Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:9][C:8]([CH3:21])=[C:7]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[N:6]=1)=O.[BH4-].[Li+].Cl.C([O-])(O)=O.[Na+]>CCO>[OH:2][CH2:3][C:5]1[N:6]=[C:7]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[C:8]([CH3:21])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: COC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(CO)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To a solution of 0.24 g (0.51 mmol) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (example 45) in 5.0 ml of EtOH were added 0.093 g (4.27 mmol) of lithium borohydride in three portions. The reaction mixture was stirred at RT for 48 hours, then poured into crashed ice, the pH was reduced to 2-3 with hydrochloric acid (25%), and the mixture subsequently neutralized with solid NaHCO3. Then, it was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.097 g (43%) of the title compound as light yellow solid. MS: 448.1 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][NH:7][C:8]([NH2:10])=[S:9].[CH3:11][O:12][CH2:13][C:14](O)=O.[OH-].[Na+]>>[NH2:10][C:8]1[S:9][C:14]([CH2:13][O:12][CH3:11])=[N:6][N:7]=1
Reactant: NNC(N)=S
Reactant: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nnc(N)s1
Yield: 69.8 %

Procedure:
Phosphoryl chloride (87 ml) was added dropwise to a vigorously stirred mixture of thiosemicarbazide (100 g), methoxyacetic acid (100 g) and petroleum ether b.p. 80°-100° (200 ml) maintained at 60°-70°. The temperature of the mixture was slowly raised to 95° and was kept at this temperature until the evolution of gas ceased. The solvent was evaporated and the residual syrup was dissolved in water (200 ml) to give a yellow solution which was adjusted to pH 7 by the addition of 10N NaOH. The mixture was filtered to give 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole (111.25 g). Recrystallisation from water gave compound with m.p. 177°-179°.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:23])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of tert-butyl 2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate 264 (0.34 g, 0.70 mmol) and Pd/C (0.30 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 265 (0.28 g, quant.) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)=[CH:22]4)[C:18]=3[CH:35]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]4[CH:16]=[CH:15][C:14]([S:13][CH:10]5[CH2:9][CH2:8][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:12][CH2:11]5)=[CH:35][C:18]=43)[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.485 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 1.5 mL) and the mixture was stirred at 0° C. for 1 h. To the reaction mixture was added EtOAc (0.5 mL) and stirring was continued for 10 min. Volatiles were then removed under reduced pressure and the resulting residue was partitioned between DCM and 10% aq. solution of Rochelle's salt. The suspension was stirred for 20 min and then filtered through a pad of Celite®. The filtrate was extracted with DCM and the combined organic phases were washed with water, followed by brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-13% 2M NH3/MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol (229 mg, 98% over two steps). LCMS: RT 2.13/2.19 min [M+H]+ 483.2
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[C:19]([O-:22])(=[O:21])[CH3:20].[K+].[CH2:24]([O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([CH2:34][Br:35])[CH:31]=[C:30]([CH2:36]Br)[CH:29]=1)[CH3:25]>C(#N)C>[C:19]([O:22][CH2:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([CH2:34][Br:35])[CH:31]=1)[C:27]([O:26][CH2:24][CH3:25])=[O:38])(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(CBr)cc(COC(C)=O)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 18-crown-6 (0.103 g) in acetonitrile (15 ml) was added potassium acetate (0.38 g). After 30 minutes 3,5-bis[bromomethyl]benzoic acid ethyl ester (2.61 g) was added and the mixture was stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated and the residue purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 0.97 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:29])[CH:14]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:15](=O)[CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:29])[CH:14]([C:15]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=12)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:11]
Reactant: CCOC(=O)C(C(=O)C1CCCC1=O)C1CCCCC1
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Yield: 51 %

Procedure:
(4-Chloro-phenyl)-hydrazine (5.63 g, 31 mmol; CAS Reg. No. 1073-69-4) was added to a solution of 2-cyclohexyl-3-oxo-3-(2-oxo-cyclopentyl)-propionic acid ethyl ester (8.8 g, 31 mmol) in ethanol (200 ml). The reaction mixture was heated under reflux conditions for 6 h. The solvent was removed under reduced pressure. The residue was suspended in dichloromethane and filtered off. The filtrate was brought to dryness under reduced pressure to give a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (6.26 g, 16 mmol; 51%) as orange oil. MS: m/e=388.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2
Reactant: CC(C)CCC=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-(5-methyl-hex-1-enyl)-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-(5-methyl-hexyl)-1H-indole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH2:23][C:22](=O)[CH2:21]1>C1C=CC=CC=1>[CH3:19][C:20]1([CH3:28])[CH2:25][C:24](=[O:26])[CH:23]=[C:22]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC(=O)C=C(N2CCCCC2)C1
Temperature: 25 °C

Procedure:
Piperdine (7.0 mL; 0.0713 mol) and a catalytic quantity of p-toluenesulfonic acid monohydrate was added to a solution of 5,5-dimethylcyclohexane-1,3-dione (10.0 g; 0.0713 mol) in benzene (100 mL) and the resultant solution was heated at reflux. After 3 hours further piperidine (0.71 mL; 7.13 mmol) was added and the solution was allowed to reflux for a further 16 hours. The reaction mixture was cooled to room temperature and washed with 10% NaCHO3 solution (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated (in vacuo) to leave an orange crystalline solid. (14.23 g, 96%). 1H-nmr (CDCl3) d: 5.3, (s 1H, H-2), 3.4-3.2 (m, 4H, H-2′, H-6′), 2.2 (s, 2H, H-6), 2.1 (s, 2H, H-4), 1.75-1.4 (m, 6H, H-3′, H-4′, H-5′), 1.00 (s, 6H, 2×CH3).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2[CH2:14][S:15][CH2:16][C:3]1=2.[S]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: [S]
Solvent: ClC(Cl)Cl
Product: CN1c2ccccc2NC(=O)c2cscc21

Procedure:
A mixture of 0.5 g. of 1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and 0.5 g. of sulfur is fused at 160°C. ± 5 for 1 hour. The fusion mixture is slurried with chloroform and filtered. The filtrate is chromatographed on silica gel with benzene:methanol 9:1 to give a solid, which is recrystallized from methanol-water to give a tan solid, m.p. 224°-225°C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(O)=CC=1[Cl:44]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[C:15]([Cl:44])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-3-chloro-phenol at Stage 6 of Scheme 2. m/z 524 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:44]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]=[O:44])[N:25]=[C:24]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:35]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C=O)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate (0.63 g, 1.06 mmol) was dissolved in dioxane (10 mL), SeO2 (0.6 g, 5.4 mmol) and water (0.096 mL) were added and the reaction mixture heated at 100° C. for 3.5 hours. The reaction mixture was concentrated in vacuum and the mixture loaded on to a column of silica gel and eluted with MeOH, dichloromethane as eluent, to give the desired compound (0.52 g). 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.53 (s, 1H), 8.56 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.26 (m, 4H), 2.35 (m, 4H)), 1.39 (s, 9H), 1.36 (t, J=6.8 Hz, 3H); MS m/z 636.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[NH3:12]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH2:12])=[CH:7][N:6]=1)=[O:4]
Reactant: N
Reactant: COC(=O)c1cnc(F)cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N)cn1
Temperature: 0 °C
Yield: 99 %

Procedure:
A large steel reaction vessel was charged with a solution of 5-fluoro-pyrazine-2-carboxylic acid methyl ester (17.45 g, 111.78 mmol) in tetrahydrofuran (200 mL). The reaction solution was cooled to 0° C. and was saturated with ammonia gas over 2–3 h. The vessel was then tightly sealed. The reaction was then mechanically agitated and allowed to warm to 25° C. overnight. The vessel was then cooled to −78° C. for 15–20 min, the vessel was carefully vented, and the contents of the vessel were diluted with diethyl ether (100 mL). The resulting precipitate was isolated via filtration, rinsed with petroleum ether (2×100 mL), and air-dried to afford 5-amino-pyrazine-2-carboxylic acid methyl ester (16.97 g, 99%) as an off-white solid: mp 229–231° C.; EI-HRMS m/e calcd for C6H7N3O2 (M+) 153.0538, found 153.0537.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].CCCCCC>CN(C)C=O>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C#CC(O)COc1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)(=O)=O.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[N:37][NH:38][N:39]=2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C@@H:8]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[C@H:7]([CH2:6][N:37]3[N:38]=[N:39][C:35]([C:32]4[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=4)=[N:36]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Cl)cc2)[C@H]1c1cc(F)cc(F)c1
Reactant: Cc1ccc(-c2nn[nH]n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2nnn(C[C@@H]3OC(=O)N(c4ccc(Cl)cc4)[C@H]3c3cc(F)cc(F)c3)n2)cn1
Temperature: 90 °C

Procedure:
To a small reaction tube is placed ((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50 mg, 0.12 mmol), ACN (1 mL), 2-methyl-5-(2H-tetrazol-5-yl)pyridine (39 mg, 0.24 mmol), and potassium carbonate (33 mg, 0.24 mmol). The tube is capped and the reaction is heated to 90° C. for 4 h. The reaction is then quenched with water (2 mL), and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product is purified by flash chromatography (12 g Redisep, 0-10% MeOH/DCM) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 9.18 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.58 (br s, 1H), 7.47-7.44 (m, 2H), 7.29-7.23 (m, 2H), 7.02 (dddd, J=9.1, 9.1, 2.3, 2.3 Hz, 1H), 5.87 (d, J=5.0 Hz, 1H), 5.54 (dd, J=14.7, 5.8 Hz, 1H), 5.46 (dd, J=14.7, 4.0 Hz, 1H), 5.12 (ddd, J=5.7, 5.1, 4.0 Hz, 1H), 2.65 (s, 3H); HPLC-MS calculated C23H17ClF2N6O2 (M+H+) 483.1, found 483.0.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:23]([O:26][OH:27])(=[O:25])[CH3:24]>CCOCC>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:25])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:23]([O:26][OH:27])(=[O:25])[CH3:24]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: CC(=O)OO
Solvent: CCOCC
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
14-Hydroxycodeinone was synthesized from the dienolsilyl ether of codeinone by oxidative hydroxylation using a peracetic acid solution preparation. The peracetic acid solution was prepared as follows:
Reaction SMILES: [CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[CH2:4][CH2:5]/[CH:6]=[C:7](/[C:9]1[S:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:26](OC)=[O:27])[C:19](=[CH:24][CH:25]=2)[C:20](OC)=[O:21])=[CH:11][CH:10]=1)\[CH3:8])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[OH:27][CH2:26][C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[CH2:20][OH:21])[O:15][CH2:14][C:12]1[S:13][C:9](/[C:7](/[CH3:8])=[CH:6]/[CH2:5][CH2:4][C:3]([CH2:30][CH3:31])([OH:32])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CCC(O)(CC)CC/C=C(\C)c1ccc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)(CC)CC/C=C(\C)c1ccc(COc2ccc(CO)c(CO)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
350 mg (0.76 mmol) of dimethyl 4-[5-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalate are dissolved in 20 mL of anhydrous ethyl ether. 70 mg (1.8 mmol) of lithium aluminium hydride are added and the reaction medium is stirred at room temperature for 30 minutes. 400 mL of water are then added slowly and the medium is filtered. The filtrate is concentrated under reduced pressure and the residue obtained is then purified by chromatography on a column of silica (eluent: 70 ethyl acetate/30 heptane). A white solid (m.p.: 100-102° C.) is obtained (m=175 mg; Y=58%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC)[CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)#[N:2].[OH-].[Na+].C1C[O:31][CH2:30]C1>O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:30])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)#[N:2]
Reactant: C1CCOC1
Reactant: CCn1c(-c2ccc(C(=O)OC)cc2)c(C#N)c2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 92 %

Procedure:
Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1Ga step B, is combined with NaOH (40 mg, 1 mmol), H2O (0.8 mL), and THF (3.4 mL) and is heated at 80° C. for 1 hour. The reaction mixture is diluted in H2O and is then ether-washed. The aqueous layer is acidified with aqueous HCl, and is extracted into EtOAc. The organic layer is dried and concentrated to yield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([OH:12])=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 2-dibenzylamino-3-difluoromethoxy-propionate (1.2 g, 3.43 mmol) was stirred with 1N LiOH (10.3 mL, 10.3 mmol) in THF (40 mL) at 50° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and acidified with 1N HCl. The organic layer was dried with sodium sulfate and concentrated with silica gel. The product was purified by column chromatography, eluting with 10-50% ethyl acetate in hexanes, to give 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (730 mg, 63.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.26-7.42 (m, 10H), 6.29 (bt, 1H), 4.45 (dd, 1H), 4.28 (dd, 1H), 3.94 (q, 4H) and 3.85 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[N:18][CH:19]=1
Reactant: CON(C)C(=O)C=Cc1cncc(Br)c1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cncc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (108.0 mL, 91.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (61.0 mL, 91.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(5-bromo-pyridin-3-yl)-N-methoxy-N-methyl-acrylamide (8.2 g, 30.3 mmol, in diethyl ether/tetrahydrofuran 50.0 mL/150.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.9 g of the titled compound as a yellow solid.
Reaction SMILES: CCC(C1NC(=O)CNC(=O)C2NC(C(C(C(O)CO)C)NC(C3N(C(C(CC(N)=O)NC(=O)C(CS(C4NC5C=C(OC)C=CC=5C=4C2)=O)NC(=O)CNC1=O)=O)CC(O)C3)=O)=O)C.[I:66]N1C(=O)CCC1=O.[Br:74][C:75]1[C:76]([OH:81])=[N:77][CH:78]=[CH:79][CH:80]=1>>[OH:81][C:76]1[C:75]([Br:74])=[CH:80][C:79]([I:66])=[CH:78][N:77]=1
Reactant: Oc1ncccc1Br
Reactant: O=C1CCC(=O)N1I
Agent: CCC(C)C1NC(=O)CNC(=O)C2Cc3c([nH]c4cc(OC)ccc34)S(=O)CC(NC(=O)CNC1=O)C(=O)NC(CC(N)=O)C(=O)N1CC(O)CC1C(=O)NC(C(C)C(O)CO)C(=O)N2
Product: Oc1ncc(I)cc1Br

Procedure:
Following a previously reported method (Meana A, et al, Synlett 2003, 1678-1682) compound I8 was prepared from N-iodosuccinimide (2.48 g, 11.0 mmol) and 3-bromo-2-hydroxypyridine I7 (1.74 g, 10.0 mmol) as a pale brown solid (2.55 g, 85%). 1H NMR (DMSO-d6) δ12.27 (br s, 1H), 8.08 (d, 1H, J=2.3 Hz), 7.71 (d, 1H, J=2.3 Hz).