Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 5-fluoro-2-nitro-phenol (234 mg, 1.49 mmol) in 5 mL THF, sodium hydride (122 mg, 2.9 mmol) was added, followed by chloromethoxy methane (113 ul, 1.49 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 10 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-fluoro-2-methoxymethoxy-1-nitro-benzene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+]>>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:23]
Reactant: CC(=O)CCCCCCCCCCCOC1CCCCO1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CCCCCCCCCCCOC1CCCCO1
Yield: 100 %

Procedure:
The title compound was prepared from 13-[(tetrahydro-2H-pyran-2-yl)oxy]-2-tridecanone (2.0 g, 0.006 mol), 2,6-diisopropylphenyl isocyanate (1.36 g, 0.006 mol), and lithium diisopropylamide (0.006 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 3.11 g (0.006 mol, 93%) of the desired product.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:29]=[CH:28][C:9]([C:10]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)CCC.Cl[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=1>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:26]2[N:25]=[CH:24][N:23]([C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:9]3[CH:28]=[CH:29][CH:6]=[CH:7][CH:8]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:27]=2)=[N:40][CH:41]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: Fc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)nc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To the solution of 4-Tributylstanny 1-trityl-1H-imidazole (1.00 g, 1.67 mmol) in toluene (1.0 ml) added 2-Chloro-5-fluoropyridine (0.31 g, 2.38 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.19 g, 0.17 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% diethyl ether in hexanes to isolate 4-(5-Fluoro-2-pyridyl)-1-trityl-1H-imidazole (0.23 g) as a clear oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CS(C)=O>[CH2:2]([N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 70 %

Procedure:
This example illustrates a synthesis of N-(9,8-Oxidononyl)phthalimide (inventive compound no. 1105). 1-bromo-8-nonene (8.2 g, 40 mmol) was added to a suspension of potassium phthalimide (7.4 g, 40 mmol) in 50 mL of dimethyl sulfoxide and stirred overnight. After 12 hours of stirring at room temperature, the reaction product was poured into a separatory funnel containing 300 mL of water and extracted with dichloromethane (5×200 mL). Organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel (using an eluant of 10% acetone/hexane) to yield 7.6 g (70.4% yield) of N-(8-Nonenyl)phthalimide (inventive compound no. 1101).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[NH:35][C:34]=2[CH:41]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[C:23]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[NH:35][C:34]=3[CH:41]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCCOCc4ccccc4)n3)cc2N1

Procedure:
8-{4-[2-(3-Benzyloxy-propoxy)-6-fluoro-phenylamino]-5-chloro pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from [2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine and 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound was isolated as a white solid (25 mg, 17%), HPLC 99% purity, LCMS: 564.25 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1H), 9.12 (s, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 7.33-7.23 (m, 4H), 7.19-7.15 (m, 3H), 6.98-6.89 (m, 3H), 6.82 (d, J=8.3 Hz, 1H), 4.26 (s, 3H), 4.06-4.03 (m, 2H), 3.34-3.31 (m, 2H), 2.04-1.95 (m, 4H), 2.00-1.81 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:20]=[C:21]([SH:27])[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]>>[Br:18][C:19]1[CH:20]=[C:21]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]
Reactant: Nc1c(Br)cc(S)cc1Br
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: Nc1c(Br)cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3,5-dibromo-4-amino-thiophenol.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCC(C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described in paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 4-methylpiperidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methylpiperidin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.66 (m, 2H), 0.92 (d, 3H), 1.13 (m, 2H), 1.68 (m, 3H), 2.30 (s, 3H), 2.83 (m, 1H), 2.99 (t, 2H), 4.07 (d, 2H), 7.03 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.01 (d, 1H), 8.39 (s, 1H), 9.95 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][CH:4]([CH2:16][Br:17])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](O)=[O:14])=[N:11][CH:12]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:13](=[O:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:4]([Br:3])[CH2:16][Br:17])=[CH:12][N:11]=1
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 8 °C

Procedure:
According to the same method as Example 1 with cooling 30% aqueous methylamine solution (100 ml) was added to the chloroform solution (200 ml) of acid chloride prepared from 10 g of 5-(3,4-dibromobutyl)picolinic acid and 10 ml of thionyl chloride, and stirred at 8°C for an hour. Chloroform layer which was separated, was washed with 0.3% aqueous hydrochloride solution, 5% aqueous sodium bicarbonate solution, and then water. Chloroform was evaporated in reduced pressure to yield 8.7 g of crude product as oil. To purify the product, above crude product was chromatographed on silicagel using ethylacetate as developing solvent. The pure product was viscous oil and showed only one spot (Rf 0.60) on TLC (silicagel; ethylacetate, IR (liquid film) 1670 cm-1, UV λmaxMeOH 268 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(C#N)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-cyanophenylboronic acid. Yield 0.524 g
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as light yellow needles, m.p. 193-194° C. Analysis: Calculated for C17H23N5O3S: %C, 54.09; %H, 6.14; %N, 18.55; Found: %C, 54.09; %H, 5.93; %N, 18.49.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]([CH:25]=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[C:24]([CH:25]=[O:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
1-(Cyclohexylmethyl)piperazine (0.42 mL, 2.2 mmol) was added to a mixture of 2-chloro-3-quinolinecarboxaldehyde (0.383 g, 2.0 mmol) and potassium carbonate (0.7 g, 5.0 mmol) in anhydrous DMF (4 mL) at ambient temperature under a nitrogen atmosphere. After being stirred for 20 minutes, the reaction mixture was heated at 110° C. for 4.5 h. After cooling to room temperature this mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and then concentrated under vacuum to give a pale brown crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol in dichloromethane afforded the title compound (0.56 g), yield: 86%.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@H:17]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH3:40])=[N:34][C:35]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH3:40][C:33]1[N:34]=[C:35]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:36]2[N:37]=[CH:38][N:30]([C:31]=2[N:32]=1)[C@@H:17]1[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@@H](N)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(N[C@H](C)COc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) was reacted with 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-Purine (0.43 g, 1 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (20 ml) in the presence of triethylamine (0.41 g, 4 mmol). The reaction mixture was heated at 50° C. for 70 h, and at 90° C. for 3 h. before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-methyl- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (0.21 g, 50%), 1H NMR (DMSO-d6)δ 1.30 (3H, d, --CH3), 2.43 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.66-3.73 (1H, m, H-5'b), 3.94 (1H, dd, --C--H), 3.99 (1H, q, H-4'), 4.12-4.22 (2H, m, H-3' and --C--H), 4.54 (1H, dd, H-2'), 4.76 (1H, m, --CH3C H--), 5.20, 5.52 (2H, 2d, 2' and 3'-OH), 5.73 (1H, t, 5'-OH), 5.87 (1H, d, H-1'), 6.90-7.31 (5H, t, m, t, Ar--H), 7.74 (1H, br d, N--H), 8.28 (1H, s, H-8).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([C:8]1[N:12]([C:14]2[CH:24]=[CH:23][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ncc[nH]2)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: OCc1ccc(-n2ccnc2Cc2ccccc2)cc1

Procedure:
Prepared from 2-benzylimidazol and ethyl 4-fluorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3cc(C)ccc3nc2OC)CC1
Yield: 66 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.49 (m, 3H), 3.10-3.16 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.17 (m, 4H), 6.88-7.11 (m, 5H), 7.26-7.32 (m, 1H), 7.48-7.64 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8].Br[CH2:21][CH2:22]Br>CN(C=O)C>[CH2:7]([O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:21][CH2:22][O:18][C:13]=2[CH:12]=1)=[O:19])[CH3:8]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight and then poured into ice-water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (petroleum ether/ethyl acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, J=1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
3.5 g of (+/-)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-4-p-toluenesulfonamidobenzamide are dissolved in 100 ml of acetonitrile and 1.0 ml of phosphorus oxychloride and the solution is stirred at 50° C. for 8 h. The reaction mixture is added to 100 ml of saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with sodium hydrogencarbonate solution and water, dried using sodium sulfate and concentrated. The residue is recrystallized from ethanol. 1.8 g (53.2% of theory) of the title compound of melting point: 122° C. (decomposition) are obtained.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([OH:26])[C@@H:21]1[OH:27])=[N+:17]=[N-:18]>C(O)C>[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([O:26][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:21]1[O:27][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=NC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Suspend 5.16 gm. of sodium hydride in 50 ml. of ahydrous dimethylformamide. Maintain the temperature at 0°C. and add 12.4 ml. of benzyl chloride, then 4.65 gm. of 6-azido-6-deoxy-D-glucal in 17 ml. of dimethylformamide. Stir for 4 hours and then add 15 ml. of ethanol, after a further 10 minutes, pour the reaction mixture on ice and then extract wth chloroform. Wash the extracts with water, then dry over MgSO4 and then reduce in vacuo. Chromatograph the residue on silica gel using 25% ethyl acetate in benzene as the eluant to obtain 6-azido-6-deoxy-3,4-di-O-benzyl-D-glucal, [α]26 D + 34.3° (EtOH); pmr (CDCl3)δ 3.52 (2H, m, -CH2N3), 4.6 (4H, m, Ar-CH2 -), 6.38 (1H, dd, J=1.5, 6-Hz, H-1); ν max (CHCl3) 2100, 1640 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([CH2:2][C:3]2[N:4]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)[CH2:22][CH2:23]1)=[O:28]
Reactant: COC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(Cc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
A solution of tert-butyl 4(4-chloromethylthiazol-2-yl)piperazine-1-carboxyate (860 mg, 2.7 mmol) and methyl piperidine-4-carboxylate (539 mg, 3 mmol) in DMF was treated with potassium carbonate (414 mg, 3 mmol). The mixture was stirred at 70° C. for 18 hours and then concentrated under vacuum. Product was purified from the residue by flash chromatography on silica gel to provide tert-butyl 4-[4-(4-methoxycarbonylpiperidin-1-ylmethyl)thiazol-2-yl]piperazine-1-carboxylate (575 mg, 50% yield). HNMR (dmso-d6): 6.58 (1H, s), 3.59 (2H, s), 3.42 (4H, m), 3.34 (4H, m), 3.32 (3H, s), 2.78 (2H, m), 2.28 (1H, m), 2.02 (2H, m), 1.77 (2H, m), 1.57 (2H, m), 1.41 (3H, s).
Reaction SMILES: Br[CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:27]C(=O)C(Cl)(Cl)Cl>[Zn].C(O)(=O)C>[CH3:8][C@@H:7]1[C@:3]2([O:35][CH2:36][C@H:37]([CH3:39])[CH2:38][CH2:2]2)[O:4][C@H:5]2[CH2:23][C@@H:22]3[C@@:9]([CH3:34])([C@@H:6]12)[C@@H:10]([OH:27])[C@H:11]([OH:26])[C@H:12]1[C@H:21]3[CH2:20][CH2:19][C@@H:18]2[C@:13]1([CH3:25])[CH2:14][CH2:15][C@H:16]([OH:24])[CH2:17]2
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)[C@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α, 11β,12α,25R)-23-bromo-12-(trichloroacetoxy)-spirostan-3,11-diol was reduced with zinc and acetic acid to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[Cl:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Through a solution of Boc-protected piperazinone from Step D (17.19 g, 55.4 mmol) in 500 mL of EtOAc at -78° C. was bubbled anhydrous HCl gas. The saturated solution was warmed to 0° C., and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HCl, and the mixture was warmed to room temperature. The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2Cl2 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (8×300 mL) until the analysis indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.