CCc2cc(OC)ccc2-3)cc1
Solvent: ClCCl
Product: CCCc1ccc(-n2ncc3c2CCc2cc(O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 7-methoxy-3-(4-propylphenyl)-4,5-dihydro-3H-benzo[e]indazole (Preparation 136B, 570 mg, 1.790 mmol) in dichloromethane (8 mL), cooled to 0° C. was added borontribromide (7.16 mL, 7.16 mmol) dropwise. The reaction mixture was allowed to warm to room temperature slowly and was stirred at room temperature overnight. The reaction mixture was slowly quenched with 1 ml of MeOH. The dark colored solid that formed was filtered and dried under high vacuum to yield 370 mg of product. (yield: 62%). LC/MS M+1=305.1.
Reaction SMILES: C(Br)(CC)C.[CH:6]([CH:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[C:11]#[N:12])([CH2:8]C)[CH3:7]>>[CH:6]([CH:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[C:11]#[N:12])([CH3:8])[CH3:7]
Reactant: CCC(C)C(C#N)c1ccc2ccccc2c1
Solvent: CCC(C)Br
Product: CC(C)C(C#N)c1ccc2ccccc2c1

Procedure:
This procedure is repeated in all essential details excepting that isobutyl bromide (1-bromo-2-methylpropane) is substituted for 2-bromopropane. This latter procedure yields α-isobutyl-2-naphthaleneacetonitrile. When the procedure is repeated with sec-butylbromide the corresponding α-sec-butyl-2-naphthaleneacetonitrile is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:66][N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([N:70]4[CH2:71][CH2:72][N:67]([CH3:66])[CH2:68][CH2:69]4)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)O)cc2)cc(OC)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)N3CCN(C)CC3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic acid (162 mg; 0.34 mmol; 1 eq.), EDC-HCl (71.10 mg; 0.37 mmol; 1.10 eq.) and HOBT (50.11 mg; 0.37 mmol; 1.10 eq.) were taken up in DCM (6 ml) then DIEA (84.89 μl; 0.51 mmol; 1.50 eq.) and 1-methylpiperazine (37.52 μl; 0.34 mmol; 1 eq.) were added. The mixture was stirred at rt for 5 h. The solution was washed successively with a saturated solution of NaHCO3, NH4Cl and NaCl. The organic phase was dried over MgSO4 and concentrated to near dryness to afford 171 mg (90%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.06 (br s, 1H), 8.80 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.44-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.31 (br d, 2H), 7.21-7.14 (m, 2H), 6.15 (t, J=2.3 Hz, 1H), 3.76 (s, 6H), 3.65-3.35 (m, 4H), 3.10-2.85 (m, 4H), 2.63 (s, 3H). HPLC (max plot) 97.1%; Rt 3.55 min. LC/MS: (ES+): 563.4, (ES−): 561.2.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].[CH2:10](Br)[CH:11]=[CH2:12]>CC(C)=O>[CH2:12]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOCCCN(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17.5 g) and dimethyl formaldehyde (400 mL) were added to a 2-L round-bottom flask. After cooling the flask to 0° C. by immersing in an ice bath, 3-dimethylamino-1-propanol (0.398 mol) was added. After stirring for about 30 minutes and adding allyl bromide (0.4378 mol), the mixture was stirred for 3 hours after raising the temperature of the reactor to room temperature. Upon completion of reaction, the reaction was terminated by adding water to the flask and the product was extracted using diethyl ether. The extract was concentrated under reduced pressure and used in the next step without further purification. After filtration under reduced pressure, 3-(allyloxy)-N,N-dimethylpropan-1-amine was obtained through fractional distillation. Structural analysis was performed by NMR spectroscopy.
Reaction SMILES: B(OC(C)C)(OC(C)C)OC(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.[ClH:36].C(=O)([O-])[O-].[Na+].[Na+].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])=[O:52])=[N:46][C:47](Br)=[CH:48][N:49]=1>O1CCCC1.CO.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].C(OCC)C>[ClH:36].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][CH2:56][O:57][CH3:58])=[O:52])=[N:46][C:47]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:48][N:49]=1
Reactant: COCCCNC(=O)c1nc(Br)cnc1N
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: COCCCNC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cnc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.4 %

Procedure:
Triisopropyl borate (0.82 mL, 3.6 mmol) was added to a stirred solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.380 g, 1.2 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965,8,548-550) in anhydrous tetrahydrofuran (15 mL) at −78° C. under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (2.4 mL, 3.6 mmol) over 10 min. The resulting mixture was allowed to warm up to room temperature and was stirred for another 10 min at ambient temperature. HCl (3 M, 1.9 mL, 6.0 mmol) was added and the mixture was stirred for another 10 min, followed by an addition of sodium carbonate (1.26 g, 11.9 mmol). After 30 min, 3-amino-6-bromo-N-(3-methoxypropyl)pyrazine-2-carboxamide (0.24 g, 0.83 mmol) and Pd(dppf)Cl2 (39 mg, 0.05 mmol) were added and the resulting mixture was heated at 65° C. for 22 h. The reaction mixture was evaporated and the residue was dissolved in NaHCO3 (aq. sat.)/ethyl acetate, the aqueous phase was extracted with ethyl acetate and the combined organic phases were evaporated. The crude product was purified on a silica gel column using methylene chloride/methanol/triethyl amine, (9:1:0.1), as the solvent. The product was eluated from the silica with methanol and the solvent was evaporated to give the free base. The base was dissolved in methanol (10 mL) and the mixture was treated with HCl (1.0 M in diethyl ether, 1 mL) followed by addition of diethyl ether (5 mL). The formed precipitate was filtered off and dried at 40° C. in vacuo to give 70 mg (19% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.02 (br s, 1H), 8.97 (s, 2H), 8.46 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz, 2H), 3.82 (d, J=13 Hz, 2H), 3.41 (m, 6H), 3.27 (s, 3H), 3.15 (m, 2H), 2.72 (m, 5H), 1.81 (m, 2H); MS (ES) m/z 449 (M++1).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][N:12]([CH3:30])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([N+:27]([O-])=O)[CH:14]=1>C(#N)C.[Pd]>[NH2:27][C:15]1[CH:14]=[C:13]([N:12]([CH3:30])[CH3:11])[CH:18]=[CH:17][C:16]=1[CH:19]=[C:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CC#N
Product: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
In a dark room, 20.5 q (0.07 mol) of (E) ethyl 3-(4-dimethylamino-2-nitrophenyl)-2-methyl-2-propenate, 33.4 g (0.33 mol) of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.), and 2.1 g of 10% Pd/C were dissolved in 200 ml of acetonitrile, and 13.8 g (0.30 mol) of formic acid (manufactured by Wako Pure Chemical Industries, Ltd.) were added dropwise thereto at room temperature. Along with the dropping, the reaction temperature rose up to 45° C. After the completion of dropping, the reaction liquid was heated to 60° C. and was stirred for 1 hour. After the completion of the reaction was verified by TLC, the reaction liquid was cooled to room temperature, insoluble matters were filtered out, the filtrate was concentrated under a reduced pressure, and thus obtained product was dissolved in 400 ml of ethyl acetate. The resulting solution was successively washed with water, a saturated aqueous sodium hydrogencarbon ate solution, and a saturated aqueous sodium chloride solution; and was further dried with sodium sulfate anhydride. Thus dried product was concentrated under a reduced pressure, whereby 17.4 g of a crude product were obtained. This product was further recrystallized from normal hexane/ethyl acetate, whereby 4.67 g of the aimed compound were obtained (yield: 27%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][O:5][C:4](=[O:8])[C:3]=1[CH3:9].[CH2:10](O)[CH3:11]>P([O-])([O-])([O-])=O>[O:5]1[C:6]2[CH:7]=[CH:2][CH:10]=[CH:11][C:9]=2[CH2:3][C:4]1=[O:8]
Reactant: Cc1c(O)ccoc1=O
Reactant: CCO
Agent: O=P([O-])([O-])[O-]
Product: O=C1Cc2ccccc2O1

Procedure:
0.40 g of the compound (7.4) are dissolved together with 0.175 g of 4-hydroxy-methyl-pyranone (Fluka) in 40 mL of phosphate buffer (0.2M, pH=5) at room temperature, and 20.0 mg of laccase (Trametes versicolor (Fluka)) are added. For better solubility, 1 mL of ethanol is also added. The mixture is stirred in an open vessel until the starting materials can no longer be detected (about 2 days). The mixture is concentrated and the residue is taken up in methanol and centrifuged. The desired product (211 mg) is obtained in the form of a brownish-beige solid. The product can be purified further by reprecipitation from ether/methanol mixtures.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13].OS(O)(=O)=O>CCOCC>[CH2:1]([O:8][CH2:13][CH:12]([CH3:14])[C:11]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=C(C)C#N
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)COCc1ccccc1
Temperature: 62.5 °C

Procedure:
Benzyl alcohol (108 g.; 1 mole) was stirred and treated with 0.3 g. of 50% by weight sodium hydride in a mineral oil dispersion. To the resulting solution was added dropwise 415 ml. (335 g.; 5 moles) of methacrylonitrile over a 40 minute period, at room temperature. The reaction mixture was heated at 60-65° C. for 5 hours then cooled, acidified with 1 N aqueous H2SO4 and diluted with ether. The ether solution was washed twice with saturated brine then dried, filtered and concentrated in vacuo. Distillation of the residue gave, after removal of low boiling materials, 149.3 g (85%) of rac. 3-benzyloxy-2-methylpropionitrile as a colorless liquid, b.p. 90-93° C. (0.02 mm Hg.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:30]=[CH:29][O:28][CH:27]=1.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[O:28]1[CH:29]=[CH:30][C:26]([CH2:25][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:27]1
Reactant: ClCc1ccoc1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine (1.5 g, 5.2 mmol) in tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice-bath. Add sodium hydride (0.25 g, 60% n in oil, 6.24 mmol). After 3.5 hours, add 3-(chloromethyl)furan (0.91 g, 7.8 mmol). Warm to ambient temperature. After 60 hours, quench by the addition of Glauber's salt (Na2SO4 10 H2O). Evaporate to remove most of the tetrahydrofuran, dilute with ethyl acetate, and extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine: Rf=0.32 (silica gel, ethyl acetate).