Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.IC.C(COC)OC.[CH3:14][O:15][N:16]([CH3:30])[C:17](=[O:29])[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>ClCCl.O>[CH3:14][O:15][N:16]([CH3:30])[C:17](=[O:29])[CH2:18][CH:19]1[CH2:1][CH:20]1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: CC[Zn]CC
Reactant: COc1ccc(/C=C/CC(=O)N(C)OC)cc1
Solvent: CI
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(C2CC2CC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
The solution of diethyl zinc in hexanes (1M, 17.4 mL, 17.4 mmol) was added slowly to the mixture of iodomethane (2.5 mL, 34.9 mmol), dimethoxy ethane (1.82 mL) in dichloromethane (25 mL) at −15° C. After stifling for 20 minutes, the solution of (E)-N-methoxy-4-(4-methoxyphenyl)-N-methylbut-3-enamide (558) (2.0 g, 8.7 mmol) in dichloromethane (10 mL) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature over 24 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAc in hexanes) to provide N-methoxy-2-(2-(4-methoxyphenyl)cyclopropyl)-N-methylacetamide (559) (1.8 g, 85.2%) as a yellow oil.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][CH:23]([N:25]=[C:26]=[O:27])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][CH:23]([NH:25][C:26]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:27])[CH3:24]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CC(C)N=C=O
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 1.8 g (0.022 mole) of 1-methylethyl isocyanate and after 0.5 hr, 5 ml of triethylamine was added. A clear yellow solution was obtained and was stirred for 18 hr, then treated with 10 ml of water, yielding 5.3 g (87.7%) of pale yellow crystals, m.p. 151°-152° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Li].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)C.CCCCCC.O1CCCC1.O>[CH3:11][O:10][CH2:9][O:8][C:7]1[C:2]([CH:25]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[OH:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOc1cccnc1Br
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1cccnc1C(O)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Under nitrogen atmosphere, to a solution of 2-bromo-3-methoxymethoxypyridine (10.00 g) in diethylether (150 ml) was added a solution of n-butyllithium in hexane (1.6M, 31.5 ml) at −78° C., and the mixture was stirred for 1 hour to prepare the lithium salt. The resulting lithium salt was dropwise added to a solution of 4-nitrobenzaldehyde (6.93 g) in tetrahydrofuran (100ml) cooled at −78° C., and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:3→1:2) to give (3-methoxymethoxypyridin-2-yl)-(4-nitrophenyl)methanol (11.78 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:31])[C@@H:11]2[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]2[CH:18](C(OC(C)(C)C)=O)[C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:5]=[CH:6][CH:7]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:31])[C@@H:11]2[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]2[CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H]1CCN(C[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline-N-(3-chlorophenylmethyl) amide (Example 1, Step H) (0.175 g, 0.39 mmol) was dissolved in EtOAc (15 mL), cooled to -20° C. and saturated with HCl gas. The solution was stirred at 0° C. for 1 h, then at 25° C. for 1 h, then concentrated to dryness to give pyrrolidin-2(S)-ylmethyl!-3(S)-ethyl-proline-N-(3-chlorophenylmethyl) amide which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23](O)([CH3:25])[CH3:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23]([CH3:25])=[CH2:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 110 °C
Yield: 94 %

Procedure:
Fifty milligrams (50 mg; 0.15 mmol) of 2-(2-benzyl-3-phenyl-2H-indazol-7-yl)propan-2-ol (Example 520) were dissolved in 2 ml of toluene followed by the addition of 11 mg of TsOH. The mixture was heated at 110° C. for 1 hour. After cooling, the resulting solution was filtered through SiO2 plug affording, after evaporation, 45 mg of pure 2-benzyl-7-isopropenyl-3-phenyl-2H-indazole. Yield: 94%.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:12])[C@H:5]([C:8](=[O:11])[O:9][CH3:10])[NH:6][CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:46][CH:47]([CH2:67][OH:68])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]#[C:57][C:58]2[CH:66]=[CH:65][C:61]([C:62]([OH:64])=O)=[CH:60][CH:59]=2)=[CH:52][CH:51]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[OH:46][CH:47]([CH2:67][OH:68])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]#[C:57][C:58]2[CH:59]=[CH:60][C:61]([C:62](=[O:64])[N:6]([CH:5]([C:4]([NH:3][CH3:2])=[O:12])[C:8]([O:9][CH3:10])=[O:11])[CH3:7])=[CH:65][CH:66]=2)=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 0.13 g), HATU (0.17 g) and DIPEA (0.33 mL) were added to a DMF (2.0 mL) solution of 4-{[4-(2,3-dihydroxypropoxy)phenyl]ethynyl}benzoic acid (0.20 g) as obtained in Example 11-(2), and the mixture was stirred for 1 hour at 80° C. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with ethyl acetate/methanol=99/1→88/12) to obtain 1-(2,3-dihydroxypropoxy)-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (white solid) (23 mg, 8.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:50])[C:10](=[C:41]2[NH:45][C:44]3[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=3[NH:42]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:23](=[NH:40])[N:24]3[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:50])[C:10](=[C:41]2[NH:42][C:43]3[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=3[NH:45]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[NH:40])(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 27.8 %

Procedure:
10% Pd—C (210 mg) was added to an ethanol (20 mL) solution of the compound (205 mg) obtained in Example 10, followed by stirring at room temperature for 19 hours under hydrogen atmosphere (1 atom). The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)piperazine-1-carboximidamide (46 mg).
Reaction SMILES: S(O[C@H:12]1[CH2:36][C@H:35]([O:37]C(=O)C)[C@@:34]2([CH3:41])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:42])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.O.[OH-].[Na+]>C1C=CC=CC=1>[OH:37][C@@H:35]1[C@@:34]2([CH3:41])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:42])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:13][CH2:12][CH2:36]1
Reactant: CC(=O)O[C@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CCC[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 0.900 mg of the tosylate 18 in 50 ml of benzene was stirred and purged with N2. Upon addition of 2.3 ml of Vitride reagent (a solution of 70% Na bis(2-methoxyethoxy aluminum hydride in benzene, Aldrich Chemical Co.), the mixture was refluxed (80°) for 18 hours. The product was isolated in the usual manner: after addition of water and 1.0 ml of 10% NaOH, the inorganic precipitate was removed by filtration and washed with ether, the aqueous phase was further extracted with ether, and the combined organic extracts were washed (10% NaOH), and dried over Na2SO4 and evaporated in vacuo. Chromatography of this residue on silica gel (using 20% ethylacetate in Skellysolve B) gave pure 1α-hydroxycholest-5-ene (19), nmr (CDCl3) δ5.53 (1H, m, C-6), 3.74 (1H, m, C-1); mass spectrum, m/e 386 (M+), 371, 368, 273.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]([NH2:34])[N:28]=2)=[CH:23][C:22]=1[CH3:35].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]([NH:34][C:12]([C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:10][CH2:11]3)=[O:14])[N:28]=2)=[CH:23][C:22]=1[CH3:35]
Reactant: COc1ncc(-c2nc(N)ccc2C)cc1C
Reactant: COc1cccc(C2(C(=O)O)CC2)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C2(C(=O)Nc3ccc(C)c(-c4cnc(OC)c(C)c4)n3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
1-(3-Methoxyphenyl)cyclopropanecarboxylic acid (38.4 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL) and thionyl chloride (43.8 μL, 0.60 mmol) was added followed by DMF (1 drop) and the reaction was stirred at room temperature for 30 minutes. Then the solvent was removed by evaporation, toluene (˜1 mL) was added twice, mixed with the residue and removed by evaporation and then the residue was placed under high vacuum for 10 minutes. It was then dissolved in dichloromethane (1 mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (45.9 mg, 0.20 mmol) and triethyl amine (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added. The reaction was stirred at room temperature for 12 hours. The reaction was then concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (10-99% CH3CN in water) to yield 41 mg (50% yield) of the product. ESI-MS m/z calc. 403.5. found 404.5 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:14][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(N)ccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc2cc[nH]c2c1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 85.2 mg (0.45 mmol) of 6-amino-1H-indole-7-carboxylic acid methyl ester in 4 mL of dioxane and 1 mL of methanol, is added 0.45 mL (0.9 mmol) of an aqueous solution of NaOH 2N. The mixture is stirred over the night at 60° C. A new addition of 0.22 mL (0.45 mmol) of an aqueous solution of NaOH 2N is made and the mixture is stirred again 6 h at 60° C. and then cooled to ambient temperature. After evaporation of all the solvents, a crude yellowish residue is obtained and used directly in the next step; 1H-NMR (MeOD4, 400 MHz): 7.51 (m, 1H), 7.05 (d, 1H), 6.55 (d, 1H), 6.33 (m, 1H) ppm.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:29])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=3[O:27][CH3:28])[N:16]=2)[CH:7]=1)(=[O:3])=[O:4]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (3.0 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.38 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. (2.62 g, yield 87%). melting point: 140-141° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=[C:19]2[CH3:20])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: Cc1nc2ccccc2n1-c1ccc(Br)cc1
Yield: 75.9 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-(4-bromophenyl)-acetamide (128 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (109 mg, 76%). 1H NMR (DMSO) δ 2.63 (s, 3 H), 7.34 (d, J=7.9 Hz, 1H), 7.41 (t, J=7.9 Hz, 1 H), 7.48 (t, J=7.9 Hz, 1 H), 7.64 (d, J=8.6 Hz, 2 H), 7.82 (d, J=7.9 Hz, 1 H), 7.92 (d, J=8.6 Hz, 2 H); 13C NMR δ 12.8, 111.7, 115.4, 123.6, 125.1, 125.2, 129.3, 132.5, 133.3, 134.5, 152.8, 157.6.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH3:25])[CH:17]=1>>[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: COc1cc(I)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1cc(I)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-iodo-2-methoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.88 (3H, s), 5.20 (2H, s), 5.77 (1H, d, J=2.0 Hz), 7.13 (1H, d, J=8.0 Hz), 7.23 (1H, d, J=1.6 Hz), 7.33 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, t, J=1.2 Hz), 8.70 (1H, d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C17H13IN4O2, 433; Found, 433.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Rh]>[CH:1]1([C@@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Agent: [Rh]
Solvent: CO
Product: C[C@@H](CC(=O)O)C1CCCCC1

Procedure:
Commercially available (S)-3-phenylbutyric acid treated with rhodium-on-carbon in methanol at 60 psi and 60° C. for 3.2 hours to yield (S)-3-cyclohexylbutyric acid. This acid was then converted to the acid chloride by treatment with 1 equivalent of oxalyl chloride and a catalytic amount of DMF, in toluene for 90 minutes. 250 mg of resulting (S)-3-cyclohexylbutyroyl chloride was dissolved in 10 mL ethyl acetate, and treated with 1.5 equivalents of the dipeptide, Val-Pec-OMe hydrochloride, followed by 3 equivalents of sodium bicarbonate dissolved in 2 mL of water. The reaction mixture stirred vigorously for 2 hours. The organic solution was then washed with 1.5 M HCl, dried over sodium sulfate, and evaporated to obtain a clear, colorless oil. This product was then treated with 3 equivalents of KOH dissolved in water and tetrahydrofuran and the reaction stirred vigorously for 12 hours. The tetrahydrofuran was evaporated, and the acid product was precipitated by acidifying the aqueous solution with conc. HCl. The mixture was extracted with ethyl acetate, the organic layer dried over Na2SO4, and evaporated to yield the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[CH3:25][N:26]=[C:27]=[O:28]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.ClCCl>[CH3:25][NH:26][C:27]([O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[O:28]
Reactant: CN=C=O
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CNC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Yield: 71.2 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.5 g), methyl isocyanate (0.705 g), and dibutyltin diacetate (2 drops) was stirred in dichloromethane at 20° C. in a sealed bottle for 2 days. The mixture was partitioned between water and dichloromethane, the organic layer dried (Na2SO4) and evaporated and the residue crystallized from ethyl acetate/hexane to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(N-methylcarbamoyl)oxime (1.22 g) m.p.146-147° C. Compound 18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:31][CH:32]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To 4-(benzyloxy)-1-chloro-2-nitrobenzene (526 mg, 2 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (670 mg, 2.1 mmol) in 12 mL dioxane was added 4 mL of a 1 M Na2CO3 (aq) solution and Tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol). The suspension was heated at reflux for 15 h under Ar atmosphere and cooled to rt. It was added EtOAc (100 mL) and washed with brine (80 mL), water (80 mL), and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford tert-butyl 4′-(benzyloxy)-2′-nitrobiphenyl-4-ylcarbamate as a yellow solid (740 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.34 (m, 8H), (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 3H), 6.50 (s, 1H), 5.12 (s, 2H), 1.51 (s, 9H); MS (ESI) m/z 443 (M+Na+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([F:48])=[C:43]([CH:47]=1)[C:44](O)=[O:45].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:44](=[O:45])[C:43]2[CH:47]=[C:39]([Cl:38])[CH:40]=[CH:41][C:42]=2[F:48])/[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc(Cl)ccc1F
Reactant: CCCCn1nc(C(C)(C)C)sc1=N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCn1nc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Temperature: 70 °C

Procedure:
To a mixture of Example 162C (250 mg, 1.17 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (179 mg, 1.17 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (225 mg, 1.17 mmol), 5-chloro-2-fluorobenzoic acid (205 mg, 1.17 mmol) in 8 mL of THF was added triethylamine (163 μL, 1.17 mmol). The mixture was heated at 70° C. for 12 hours then cooled to ambient temperature and diluted with ethyl acetate and aqueous NaHCO3. The organic extract was concentrated and the residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hex-EtOAc, 0 to 30% gradient) to give the title compound. LC/MS m/z 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1>>[NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2c1[nH]c1cc(Cl)ccc12
Reactant: c1cncc(B2OCCCO2)c1
Product: NC(=O)c1cnc(N)c2c1[nH]c1cc(-c3cccnc3)ccc12

Procedure:
The title compound was prepared from 1-amino-7-chloro-5H-pyrido[4,3-b]indole-4-carboxamide (Example 27, step 5) and pyridine-3-boronic acid 1,3-propanediol cyclic ester using conditions described in example 2.