Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]=[O:7].[NH4+].[Cl-]>CCOCC>[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:2]
Reactant: COc1cc(I)c(C=O)cc1OC(C)C
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(I)c(C(C)O)cc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of Mg turnings (195 mg, 8.02 g·atom) in dry Et2O (3.0 mL) was stirred at 0° C. under a nitrogen atmosphere then treated, dropwise, with a solution of iodomethane (0.58 mL, 9.31 mmol) in dry Et2O (7.5 mL). After 0.5 h a solution of aldehyde 5 (1.00 g, 3.12 mmol) in dry Et2O (7.5 mL) was added, dropwise, and the ensuing mixture then allowed to warm to 18° C. Stirring was continued at this temperature for a further 1 h then the reaction mixture was treated with NH4Cl (5 mL of a 20% w/v aqueous solution) and Et2O (10 mL). The separated organic phase was washed with H2O (1×5 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 6 (1.05 g, quant.) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[NH:30]1[C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:30]1[C:34]2[CH:35]=[C:36]([C:2]3[S:3][C:4]4[C:10]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=4[N:6]=3)[CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccc2nc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc[nH]c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (78 mg, 0.16 mmol), (1H-benzo[d]imidazol-6-yl)boronic acid (44 mg, 0.27 mmol), then Pd(PPh3)4 (22 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.5 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.2 (M+H+); Found: 534.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:37][C:38]([NH2:40])=[S:39]>CC(N(C)C)=O>[NH2:40][C:38]1[S:39][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:37]=1
Reactant: NC(N)=S
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: Nc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol) in 40 mL of DMA was added NBS (0.88 g, 4.95 mmol). The mixture stirred at room temperature for 30 min. Thiourea (0.36 g, 4.72 mmol) as added and the mixture heated to 80° C. for 1 h. The mixture was poured into 300 mL of ice water and the product was collected by filtration. The crude product was then purified by flash chromatography to give the title compound of Step A (1.61 g, 3.35 mmol, 67.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.94 (s, 2H), 7.64-7.75 (m, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.16-7.29 (m, 5H), 6.52 (d, J=5.6 Hz, 1H).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][NH2:16])[C:8]([O:10][CH3:11])=[O:9].O>N1C=CC=CC=1>[S:3]=[C:1]1[NH:16][CH2:15][C:14]2[C:5](=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[NH:4]1
Reactant: S=C=S
Reactant: COC(=O)c1ccc(CN)c(N)c1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=S)NC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Carbon disulfide (1.36 mL, 22.6 mmol) was added to a solution of methyl 3-amino-4-(aminomethyl)benzoate (2.0 g, 11.3 mmol) in pyridine (10 mL) and the resultant reaction mixture was stirred at 60° C. overnight. After cooling, water was added to the reaction mixture. The solid formed was filtrated to afford methyl 2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (2.2 g) which was carried to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>C(O)C.[Fe]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17]
Reactant: Cc1cccc(NCc2cccc([N+](=O)[O-])c2)c1C
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(NCc2cccc(N)c2)c1C

Procedure:
To a solution of 15 (0.40 g) in ethanol (8 mL) was added elemental iron (Fe) (0.31 g) and acetic acid (0.66 g). The mixture was refluxed for 18 h. The mixture was filtered, concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil. NMR (300 MHz, CDCl3) δ 7.13 (1H, t, J=3 Hz), 6.99 (1H, t, J=3 Hz), 6.77 (1H, d, J=3 Hz), 6.72 (1H, s), 6.60 (2H, d, J=3 Hz), 6.50 (1H, d, J=3 Hz), 4.25 (2H, s), 3.85 (1H, s), 3.65 (1H, s), 2.29 (3H, s), 2.05 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CC#N>[CH:26]1([CH2:25][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC1CC1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a suspension of commercially available ethyl 5-nitro-1H-indole-2-carboxylate (0.5 g, 2.13 mmol) in MeCN (7 mL) was added Cs2CO3 (1.39 g, 4.27 mmol) and (bromomethyl)cyclopropane (0.58 g, 4.27 mmol). The mixture was heated at 90° C., under N2, for 5 h. Upon cooling, the mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-30% EtOAc-hexanes gradient). The product slowly crystallized from CH2Cl2-hexanes to afford the title compound as a light yellow solid (0.42 g, 68% yield): MS (ES) m/z 289 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])O.[Na+].[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15]
Reactant: CCO
Reactant: COc1ccc(OC)c(CCCC(=O)O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCCc1cc(OC)ccc1OC
Reaction time: 5 h

Procedure:
To an ethanol solution (180 ml) of 4-(2,5-dimethoxyphenyl)butyric acid (52.4 g, 0.23 mole), several drops of conc. sulfuric acid are added, and the mixture is boiled for 5 hours. After cooling in the air, a saturated aqueous solution of sodium hydrogen carbonate is added for neutralization, and the mixture is concentrated under reduced pressure. The residue is diluted with ether (300 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml×2), water (50 ml×2) and a saturated aqueous solution of sodium chloride (50 ml×1) and dried over anhydrous magnesium sulfate. After filtration and evaporation, a dark red oil (55 g) is obtained, which is subjected to distillation under reduced pressure twice for purification to obtain the objective compound as a pale yellow oil (37 g, 63%). B.P. 155°-158° C. (3 mmHg). IRνmaxfilm cm-1 : 1720 (CO2Et). NMR (in CDCl3): 1.19 (3H, t, J=7.5Hz, CO2CH2CH3), 1.56-2.06 (2H, m, CH2CH2CO2Et), 2.06-2.46 (2H, m, CH2CH2CO2Et), 2.46-2.76 (2H, broad t, J=6.6Hz, CH2CH2CH2CO2Et), 3.67 (6H, s, OCH3 ×2), 4.15 (2H, q, J=7.5Hz, CO2CH2CH3), 6.15 (3H, s, aromatic proton).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=[O:26])[C:14](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[CH:14]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13](=[O:26])[CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)C(=Cc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)C(=O)C(Cc1ccccc1)C(=O)OC
Yield: 58.6 %

Procedure:
Dimethyl 2,4-bis(phenylmethylene)-3-oxo-glutarate (630 mg, 1.8 mmol) (C. H. Chen, et al, J. Org. Chem., 1981, 46, 2752-2757) was dissolved in about 100 mL of methanol and 250 mg of 10% palladium on carbon was added. The reaction mixture was shaken at ambient temperature under 4 atmospheres of hydrogen for about 12 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue (750 mg) was taken up in ~15 mL of methylene chloride and applied to a 1.0×45 cm column of silica gel. The column was eluted @5 p.s.i. with 150 mL of methylene chloride to give 374 mg (58% yield) of the title compound. The 300 MHz 1H NMR was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][O:15][CH2:16][C@@H:17](O)[CH3:18]>>[F:1][C:2]1[C:3]([O:13][C@H:17]([CH3:18])[CH2:16][O:15][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(O)c(F)c2n1
Reactant: COC[C@H](C)O
Product: COC[C@@H](C)Oc1ccc2ccc(C)nc2c1F

Procedure:
Prepared as described in Example 140, Step A, using 8-fluoro-2-methylquinolin-7-ol (0.30 g, 1.69 mmol) in place of 2-methylquinolin-8-ol and using (S)-1-methoxypropan-2-ol (0.196 g, 46%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (described in Example 8b) and 3-phenylpropionyl chloride, the title compound was obtained as a white solid (46%) by crystallization from ether-ethyl acetate, mp 149.0°-50.0° C.; MS(CI): 437 (M+H); NMR (300 Hz, DMSO-d6): 1.20-1.40(m, 2H), 1.55-1.69(m, 2H), 2.17-2.40(m, 4H), 2.44(s, 2H), 2.79(t, 2H, J=8.1 Hz), 2.85-2.98(m, 2H), 3.33(m, 2H), 3.53(m, 1H), 4.30(s, 1H), 6.85-6.98(m, 4H), 7.10-7.32(m, 9H), 7.66(d, 1H, J=7.5 Hz).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])#[N:5].O>O1CCCC1>[C:4]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH3:1])#[N:5]
Reactant: C[Mg]Br
Reactant: N#Cc1ccccc1C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccccc1C#N
Temperature: 25 °C

Procedure:
A 1M solution of methylmagnesium bromide in tetrahydrofuran (12 ml, 12 mmol) was dropwise and portionwise added to a solution of 2-cyanobenzaldehyde (1.31 g, 10.0 mmol) dissolved in dried tetrahydrofuran (25 ml), followed by stirring at room temperature for one night. After the reaction, water was added to the reaction mixture followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solution was concentrated under reduced pressure to give 1-(2-cyanophenyl)ethanol (1.47 g, quantitative).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]([O:18][C:19](ON1C(=O)CCC1=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:18][C:19]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
4.5 g (295 mmol) of (R)-2-amino-2-phenylethanol are dissolved in 385 ml of absolute dimethylformamide. 73.5 g of N-(benzyloxycarbonyloxy)succinimide (295 mmol) are added, at 0° C. and while stirring, and the mixture is then stirred at 0° C. for 1 hour. The ice bath is removed and the mixture is left to stand at room temperature for 48 h. The reaction solution is concentrated in vacuo and the residue is then taken up in 500 ml of ethyl acetate. The organic phase is washed twice with a 10% aqueous solution of citric acid and once with water. It is then dried over anhydrous sodium sulphate and concentrated. The resulting crystalline crude product (82.3 g) is once again dissolved in ethyl acetate. The organic phase is washed twice with a 10% aqueous solution of citric acid and once with water. Recrystallization subsequently takes place from ethyl acetate/petroleum ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13](=[O:20])[C:12]2=[O:21].Br[CH2:23][CH2:24][Cl:25]>CN(C=O)C>[Cl:25][CH2:24][CH2:23][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[C:17]([O:18][CH3:19])[CH:16]=2)[C:12](=[O:21])[C:13]1=[O:20]
Reactant: ClCCBr
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(CCCl)C(=O)C2=O
Temperature: 70 °C

Procedure:
Anhydrous potassium carbonate (2.44 g) was added to a solution of 5,6-dimethoxy-1H-indole-2,3-dione (1.2 g) in dry DMF (5 ml). 2-Bromo-1-chloroethane (4.1 g) was added and the mixture was heated at 70° C. for 2 hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel. The 1-(2-chloroethyl)-5,6-dimethoxy-1H-indole-2,3-dione thus obtained was dissolved in dry DMF (5 ml) and anhydrous potassium carbonate (2.44 g), potassium iodide (100 mg) and 1-(phenylmethyl)piperazine (3.06 g) were added. The mixture was stirred and heated at 70° C. for 2 hours and then evaporated to dryness under reduced pressure. The residue was purified by chromatography to yield a red oil which on treatment with ethanolic HCl afforded 5,6-dimethoxy-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-1H-indole-2,3-dione dihydrochloride (33%), m.p. 205°-207° C. (dec.).
Reaction SMILES: [SH:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C>[CH2:24]([S:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1)[CH3:25]
Reactant: CCI
Reactant: CCOC(=O)c1c(S)nc2ccncc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2ccncc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of ethyl 2-mercapto-4-methyl-1,6-naphthyridine-3-carboxylate (0.22 g, 0.89 mmol, 1 eq.) in dry DMF (5 ml) was added K2CO3 (0.37 g, 2.66 mmol, 3 eq.) at 0° C. followed by the addition of ethyl iodide (0.41 g, 2.66 mmol, 3 eq.). The reaction mixture was stirred at RT for 1 h. Afterwards the mixture was poured into ice water (10 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over anhydrous Na2SO4 to provide the crude product, which was purified by CC (EtOAc/hexane 2:3) to yield ethyl 2-(ethylthio)-4-methyl-1,6-naphthyridine-3-carboxylate (0.18 g, 0.65 mmol, 73%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:24]2[CH2:36]I)=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>CN(C)C=O.O>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31])[CH2:25][C@H:24]2[CH2:36][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:22])=[CH:38][CH:39]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl malonate (660 mg) and 180 mg of 50% sodium hydride in 12.5 ml of dry dimethylformamide were stirred at room temperature in a nitrogen stream for 15 minutes, and 1.34 g of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine was added thereto. The resulting mixture was stirred at room temperature for 15 hours, neutralized with 3.75 ml of 1N hydrochloric acid, diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatogrphy to obtain (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH2:63])([CH3:54])[CH3:53]>CN(C)C=O>[C:52]([O:55][C:56](=[O:64])[NH:57][CH:58]1[CH2:62][CH2:61][CH2:60][CH:59]1[NH:63][C:5](=[O:7])[C:4]1[C:8]([S:16][CH3:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[O:2][CH3:1])([CH3:54])([CH3:51])[CH3:53]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 1.1 g, 4.1 mmol) was dissolved in 40 mL dimethylformamide. N,N-Diisopropyl ethyl amine (763 mg, 5.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.57 g, 4.1 mmol) were added. After 5 minutes of stirring at room temperature [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) (993 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane ethyl acetate 100:0->1:1) yielded the title compound as a white solid (1.8 g, 100%), MS: m/e=449.2 [(M+H)+].
Reaction SMILES: O([C:8]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N+:10]([O-:12])=[O:11])C1C=CC=CC=1.[NH2:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[N:26]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[S:28][CH:29]=1.C(O)(C)C>C(Cl)Cl>[CH3:33][N:31]([CH2:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:8]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N+:10]([O-:12])=[O:11])[N:26]=1)[CH3:32]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1

Procedure:
A solution of 0.4 g (1.32 mmol) of 85% pure 1,1-diphenoxy-2-nitroethene, 0.35 g (1.52 mmol) of 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine, 5 ml of isopropyl alcohol and 5 ml of methylene chloride ws stirred at room temperature for about two hours to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine in situ. The product was not isolated but used directly in the reaction described in part B.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH:3]=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=O>>[O:22]([C:18]1[CH:17]=[C:16]([CH2:14][CH2:13][CH2:3][C:2]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)([CH3:5])[CH3:1])[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
In the same manner as described in Synthesis Example 2, the equivalent mixture of α,α-dimethyl-(4-chlorophenyl)acetaldehyde and 3-phenoxyacetophenone was treated to give 1-(3-phenoxyphenyl)-4-(4-chlorophenyl)-4-methylpentane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].I[CH3:22]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])[CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc([N+](=O)[O-])cc1N
Temperature: 40 °C
Yield: 67.1 %

Procedure:
A mixture of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (0.33 g, 1.16 mmol), iodomethane (0.22 mL, 3.5 mmol) and 2-tert-butylimino-2-diethyl-amino-1,3-dimethyl-perhydro-1,2,3-diazaphosphorine on polystyrene (Fluka) (2.6 g, 5.8 mmol) in THF (15 mL) was heated at 40° C. for 6 hours. Filtration, filtrate solvent evaporation, and chromatography on preparative TLC with methylene chloride and methanol (40:1) gave 0.23 g of [(2-amino-4-nitro-benzyl)-methyl-amino]-acetic acid tert-butyl ester in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, 1H), 7.52 (s, 1H), 7.18 (d, 1H), 5.43 (br, 2H), 4.73 (s, 2H), 4.25 (s, 2H), 2.35 (s, 3H), 1.37 (s, 9H); MS (m/e): 296.4 (M+1).