Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]3=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH:36]=[C:35]([CH2:37][CH2:38]OS(C)(=O)=O)[CH:34]=[N:33]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH:22][CH2:38][CH2:37][C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH2:13][C:12]3=2)=[O:7])=[CH:23][CH:24]=1
Reactant: Cn1cc(CCOS(C)(=O)=O)cn1
Reactant: NC1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(CCNC2CCc3[nH]c4ccc(NC(=O)c5ccc(F)cc5)cc4c3C2)cn1
Temperature: 150 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a mixture of 0.40 gm (1.24 mMol) 6-(4-fluorobenzoyl)amino-3-amino-1,2,3,4-tetrahydro-9H-carbazole and 0.257 gm (1.86 mMol) potassium carbonate in 8.0 mL dimethylform-amide were added 0.303 gm (1.49 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane in 2.0 mL dimethylformamide and the mixture was stirred at 60°-75° C. for 18 hours. An additional 0.101 gm (0.50 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane were added and the reaction heated to 150° C. After 1.5 hours the reaction mixture was cooled to room temperature and was then partitioned between water and dichloromethane. The aqueous phase was extracted again with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 95:5:0.5 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.180 gm (33.6%) of 6-(4-fluorobenzoyl)amino-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)amino-1,2,3,4-tetrahydro-9H-carbazole. The corresponding hydrochloride salt was prepared to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH2:82])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1>>[CH3:55][C:56]1[O:60][C:59](=[O:61])[O:58][C:57]=1[CH2:62][O:63][C:64](=[O:84])[C@H:65]([OH:83])[CH2:66][C@H:67]([NH:82][C:13]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=1)=[O:15])[CH2:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[CH:76]=2)=[CH:71][CH:70]=1
Reactant: O=C(O)c1cc(O)n(-c2ccccn2)n1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
5-Hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carboxylic acid (8.1 mg, 39 μmol) and HCTU (16.2 mg, 39 μmol) were combined in DMF (166 μL, 2.1 mmol) and stirred at room temperature for 15 minutes. DIPEA (19 μL, 0.1 mmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (15.4 mg, 36 μmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to yield the title compound (18 mg). MS m/z [M+H]+ calc'd for C31H27ClN4O8, 619.15. found 619.1.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])=[O:5])C.C(O)=O>C(O)C.O>[C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1cccc(O)c1=O
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1cccc(O)c1=O
Temperature: 60 °C
Yield: 81.6 %

Procedure:
1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (2 g) is dissolved in 15 ml of 1:2 v/v ethanol/water containing sufficient ammonium hydroxide to create a pH of 12.0. The solution is heated at 60° C. for 30 minutes, cooled, and acidified to pH 3.0 by the addition of formic acid. The solution is rotary evaporated to remove most of the ethanol and then freeze dried for 20 hours to remove the water, formic acid and ammonium formate. The resulting solid is recrystallised from water to yield white crystals (1.4 g), m.p. 203°-205° C.; νmax (nujol) 1540, 1590, 1640, 1695, 3240 cm-1 ; δ(d6DMSO) 4.5 (s, 2H), 5.95 (t, 1H), 6.6 (d, 1H), 7.0 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@@:8]2([CH3:28])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[CH2:11][S:10](=[O:27])(=[O:26])[CH2:9]2)[CH:7]=1.[CH2:30](Br)[CH:31]=[CH2:32].C(=O)([O-])[O-].[K+].[K+].[CH3:40][C:41]([CH3:43])=O>>[CH2:30]([C:11]1([CH2:43][CH:41]=[CH2:40])[S:10](=[O:26])(=[O:27])[CH2:9][C@:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:29])([CH3:28])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[C:12]1=[O:25])[CH:31]=[CH2:32]
Reactant: COc1ccc(CN2C(=O)CS(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Reactant: CC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCC1(CC=C)C(=O)N(Cc2ccc(OC)cc2OC)[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Reaction time: 96 h
Yield: 53.2 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (1 g, 2.06 mmol, Eq: 1.00) in acetone (8 ml) was added allyl bromide (547 mg, 391 μl, 4.52 mmol, Eq: 2.2), then potassium carbonate (853 mg, 6.17 mmol, Eq: 3.0). The reaction suspension was stirred in a sealed tube for 4 days. Extracted with water and ethyl acetate, the organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed on 20 g silica gel with 0% to 50% ethyl acetate in heptane to give (R)-2,2-diallyl-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (620 mg, 1.09 mmol, 53.2% yield) as a white foam. MS (ISP): m/z=566.2 [M+H]+ and 568.1 [M+2+H]+.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:39][O:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)=[CH:37][N:36]=1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)nc4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 9.6 %

Procedure:
To the solution of 2-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}phenyl)ethyl imidocarbamate (400 mg, 0.913 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (246 mg, 1.095 mmol) in NMP (3 mL) was added K2CO3 (505 mg, 3.65 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (44 mg, 9.65% yield). LCMS: rt=3.10 min, [M+H+]=500
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)OC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)OC1(c2ccc(CC[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 96.2 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (18.0 mg, 0.094 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 0.094 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (250.0 mg, 98%) was isolated by chromatography (0-3% EtOAc-hexanes) as an orange oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[Si]([CH:22]=[N+:23]=[N-:24])(C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.CN(C=O)C>[Br:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10](=[O:12])[CH:22]=[N+:23]=[N-:24]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C=[N+]=[N-])c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.891 mL, 10.2 mmol) was slowly added to a solution of 2-bromo-4-methylbenzoic acid (813 mg, 3.78 mmol) and DMF (0.16 mL) in THF (35 mL) under nitrogen. The resulting mixture was stirred at room temperature for 30 minutes, then the volatiles were removed in vacuo and the residue azeotroped with toluene (2×20 mL). The resulting residue was taken up in anhydrous acetonitrile (40 mL) and chilled to 0° C. under a nitrogen atmosphere. A solution of TMS-diazomethane (2.0 M in Et2O; 4.35 mL, 8.70 mmol) was rapidly added and the resulting mixture was stirred at room temperature for 1 hour. EtOAc (30 mL) and saturated aqueous NaHCO3 (20 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL), then the combined organic extracts were washed with water (×2), brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 10-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound A83 as a yellow oil (667 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=0.6 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.15 (dd, J=7.8, 0.7 Hz, 1H), 5.73 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=1)=O.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH:54][CH2:15][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=3)=[CH:50][CH:49]=2)=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (90 mg, 0.42 mmol) was added to a THF solution (1.5 mL) of tert-butyl 3-(5-(2-formylphenyl)picolinamido)propanoate (100 mg, 0.28 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (86 mg, 0.42 mmol), and AcOH (16 μL, 0.28 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](OC[C@H]2CCN2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[C:21]([OH:27])([C:23](F)(F)F)=[O:22]>C(Cl)Cl>[C:21]([OH:27])(=[O:22])[C:23]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:27])(=[O:22])[C:23]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1ccc(F)nc1
Solvent: ClCCl
Product: Fc1ccccn1
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of triphenylphosphine (0.8 g, 3.0 mmol) in THF (20 mL) was added diethyl azodicarboxylate (4.7 mL, 3.0 mmol) at 0° C., and the mixture was stirred for 0.5 h. 1-t-butyloxycarbonyl-2-(R)-azetidinemethanol (0.51 g, 2.7 mmol, from Example 1c above) and 2-fluoro-5-hydroxypyridine (0.32 g, 2.8 mmol, Step 8e below) were then added. The mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was chromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) to provide 0.80 g of the coupled product: MS (CI/NH3) m/z 283 (M+H)+, 300 (M+NH4)+; 1H NMR (CDCl3, 300 MHz) δ1.42 (m, 9H), 3.33 (m, 1H),3.89 (t, J=7.31 Hz,1H), 4.11 (m 1H), 4.31 (m, 1H), 4.51 (m, 1H), 6.85 (m, 1H), 7.38 (m, 1H), 7.87 (m, 1H). The 6-fluoro-3-(1-t-butyloxycarbonyl-2-(R)-azetidinylmethoxy)pyridine (760 mg, 2.70 mmol) was combined with TFA (2 mL) in methylene chloride (2 mL) at 0° C., and the solution was stirred for 30 minutes. The volatile components were then removed under vacuum. The residue was basified with saturated aqueous NaHCO3 and extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel:methylene chloride:methanol:NH4OH 10:1:0.1) to afford of the free base of the title compound (240 mg, 49%). The base was converted to the dibenzoic acid salt by treatment with benzoic acid in ether to give the title compound (235 mg, 42%): mp 76-80° C.; [α]D2.9 (c 1, MeOH); MS (CI/NH3) m/z 183 (M+H)+; 1H NMR (D2O, 300 MHz) δ2.23 (m, 1H), 2.34 (m, 1H), 3.49(m, 1H), 3.66 (m, 1H), 4.14 (m, 1H), 4.35 (m, 1H), 7.12 (dd, J=2.44, 8.81 Hz, 1H), 7.45 (m, 4H), 7.56 (m, 2H), 7.63 (m, 1H), 7.93 (m, 3H); Anal. Calcd. for C9H11N2OF.2 C6H5COOH: C, 64.78 H, 5.44; N, 6.57. Found: C, 64.65; H, 5.48; N, 6.45.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C(#N)C.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 40 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (772 mg, 2.95 mmol), 4-nitrobenzoic acid (493 mg, 2.95 mmol), and acetonitrile (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (692 mg, 2.95 mmol) dissolved in acetonitrile (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 40 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (202 mg, yield: 30%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].CO.C1COCC1>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(CN2CCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 0.3 g (1.15 mmol) of ethyl (E)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylate and 0.4 g (9.53 mmol) of lithium hydroxide monohydrate in 20 mL of a 1:1 mixture of methanol, THF, and water is stirred for 48 hours at ambient temperature. Then the reaction mixture is evaporated down, the residue is diluted with water and acidified with hydrochloric acid. The mixture is evaporated down, combined with methanol and dichloromethane, filtered, and the filtrate is evaporated to dryness. Yield: 0.27 g, C14H17NO2 (M=231.29); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: starting spot (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:51]([CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:52]
Reactant: O=C(Cl)C1CCCCC1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:27][CH:26]=[N:25][CH:24]=1)CCC.CCOC(C)=O.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[S:27][CH:26]=[N:25][CH:24]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of Example A1 (0.3 g, 1.192 mmol) in toluene (10 mL) was sparged with Ar, treated with 5-(tributylstannyl)thiazole (0.446 g, 1.192 mmol), Pd(PPh3)4 (0.138 g, 0.119 mmol) and heated at 110° C. for 16 h. The mixture was cooled to RT, treated with EtOAc and 10% aq. KF solution (30 mL) and stirred for 1 h. The solids were removed via filtration through diatomaceous earth, and the layers of the filtrate were separated. The aqueous layer was extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (180 mg, 50%) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.64-8.63 (m, 2H), 8.57 (d, J=5.7 Hz, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.04 (dd, J=8.9, 2.8 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.15 (dd, J=5.7, 2.4 Hz, 1H); MS (ESI) m/z: 301.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[C:4](=[O:9])[CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1ccc2[nH]ncc2c1
Temperature: 90 °C

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (3.75 g, 0.029 mol) and 5-aminoindazole (4.0 g, 0.03 mol) in water (70 ml) was heated at 90° C. under argon for 1 h. The mixture was cooled, decanted the supernatant and residue was triturated with ethanol, cooled and filtered the solid. It was washed with cold ethanol, and dried. 1H NMR (CD3OD/400 MHz) δ 8.11 (s, 1H), 7.64 (m, 2H), 7.18 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2.0 Hz), 6.07 (m, 1H), 5.81 (d, 1H, J=2.8 Hz), and 1.94 (s, 3H); ES-HRMS m/z 242.0962 (M+H calcd for C13H12N3O2 requires 242.0924).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:8])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1.O>[CH3:1][C:2]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)N1CCCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
Ethyl 2-methyl-2-pyrrolidin-1-ylpropanoate (0.6162 g, 3.3308 mmol) was taken up in dry THF (5 mL). A 1M solution of LAH in THF (3.7 mL, 3.6639 mmol) was added drop wise. The reaction was warmed to 50° C. and stirred for 18 h. Cooleed to 0° C. in an ice bath and methanol (5 mL) was added slowly. The reaction was diluted with water (50 mL) and extracted with Et2O (2×50 mL). The organics were concentrated by blowing a slow stream of N2 over the flask to give 0.3578 g (2.0682 mmol, 62%) of the product as a light brown oil. 1H NMR (CDCl3) δ 3.22 (s, 2H), 2.61 (bs, 4H), 1.79 (bs, 4H), 1.01 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].C1N=C[N:28](C(N2C=NC=C2)=O)C=1.N>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH2:28])=[O:20])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:23])([F:24])[F:25])([O-:3])=[O:2]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a heated solution (60° C.) of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (300 mg, 0.83 mmol) in tetrahydrofuran (25 ml) was added CDI (300 mg, 1.85 mmol, 2.2 eq) at reflux and then stirred for 1 hour at 60° C. (oil bath temperature). The resulting solution was poured into ammonia (25 ml) at room temperature and stirred for an additional 1 hour. The contents were diluted with water (100 ml) and the resulting mixture was extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide as yellow solid (220 mg, 74%). (ES, m/z) [M+H]+ 362; 1H NMR (300 MHz, DMSO): δ 8.06 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 7.07 (s, 2H), 6.85 (dd, J=2.4 Hz, 9.3 Hz, 1H), 3.82 (s, 2H), 3.40-3.55 (m, 2H), 1.90-2.10 (m, 4H), 1.10-1.50 (m, 4H)