Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]=[C:15]1[O:19][C:17](=[O:18])[CH2:16]1>CN(C=O)C>[C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:18])[CH2:16][C:15]([CH3:14])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonylpiperazine (103 g) was dissolved in DMF (600 mL) and diketene (56 mL) was added over 20 min at room temperature. The mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The mixture washed with water and saturated brine and dried. The solvent was evaporated under reduced pressure to give 1-acetoacetyl-4-tert-butoxycarbonyl piperazine (129 g) as a pale-brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (7.6 g, 0.03 mol), phenyl isothiocyanate (3.95 ml, 0.033 mol) and toluene (25 ml) was refluxed for 2.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 8.47 g (73%), m.p. 143°-145 ° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[NH:20]1[C:19]([C:17]2[CH:16]=[CH:15][C:11]3[C:12](=[O:13])[C:6]4[C:1]([S:7](=[O:9])(=[O:8])[C:10]=3[CH:18]=2)=[CH:2][CH:3]=[CH:4][CH:5]=4)=[N:23][N:22]=[N:21]1
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1S(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21

Procedure:
2-Phenylsulphonyl-4-(5-tetrazolyl)benzoic acid (200 mg) was heated with concentrated sulphuric acid (10 ml) for 5 hrs. at 120° C. After cooling and dilution with water, a solid product separated and was filtered off, washed with water, and recrystallised from acetic acid to give 3-(5-tetrazolyl)thioxanthone-10,10-dioxide, identified by its infrared spectrum.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:20](=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH:22]1[CH2:24][CH2:23]1)=[O:10])[CH3:7].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH:22]2[CH2:24][CH2:23]2)=[N:13][C:14]2[C:19]([C:20]=1[Cl:3])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C2CC2)[nH]c2ccccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Temperature: 75 °C
Yield: 10.2 %

Procedure:
Phosphorus oxychloride (0.77 ml, 0.082 mols) was added in one portion to a suspension of 2-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 g, 0.041 mols) in acetonitrile and the mixture was heated at 75° C. for 90 minutes (becomes a clear solution above 65° C.). The resulting light brown solution was poured into saturated sodium bicarbonate (100 ml); the suspension was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to leave 4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 106%) as an off-white solid. Rf (AcOEt)=0.73.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (88 mg, 0.29 mmol) and (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (86 mg, 0.29 mmol) in DCM (10 mL) and Diisopropylethylamine (0.22 mL, 1.3 mmol) was added HBTU (110 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with water (6×50 ml). The organic phase was dried and concentrated to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (116 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 7.34-7.20 (m, 4H), 5.15-5.09 (m, 2H), 4.15-4.05 (m, 1H), 3.87-3.85 (m, 2H), 3.78-3.38 (m, 7H), 3.22-3.19 (m, 1H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.41 (s, 9H), 1.14-1.12 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H] +516.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.N1C=CC=CC=1.Cl[C:26](OC1C=CC=CC=1)=[O:27].[OH:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl.O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH:18][C:26]([N:40]3[CH2:41][CH2:42][CH:37]([CH2:36][OH:35])[CH2:38][CH2:39]3)=[O:27])[S:15][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CCNCC1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a stirred suspension of 17 mg (0.06 mmol) 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine and 0.015 ml (0.19 mmol) pyridine in 1.5 ml dichloromethane and 0.5 ml tetrahydrofuran was added 0.009 ml (0.07 mmol) phenyl chloroformate and stirring continued at 50° C. for 1 h. 37 mg (0.32 mmol) 4-(hydroxymethyl)piperidine was then added and stirring continued at 50° C. for a further 1 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (methanol/dichloromethane 1/40 then 1/20) afforded 11 mg (42%) 4-hydroxymethylpiperidine-1-carboxylic acid [7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-amide as a white crystalline solid. ES-MS m/e (%): 407 (M+H+, 100).
Reaction SMILES: [SH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17].[OH-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:11][C:2]=2[S:1][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]
Reactant: N#Cc1cc2c(cc1S)CCCC2
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)sc2cc3c(cc12)CCCC3
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a solution of crude 3-mercapto-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (121 mg, 0.64 mmol) and 2,2′,4′-trichloroacetophenone (143 mg, 0.64 mmol, 1.0 eq) in anhydrous N,N-dimethylformamide (5 mL) was added powdered potassium hydroxide (177 mg, 1.28 mmol, 2.0 eq). The reaction mixture was stirred under argon at 80° C. for 16 h. The brown reaction mixture was cooled and poured into ethyl acetate and water. The organic layer was washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, and the crude product was purified on the MPLC (Biotage), eluted with 30% ethyl acetate-hexane. Trituration from hexane afforded 92.4 mg (38.4%) of the benzothiophene. 1H-NMR (Acetone-d6) δ 7.88 (broad, s, 3H), 7.62 (d, J=1.5 Hz, 1H), 7.53 (m, 2 H), 7.42 (s, 1H), 2.85 (m, 4H), 1.83 (m, 4H); MS ES (MH+=376/378); Rf=0.60 (30% ethyl acetate-hexane).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:66])[C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[Cl:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[Cl:65][C:59]1[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:56][CH2:55]1)=[O:66]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 53.39 %

Procedure:
HOBt (24 mg, 0.18 mmol) and DIPEA (74 mg, 0.57 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (27 mg, 0.14 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (34 mg, 0.18 mmol) followed by 2-amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.15 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration under reduced pressure and dried in vacuo to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid 53.39% yield. LC-MS purity: 92.758%. 1H-NMR (DMSO): δ 8.78 (t, 1H), 8.0 (m, 2H), 7.6 (m, 6H), 7.47 (s, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.7 (m, 2H), 3.56 (m, 2H), 3.2 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccnc4)ncnc32)CC1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-hydroxypyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 18 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 34%) as a white powder. Mass spectrum (ES) MH+=397. HRMS Calcd. for C20H25N6O3 (MH+): 397.1983. Found: 397.1983.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH:12][C:16](=[O:18])[CH3:17])[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2sccc2n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
An ice-cold solution of 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (130 mg, 0.6 mmol) in pyridine (1 mL) was treated with acetyl chloride (47 μL, 0.66 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1) to give the title compound (125 mg, 80%) as a cream solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][C@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=1[F:41]>CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][C@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:38](=[O:39])[C:36]2[CH:35]=[CH:34][C:33]([F:41])=[C:32]([Br:31])[N:37]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C[C@H](c2ccncc2N)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 9, 4-((1S,3S,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, N-(4-((1S,3S,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-yl)-6-bromo-5-fluoropicolinamide was obtained. LCMS (m/z): 652.5, 652.4 (MH+); LC Rt=5.83 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>CN(C=O)C.N1C=CC=CC=1.O>[C:34](=[O:35])([O:36][CH2:37][CH2:38][O:39][CH3:40])[O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1
Reactant: COCCOC(=O)Cl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COCCOC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.2 g, 0.46 mmol) was dissolved in DMF (4 ml) and pyridine (0.5 ml), then cooled to 0° C. 2-Methoxyethyl chloroformate (0.2 ml, 1.73 mmol) was added, the mixture was stirred at 0° C. for 45 minutes followed by addition of a second portion of 2-methoxyethyl chloroformate. The mixture was stirred for one additional hour at 0° C., then diluted with water, extracted twice with ethyl acetate and dried over sodium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0 to 10% acetonitrile in ethyl acetate). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.20 g), melting point: 112° C.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.[CH2:32]([C@H:34]1[O:36][CH2:35]1)Cl.[OH2:37]>[Cl-].C[N+](C)(C)C.C(Cl)Cl>[C:18]1([CH2:17][O:16][C:15]2[CH:10]=[CH:11][C:12]([O:37][CH2:32][C@H:34]3[CH2:35][O:36]3)=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC[C@@H]1CO1
Reactant: O
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: c1ccc(COc2ccc(OC[C@H]3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
A mixture of hydroquinone monobenzylether (1.7 g, 8.5 mmol) and tetramethylammoniumchloride (0.19 g, 1.7 mmol) in (S)-epichlorohydrine (2.0 ml, 25.5 mmol) was stirred at room temperature for 4 days. H2O (30 ml) and CH2Cl2 (50 ml) were added and the organic phase was separated. The water phase was extracted two times with CH2Cl2. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated. The residue was chromatographed over silica gel (hexane-Et2O, 3:1) to give (R)-{[4-(Phenylmethoxy)phenoxy]methyl}-oxirane (1.1 g, 50%) as a colorless solid, m.p. 70°-73° C., [α]D20 =-8.1° (c=1.0, methanol) and MS: m/e=256 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25]1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3c[nH]c4ccccc34)nn12

Procedure:
The title compound, MS m/e (%): 328 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonyl-hydroxylamine, and indole-3-carboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[C:5]([CH3:8])=[N:6][CH:7]=1.Cl.[O:11]1[CH2:16][CH2:15]OCC1.N(O[CH2:20]CC(C)C)=O>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH:16]([CH3:20])[CH3:15])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: C1COCCO1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CC(C)O
Product: Cc1ncc(Br)cc1OC(C)C
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 400 mg, 2.13 mmol) in isopropanol (33 ml) were added 4 M HCl in dioxane (0.535 ml, 2.13 mmol) and isoamyl nitrite (1.25 g, 10.7 mmol). The reaction mixture was heated at 80° C. for 2.5 h, before being evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% to 30%) to give the title compound as an orange oil (HPLC: tR 2.47 min (Method A); M+H=230, 232 MS-ES).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.[H-].[Na+].[CH3:19]I.[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[CH3:19][O:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@H]1CN[C@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (25.6 g, 111 mmol), is treated under nitrogen with sodium hydride (9.3 g, 388 mmol) and methyl iodide (31.5 g, 222 mmol), using a procedure similar to that published for the CBZ analog in J. Med. Chem. 1988, 31, 875, except that reflux is carried out for 16 h. The crude extracted product of this alkylation reaction, (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid, is then dissolved in dichloromethane (200 mL), cooled to 0° C., treated with 4 N HCl in dioxane (100 mL), and then stirred at room temperature overnight. After further cooling at −20° C. for 3 h, the precipitate is collected by filtration, washed with ethyl ether, and dried in vacuo to give 18.5 g (92%) of the pure mono HCl salt of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid: MS: 146 (M+H)+; 1H NMR (d6-DMSO) δ 14.02 (brs, 1H), 10.30 (brs, 1H), 8.98 (brs, 1H), 4.33-4.22 (m, 1H), 4.10 (brs, 1H), 3.43-3.34 (m, 1H), 3.24 (s, 3H), 3.26-3.19 (m, 1H), 2.45-2.36 (m, 1H), 2.10-2.00 (m, 1H); [α]22D −29.7 (CH3OH).
Reaction SMILES: [CH2:1](SCCCC)[CH2:2]CC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Li].[CH3:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=2)[CH:21]=[C:20]([CH2:35][CH:36]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:19]=1>CCOCC>[CH2:1]([C:13]1[CH:14]=[CH:15][N:10]=[C:11]([CH:36]([CH2:35][C:20]2[CH:19]=[C:18]([CH3:17])[C:26]3[C:22](=[CH:23][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:25]=3)[CH:21]=2)[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=CCc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Reactant: CCCCSCCCC
Reactant: [Li]c1ccccn1
Solvent: CCOCC
Product: CCOC(=O)CC(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)c1cc(CC)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a 50-mL oven-dried flask was added di-n-butylsulfide (244 mg, 1.665 mmol, 4.4 equiv) and cuprous iodide (159 mg, 0.832 mmol, 2.2 equiv) under nitrogen. Anhydrous ether (1.2 mL) was added and the suspension was cooled to 0° C. before the solution of 2-pyridinyl lithium was added via canuula. A yellowish brown precipitate was formed. After stirring at 0° C. for 20 min, the cooling bath was removed and ethyl 4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)but-2-enoate (141.7 mg, 0.378 mmol, 1.0 equiv.) in anhydrous ether (1.2 mL) was added via syringe. The solution was stirred at room temperature for 1 h. The reaction mixture was then partitioned between an aqueous ammonium hydroxide/ammonium chloride solution and ethyl acetate (upon shaking, the solids gradually dissolved to a give blue aqueous solution). The layers were separated and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography (5% methanol in methylene chloride) afforded the desired product (80 mg, 44%) which was carried on without farther purification. MS (ESI) 482 (MH)+.