Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a homogeneous solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 eq), triphenyl phosphine (1.5 eq), and phthalimide (1.5 eq) in THF (0.2 M) cooled to 0° C., ditertbutylazodicarboxylate (1.5 eq) in THF was added to the solution. The mixture was stirred at 0° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (99%). LC/MS (m/z): MH+=378.2, Rt=1.10.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[F:28][C:29]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH2:31][NH:32][CH3:33].[Cl-].[Na+]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:31][CH:30]=[C:29]([F:28])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH3:33]
Reactant: CNCC=C(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 3 h
Yield: 181.7 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)oestra-1,3,5(10)-trien-17-one and 1.26 g of (3,4,4,5,5,5-hexa-fluoropent-2-enyl)methylamine are dissolved in 20 ml of N-methylpyrrolidone and stirred at a bath temperature of 80° C. for 3 hours. After the reaction solution has cooled to room temperature, the mixture is added to saturated sodium chloride solution, extracted with diethyl ether, dried and concentrated in vacuo. 1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoropent-2-enyl)methylamino]pentyl}-3-hydroxyestra-1,3,5(10)-trien-17-one are obtained as a crude product which is employed in the next stage without purification.
Reaction SMILES: Br.C([O:9][C:10]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:11]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])C1C=CC=CC=1>CC(O)=O.C(Cl)Cl>[CH2:16]([O:15][C:14]1[C:10]([OH:9])=[C:11]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:12]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:13]=1[C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
HBr (33% in AcOH, 970 μL, 5.34 mmol) was added to a stirred solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (2.82 g, 5.34 mmol) in AcOH (40 mL) and the reaction was allowed to stir for 16 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), brine (2×100 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was redissolved in AcOH (40 mL) and HBr (33% in AcOH, 970 μL, 5.34 mmol) was added dropwise and the reaction was allowed to stir at RT for 40 h. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL) and brine (2×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g, 0-30% EtOAc in toluene) to afford ethyl 4-(benzyloxy)-5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (60) (1.48 g, 57%) as a colourless oil: m/z 439 (M+H)+ (ES+); 437 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 7.42-7.28 (m, 5H), 7.12-7.05 (m, 2H), 6.91-6.84 (m, 2H), 5.01 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H), 1.0 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O[C@@H:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:27]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c(C)ccc1-c1ccc(O[C@H](Cc2ccccc2)C(=O)OCC)cc1
Yield: 33 %

Procedure:
To a solution of 4-(1-dodecyl-5-methyl-1H-pyrrol-2-yl)phenol (2.97 g, 8.70 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.86 g, 9.58 mmol) and triphenylphosphine (2.51 g, 9.57 mmol) in toluene (120 ml) was added diethyl azodicarboxylate (1.67 g, 9.57 mmol) and the mixture was refluxed for 20 hours under heating. The insoluble matter was filtered out and the filtrate was diluted with ethyl acetate. The obtained solution was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 1.49 g (yield: 33%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[N:30][CH:29]=[C:28]([CH3:32])[N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Solvent: Cc1ccccc1C
Product: Cc1cncc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) in xylene (10 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (329 mg, 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.O.O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-nitropyridine (4.48 g) was added in portions to a mixture of sodium phenoxide trihydrate (4.80 g) in DMF (140 ml) with stirring at ambient temperature under nitrogen. The mixture was then heated at 60° C. for 2 hours and then at 90° C. for 3 hours. The mixture was allowed to cool over 18 hours. The mixture was poured into ice water and extracted with dichloromethane to give a residue which was stirred in petroleum ether, b.p. 60°-80° C. at ambient temperature for 30 minutes and then filtered to give 5-nitro-2-phenoxypyridine, m.p. 84°-86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(N3CCNCC3)c2n1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc2cccc(N3CCN(C4CCN(c5cccc6cccnc56)CC4)CC3)c2n1

Procedure:
Using the synthetic methods described in previous examples, 2-methyl-8-(piperazin-1-yl)quinoline (Oruz, et al., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a light brown semi-solid; MS (ES) m/z (relative intensity) 438 (M+H)+ (100).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:25][CH2:26][CH3:27])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O1CCCC1>[CH2:26]([S:25][C:19]1([S:23][CH3:24])[CH2:18][CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:30])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:29])[C:12](=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH3:27]
Reactant: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 97.8 %

Procedure:
A solution of 11β-acetyloxy-17-(ethylthio)-9-fluoro-17-(methylthio)androsta-1,4-diene-3-one (620 mg) in a mixture of methanol (20 ml) and tetrahydrofuran (10 ml) is stirred under nitrogen with 3 M aqueous sodium hydroxide (1.5 ml). After eighteen hours, a slight excess of acetic acid is added. The mixture is concentrated in vacuo, diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried, evaporated and chromatographed over a column of silica gel (10 g) eluting the column successively with chloroform-hexane (4:1), chloroform and chloroform-ethyl acetate (95:5) to isolate the title compound (550 mg). Crystallization of this from ethyl acetate-hexane and drying (110° C., 0.3 mm of Hg, 7 hours) gives the analytical specimen, melting point 275° C., dec. (contracts from approximately 200° C., discoloration starts from approximately 220° C. and becomes deeper until spontaneous melting at 275° C. with decomposition) with consistent spectral data. The nmr spectrum shows that this is an essentially 1:1 mixture of the two 17-stereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH:17]=[CH2:18])=[O:15])[C:12]([OH:20])=[CH:11][CH:10]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH:17]([Cl:22])[CH3:18])=[O:15])[C:12]([OH:20])=[CH:11][CH:10]=1
Reactant: C=COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Product: CC(Cl)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Reaction time: 1 h

Procedure:
To a mixture of vinyl 5-(2,4-difluorophenyl)salicylate (15 g) and 0.1 g dry PCl5, HCl gas is passed for about one hour at about 120°-125° C. Upon cooling, the crude product crystallizes and is collected by filtration. Recrystallization from methanol yields pure 1-chloroethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].BrBr.C(O)(=[O:16])C>>[OH:16][CH2:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: CC(=O)O
Agent: BrBr
Product: Cc1c(CO)[nH]c2ncccc12

Procedure:
2,3-dimethylpyrrolo[2,3-b]pyridine(0,2 g 0.0014 mol) was treated in 3 ml acetic acid with an equimolecular amount of bromine and after 5 min yellow precipitate was formed. The solid was filtered off and treated with 3 ml water for 60 min. The mixture was made alkaline with bicarbonate and extracted with methylene chloride. When the organic layer had been dried and evaporated the product was isolated as a yellow oil. (0,12 g, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH2:19][CH3:20])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH2:19][CH3:20])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCc1nc(Br)sc1C(=O)OC
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OC
Yield: 66.5 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (124 mg, 0.72 mmol), methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (22c) (158 mg, 0.63 mmol) and diisopropylethylamine (0.21 mL, 1.20 mmol), to obtain 143 mg of the title compound as a white solid (66%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5]2.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[CH:5]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COCC12C=CC(COC)(CC(OS(=O)(=O)C(F)(F)F)=C1)O2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC12C=CC(COC)(CC(c3ccc(N)cc3)=C1)O2
Yield: 81 %

Procedure:
The title compound was prepared by the procedure of Example 4, step (b) using trifluoromethanesulfonic acid 1,5-bis-methoxymethyl-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl ester (as prepared in the previous step, 3.25 g, 9.45 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.28 g, 10.4 mmol). Silica gel chromatography (5-10% EtOAc/DCM) afforded the title compound (2.19 g, 81%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H21NO3, 288.2 (M+H), found 288.2.
Reaction SMILES: C(O[C@@H:5]1[O:17][C@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Br-:23]>C1C=CC=CC=1.[N+](C)([O-])=O.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:17][C@H:5]1[Br:23])(=[O:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 10 g of 5,6-O-isopropylidene- 1,2'3,6'-tetrakis-N-(trifluoroacetyl)neamine (3) in 330 ml of benzene and 220 ml of nitromethane is heated to boiling and 110 ml of distillate collected. 2,3,5-Tri-O-acetyl-β-D-ribofuranosyl bromide is prepared from 16.5 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose, as described above. The bromide is dissolved in 30 ml of nitromethane. One third of this solution and 7 g of mercuric cyanide is added to the original reaction mixture. The mixture is heated to reflux. Two similar additions of bromide and mercuric cyanide are made after 1 and 2 hours of reflux. The mixture is refluxed a final hour. The cooled reaction mixture is diluted with 750 ml of ethyl acetate and extracted with two 500 ml portions of 5% KHCO3 solution. The organic layer is washed with brine and filtered through Na2SO4. The solvent is evaporated under vacuum. The residue is chromatographed over 1 kg of silica gel, and eluted with chloroform-methanol (20:1). Fractions of 50 ml are collected and monitored by tlc. Fractions 1-30 contain fast moving impurities and are discarded. Fractions 30-40 (27A) weigh 13.4 g. while fractions 41-48 (27B) weigh 3.23 g. A 12.4 g portion of 27A is rechromatographed over 1 kg of silica gel using chloroform-methanol (30:1) for elution. The center cut based on tlc of the fractions is combined and evaporated to give 6.66 g of blocked analog (12β). CMR data, after removal of the blocking group as described infra, shows this compound to be chiefly the 3' β isomer.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>O>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:11]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=3)[CH2:8]2)=[O:12])=[CH:32][CH:33]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N2CC(Oc3cccc(C(F)(F)F)c3)C2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1.88 g (0.0067 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1 g (0.007 mole) of potassium carbonate was added 20 ml of tetrahydrofuran and 0.75 g (0.007 mole) of 4-toluidine. After stirring for 0.5 hr, ice was added and stirring continued for 18 hr. The reaction mixture was diluted with water and then decanted from an oil residue which separated. Upon standing, this residue solidified and was recrystallized from acetone to yield 1.1 g (47%) of large, white crystals, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:20].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:20]
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1C
Yield: 93.4 %

Procedure:
A mixture of 3-(4-Benzyloxy-2-methyl-phenyl)-propionic acid methyl ester (13.7 g, 48.5 mmol) and Pd/C (5%, 13.7 g) in MeOH (423 mL) is stirred under 60 psi of hydrogen for 24 hrs. Catalyst is filtered off, filtrate is concentrated giving the title compound (8.8 g, 93.5%).
Reaction SMILES: C1(S([Cl:10])(=O)=O)C=CC=CC=1.[CH3:11][N:12]([CH2:25][CH2:26][CH2:27]O)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1>C(Cl)Cl>[Cl:10][CH2:27][CH2:26][CH2:25][N:12]([CH3:11])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1
Reactant: COc1ccc(CCN(C)CCCO)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCCl)cc1OC
Reaction time: 0.5 h

Procedure:
275 gm of benzenesulfonic acid chloride were added to 4 gm of 3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)amino]-propanol. After standing for 30 minutes, the mixture was dissolved in methylene chloride, washed with an aqueous 30% sodium hydroxide solution and water, dried over sodium sulfate and evaporated in vacuo. After purifying the residue on a silica gel column (eluant: methylene chloride/ethanol) a colorless oil was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25]C)C(O)=O)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[C:18]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Product: CC(C)(C)c1cc(-c2nc3ccc(O)cc3o2)ccc1O

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-tert-butyl-4-methoxybenzoic acid and was obtained as a white solid, m.p. 220-222° C.; MS m/e 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:27]>[Pd].CO>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[CH:18]=2)[CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[F:27]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3[nH]2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C)cnc3[nH]2)cc1F
Temperature: 50 °C
Yield: 16.1 %

Procedure:
A mixture of 4-[2-cyclopentyl-1-(5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (0.8 g, 2.1 mmol) and 10% palladium on activated carbon (600 mg) in methanol (100 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 4-[2-cyclopentyl-1-(5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-2-fluoro-benzoic acid methyl ester as a white solid (129 mg, 16%): LC/MS m/e calcd for C23H25FN2O2 [M+H]+ 381.47, observed 381.0.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(O)C.C(=O)=O.C([Li])CCC.[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37](=[O:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][CH2:34][CH:35]1[CH2:38][C:37]([C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)([OH:39])[CH2:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc(CN2CCCC2)cc1
Reactant: O=C1CC(COCc2ccccc2)C1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OC1(c2ccc(CN3CCCC3)cc2)CC(COCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.9 g, 7.9 mmol) in 13 mL of tetrahydrofuran at −78 C (iPrOH/dry ice) was added slowly down the side of the flask a solution of n-butyl lithium (3.2 mL, 7.9 mmol, 2.5 M in THF). After 30 minutes a precooled −78 C (iPrOH/CO2 ice) solution of 3-benzyloxymethyl-cyclobutanone (1.0 g, 5.3 mmol, in 1 mL of THF) was added via cannula down the side of the flask (wash 1 mL). The resulting solution was stirred at −78 C for 30 minutes, then quenched with a saturated solution of aqueous NH4OH and diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH through 30% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (1.3 g, 71% yield) as a colorless oil and a 3:1 mixture of cis:trans isomers.