Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1.[CH3:34][S:35]([CH2:38][CH2:39][NH2:40])(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH2:27][NH:40][CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)cc4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.40 (s, 1H); 8.67 (s, 1H); 8.30 (d, 1H); 7.86 (d, 1H); 7.75 (d, 2H); 7.43 (m, 1H); 7.30-7.21 (m, 3H); 7.15 (m, 1H); 7.07 (d, 2H); 6.80 (d, 1H); 5.15 (s, 2H); 4.40 (s, 2H); 3.65 (m, 2H); 3.40 (m, 2H); 3.11 (s, 3H); MS m/z 547 (M+1).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][Si](C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]=[CH2:21])=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]2[CH2:21][CH2:5][N:4]([CH2:10][CH2:11][CH3:12])[CH2:3]2)=[N:18][CH:19]=1
Reactant: CCCN(COC)C[Si](C)(C)C
Reactant: C=Cc1ncc(Br)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylmethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([OH:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:16][C:15]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][C:6]=3[C:7]=2[N:8]=1)=[O:17]
Reactant: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 85 °C
Yield: 57 %

Procedure:
To a stirred mixture of 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (20.0 g, 61.3 mmol) in MeOH (280 mL), was added H2SO4 (45.1 g, 450 mmol) dropwise at room temperature. Then the mixture was heated to reflux (85° C.) mixture was filtered and the solid was washed with saturated aqueous NaHCO3 solution, dried in vacuo to afford 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (12 g, 57%) as a yellow solid which was directly used for the next step without any further purification. LC-MS: 341.8 (M+2).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F-].[Cs+].[CH2:42]([Sn](CCCC)(CCCC)C=C)[CH2:43]CC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:42]([C:2]1[N:7]=[C:6]2[C:8]3([CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH2:43]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(Br)c(N3CCOCC3)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=Cc1nc2c(cc1N1CCOCC1)N(c1c(C)c(-c3ccccn3)nc3cc(F)ccc13)CC21CCOCC1
Temperature: 120 °C

Procedure:
To a stirred solution of 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (140 mg, 0.237 mmol) in 1,4-dioxane (4 mL) was added bis(tri-tert-butylphosphine)palladium (0) (12.12 mg, 0.024 mmol), cesium fluoride (36 mg, 0.237 mmol) and tri-n-butyl(vinyl)tin (90 μL, 0.285 mmol) and the reaction was heated at 120° C. for 3 h in the microwave. After this time the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude reaction was purified by column chromatography on silica gel (DCM to DCM:MeOH:—NH4OH (9:1:0.4), 1:0 to 2:1 as eluent) to give 5′-ethenyl-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66-8.80 (1H, m), 7.85-7.96 (3H, m), 7.73 (1H, dd, J=9.3, 6.0 Hz), 7.42 (1H, ddd, J=6.8, 4.8, 2.1 Hz), 7.23-7.30 (1H, m), 7.09 (1H, dd, J=17.2, 10.8 Hz), 6.30 (1H, dd, J=17.3, 2.6 Hz), 5.96 (1H, s), 5.18-5.36 (1H, m), 4.23-4.32 (2H, m), 3.93-4.03 (2H, m), 3.77 (4H, t, J=4.6 Hz), 3.61-3.69 (2H, m), 2.68-2.80 (4H, m), 2.27-2.47 (5H, m), 1.77-1.90 (2H, m). Mass Spectrum (ESI) m/e=538.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([O:20][CH3:21])[C:5]2[O:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])([CH3:10])[CH2:7][C:6]=2[C:18]=1[CH3:19].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[OH:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([O:20][CH3:21])[C:5]2[O:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:16])([CH3:10])[CH2:7][C:6]=2[C:18]=1[CH3:19]
Reactant: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)O)C2
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCCCC(=O)N1CCOCC1)C2
Yield: 85 %

Procedure:
A solution (25 ml) of 5-(2,3-dihydro-5-hydroxy-6,7-dimethoxy-2,4-dimethylbenzofuran-2-yl)valeric acid (2.0 g), morpholine (0.81 ml) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.4 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at room temperature for 2 hours. The reaction mixture was made acidic by adding 1N hydrochloric acid to the mixture, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound (2.1 g, 85%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[I:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=5)=[C:17]4[CH:18]=3)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Reactant: N#CCc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5cccc(I)c5)c4c3)OCCO2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3dioxolane (38.7 g, 127 mMol) was suspended in 190 mL of methanol (MeOH) under an atmosphere of dry N2. To this solution was added (3-iodophenyl)acetonitrile (46.3 g, 190 mMol) and 25.4 g (625 mMol) of sodium hydroxide (NaOH). The solution was then heated to reflux and reacted at this temperature for 2 hours. The reaction mixture was cooled to ambient temperature and the MeOH was removed under vacuum. The resulting red oil was partitioned between dichloromethane (DCM) and 0.1 N aqueous NaOH. The DCM layer was washed successively with 0.1 N aqueous NaOH and then brine. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give a dark red oil. The oil was stirred in MeOH and the titled compound precipitated out as a yellow solid. The yellow solid was washed with MeOH and dried under vacuum to give 52.4 g of the titled compound which was used without further purification.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)([CH2:21][NH2:22])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.C(O)=O>[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([CH2:21][NH:22][S:2]([NH2:5])(=[O:4])=[O:3])([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cccc(NC2(CN)CCN(Cc3ccccc3)CC2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1cccc(NC2(CNS(N)(=O)=O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 8 h

Procedure:
To a cold (5° C.) solution of chlorosulfonyl isocyanate in THF, anhydrous formic acid is added (Journal of Organic Chemistry, vol 54, page 5825,(1989)). The resultant mixture is stirred until gas evolution ceased, and treated with a solution of 1-benzyl-4-(3-methylphenylamino)-4-aminomethylpiperidine in THF. The mixture is stirred at room temp. overnight to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c(Cl)cc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 27.3 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added the 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane-EtOAc=2.5:1) to give the title compound as a yellow solid (0.77 g, 27%). 1H NMR (400 MHz) δ 12.26 & 11.64 (s, 1H), 10.42 & 10.04 (s, 1H), 8.81 & 8.77 (s, 1H), 6.02 & 5.94 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 (d, J=6.0 Hz, 3H), 1.27 (d, J=6.0 Hz, 1H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: F[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCCl>[CH:25]1([NH:31][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(F)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)c1c(NC2CCCCC2)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Yield: 116 %

Procedure:
Ethyl 5-methyl 2-fluoro-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (14 mg, 0.042 mmol) was dissolved in DCE (1 mL). Cyclohexylamine (9.67 ul, 0.085 mmol) and triethylamine (5.89 ul, 0.042 mmol) were added and the reaction was heated at reflux 18 hours. The mixture was concentrated, diluted with ethyl acetate and brine, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to afford the title compound (20 mg) that was used without further purification: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08-7.15 (m, 2 H) 6.97-7.07 (m, 2 H) 4.04-4.19 (m, 1 H) 3.75-3.88 (m, 2 H) 3.41 (s, 3 H) 2.43 (s, 3 H) 2.35 (s, 3 H) 1.96-2.17 (m, 2 H) 1.55-1.93 (m, 4 H) 1.36-1.53 (m, 2 H) 1.17-1.37 (m, 2 H) 0.56-0.71 (m, 3 H); LCMS (m/z) ES+=411 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17](=[O:51])[NH:18][CH:19]1[C:25](=[O:26])[N:24]([C:27]([CH:37]([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:30])[NH2:29])[C:23]2[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=2[N:21]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:20]1=[O:50])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]([C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:28](=[O:30])[NH2:29])[N:24]1[C:25](=[O:26])[CH:19]([NH:18][C:17]([C:9]2[N:8]([CH2:7][C:6]([OH:52])=[O:5])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:51])[C:20](=[O:50])[N:21]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:22]2[CH:43]=[CH:42][CH:41]=[CH:40][C:23]1=2)([CH3:39])[CH3:38]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)O)C(=O)N(c2ccccc2)c2ccccc21
Yield: 75.5 %

Procedure:
To a solution of {2-[1 -(Isopropyl-phenyl-carbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-indol-1-yl}-acetic acid tert-butyl ester (0.072 g) in dichloromethane (4 ml) at ambient temperature was added trifluoroacetic acid (1.5 ml) gradually with stirring. After the reaction was stirred 30 minutes, the dichloromethane and trifluoroacetic acid were evaporated under reduced pressure to afford a clear glass. The glass was purified by purified RP-HPLC on a C-18 column with a gradient elution of 45-55% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to afford the title compound (0.050 g) as a white powder. 1H NMR (300 MHz, CDCl3): d 1.07 (d, J=4.4 Hz, 3H), 1.10 (d, J=4.4 Hz, 3H), 4.23 (d, J=16.6 Hz, 1H), 4.40 (d, J=16.6 Hz, 1H), 5.01 (m, 1H), 5.06 (s, 2H), 5.44 (d, J=7.1 Hz, 1H), 7.03 (dd, J=1.2, 8.1 Hz, 1H), 7.17-7.52 (m, 17H), 7.67 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.1 Hz, 1H); MS (ES): m/z=644.2 (MH+); TLC (CH2Cl2 /CH3OH(19:1)): Rf =0.15; RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 45-55% CH3CN in H2O with 0.1% TFA buffer;, 30 minutes; 1 ml/min): tf =22 min (to =3 min).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cccc(C2(O)CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C2(O)CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-8.13 (c=0.69, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 69.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 96 mg, 0.28 mmol), 2-aminobenzothiazole (42 mg, 0.28 mmol) and N,N-diisopropylethylamine (145 μL, 0.83 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (93 mg, 70%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C21H20ClN3O4S2 [M+] 477.06, found 478 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.35 (ddd, Jo=7.9, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.48 (ddd, Jo=8.2, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.61 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.72 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.21 (s, 1 H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 99.6 %

Procedure:
The alcohol from Step 1, 6-(3-nitro-quinolin-4-ylamino)hexan-1-ol (10.0 g, 34.6 mmol), was oxidized by the general method described in Step 6 of Example 1 with DMSO (4.05 g, 51.8 mmol), oxalyl chloride (4.83 g, 38.0 mmol), and triethylamine (10.5 g, 104 mmol) to provide 6-(3-nitroquinolin-4-ylamino)hexanal (9.9 g) as a bright yellow solid that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
To a 0° C. solution of (5-chloropyridin-2-yl)methanol Part D (10 mg, 0.070 mmol) and triphenylphosphine (32.9 mg, 0.125 mmol) in DCM (0.170 mL) was added a solution of carbon tetrabromide (31.4 mg, 0.095 mmol) in DCM (0.084 mL) dropwise. The mixture was stirred at RT for 2.0 h at which point the solvent was removed in vacuo and the crude product was subjected to flash chromatography (silica gel/DCM-EtOAc 100:0 to 0:100 gradient) to afford 2-(bromomethyl)-5-chloropyridine 16E (2.4 mg, 16.8% yield) as a light brown oil. LC-MS, [M+H]+208. 1H NMR (400 MHz, CDCl3) δ 8.47 (1H, d, J=2.2 Hz), 7.61 (1H, dd, J=8.4, 2.2 Hz), 7.33 (1H, d, J=8.4 Hz), 4.46 (2H, s). HPLC-Method 8; 2.42 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: c1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a continuously stirred mixture of 13.8 grams of 1,2,4-triazole in 120 ml of methanol cooled at 0° was added 11.9 grams of sodium methoxide. The mixture was allowed to warm to room temperature and stir for 45 minutes whereupon the mixture was again cooled at 0° C. and there was added 25.3 ml of benzyl chloride. After being warmed to room temperature and continuously stirred for 14 hours, the mixture was concentrated and the residue extracted well with dichloromethane. The extract was washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated to give a crude product that was purified by flash column chromatography over silica gel and eluted with dichloromethane/ ethyl acetate (2:1) to give 28.5 grams of pure 1-benzyl-1,2,4-triazole as a solid melting at 44°-45° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([F:33])[CH:25]=1.CC(C)=O>CC(C)=O.O>[CH2:10]([O:9][CH2:8][CH2:7][CH:3]([NH:2][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Br:23])=[CH:25][C:26]=1[F:33])[C:4]([OH:6])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(CCOCc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(CCOCc1ccccc1)C(=O)O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-amino-4-benzyloxy-butyric acid hydrochloride salt (1.0 mmol) (See Intermediate 34) and sodium carbonate (3.0 mmol) in 1:1 acetone/water (0.5M) in a 0° C. ice bath, slowly add 4-bromo-2-fluoro-benzoyl chloride (1.2 mmol) diluted in acetone (prepared from 4-bromo-2-fluoro-benzoic acid (1.0 mmol) and oxalyl chloride (1.0 mmol) in dichloromethane using catalytic dimethylformamide). Stir for 30 minutes at 0° C. After this time, wash the reaction with 1N hydrochloric acid while extracting with ethyl acetate. Concentrate the organics in vacuo. Purify on an Isco CombiFlash® chromatography system eluting with 1% acetic acid in ethyl acetate and hexane. MS (m/e) (79Br/81Br): 410.3/412.3 (M+1)
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-methyl-3-phenylbutyric acid (0.508 g, 2.85 mmol) in dichloromethane (10 μL) at −78° C. was treated with oxalyl chloride (3.62 , 28.5 mmol) and 1 drop of dimethylformamide. The reaction mixture was stirred at −78° C. for 10 min, and dry ice/acetone bath was removed to stir at room temperature over night. Solvent was removed under reduced pressure, and dried under high vacuum. The product was used directly for subsequent reaction without analysis.