Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[CH3:20][N:21]([CH3:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:30])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]([CH3:32])[CH3:20])[CH2:13]2
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C1(O)CC(C)CC2CN(C(=O)Cc3ccccc3N(C)C)CC21
Temperature: 5 °C
Yield: 71.4 %

Procedure:
To a solution of 0.78 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 80 cm3 of dichloromethane is added 0.5 cm3 of triethylamine. The reaction mixture is cooled to 5° C. and 0.54 g of (2-dimethylaminophenyl)acetic acid, 0.05 g of 1-hydroxybenzotriazole monohydrate and 0.63 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is maintained for 1 hour at 5° C. and for 16 hours at 20° C. and is then washed twice with 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 4 cm, height 50 cm), eluting under a pressure of 0.7 bar with a mixture of dichloromethane and methanol [97.5/2.5 by volume] and collecting 65 cm3 fractions. Fractions 17 to 23 are concentrated and, after drying at 40° C. at 15 Pa, 0.90 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisoindolol is obtained in the form of a white powder which is dissolved in 50 cm3 of dioxane. 3 cm3 of 5M hydrochloric acid solution in dioxane are added and, after 1 hour at room temperature, the solution is concentrated under reduced pressure (2.7 kPa), triturated in isopropyl ether, filtered and dried at 40° C. at 15 Pa. 1.0 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisoindolol hydrochloride is obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([O:13][CH2:14][CH3:15])=[N:11][CH:12]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>CCOCC>[CH2:14]([O:13][C:10]1[C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:7]([B:20]([OH:25])[OH:21])=[CH:12][N:11]=1)[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ncc(Br)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1ncc(B(O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Alternatively, n-butyl lithium (1.6 M solution in hexane, 0.9 mL, 1.43 mmol) was slowly added to a solution of 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (352 mg, 1.3 mmol) in 2.6 mL anhydrous Et2O at −78° C. under nitrogen. The mixture was kept at −78° C. for 1 hr, and then to this mixture was added triisopropyl borate (489 mg, 2.6 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by water and the pH was adjusted to 5 by carefully addition of 1N aqueous HCl. Two layers were separated and the aqueous layer was extracted with ethyl acetate three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethylpyridine-5-boronic acid as a brown oil (240 mg, 67% yield). The product was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:17])([F:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[Br:25][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:16])([F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1

Procedure:
To tert butyl 2-{4-(methyl)phenyl}-2,2-difluoroacetate(see X. Creary, J. Org. Chem. 1987, 52, 5026) (4.8 g) in CC14 (80 mL) was added NBS (3.8 g), followed by benzoyl peroxide (100 mg). The reaction mixture was heated at reflux and was irradiated with a sun lamp for 1.5 h. The mixture was cooled down and diluted with hexane (50 mL) purified by filtration on a pad of silica gel. The filtrate was concentrated to give the title product for step 2 as a yellow-brown liquid (6.4 g) 1H NMR δ: (CD3COCD3), 1.48 (9H, m), 4.70 (2H, s), 7.62 (4H, m).
Reaction SMILES: [C:1]1([C:7]2([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[CH3:19][O:18][N:17]([CH3:16])[C:12](=[O:14])[CH2:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: CNOC
Reactant: O=C(O)CC1(c2ccccc2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)CC1(c2ccccc2)CCC1
Yield: 89.5 %

Procedure:
A suspension of Example 68C (2.0 g, 10.5 mmol), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.8 mmol), HATU (4.8 g, 12.6 mmol) and triethylamine (2.1 g, 21.0 mmol) in 100 mL dichloromethane was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford yellow oil. The crude product was purified by reserve-phase C18 column chromatography (H2O/CH3OH=1:4) to afford desired compound (2.2 g, 9.4 mmol, 89.5%) of title compound. LC-MS: m/e=234.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc2cc(C(=O)O)cnc2c1
Temperature: 75 °C
Yield: 87.5 %

Procedure:
A mixture of Ethyl 7-tert-butylquinoline-3-carboxylate (1.63 g, 6.33 mmol) in 2M sodium hydroxide aqueous solution (6.4 ml, 12.8 mmol) and ethanol (50 ml) was heated at 75° C. for 2 hours. After the solvent was evaporated in vacuo, the residue was diluted with water. The aqueous solution was acidified to pH3 with 2M hydrochloric acid aqueous solution with ice-cooling and extracted with ethyl acetate. The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude product, which was recrystallized from ethyl acetate and hexane to give the title compound (1.27 g, 88%) as a white solid. MS (ESI) m/z 228 (M−H)−, 230 (M+H)+. LC-MS: 2.46 min (Neutral full range 4—96)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[C:7]([CH2:9][N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC1(F)CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCC(F)(F)C2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(3,3-difluoro-cyclopentyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:33](=[O:35])[CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2,4-Difluorobenzyl)-N-heptylamine (106 mg, 0.44 mmol) was added into (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (120 mg, 0.4 mmol) in DCM (10 ml) and followed by EDC (84.3 mg, 0.44 mmol) and then DMAP (54 mg, 0.44 mmol). The mixture was stirred at room temperature overnight, and then washed with 1% hydrochloric acid, water and brine and dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE®SI, 5 g/15 ml) using DCM and MeOH/DCM (0.5:99.5) as eluant gave 155 mg desired product, yield 74%.
Reaction SMILES: Cl.[CH2:2]([NH:4][O:5][CH3:6])[CH3:3].[C:7]([C:11]1[O:12][C:13]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[C:18]([Cl:24])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CCOC(C)=O>[CH2:2]([N:4]([O:5][CH3:6])[S:20]([C:19]1[C:13]2[O:12][C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])=[N:15][C:14]=2[CH:16]=[CH:17][C:18]=1[Cl:24])(=[O:21])=[O:22])[CH3:3]
Reactant: CCNOC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(OC)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N-Ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) (3.39 g, 30.4 mmol) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring. TEA (4.24 ml, 30.4 mmol) was added followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (4.68 g, 15.19 mmol) in THF (10 ml) over 2.5 hours. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 0-10% EtOAc in iso-hexane, to yield a white solid [M+H]+ 347.2
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[NH:11][C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)[CH2:8][CH3:9].[C:25]([N:44]1[C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]2[CH:62]=[CH:61][C:58]([CH2:59]Br)=[CH:57][CH:56]=2)=[N:47][N:46]=[N:45]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C(=O)C.O>[CH2:7]([C:10]1[N:14]([CH2:59][C:58]2[CH:57]=[CH:56][C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[C:48]3[N:44]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:45]=[N:46][N:47]=3)=[CH:62][CH:61]=2)[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
0.441 g of potassium t-butoxide was added to a solution of 1.00 g of diethyl 2-propylimidazole-4,5-dicarboxylate (prepared as described in Preparation 12) in 15 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 2.19 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 15 ml of N,N-dimethylacetamide was then added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. At the end of this time, it was diluted with water and then extracting with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.24 g of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: Cc1cccc2c(=O)nc(-c3cccc(C(=O)O)n3)sc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)NCCCCCCNC(=O)OC(C)(C)C)n3)sc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
6-(8-Methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (1.5 g, 5.0 mmol) was dissolved in DMF (15 ml), and N-(tert-butoxycarbonyl)-1,6-diaminohexane (2.1 g, 10.0 mmol), WSC (3.0 g, 15.5 mmol) and HOBt (2.0 g, 14.9 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 10 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.1 g, 45%) as white crystals.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=3)[CH:13]=[CH:12]2)[CH2:10][CH2:9]1.Cl.[O:26]=[C:27]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=3)[C:45]([OH:47])=[O:46])[CH:40]=2)[O:35][C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1.Cl>CN(C=O)C.O>[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([N:32]4[CH2:33][CH2:34][C:29]5([CH2:28][C:27](=[O:26])[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([C:42]7[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=7)[C:45]([OH:47])=[O:46])[CH:40]=6)[O:35]5)[CH2:30][CH2:31]4)=[O:22])[CH:18]=3)[CH:13]=[CH:12]2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1cccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cccc(C(=O)O)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
N,N′-carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (185 mg) in DMF (4 mL), and stirred at 70° C. for 7 hours. To the reaction mixture was added 3-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)benzoic acid hydrochloride (374 mg), which was further stirred at that temperature for 16 hours. 1 N hydrochloric acid and water were added to the reaction mixture, and the formed solid was collected by filtration. The resulting solid was recrystallized from methanol, and purified through silica gel column chromatography (chloroform/methanol) to obtain 3-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}benzoic acid. This was suspended in water (5 mL), and aqueous 1 N sodium hydroxide solution (0.762 mL) was added thereto and stirred at room temperature for 30 minutes. The solution was purified through ODS reversed-phase column chromatography (water/methanol) to obtain the intended compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.11-8.09 (1H, m), 7.96-7.93 (1H, m), 7.90 (1H, dd, J=8.5, 2.4 Hz), 7.83-7.79 (1H, m), 7.56-7.50 (1H, m), 7.32 (1H, dd, J=7.6, 7.6 Hz), 7.29 (1H, d, J=3.2 Hz), 7.23 (1H, s), 7.20 (1H, d, J=8.5 Hz), 6.59 (1H, s), 6.41-6.39 (1H, m), 4.45-4.11 (1H, br m), 3.86 (3H, s), 3.86-3.55 (1H, br m), 3.52-3.22 (3H, m), 2.93 (2H, s), 2.17-1.64 (4H, br m), 1.11-1.00 (2H, m), 0.96-0.88 (2H, m); MS [M+Na]+=573.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CC(O)=O.[Pt]=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:17]=2)=[CH:30][C:31]=1[CH3:36]
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc(F)c(C)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)ccc1F
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(4-fluoro-3-methylphenylamino)nicotinate (75 mg, 0.151 mmol) and platinum oxide (34.2 mg, 0.151 mmol) in DCM (2 mL) and HOAc (0.5 mL) was stirred at RT under H2 atmosphere. The mixture was subsequently filtered through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give the title compound (50 mg, 70.6%). [M+H] calc'd for C25H32FN5O3, 470. found, 470.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Cl:26][C:4]1[O:5][C:6]([C:7]2[CH2:12][CH2:11][C@@H:10]([C:13]([CH3:15])=[CH2:14])[CH2:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C=C(C)[C@H]1CC=C(c2ocnc2C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)[C@H]1CC=C(c2oc(Cl)nc2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of Example 32A (0.55 g, 2.7 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1 M in THF, 3.25 mL, 3.25 mmol) dropwise over a period of 6-8 min. After 30 min hexachloroethane (1.28 g, 5.41 mmol) was added at once as a solid and the mixture was left to stir overnight warming to ambient temperature. The mixture was diluted with Et2O and washed with aqueous NH4Cl solution and water. The organic layer was separated and concentrated in vacuo, and the residue chromatographed on silica gel with EtOAc/hexanes (0%-20%) to yield 0.47 g (73%) of the title compound as an oil. 1H NMR (300 MHz, DMSO-d6) δ 6.11 (m, 1H), 4.74 (m, 2H), 2.48-2.24 (m, 3H), 2.23-2.00 (m, 5H), 1.92-1.82 (m, 1H), 1.73 (s, 3H), 1.57-1.41 (m, 1H). MS (ESI+) m/z 238 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[O:11]1[CH:12]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH2:1][Br:13])[CH:9]=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2cnoc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2cnoc2)c1
Reaction time: 3 h
Yield: 76.2 %

Procedure:
185 mg of 4-(3-methylphenyl)isoxazole [see J. Heterocyclic Chem., 11, 51 (1974); and J. Chem. Soc., Perkin II, 1121 (1977)] was dissolved in 8 ml of carbon tetrachloride, and 206 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added. The mixture was refluxed with stirring for 3 hours. The insoluble material was separated by filtration and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 30 g; eluting solvent: hexane/ethyl acetate=10/1 to give 210 mg (yield 76%) of the captioned compound as a colorless powder
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20](O)=[O:21])[CH:11]=1)#[N:2].[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:19])[CH2:17][OH:18])[CH:13]=[C:12]([C:20]([NH:31][CH2:30][C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:21])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)CO)c2)c(C#N)c1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)CO)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-5-(1,2-dihydroxyethyl)-4′-methylbiphenyl-3-carboxylic acid (30 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (35 mg, 0.26 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.