Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]1)(=[O:4])=[O:3].[Cl:23]CCOC(Cl)=O>ClCCl>[ClH:23].[CH3:1][S:2]([O:5][CH:6]1[CH2:9][NH:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: O=C(Cl)OCCCl
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CNC1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (WO 97/25322, p 64), (20 g, 63 mmol) and chloroethylchloroformate (10 mL, 95 mmol) in dichloromethane (100 mL) was heated under reflux for 2.5 hours. The reaction mixture was then concentrated in vacuo and the residue was re-dissolved in methanol (100 mL) and heated under reflux for a further 2.5 hours. The mixture was then cooled to room temperature and concentrated in vacuo to afford the title compound as a white solid in quantitative yield, 9.6 g. 1H NMR (400 MHz, DMSO-d6) δ: 3.28 (s, 3H), 4.06 (m, 2H), 4.31 (m, 2H), 5.34 (m, 1H)
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7]([Br:10])[C:4]=2[S:5][CH:6]=1.[C:11]([O:15][C:16]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(N1CCC[C@H]1C1NC(C2SC3C=C(C4C=CC(C5NC([C@@H]6CCCN6C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=5)=CC=4)SC=3C=2)=CN=1)=O)(C)(C)C>>[C:11]([O:15][C:16]([N:18]1[CH:22]=[C:21]([C:2]2[C:3]3[S:9][CH:8]=[C:7]([Br:10])[C:4]=3[S:5][CH:6]=2)[N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Reactant: Brc1csc2c(Br)csc12
Agent: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)cn1C(=O)OC(C)(C)C

Procedure:
Compound 76 was synthesized from 3,6-dibromothieno[3,2,b]thiophene (6.71 mmol) and compound 61 (6.71 mmol), following the procedure as described for compound 63 to give compound 76 as a yellow cristal. MS (ESI, EI+) m/z=554-556 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]([CH:28]=1)[C:8]1[N:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:29]([O:32][CH2:33][CH2:34]Br)(=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:8]3[N:27]4[CH:28]=[C:2]([O:1][CH2:34][CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]4=[N:6][C:7]=3[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:17])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of compound 10 (1.0 equiv., 0.806 mmol, 0.300 g), 2-bromoethyl acetate (2.0 equiv., 1.611 mmol, 0.269 g) and K2CO3 (3.0 equiv., 2.417 mmol, 0.334 g) in dry DMF (5 ml) was stirred at 60° C. for 4 h. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (dichloromethane/methanol 97.2:2.5) afforded 6-(4-nitrophenyl)-9-[2-[(1-oxoethyl)oxy]-ethoxy]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (73) (0.245 g, yield=66%, purity (LC)=97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:27]([N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1Br)N(Cc1ccccc1)Cc1ccccc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) and triethylamine (455 mg, 0.63 mL, 4.5 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 10° C. Dibenzylamine (849 mg, 0.83 mL, 4.3 mmol) was then added dropwise. The cooling bath was removed, and the reaction mixture was stirred for 10 h at rt and then an additional 6 h at 60° C. After cooling to rt, the solvent was removed under reduced pressure, and ethyl acetate was added. The organic layer was successively washed with 1N HCl, water, semi-saturated aq Na2CO3 solution, water, and brine. After drying with Na2SO4 and filtration, the solvent was removed under reduced pressure to afford the title compound as off-white crystals (1.44 g, 88%). 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 4H), 7.08 (m, 4H), 7.27 (m, 6H), 7.41 (m, 2H), 7.78 (d, 1H), 8.19 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7]/[C:8]/2=[CH:13]\[C:14](=[N:23]/[CH2:24][C:25](OCC)=[O:26])\[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.Cl.C(OC(=O)CN)C>CCO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH2:24][N:23]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH:13]=[C:8]12
Reactant: CCOC(=O)C/N=C(\C=C1/NCCc2c(OC)cccc21)c1cccc(OC)c1
Agent: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(C2=NCC(=O)N3CCc4c(OC)cccc4C3=C2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
ethyl 2-((E)-((Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethylidene)amino)acetate. 1-2. A mixture of 1-1 (5.8 g, 18.81 mmol) and glycine ethyl ester hydrochloride (13.1 g, 94 mmol) in EtOH (200 mL) was heated to 100° C. and stirred for 2 h. The reaction was then cooled to RT and the mixture was concentrated in vacuo. The residue obtained was taken up in DCM and washed with a 1M aq. solution of NaOH. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.0 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 395.3 (M+H+); UPLC rt 0.80 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:28]=2[O:27][CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:29]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=510.3.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
The compound of Structure (I-C) was prepared as follows. 2-carboxyanthraquinone was reacted with oxalyl chloride in dichloromethane (catalyzed by dimethylformamide) to yield 2-chlorocarbonylanthraquinone, which was then reacted with 1-hexanol in tetrahydrofuran (in the presence of triethylamine) to yield 2-n-hexoxycarbonylanthraquinone, which was then treated in a manner similar to Preparation A to prepare the Structure (I-C) compound with a yield of 50%. Structure was confirmed by IR and NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13](=O)[CH3:14].N1CCCC1.CCOC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]([CH3:14])([CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(=O)c2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
In a 500 mL round-bottomed flask was added 1-(5-fluoro-2-hydroxyphenyl)ethanone (20.0 g, 130 mmol, Aldrich Chemical), propan-2-one (19.0 mL, 260 mmol), and pyrrolidine (21.5 mL, 260 mmol) in methanol (150 mL) to give a orange solution. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was poured into EtOAc (200 mL) and washed with 1N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to provide an orange residue which was purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to provide the title compound (14.2 g, 73.1 mmol, 56%) as a white solid. MS (DCI/NH3) m/z 208 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2C(O)=C[CH:3]=1.[C:13](Cl)(=[O:23])[C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16](Cl)=[O:17].[CH3:25][CH2:26][OH:27]>>[OH:27][C:26]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([OH:1])=[C:3]2[C:25]=1[C:13](=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]2=[O:17]
Reactant: CCO
Reactant: Oc1ccc(O)c2c1CCCC2
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Product: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CCCC3
Yield: 88 %

Procedure:
The method was similar to Example 1 but using 16.4 g (0.1 mols) of 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene and 20.2 g (0.1 mol) of phthalic acid dichloride. The product was 33.7 g (88% yield) of 6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphtacenequinone (9), m.p.=194°-196° C. (EtOH).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([SH:34])[NH:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([S:34][CH2:16][C:14]2[N:15]=[C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[S:12][CH:13]=2)[NH:32][CH:33]=1)=[O:28])[CH3:25].[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][S:34][C:31]3[NH:32][CH:33]=[C:29]([C:27]([OH:28])=[O:26])[N:30]=3)[N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Product: CCOC(=O)c1c[nH]c(SCc2csc(NC(=O)N(C3CCCCC3)C3CCCCC3)n2)n1
Product: O=C(O)c1c[nH]c(SCc2csc(NC(=O)N(C3CCCCC3)C3CCCCC3)n2)n1
Yield: 20 %

Procedure:
2-[2-(3,3-Dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidazole-4-carboxylic acid ethyl ester was prepared in 20% yield as described in general procedure L from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and 2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester. The ester (30 mg, 0.06 mmol) was hydrolysed using general procedure F to give 2-[2-(3,3-dicyclohexylureido)-thiazol-4-ylmethylsulfanyl)-1H-imidazole-4-carboxylic acid in 80% yield (22 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.CCOC(C)=O>C1COCC1.O>[C:21]([O:20][C:18](=[O:17])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([Br:2])=[CH:4][CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reaction time: 12 h
Yield: 90.9 %

Procedure:
A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]([C:16]#[N:17])=[C:11]([S:14][CH3:15])SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[C:1]1([S:7]([C:10]([C:16]#[N:17])=[C:11]([S:14][CH3:15])[NH:28][CH2:27][CH2:26][S:25][CH2:24][C:23]2[NH:22][CH:21]=[N:20][C:19]=2[CH3:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC(SC)=C(C#N)S(=O)(=O)c1ccccc1
Reactant: Cc1nc[nH]c1CSCCN
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1

Procedure:
Equimolar amounts of 1-benzenesulfonyl-1-cyano-2,2-bis(methylthio)ethylene [prepared according to the procedure described by M. Augustin et al., Z. Chem., 17, 289 (1977)] and 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine [prepared according to the procedure described in U.S. Pat. No. 3,950,353] are reacted according to the general procedure of Example 6A, and the title product is produced.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1)OCC
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethenylphosphonate as a colorless oil (0.43 g, yield 69%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To a stirred solution of 8.0 g (0.042 mole) of 2-chloro-4-fluoro-5-nitrophenol in 200 mL of acetone was added 6.09 g (0.0435 mole) of potassium carbonate. The mixture was heated at reflux temperature for 15 minutes, and 8.9 g (0.063 mole) of iodomethane was added. The resultant mixture was heated at reflux temperature for 5 hours, then stirred at room temperature for approximately 18 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to leave a residue. The residue was dissolved in diethyl ether, filtered, and the filtrate washed with a saturated sodium chloride solution. The ether solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to yield 6.6 g of 1-chloro-5-fluoro-2-methoxy-4-nitrobenzene as a solid, 63°-65° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](C(OC(C)(C)C)=O)[CH:22]=[C:23]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:16]=23)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>>[ClH:45].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[C:23]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[C:16]=23)[CH2:10]1
Reactant: ClCCl
Reactant: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2nccc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)Nc1c[nH]c2nccc(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.010 g, 0.020 mmol; Example 81, Step B) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% ACN in water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.002 g, 27% yield). LCMS (APCI+) m/z 302 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][N:12]1C(=O)C2=CC=CC=C2C1=O.C(O)(=[O:25])C>>[N+:12]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([O-:11])=[O:25]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=[N+]([O-])C12CC3CC(CC(C3)C1)C2

Procedure:
The nitration reaction was effected in the same manner as Example 9 except that 1.8 g (0.024 mole based on N2O3) of the frozen blue liquid, 1 mole of adamantane, 0. 05 mmole of N-hydroxyphthalimide and 5 ml acetic acid were mixed and then the mixture was reacted for 16 hours at 25° C. with stirring. As a result, nitroadamantane was formed. The conversion of adamantane was 83% and the yield of the nitroadamantane was 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH:16](C)[CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33]C[CH2:31][CH2:30]1.[CH:35]([N:38](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:35][N:38]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])[CH2:30][CH2:31]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1N1CCCCC1
Reactant: COc1ccc(-c2cc(C(C)CC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCCN3CCN(c4ccccc4C)CC3)on2)cc1OC
Yield: 61.4 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]butanal (34.4 mg, 0.125 mmol), 1-(2-methylphenyl)piperidine HCl (24.2 mg, 0.114 mmol) and diisopropylethyl amine (19.9, 0.114 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (72.5 mg, 0.342 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3 hr and followed the same processes as in Example 1 to obtain 30.5 mg (61.4%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[C:37]2[O:33][C:34](=[O:39])[NH:35][C:36]2=[O:38])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(CCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(CCCCCC=C2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 16 h

Procedure:
A mixture of 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-1,3-dioxolan (3.6 g), 2,4-oxazolidinedione (1.7 g), piperidine (0.72 g) and acetic acid (50 ml) was stirred for 16 hours under reflux. The reaction mixture was concentrated under reduced pressure, which was dissolved in ethyl acetate. The solution was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N HCl and water, followed by drying (MgSO4). The ethyl acetate layer was concentrated under reduced pressure, which was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), was obtained 5-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexylidene]-2,4-oxazolidinedione as an oily product. The oily product was dissolved in tetrahydrofuran (THF) (80 ml), to which was added palladium-carbon (5%, 1.0 g). The mixture was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), was obtained 5-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms, m.p.113-117° C.
Reaction SMILES: C[Li].Br[C:4]1[CH:19]=[CH:18][C:7]2[C@:8]3([CH3:17])[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3.C([Li])(C)(C)C.CN(C)[CH:27]=[O:28]>C(OCC)C.C1COCC1.CCCCC>[CH:27]([C:4]1[CH:19]=[CH:18][C:7]2[C@:8]3([CH3:17])[C@@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)=[O:28]
Reactant: CN(C)C=O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(C=O)ccc12
Reaction time: 0.5 h

Procedure:
Methyllithium (1.5 mL, 2.1 mmol of a 1.4M solution in diethyl ether) was added to (4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (0.500 g, 1.7 mmol) in 25 mL of anhydrous THF which had been cooled in a dry ice/isopropanol bath under nitrogen, and was stirred for 15 min before addition of t-butyllithium (2.0 mL, 3.4 mmol of a 1.7M solution in pentane.) After 30 min, dimethylformamide (0.4 mL) was added, and the mixture was allowed to warm to 0°, and additional dimethylformamide (0.2 mL) was added. The ice bath was removed and the reaction was quenched with 1N hydrochloric acid to make pH=2, and then the mixture was extracted with 10% isopropanol/chloroform. The combined organic extracts were washed well with water, dried over sodium sulfate, and evaporated. The resulting product was slurried in diethyl ether before recrystallizing from 50% ethyl acetate/hexane to give off-white crystals: mp 185°-189°. FD MS 243M+; Calcd for C15H17N1O2 : C, 74.05; H, 7.04; N, 5.76; Found: C, 73.85; H, 7.11; N, 5.91.