Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Yield: 16 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-methylimidazo[5,4-b]pyridin-2-ylmethanol (prepared as described in Preparation 15), 1.43 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.83 ml of tributylphosphine, 0.773 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give 0.3 g of the title compound, melting at 97-102° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25](=[O:27])[CH3:26])C=CC=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:24]\[C:25](=[O:27])[CH3:26])[CH:9]=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:3])=[O:2]
Reactant: CCCCSc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Product: CCCCSc1ccc(/C=C\C(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(i) A mixture of 3-nitro-4-(n-butylthio)-benzaldehyde (12.0 g), 1-triphenylphosphoranylidene-2-propanone (1.2 equiv.) dimethyl sulfoxide (300 ml) was stirred at ambient temperature for 24 hr. The solution was poured into water (1 liter) and the resulting mixture was extracted with ethyl acetate. The dried (MgSO4) organic extract was evaporated under reduced pressure and the residue was purified by column chromatography over silica with chloroform elution to give cis-1-[3-nitro-4-(n-butylthio)phenyl]but-1-en-3-one, mp 100° C. Pmr spectrum (CDCl3 ; δ in ppm): 0.97 (3H, t); 1.63 (4H, m); 2.40 (3H, s); 2.98 (2H, t); 6.75 (1H, d); 7.38-7.75 (3H, m); 8.36 (1H, d).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:5][CH2:4]1)#[N:2].[OH-:26].[Na+]>C(COC)OC.Cl>[C:1]([N:3]1[CH2:4][CH2:5][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:7][CH2:8]1)(=[O:26])[NH2:2]
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Temperature: 0 °C

Procedure:
9.93 g of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] of Example 37 in 150 ml glyme and 100 ml 6 M aqueous hydrochloric acid is heated at reflux under nitrogen for 1.5 hours. The mixture is cooled to 0° C., made basic with 50% aqueous sodium hydroxide (40 ml) and concentrated. The residue is dissolved in hot chloroform, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and contrated to give a crude product. Recrystallization from hot dimethylsulfoxide-dioxane-ether affords 1'-carbamoyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], mp 217.5°-219.0° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].ClCCC1SC(C2NC3C(C=2)=CC=CC=3N(C)S(C2SC=CC=2)(=O)=O)=NC1>O1CCCC1.O>[CH3:35][S:36]([O:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)(=[O:38])=[O:37]
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Agent: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CCOS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (200 mg) and triethylamine (70 μL) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (60 mg) at room temperature, and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl methanesulfonate (126 mg, yield 54%, MS: 500 (MH+)) and N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (16 mg, yield 8%,
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:17]([N:24]1[CH2:28][C@:3]2([O:2][CH3:1])[C:4](=[O:9])[NH:5][C:6](=[O:8])[C@@H:7]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC1=CC(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 0° C. solution of 3-methoxy-1H-pyrrole-2,5-dione ({see M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube, J. T. Negri, Org. Lett., 2001, 3, 465-467}, 950 mg, 7.47 mmol) and TFA (0.070 mL, 0.897 mmol) in DCM (70 mL) was added slowly a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (3.06 mL, 12.0 mmol) in DCM (30 mL) at a rate such to maintain the internal reaction temperature <2° C. The resulting bright yellow solution was slowly warmed to ambient temperature and stirred for 18 hrs. The reaction mixture was then cooled to 0° C. and a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (0.956 mL, 3.74 mmol) in DCM (1 mL) was added dropwise and was warmed to rt and stirred for 3 hrs. The reaction mixture was diluted with saturated sodium bicarbonate (25 mL), the layers were separated and the organic solution was dried (magnesium sulfate), filtered and concentrated under reduced pressure, giving a thick, yellow oil. The crude residue was purified by column chromatography eluting with 5%-50% EtOAc/heptane and again with 0%-25% EtOAc/Heptane to afford the titled compound (1.19 g, 61% yield, 70% purity) as a clear oil that was carried forward to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([CH3:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].[C:31]([O-:34])([O-])=O.[K+].[K+].[CH3:37][C:38]#N>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([CH3:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:37][CH2:38][O:34][CH3:31])[CH2:28][CH2:29]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: Cc1ncc(-c2cnn(C3CCNCC3)c2)cc1OC(C)c1c(Cl)ccc(F)c1Cl
Agent: [K+]
Product: COCCN1CCC(n2cc(-c3cnc(C)c(OC(C)c4c(Cl)ccc(F)c4Cl)c3)cn2)CC1
Yield: 44.4 %

Procedure:
A mixture of Example 10 (78 mg, 0.174 mmol), 23a (48 mg, 0.348 mmol), K2CO3 (120 mg, 0.870 mmol) and KI (32 mg, 0.191 mmol) in CH3CN (10 mL) was reacted under microwave condition at 160° C. for 2 h. After the reaction was complete, the mixture was filtered and evaporated. The residue was purified by column chromatography (EA:MeOH=10:1) to afford the title compound (44 mg, 44.4% yield) as solid. 1H-NMR (300 MHz, CDCl3): δ=8.14-8.15 (d, 1H), 7.62-7.63 (d, 1H), 7.59 (s, 1H), 7.28-7.33 (m, 1H), 6.95-7.06 (dd, 1H), 6.94-6.95 (d, 1H), 6.01-6.03 (m, 1H), 4.02 (m, 1H), 3.59-3.63 (t, 2H), 3.37 (s, 3H), 3.18-3.22 (m, 2H), 2.71-2.75 (t, 2H), 2.56 (s, 3H), 2.00-2.43 (m, 6H), 1.84-1.86 (d, 3H). LC/MS [M+H]+: 507.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:27]#[N:28].[K+].[I-].[K+].O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][C:27]#[N:28])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 24 h
Yield: 96.7 %

Procedure:
A solution of methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (1.21 g, 3.07 mmol), potassium cyanide (0.799 g, 12.27 mmol) and potassium iodide (0.25 g) in 50 mL of DMF was heated to 95° C. under argon with stirring for 24 hours. The reaction mixture was cooled and poured into 500 mL of water. The aqueous mix was extracted three times with EtOAc, and the combined organic phases were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (hexanes:EtOAc 1:1). Removal of the solvent under reduced pressure yielded 0.950 g (2.97 mmol, 95.1% of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile as a white crystalline solid. MS: 326 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][P:4](=[O:6])=[O:5].[CH:7]1N=CN([C:12]([N:14]2[CH:18]=N[CH:16]=[CH:15]2)=O)C=1.C([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C.CN([CH:29]=[O:30])C>CN1C(=O)N(C)CCC1.CC(N(C)C)=O.CN1C(=O)CCC1>[CH3:1][CH2:2][CH2:3][P:4](=[O:6])=[O:5].[CH3:12][N:14]1[CH2:18][CH2:29][O:30][CH2:16][CH2:15]1.[CH:2]([N:21]([CH:22]([CH3:23])[CH3:7])[CH2:24][CH3:25])([CH3:3])[CH3:1]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCCP(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CN1CCCC1=O
Solvent: CN1CCCN(C)C1=O
Product: CCN(C(C)C)C(C)C
Product: CN1CCOCC1

Procedure:
reacting (V) with an activating agent such as propylphosphonic anhydride or CDI (N,N-carbonyldiimidazole), (preferably propylphosphonic anhydride), and an amine of the formula (VI) in the presence of an amine base such as N-methylmorpholine, triethylamine, or diisopropylethylamine, in a suitable polar aprotic solvent such as DMF, or NMP, DMAC, DMPU to provide (I), and subsequently isolating (I),
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:13][CH2:14][CH2:15][N:16]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=[C:17]1[CH3:24].CCN=C=NCCCN(C)C.C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:24][C:17]1[NH:16][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=1.[N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ncc([N+](=O)[O-])n1CCCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCOC(=O)c1ccc([N+](=O)[O-])o1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The reaction mixture of 5-nitro-2-furoic acid (157 mg, 1.0 mmol), 1-(3-hydroxypropyl)-2-methyl-5-nitroimidazole (184 mg, 1.0 mmol), EDCI (260 mg, 1.3 mmol), DMAP (10 mg, 0.1 mmol) and THF (5 ml) will be stirred at room temperature for 10 h. Evaporation of THF gives a residue which will be dissolved in ethyl acetate. The organic layer of ethyl acetate will be washed with H2O, 5% Na2CO3, H2O and brine, and then dried over MgSO4. The solvent will be removed under vacuum. The resulting solid will be recrystallized from C2H5OH to give 2-methyl-5-nitro-1H-imidazole-1-propyl 5-nitro-2-furoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][CH:19]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:13][CH2:14][C:15]2[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:18][CH:19]=2)[CH:5]=1)(=[O:31])=[O:30]
Reactant: COc1ccc(CCCO)cc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(CCCOS(C)(=O)=O)cc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 94%. Recrystallization from ethyl acetate-hexane gave pale yellow needles, mp 112-113° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:43]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:5]([N:51]2[CH2:52][CH2:53][CH:48]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:49][CH2:50]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
0.22 g (1.0 mmol) of 3-bromo-2-methyl-benzoic acid was dissolved in 10 ml of DMF and the solution was treated with 0.38 g (1.0 mmol) of HATU. Then, 0.42 ml=0.30 g (3.0 mmol) of Et3N was added and after 30 min, a solution of 0.16 g (1.0 mmol) of 4-pyrrolidin-1-yl-piperidine in 5 ml of DMF. After 3 hours, the reaction mixture was poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.33 g (95%) of the title compound as light red solid. MS: 351.2 (MH+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO.[Pd]>[F:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCNc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CCCCCCNc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 2-fluoro-N-hexyl-4-nitroaniline (4.37 g, 18.2 mmol) in MeOH (50 mL) was added catalyst Pd/C (0.50 g). The reaction mixture was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as blackish oil (3.36 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Product: C=CC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol 13 was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane while heating to afford (14) as a tan solid after workup.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(O)C1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate as a pale yellow solid; MS: 642 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH:5]=[O:6].Br[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]>>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[CH:17]([N:13]1[CH2:14][CH2:15][N:10]([C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH2:11][CH2:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=Cc1ccc(N2CCNCC2)c(F)c1
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C=O)cc2F)CC1
Yield: 90.1 %

Procedure:
3-Fluoro-4-piperazin-1-yl-benzaldehyde (0.65 g, 3.1 mmol) was treated with 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.95 g) as described in previous examples to provide 1.11 g of the title compound. MS (ESI): mass calcd. for C21H29FN2O3, 376.47. m/z found, 377.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]#[N:14].C([OH:17])C>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:14])=[O:17]
Reactant: N#Cc1sc(-c2ccccc2)cc1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1sc(-c2ccccc2)cc1N
Yield: 45 %

Procedure:
To a suspension of 3-amino-5-phenylthiophene-2-carbonitrile (150 mg) in aqueous sodium hydroxide solution (20 mL, 10%) was added ethanol (10 mL) and the mixture was refluxed for 1 h. The reaction mixture was allowed to attain rt and the crystals separated were filtered off, washed with cold water and dried to give the product as a golden yellow color solid (70 mg, 45%), mp 180-182° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[N:39]1([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[CH:40]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc2c(c1)ncn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5ccccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5) and 70 mg of 1-piperidin-4-yl-1-H-benzoimidazole (from Step C) in 4 mL THF and 1 mL of DMF was added 1 spatula tip of 4Å molecular sieves. After stirring at room temperature for 10 minutes, 80 mg sodium triacetoxyborohydride was added. Continued to stir at room temperature for another 10 hours. The reaction was concentrated and diluted with 20 ml of EtOAc and washed with 10 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phas was extracted with 2×10 mL EtOAc. The combined organic phases were washed with 8 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 40 mg of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ1.17-3.73 (m, 31H), 4.07 (m, 1H), 5.10(d, J=2.1 Hz, 2H), 6.86 (d, J=8.5, 2H), 7.16-7.36 (m, 10H), 7.78(m, 1H), 7.93(s. 1H). ESI-MS 621 (M+H); HPLC A: 2.96 min.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:28]=[CH:27][C:17](/[CH:18]=[CH:19]/[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[CH:28]=[CH:27][C:17](/[CH:18]=[CH:19]/[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1CCCC1
Product: O=C(/C=C/c1ccc(-c2cc3ccccc3s2)cc1)N1CCCC1
Yield: 43 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-(trans-4-bromocinnamoyl)pyrrolidine (Part A) in 43% yield following chromatography.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C=O)C.Cl[CH2:27][C:28]([NH2:30])=[O:29]>O>[Br:7][C:8]1[C:18]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)c(OCC(N)=O)c1Br
Temperature: 120 °C

Procedure:
0.853 g (6.20 mmol) of K2CO3, 0.154 g (0.90 mmol) of Kl and 1.000 g (3.10 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced into 15 ml of DMF. 0.346 g (3.70 mmol) of chloroacetamide was added at RT, and the mixture was heated for 6 hours at 120° C. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and concentrated completely. Drying in an oil-pump vacuum gave ethyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate as a brown oil.