Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]>ClCCCl>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:1])=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1Cl
Reactant: BrBr
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)cc2)c(F)c(N)c1Cl
Temperature: 23 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
Bromine (47 μL, 0.92 mmol, 1.2 equiv) was added to a stirred solution of methyl 4-amino-3-chloro-5-fluoro-6-(4-(trimethylsilyl)phenyl)picolinate (270 mg, 0.77 mmol, 1.0 equiv) in 1,2-dichloroethane (5.1 mL) at 23° C. The resulting dark orange solution was stirred at 23° C. for 24 h. The reaction mixture was quenched with a saturated solution of sodium thiosulfate (5 mL) and then adjusted to pH 10 using 2 M sodium hydroxide. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the title compound as a tan powder (160 mg, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[N:3]=[CH:4][N:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Temperature: 80 °C
Yield: 96.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Aldrich, 0.79 g, 5.0 mmol) and DMF (10 ml) was treated with potassium carbonate (0.72 g, 5.2 mmol) and heated at 80° C. for 3 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4), and concentrated to give the crude product as a yellow solid. The crude product was triturated with isopropyl ether to give 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine as a yellow solid (1.3 g, 94%). 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.51 (dd, 1H, J=8.6, 2.5 Hz), 8.31 (d, 1H, J=9.1 Hz), 7.87 (d, 1H, J=9.1 Hz), 7.84 (s, 1H).
Reaction SMILES: [Br:1][CH:2]1[C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][C:4]([CH:17]=[CH:18][O:19][CH3:20])([CH2:5][O:6]2)[CH2:3]1.[Cr](Cl)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[CH3:20][O:19][C:18](=[O:22])[CH2:17][C:4]12[CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)([CH:2]([Br:1])[CH2:3]1)[O:6][CH2:5]2
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COC=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a stirred solution of the cis and trans mixtures of 6-bromo-1-(4-chloro-phenyl)-4-(2-methoxy-vinyl)-2-oxa-bicyclo[2.2.2]octane (1.7 g, 4.75 mmol) in dichloromethane (12 ml) and tetrahydrofuran (25 ml) at room temperature, was portionally added pyridinium chlorochromate (3.07 g, 14.26 mmol). The reaction mixture was stirred at room temperature for 2 hours. More pyridinium chlorochromate (2.05 g, 9.51 mmol) was added, and the mixture was stirred for another 60 hours at room temperature. The mixture was filtrated and the filtrate was concentrated, and diluted with ethyl acetate (100 ml). The organic phase was washed with water, brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (heptanes/acetone 2/1) to afford [6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (1.08 g, 61%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.79 (m, 1H) 1.87-1.98 (m, 1H) 2.01-2.11 (m, 1H) 2.14 (s, 2H) 2.23-2.30 (m, 1H) 2.52-2.63 (m, 1H) 2.75-2.87 (m, 1H) 3.62 (s, 3H) 3.84 (dd, J=10.11, 2.65 Hz, 2H) 4.19-4.29 (m, 1H) 7.23 (d, J=8.80 Hz, 2H) 7.33 (d, J=8.80 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[N:16]([CH3:29])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (22.0 mmol) of ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate, 0.88 9 (22.0 mmol) of 60% sodium hydride, 6.25 g (44.0 mmol) of methyl iodide and 150 ml of dimethylformamide. Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 7.40 g (89.1%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:34][Si:35]([CH3:51])([CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:35]([CH3:34])([CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)=[N:32][CH:31]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cn2)cc1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 6-(4-octylphenyl)-pyridin-3-ol (0.085g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([O:23]C)=[CH:7][CH:6]=1)=[O:4].[H][H]>CCO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:23])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2nc3c(C(=O)O)ccc(O)c3[nH]2)cc1
Yield: 100 %

Procedure:
2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (0.63 g, 1.92 mmol) obtained in step 2 was dissolved in 15 ml of EtOH, 0.1 g of 10% Pd/C was added thereto and stirred for 24 hours while hydrogen was supplied thereto from a balloon fulfilled with H2 gas. The resulting solution was filtered and dried to obtain the title compound (0.57 g, 1.92 mmol) in a yield of 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([O:19][C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:21]=2)=[CH:17][C:16]=1[F:40].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:40][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:15]=1[NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[S:13])[O:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[CH:21]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)c(F)c3)ncn2)CC1
Reaction time: 4 h
Yield: 10 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.4 ml) to a solution of crude 3-[6-(4-amino-3-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea and (+)-10-camphorsulfonic acid (86.2 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and diethyl ether (2.0 ml) was added to the resultant residue to precipitate crystals. The crystals were filtered and then subjected to aeration drying to provide the title compound (21.0 mg, 10%) as white crystals.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]([CH3:23])[CH2:20][CH:21]=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:24][CH:20]([CH:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH3:23])[CH:21]=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(CC=O)c1ccc2ncccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: CC(c1ccc2ncccc2c1)C(Cl)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
L-Proline (5.8 mg, 0.050 mmol) was added to a solution of 3-quinolin-6-ylbutanal (50 mg, 0.25 mmol) in chloroform (0.5 mL) at 0° C. followed by addition of N-chlorosuccinimide (36.9 mg, 0.276 mmol). The mixture was stirred at RT for 2 h, diluted with hexanes and filtered. The filtrate was concentrated and purified by chromatography on silica gel with EtOAc in methylene chloride (0-10%) to afford the desired product (0.048 g, 82%). LCMS: (M+H)=234.1/236.1.
Reaction SMILES: [OH:1][CH:2](/[CH:16]=[CH:17]/[CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CN(C)C=O>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:4]([CH2:3][CH:2]([OH:1])[CH:16]=[CH:17][CH3:18])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([CH3:32])([CH3:31])[CH3:30]
Reactant: C/C=C/C(O)CNS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC=CC(O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+)-(E)-N-(2-hydroxy-pent-3-enyl)-4-methoxybenzenesulfonamide (1.2 grams, 4.42 mmol) in tetrahydrofuran-dimethylformamide (10 mL, ca. 3:1) at 0° C. is added sodium bis(trimethylsilyl)amide (4.9 mL, 1.0M solution in tetrahydrofuran). After 10 minutes, t-butylbromoacetate (786 mL, 4.83 mmol) is added. The mixture is warmed to room temperature, stirred for 1 hour and quenched with saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 1:1 ethyl acetate-hexanes) to provide [(2-hydroxy-pent-3-enyl)-(4-methoxybenzenesulfonyl)-amino]-acetic acid t-butyl ester.
Reaction SMILES: C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C.C(O)=[O:53]>O>[C:32]1([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[OH:53])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: O=CO
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 4.91 g of raw product of Example 12 in 30 ml of 50% aqueous formic acid was stirred in a water bath at 60° C. and was then diluted with water and vacuum filtered. The filter was rinsed with water and the product was dried to obtain 1.39 g of triphenylcarbinol. The filtrate was evaporated to dryness and the residue was taken up in water and effloresced. The mixture was vacuum filtered and therecovered product was rinsed with water and dried to obtain 800 mg of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(1-methylethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid. 972 mg of the product were dissolved in 4 ml of methanol and the solution was diluted with 20 ml of ether and vacuum filtered. The product was rinsed and dried to obtain 404 mg of the said acid for analysis in the syn configuration and melting at ≃200° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:20])=[O:19])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([S:18]([Cl:21])(=[O:19])=[O:20])[C:10]2[C:15]([C:16]=1[Br:17])=[CH:14][CH:13]=[CH:12][C:11]=2[N+:27]([O-:29])=[O:28])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2ccccc2c1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc2c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
An ice-cold, stirred solution of 3-(2-acetoxy-ethyl)-4-bromonaphthalene-1-sulfonyl chloride (17.66 g, 45.1 mmol) in trifluoroacetic acid (150 mL) was treated with 96% sulfuric acid (12.5 mL, 225 mmol) and with 90% nitric acid (2.65 mL, 56.4 mmol) added dropwise over 3 minutes. The reaction mixture was removed from the ice bath, stirred at room temperature for 15 minutes, re-cooled in an ice bath, and treated with water (850 mL) added dropwise. The resulting mixture was filtered through a celite pad to collect the solid which was washed with water (100 mL) and dissolved in methylene chloride (350 mL). The methylene chloride solution was washed with water (500 mL) containing brine (100 mL), dried over magnesium sulfate, and evaporated under vacuum to an oil (21.23 g). This material was shown to be a 42:58 mixture of the 5-NO2 to 8-NO2 products by 1H NMR). The crude product was mixed with ethyl acetate (20 mL) and sonicated to provide a crystalline precipitate. This material was collected, washed with ethyl acetate, and dried under vacuum to afford the title compound (8.11 g, 41% yield) as an off-white solid. The mother liquors yielded an additional 1.47 g of the title compound following flash chromatography on silica gel (eluting with 30-35% ethyl acetate in hexane) and crystallization from diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.Br[CH:14]([CH2:16][CH3:17])[CH3:15]>CC#N>[CH:14]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCC(C)Br
Solvent: CC#N
Product: CCC(C)c1c[nH]c2cc(N)ccc12

Procedure:
3-sec-Butyl-1H-indol-6-ylamine (B-14) was synthesized following the general scheme above starting from 6-nitroindole and 2-bromobutane. Overall yield (20%). HPLC ret. time 2.32 min, 10-99% CH3CN, 5 min run; ESI-MS 189.5 m/z (MH+).
Reaction SMILES: [CH:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[CH:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:11]([O:13][CH3:14])=[O:12].[H][H]>C(Cl)Cl.[Pd]>[CH:1]1([C:15]([O:17][CH3:18])=[O:16])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1C=CC(C(=O)OC)C(C(=O)OC)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)OC)C(C(=O)OC)C1

Procedure:
A solution of trimethyl cyclohex-5-ene-1,2,4-tricarboxylate (0.50 g, 1.9 mmol) in methylene chloride (15 ml) containing a catalytic amount of palladium on carbon (150 mg, 5 percent Pd/C, 7.5 mg Pd, 4 mole percent) is stirred at room temperature under balloon pressure of hydrogen gas for 2 hours, at which point GC-MS analysis shows complete conversion. Filtration and removal of the solvent provides trimethyl cyclohexane-1,2,4-tricarboxylate as a clear, colorless gel (0.42 g, 1.6 mmol, 85 percent yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]12[NH:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22][CH2:21]2>ClCCl.Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:24]23[NH:27][CH:20]([CH2:26][CH2:25]2)[CH2:21][CH2:22][CH2:23]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CC2CCC(C1)N2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C23CCCC(CC2)N3)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (1.78 g, 8.0 mmol), pyridine (0.78 mL, 9.6 mmol), and 8-azabicyclo[3.2.1]octane (0.796 g, 8.02 mmol) in dichloromethane (22 mL) was stirred for 5 hrs at 0° C., diluted with 1N HCl, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered, concentrated, and triturated with diethyl ether to give 1-(4-nitro-benzenesulfonyl)-8-azabicyclo[3.2.1]octane as a brown solid. The solid was added to a mixture of HCO2NH4 (1.91 g, 30.3 mmol) and 10% Pd/C (catalytic amount) in methanol (20 mL) and ethyl acetate (4 mL), stirred overnight at about 25° C., filtered, concentrated, diluted with water, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), 7.02 (d, 2H), 4.17 (brs, 2H), 1.42-1.86 (m, 10H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:25]([NH:29][CH3:30])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([N:29]([CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CNC(C)(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CN(CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 1C and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:16][O:15]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][SH:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][S:29][CH2:16][C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])([OH:15])[CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:26][CH:25]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CSCc1ccc(Cl)cc1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 53.6 %

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane methanesulphonate salt (0.336 g, 1 mmole), 4-chlorobenzyl mercaptan, (0.159 g, 1 mmole) and anhydrous potassium carbonate (0.414 g, 3 mmole) were stirred in dry N,N-dimethylformamide (15 ml) at 70° C. for 72 hours. The reaction mixture was diluted with water (70 ml) and extracted with ethyl acetate (2×70 ml). The extracts were combined and evaporated to give an oil which crystallized on standing. Recrystallization from a mixture of ethyl acetate and n-hexane gave the title compound (0.23 g, 53%) m.p. 106°-107° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:16][C@H:17]1[CH2:26][CH2:25][C@@H:24]2[C@@H:19]([CH2:20][C@@H:21]([C:34]([OH:36])=[O:35])[N:22](C(OC(C)(C)C)=O)[CH2:23]2)[CH2:18]1)([OH:3])=[O:2].C(OCC)(=O)C.[ClH:43]>C(OCC)C>[ClH:43].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[O:16][C@H:17]1[CH2:26][CH2:25][C@@H:24]2[C@@H:19]([CH2:20][C@@H:21]([C:34]([OH:36])=[O:35])[NH:22][CH2:23]2)[CH2:18]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](Oc3cc(-c4ccccc4)ccc3C(=O)O)C[C@@H]2C[C@H]1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2ccccc2)cc1O[C@H]1CC[C@H]2CN[C@H](C(=O)O)C[C@H]2C1

Procedure:
The material from step B (350 mg, 0.71 mmol) was treated with ethyl acetate saturated with hydrogen chloride (7 mL) for 4 hours at room temperature. The mixture was concentrated in vacuo to afford, after trituration with ethyl acetate and diethyl ether, the desired aminoacid (250 mg, 82%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21]([C:24](=[CH2:28])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:17]([F:16])([F:30])[C:18]1[N:23]=[CH:22][C:21]([CH:24]([CH2:28][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1
Reactant: C=C(C(=O)O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C(=O)O)c2ccc(C(F)(F)F)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.[H-].[Na+].CN(C)C=O>O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:1][C:2]2[N:17]=[CH:16][CH:15]=[CH:14][C:3]=2[C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[N:21]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Nc1ncccc1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Nc2ncccc2C(=O)OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
2.3 g (0.01 mol) of benzyl 2-aminonicotinate, 2.2 g (0.01 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.4 g (0.01 mol) of 60% sodium hydride were weighed, and 10 ml of dimethylformamide was added thereto and the mixture was stirred at 100° C. for 2 hours. The mixture was then poured into water, and was extracted with 100 ml of ethyl acetate. The extracted material was then washed with water and a saturated sodium chloride aqueous solution, and was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was recrystallized with ethanol to obtain 1.6 g of a yellow-brownish powder of the aimed product.