Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:23][C@H:24]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:23][C@H:24]([C:26]1[CH:27]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)OC(C)(C)C)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)O)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.1 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 128a; 3.28 g, 5.18 mmol) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid added (8 ml) and the reaction mixture stirred overnight at room temperature. The reaction mixture was concentrated in vacuo then triturated with diethyl ether (×3) to give the title compound as a brown solid (4.82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:16]3[C:17]([F:22])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=3[O:14][CH2:13][CH:12]2[CH2:23]OS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[I-].C(O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:16]3[C:15](=[C:20]([F:21])[CH:19]=[CH:18][C:17]=3[F:22])[O:14][CH2:13][CH:12]2[CH3:23])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Methanesulfonic acid O-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl-methyl]ester (0.5 g, 1.1 mmole), NaI (0.83 g, 5.5 mmole) Zinc dust (0.71 g, 11 mole) and 0.1 mL acetic acid were refluxed in 15 mL ethylene glycol dimethyl ether for 6 hours. The solid was filtered and the filtrate was partitioned between 100 mL 0.1N Na2SO3 solution and 100 mL EtOAc. The organic layer was washed with 0.5N NaOH solution (2×50 ml), brine, dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane to pure product (0.33 g, 83%) 1H NMR (400 MHz, CDCl3) 7.71 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 6.40 (m, 1H), 4.92 (dd, J=11.7 and 2.9 Hz, 1H), 4.21 (m, 2H), 3.02 (m, 1H), 1.07 (d, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Combine 6-chloro-pyridine-3-carbaldehyde (1.00 g, 7.09 mmol), 3-bromo-4-hydroxy-benzonitrile (1.48 g, 7.80 mmol) in dimethylacetamide (40 mL). Add potassium carbonate (1.47 g, 10.64 mmol) and stir and heat the reaction at 130° C. for 2 h. Let cool down the reaction to room temperature and poured into water. Filter the precipitate formed, washing with water, to give the title compound (1.55 g, 72%)
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH:5]=[CH2:6].[CH:8]([O:10][C:11](Cl)=[O:12])=[CH2:9]>>[CH:8]([O:10][C:11](=[O:12])[N:3]([O:2][CH3:1])[C:4](=[O:7])[CH:5]=[CH2:6])=[CH2:9]
Reactant: C=CC(=O)NOC
Reactant: C=COC(=O)Cl
Product: C=COC(=O)N(OC)C(=O)C=C

Procedure:
The synthesis was carried out analogously to synthesis example 8 using N-methoxy-acrylamide and chloroformic acid vinyl ester. Purification by column chromatography on silica gel (PE:EE=9:1) yielded 1.6 g (91% of th.) of the title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1>CO.O.[Pt]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Pt]
Solvent: CO
Solvent: O
Product: COc1cc(Br)cc(N)c1N
Yield: 85.3 %

Procedure:
A solution of 2.0 g (8.1 mmol) 4-Bromo-2-methoxy-6-nitro-phenylamine [Zhou, Q-T., et al. Huaxue Xuebao 1980, 38(5), 507-10] in 50 ml methanol/water (2:1) is hydrogenated in the presence of 200 mg Pt/C (Engelhard 4709) at normal pressure for 3 h. Then the catalyst is filtered off and the filtrate is concentrated in vacuo to afford 1.5 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:21]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (97 mg, 0.45 mmol), ethyl (trans-4-aminocyclohexyl)acetate hydrochloride (from Activate Scientific, 120 mg, 0.54 mmol) and triethylamine (0.19 mL, 1.4 mmol) in isopropyl alcohol (4 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C17H22N3O4S (M+H)+: m/z=364.1. Found: 364.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][OH:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C=O)c(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(CO)c(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11.8 G. of 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde was dissolved in 250 ml. of dry ethanol and stirred at 20° C. 0.52 G. of sodium borohydride was added and the resulting solution was stirred for 30 minutes, then poured into ice water and extracted with ethyl ether. The combined ether extracts were washed with a solution of 5% sodium carbonate and a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Crystallization from cold hexane yielded 4-bromo-3,5-dimethyl-2-hydroxymethylthiophene, m.p. 85°-90° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)(Cl)=[O:2].[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1>>[P:1]([Cl:5])(=[O:2])([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:13])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1O
Product: Cc1ccccc1OP(=O)(Cl)Oc1ccccc1C

Procedure:
While it is known to form compounds of the formula (ArO)2P(O)Cl (see U.S. Pat. No. 3,965,220), only a few disclosures are known to exist in which such polyphosphate compounds are formed in which the initial reaction is between monohydroxy compound and phosphorus oxychloride with the second reaction step using diol as the reagent. In U.S. Pat. No. 4,133,846 it is taught in Example 4 that bis(2-chloroethyl) chlorophosphate and pentaerythritol were to be reacted to form the desired product. Presumably, the bis(2-chloroethyl) chlorophosphate could be formed by reaction of phosphorus oxytrichloride and appropriate monohydroxy compound (i.e., 2-chloroethanol). U.S. Pat. No. 3,254,973, at Col. 5, line 66 and following, illustrates preparation of 4,4'-isopropylidene diphenol bis(di-o-tolylphosphate) by first reacting phosphorus oxychloride with o-cresol to form a reaction mixture in which di-o-tolyl phosphorochloridate cuts are removed by distillation. The di-o-tolyl phosphorochloridate from the first reaction step was then reacted with the diol (i.e., bisphenol A) to make the desired bisphosphate.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([OH:19])(C)C>CC(C)=O.OS(O)(=O)=O>[C:1]([OH:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)O
Reactant: CCCCCCC#CCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCC#CCCCCCC(=O)O
Reaction time: 30 h

Procedure:
A solution of 7-tetradecyne-1-ol (2.10 g) in acetone (100 ml) was added dropwise to a vigorously stirred solution of 20 ml of 1M CrO3 in 10N H2SO4 cooled in ice. The addition took 30 hours after which 5 ml of isopropyl alcohol was added and the reaction mixture was filtered. The filtrate was diluted with 50 ml of water and extracted five times with ether. The combined organic phases were washed with water and saturated NaCl solution. The ether solution was then washed two times with 2N NaOH. The combined basic washes were extracted again with ether and acidified with 6 N HCl. Extraction with CHCl3 (3 times), drying (MgSO4) and removal of solvent under reduced pressure gave 1.95 g of 7-tetradecynoic acid as a yellow oil, which solidified on standing.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:15]2[C:19]([Cl:20])=[C:18]([O:21][CH:22]([F:24])[F:23])[N:17]([CH3:25])[N:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14])(=O)C.Cl>O1CCOCC1.O>[Cl:20][C:19]1[C:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([CH2:7][OH:6])[CH:9]=2)=[N:16][N:17]([CH3:25])[C:18]=1[O:21][CH:22]([F:24])[F:23]
Reactant: CC(=O)OCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(Cl)c(CO)c2)c(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
6.3 ml (16 mmol) of 10% strength sodium hydroxide solution were added dropwise to a solution of 3.2 g (8.8 mmol) of 3-(3-acetoxymethyl-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 10 ml of dioxane and 10 ml of water. The mixture was stirred for 1 hour and then neutralized with 3N hydrochloric acid. The product was extracted from the aqueous phase with ethyl acetate, after which the organic phase was dried over magnesium sulfate and then concentrated. The crude product thus obtained was purified by column chromography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1.3 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:8]3[CH:9]=[CH:10][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[C:6]=4[CH:7]=3)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Cn1cnc2ccc(B(O)O)cc21
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2ncn(C)c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using (1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H), 3.83 (s, 3 H), 7.11 (dd, J=8.34, 1.52 Hz, 1 H), 7.49 (d, J=1.01 Hz, 1 H), 7.55 (br s, 1 H), 7.72 (t, J=8.46 Hz, 2 H), 8.22 (s, 1 H), 8.35 (s, 1 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 333.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), isopropylsulfonyl chloride (0.26 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[C:18]([Cl:20])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 6-chloro-3-nitropicolinonitrile (3.70 g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at 70° C. for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase is dried with sodium sulfate and the residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH3:1])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cccc(CC(=O)O)c1
Solvent: CO
Product: COC(=O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 17.25 h
Yield: 95.9 %

Procedure:
Trimethylsilyl chloride (182 g, 1.68 mol) was added dropwise to a solution of 3-methoxyphenylacetic acid (127 g, 0.77 mol) in methanol (1.0 L) over 1.1 hours. The reaction was stirred at room temperature for 17.25 hours, concentrated in vacuo, dissolved in ethyl acetate, dried over MgSO4, and concentrated in vacuo, to give a brown oil (133 g, 97%): 1H NMR (CDCl3/300 MHz) 7.24 (t, 1H, J=7.5 Hz), 6.83 (m, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: C(OC([C@]1(C)CCCN([CH2:12][C@H:13]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:17]([O:25][C@@H:26]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[CH3:27])[CH2:16][O:15][CH2:14]2)C1)=O)C.[O:43]1CCCC1>>[F:39][C:38]([F:40])([F:41])[C:30]1[CH:29]=[C:28]([C@H:26]([O:25][C@H:17]2[CH2:16][O:15][CH2:14][CH:13]([CH2:12][OH:43])[C@@H:18]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:27])[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=1
Reactant: CCOC(=O)[C@]1(C)CCCN(C[C@@H]2COC[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccccc2)C1
Reactant: C1CCOC1
Product: C[C@@H](O[C@H]1COCC(CO)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M, 25 ml) was added dropwise to a stirred, ice-bath cooled solution of the product from Description 44 (5.8 g, 13.5 mmol) in tetrahydrofuran (70 ml). The cold-bath was removed and the mixture was stirred at ambient temperature. After 30 minutes, the mixture was cooled to 0° C. and carefully treated with 2M aqueous NaOH (20 ml) and 35% hydrogen peroxide (20 ml). The cold bath was removed and the mixture was stirred for 1 hour. After cooling to 0°, the reaction was carefully treated with 25% aqueous solution of Na2S3O5 (125 ml) and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica (i-hexane:ethyl acetate) to give a mixture of diastereoisomeric alcohols (5.34 g) in the ratio (3S):(3R)=1.9:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26].C[O-].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
5,6-Dichloro-2-bromo-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.136, 101 mg, 0.22 mmol) was dissolved in dry MeOH (10 mL) to which was added sodium methoxide (25 mg, 0.46 mmol). The solution was stirred at room temperature for 15 min, until the starting material was consumed (TLC). Water (30 mL) was added and the solution evaporated until the MeOH was completely removed. The residual aqueous suspension was extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine (20 mL), dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH and H2O to yield 43 mg (47%) of 4.137 as a pale tan powder: mp 210-211° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 6.06 (d, 1H), 5.49-5.43 (m, 2H, D2O exch.), 5.31 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.18 (m, 1H), 4.04 (d, 1H), 3.77-3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 185.53, 134.05, 128.85, 126.58, 126.47, 125.31, 120.56, 116.00, 114.68, 90.27, 86.55, 71.69, 69.62, 60.98. HRMS (EI) m/z calcd. for C14H12BrCl2NO5 422.9276. found 422.9271. Anal calcd for C14H12BrCl2NO5: C, 39.56; H, 2.85; N, 3.30. Found: C, 39.77; H, 3.03; N, 3.32.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27]>>[CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14][S:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)(=[O:24])=[O:23])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCCC2CC2)n1
Product: O=S(=O)(Nc1cccc(COCCC2CC2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluormethyl)-benzenesulfonyl chloride (0.12 g) as a light yellow gum (0.08 g). MS (ESI−): 417.0 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[C:40]1([CH2:46][S:47](Cl)(=[O:49])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:39])=[CH:9][CH:8]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:47]([CH2:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:49])=[O:48])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(NCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 72 %

Procedure:
The intermediate from step 12 was treated with α-toluenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 72% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1.[CH3:19]I.[H-].[Na+]>C1COCC1>[CH3:19][O:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCC(O)CN1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of benzyl (2R)-5-hydroxy-2-methylpiperidine-1-carboxylate (368 mg, 1.47 mmol) dissolved in THF (4.9 mL) at 0° C. was added methyl iodide (0.32 mL, 5.08 mmol) followed by sodium hydride (78 mg, 3.25 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl (2R)-5-methoxy-2-methylpiperidine-1-carboxylate. MS ESI calc'd. for C15H21NO3 [M+H]+ 264. found 264.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N+:54]1([O-:61])[C:55]([NH2:60])=[CH:56][CH:57]=[CH:58][CH:59]=1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][N+:54]=3[O-:61])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc[n+]1[O-]
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1cccc[n+]1[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (88 mg, 0.219 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.053 mL, 0.482 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (86 mg, 0.263 mmol). The solution was stirred for 15 min, and then 2-pyridinamine 1-oxide (31.4 mg, 0.285 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated away, and residue was dissolved in DCM. The solution was washed with 5% aq. NaHSO4 followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude oil, which was purified by RP-HPLC to provide (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide as a colorless gum (67 mg, 62%). LCMS: (M+H)+: 494.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26]OC1C=CC(C(C)(C)C)=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]>>[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Reactant: Oc1ccccc1F
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccccc1F

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of 2-fluorophenol is substituted for the 4-tert-butylphenol of Example 10. The title compound is obtained as a viscous oil after purification by silica gel column chromatography.