Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[CH2:14][CH2:13][C@@H:12]3[C@:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]3([CH3:16])[CH3:15])[C@@H:6]1[C@@H:5]([OH:18])[CH:4]([OH:19])[O:3]2.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1.C(OCC)C>[CH:4]([O:3][C@:2]1([CH3:1])[CH2:14][CH2:13][C@@H:12]2[C@:7]([CH3:17])([CH2:8][CH2:9][CH2:10][C:11]2([CH3:15])[CH3:16])[C@H:6]1[CH:5]=[O:18])=[O:19]
Reactant: CC1(C)CCC[C@@]2(C)[C@H]1CC[C@@]1(C)OC(O)[C@H](O)[C@@H]21
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(C)CCC[C@]2(C)[C@@H](C=O)[C@](C)(OC=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a solution of 0.30 g (1.1 mmol) of lactols 9S and 9R in 15 mL of benzene under argon was added 0.60 g (1.3 mmol) of lead tetraacetate. After the mixture was stirred at 25° C. for 4 h, it was diluted with diethyl ether, the organic layer was washed with water, and brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent to give 0.25 g (85% yield) of aldehyde 11. [α]22D=−54.4° (c 0.25, CHCl3); 1H NMR (CDCl3) δ 9.98 (d, J=4Hz, 1H, CHO), 7.92 (s, 1H, OCHO), 2.55 (dd, J=9.6, 3.2Hz, 1H, C4a-H), 2.49 (d, J=4Hz, 1H, C1-H), 1.85 (s, 3H, Me), 1.84˜0.90 (m, 10H), 1.18 (s, 3H, Me), 0.89 (s, 3H, Me), 0.83 (s, 3H, Me); 13C NMR (CDCl3) δ 204.2 (C═O), 160.1 (C═O), 85.9, 68.9, 55.1, 41.7, 40.0, 39.9, 39.1, 33.4, 22.3, 21.6, 21.5, 20.0, 18.1, 17.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][C:20]=1[NH2:21].C(O)(C(F)(F)F)=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:21][C:20]1[C:19]([Cl:18])=[CH:25][C:24]([Cl:26])=[C:23]([N:27]2[CH2:28][CH2:29][N:30]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:32]2)[CH:22]=1
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1Cl
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The reaction mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (0.131 g, 0.561 mmol), 2,4-dichloro-5-(piperazin-1-yl)aniline, 2 TFA (0.253 g, 0.534 mmol), EDC (0.123 g, 0.641 mmol) and DMAP (0.130 g, 1.07 mmol) in DCM (4 mL) was stirred at RT overnight. The crude product was purified by flash chromatography (MeOH/DCM, gradient 2%-4%, Rf 0.31 with 3% MeOH) to give 0.221 g of the title compound (90% yield). 1H-NMR (CD3OD, 400 MHz): δ 7.57-7.50 (2H, m), 7.19 (1H, s), 7.18-7.07 (2H, m), 6.43 (1H, s), 3.81 (3H, s), 3.74 (2H, s), 3.24 (2H, s), 2.88 (2H, s), 2.53 (3H, s), 2.35 (2H, s).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:19]([NH2:22])(=[O:21])=[O:20])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:4]1.[N+:29]([O-])([O-:31])=[O:30].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:19]([NH2:22])(=[O:21])=[O:20])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:29]([O-:31])=[O:30])=[CH:7][C:6]=2[N:5]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:4]1
Reactant: NS(=O)(=O)c1cc2c3c(ccc2cc1[N+](=O)[O-])N(C(=O)C(F)(F)F)CC3CCl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: NS(=O)(=O)c1cc2c3c(cc([N+](=O)[O-])c2cc1[N+](=O)[O-])N(C(=O)C(F)(F)F)CC3CCl
Temperature: 0 °C
Yield: 21 %

Procedure:
Ice cold H2SO4 (98%, 5 mL) was added to 218 (30 mg, 0.069 mmol) at 0° C. with stirring. An ice-cold solution of KNO3 (9 mg, 0.089 mmol) in H2SO4 (98%, 1 mL) was then added dropwise. After 1 h the mixture was poured into ice water and extracted with EtOAc (×3). The combined EtOAc extracts were washed with H2O, brine and dried. Chromatography eluting with petroleum ether/EtOAc (1:1) gave 1-(chloromethyl)-5,7-dinitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-8-sulfonamide (219) (7 mg, 21%) as an orange powder: mp 201-204° C.; 1H NMR (CDCl3) δ 9.49 (s, 1H), 9.29 (s, 1H), 8.71 (s, 1H), 5.67 (s, 2H), 4.73 (d, J=10.8 Hz, 1H), 4.62 (dd, J=11.3, 8.8 Hz, 1H), 4.52-4.45 (m, 1H), 3.97 (dd, J=11.8, 3.5 Hz, 1H), 3.85 (dd, J=11.8, 6.3 Hz, 1H). HRMS (FAB) calcd. for C15H1135ClF3N4O7S (MH+) m/z 482.9989, found 482.9988.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[Cl:19][CH:20]([F:23])[CH2:21]Cl>CO>[Cl:19][CH:20]([F:23])[CH2:21][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FC(Cl)CCl
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1ccccc1SCC(F)Cl
Reaction time: 24 h

Procedure:
A mixture of 217.8 g of the triethylamine salt of 2-mercaptophenylsulfonamide obtained in accordance with Example P6 and 101 g of 1,2-dichloro-1-fluoroethane in 950 ml of methanol is stirred in an autoclave for 24 hours at a temperature of from +65° C. to +70° C. and for a further 24 hours at from +95° C. to +100° C. The reaction mixture is then concentrated by evaporation and the residue is stirred with water. By extracting with ethyl acetate, washing with water, drying over sodium sulfate, concentrating by evaporation and purifying the residue by chromatography with methylene chloride, 99.5 g (49.2% of the theoretical yield) of 2-(2-chloro-2-fluoroethylthio)-phenylsulfonamide having a melting point of from +88° C. to +89° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.O>C(#N)C>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCN
Solvent: O
Solvent: CC#N
Product: CNCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of N-methylethylenediamine (27.0 g, 364 mmol) and ethyl trifluoroacetate (96.6 mL, 812 mmol) in a mixture of ACN (350 mL) and water (7.8 mL, 436 mmol) was refluxed with stiffing overnight. Solvents were evaporated in vacuo. The residue was re-evaporated with i-PrOH (3×100 mL), followed by heat-cool crystallization from DCM (500 mL). Formed crystals were filtered, washed with DCM and dried in vacuo to provide compound AA (88.3 g, 85%) as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:11]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1cccc1C(=O)OC
Temperature: 80 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of methylpyrrole-2-carboxylate (1.01 g, 8.07 mmol) in N,N-dimethylformamide (12 ml) were added 1-bromohexane (1.36 ml, 9.69 mmol) and potassium carbonate (1.474 g, 10.7 mmol), and the mixture was stirred at 80° C. for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 1-hexylpyrrole-2-carboxylate (0.980 g, 4.68 mmol, yield 58%). This was dissolved in methanol (8 ml), 1N-aqueous sodium hydroxide solution (8 ml) was added at room temperature, and the mixture was stirred at 60° C. for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 1-hexylpyrrole-2-carboxylic acid (0.877 g, 4.49 mmol, yield 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C=O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Clc1ccnc2ccccc12
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccnc3ccccc23)c1C
Temperature: 20 °C
Reaction time: 0.2 h
Yield: 103.6 %

Procedure:
2.75 g (17.9 mmol) of 3-ethoxycarbonyl-2-methyl-1H-pyrrole are added at 20° C. under an argon atmosphere to 0.756 g (18.9 mmol) of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 mL of dimethylformamide. After stirring at 20° C. for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.35 mL (17.9 mmol) of 4-chloroquinoline are added. After stirring at 140° C. for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 mL of water and then extracted with 3 times 70 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 5.2 g of a brown oil which is purified by flash chromatography [eluent: dichloromethane/ethyl acetate (97/3 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 3 g of 3-ethoxycarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole are obtained in the form of an orange-coloured oil. Mass spectrum (EI): m/e 280 (M+.), m/e 251, m/e 235.
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Br[CH2:44][C:45]([O:47]C)=[O:46].C([O-])([O-])=O.[K+].[K+].CC(C)=O>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:44][C:45]([OH:47])=[O:46])=[C:10]([CH:9]=1)[C:15]([OH:17])=[O:16])([OH:3])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(C[C@H](N)C(=O)OC)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccc(CC(NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)cc1C(=O)O

Procedure:
Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner. The phenolic hydroxyl group was alkylated with methyl bromoacetate in the usual manner (K2CO3/acetone at reflux) and saponified to give the title compound of example 126.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH:25]=[CH2:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Yield: 76.8 %

Procedure:
A catalytic amount of 5% Pd-C was added to a solution of 250 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-allylphenyl)thiazole in 10 ml of methanol. The mixture was stirred in a hydrogen atmosphere at room temperature for 6 hours. After the completion of a reaction, the reaction mixture was filtered. The filtrate was concentrated. The residue was recrystallized from ethanol to obtain 193 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-propylphenyl)thiazole.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:10]([O-])=O.[Na+].O.O.[Cl:16][Sn]Cl>O.Cl>[ClH:16].[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][NH2:10])[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1ccccc1N
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1ccccc1NN
Reaction time: 15 h

Procedure:
A vigorously stirred solution of 487 ml concentrated hydrochloric acid and 218 ml of water at 0° C. was treated dropwise with 1.93 moles (234 g) of 2-ethylaniline. To the resulting thick suspension was added a solution of sodium nitrite (143 g, 2.07 moles) in 218 ml of water over 1.5 hours while maintaining the internal temperature between 8° C. and 14° C. Next, a solution of SnCl2.2H2O (4.37 moles, 985 g) in 1.312 l of 1:1 concentrated hydrochloric acid:water was added over 5 hours while the internal temperature was kept between 5° C. and 10° C. After 15 hours, the solid was collected on a filter paper and boiled in 1.2 l of water with decolorizing carbon. The solution was filtered through Celite, treated with 400 ml of concentrated hydrochloric acid and put in an ice bath for 0.5 hours. The tan plates were filtered and dried in vacuo over phosphorous pentoxide for 24 hours affording title compound, m.p. 181°-183° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]#[N:9])[CH2:2][CH2:3]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: N#CCN1CCNCC1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of piperazin-1-yl-acetonitrile (0.32 g, 2.3 mmol) and Et3N (350 mg, 3.4 mmol) is added 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (615 mg, 2.3 mmol) at 0° C. The reaction is warmed to room temperature and stirred 4 h. The reaction is diluted with CH2Cl2, washed with 1 N HCl, NaHCO3 and dried over MgSO4. The solution is concentrated and the residue is triturated with PE, triturated with Et2O, and pumped to yield [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile which can be used without further purification. 1H NMR (300 MHz, CDCl3) δ7.89-7.84 (m, 3H), 7.48 (dd, 1H), 4.36 (s, 2H), 3.92 (s, 2H), 3.64-3.61 (m, 2H), 3.57-3.54 (m, 2H); MS (Ion Spray) 444 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:12])([OH:11])[CH3:10].C([Li])CCC.C([O:21][B:22](OC(C)C)OC(C)C)(C)C.Cl>C1COCC1.CCOC(C)=O.O>[CH3:10][C:9]1([CH3:12])[O:11][B:22]([OH:21])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(O)Cc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Cc2ccccc2B(O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol (3.48 g, 15 mmol) in THF (100 mL) cooled to −78° C. was added n-butyllithium (15.2 mL, 2.5M in hexanes) in a dropwise fashion. The reaction was permitted to stir for 10 minutes, prior to the addition of triisopropylborate (10.5 mL, 45 mmol). The reaction was permitted to stir for 16 hours, gradually warming to room temperature. Aqueous hydrochloric acid (10 mL, 6M) was added, and the mixture stirred for 1 hour. The reaction was diluted with EtOAc (250 mL) and water (50 mL). The organic portion was washed with brine, dried over sodium sulfate, and evaporated. The resultant crude material was purified by silica gel chromatography to yield 3,3-Dimethyl-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white semisolid product. 1H NMR (400 MHz, acetone) δ ppm 1.13 (s, 6H) 2.76 (s, 2H) 6.99-7.04 (m, 1H) 7.05-7.14 (m, 1H) 7.21-7.27 (m, 1H) 7.58-7.64 (m, 1H). Amount obtained: 830 mg, 31% yield.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=1>O.C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=1)[C:24]([CH3:25])=[C:7]2[C:8]([OH:13])=[O:1]
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc2c1C(=O)O
Yield: 100.2 %

Procedure:
Potassium hydroxide (20.39 g, 363 mmol) in water (40 mL) was added to a suspension of 5-fluoro-1H-indole-2,3-dione (10.0 g, 60.6 mmol) in ethanol (100 mL) slowly. 1-[3-(Trifluoromethyl)phenyl]-1-propanone (12.24 g, 60.6 mmol) was added, and the mixture was heated to reflux for 1 h. The solvent was removed under reduced pressure, the residue was dissolved in water, and the mixture was washed with ether (3 times). The aqueous mixture was chilled and adjusted to pH˜3 with concentrated HCl. The solid was collected by filtration, washed with water, and air dried to afford 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (21.2 g, >99% yield). MS (m/z) 350.1 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]#[N:12])=[C:9]([OH:13])[CH:8]=[CH:7][C:6]=1[OH:14])#[N:4].[CH:15]([N:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[CH2:20]Br)([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([N:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[CH2:20][O:14][C:6]1[CH:7]=[CH:8][C:9]([OH:13])=[C:10]([C:11]#[N:12])[C:5]=1[C:3]#[N:4])([CH3:17])[CH3:16]
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: CC(C)N(C(=O)CBr)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)COc1ccc(O)c(C#N)c1C#N)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
960 mg of sodium hydride (50% in oil) were added to a solution of 1.6 g of 2,3-dicyano-4-hydroxy-phenol in 100 ml of dimethylformamide, and after stirring for 30 minutes at ambient temperature, then 2.3 g of N,N-bis(isopropyl)-2-bromoacetamide (preparation 8) were added. After stirring for 48 hours, the solvent was evaporated under reduced pressure and 200 ml of 2N hydrochloric acid were added. Extraction was carried out with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed, eluting with a cyclohexane-ethyl acetate mixture (50/50), then with pure ethyl acetate, and finally an ethyl acetate-methanol mixture (98/2) to obtain 1.8 g of the expected product is obtained which was used as is for the following stage.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[CH2:20][C@@H:21]([OH:23])[CH3:22])[CH:13]=1.C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][C@H:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)C/C=C/c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
Under a nitrogen atmosphere, p-toluenesufonyl chloride (7.01 g, 36.77 mmol) was added to a stirring solution of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in dry triethylamine (20 mL) at 0° C. After stirring and warming to ambient temperature over 18 h, the mixture was stirred with cold, saturated NaHCO3 solution (50 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, dark-brown mass (˜7 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g (68.6%) of a light-brown syrup.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[ClH:14]>C(O)C.[Pd]>[ClH:14].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 2-azido-1-(4-fluoro-phenyl)-ethanone in ethanol is added concentrated HCl (aq) and 10% Pd/C (10 mol %). The mixture is stirred under hydrogen (H2) atmosphere at 45 psi for 1 hour. The mixture is filtered through celite and the celite cake is washed with copious amounts of methanol. The solvent is removed under reduce pressure and the resulting residue is triturated with diethyl ether, filtered and dried to give 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[O:17][N:16]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc(I)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 2 ml DMF 1.1 g caesium carbonate and 547 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 630 mg.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:3][CH:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CC=C(c2ccccc2)CC1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CC=C(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 12 %

Procedure:
The title compound was prepared according to method A as described above by reacting crude 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine (prepared by the procedure outlined in Example 6) (1.25 g) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.9 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-Chloro-N-(4-phenyl-1,2,3,6-tetrahydro-1-pyridinyl)adenosine (0.20 g 12%) (after column chromatography) as a foam, 1H NMR (DMSO-d6) δ3.53-3.70 (4H, m, H-5'a, H-5'b and --CH2 --), 3.94 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1' ), 6.15 (1H, br s, vinylic C-H), 7.24-7.51 (5H, m, Ar-H), 8.43 (1H, s, H-8), 9.55 (1H, s, N-H).