Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[C:10]([O:14][C:15](=[O:26])[CH2:16][N:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]1=[O:25])([CH3:13])([CH3:12])[CH3:11].[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:10]([O:14][C:15](=[O:26])[CH2:16][N:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([NH:24][S:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[C:18]1=[O:25])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
Collidine (0.59 mL, 4.5 mmole) was added in one portion to a stirred solution of the compound of Example 94 (0.89 g, 3.7 mmole) and benzylsulfonyl chloride (0.86 g, 4.5 mmole) in acetonitrile (20 ml) cooled in an ice bath. The solution was stirred for 5 minutes at 0° C., followed by 45 min at room temperature. The reaction mixture was quenched with water, then diluted with ethyl acetate (100 mL), washed with 3% HCl (until aqueous layer is pH 1), and brine, dried over magnesium sulfate, and the solvent was removed. The residue was dissolved in methanol, concentrated to a volume of approximately 3 mL, and the product was precipitated with the addition of diethyl ether. The precipitate was filtered to give 0.67 g of the title compound. The filtrate was concentrated and chromatographed on flash silica gel using 20-67% ethyl acetate hexanes as eluent. An additional 0.20 g of the title compound was recovered. A total of 0.87 g of the title compound (59% yield) was recovered. Rf=0.29 (silica gel, 33% ethyl acetate/hexanes).
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10]([O:12]CC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:1]1([C:8]2[N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[N:25]=[C:10]([OH:12])[C:9]=2[C:15]2[C:16]([F:23])=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Reactant: Nc1ncc[nH]1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Oc1nc2nccn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (342 mg, 1.0 mmol), 2-aminoimidazole (Hel. Acta. Chim. 76, 2066 (1993)) (83 mg, 1.0 mmol), and 0.5 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 1.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acide (×2) and saturated sodium chloride, dried over magnesium sulfate, and concentrated to give crude 5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-7-ol as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[Li+].[CH3:18][CH:19]([N-]C(C)C)[CH3:20].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH:19]=[CH2:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 2 (see Example 1, Step 1) (4.58 g, 20 mmol) was dissolved in THF (100 mL) and cooled down to −78° C. in a dry ice-acetone bath. LDA (12 mL, 2.0 M, 24 mmol) was then added dropwise. The mixture was stirred at −78° C. for 1 hr. Allyl bromide (5.3 mL, 61 mmol) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4Cl solution, extracted with ethyl acetate 2×150 mL. The organic layer was washed with brine, dried (MgSO4) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (3.6 g) as a yellow oil. MS (292, MNa).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCCl.O>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
tert-Butyl 2-[(4-nitrophenyl)amino]acetate (4.5 g) is added at a temperature in the region of 20° C. to a suspension, maintained under an argon atmosphere, of 2-[3-(3-methylphenyl)ureido]acetic acid (3.7 g) in 1,2-dichloroethane (230 cc). The reaction mixture is heated with stirring to reflux of the solvent. Sulphinyl chloride (2.12 g) is then added dropwise while refluxing is maintained. When the addition is complete, heating to reflux is continued for 10 minutes and the reaction mixture is then cooled to a temperature in the region of 10° C. and poured into a solution of sodium hydrogen carbonate (15 g) in water (300 cc). The aqueous phase is separated after settling has taken place and re-extracted with 1,2-dichloroethane (2×50 cc). The organic phases are combined, washed with water (3×20 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm) (200 g) contained in a column 3.5 cm in diameter [eluent: cyclohexane/ethyl acetate (50:50 by volume)], collecting 30-cc fractions. Fractions 16-25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(4-nitrophenyl)acetamido}acetate (2.9 g), m.p. 152° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.N1C=C[CH:21]=[CH:20][CH:19]=1.C(O)(C)C>ClCCl.CN(C)C=O>[CH2:7]([C:6]1[S:5][C:4]([C:9]([O:11][CH:20]([CH3:21])[CH3:19])=[O:10])=[CH:3][C:2]=1[Br:1])[CH3:8]
Reactant: c1ccncc1
Reactant: CCc1sc(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCc1sc(C(=O)OC(C)C)cc1Br
Yield: 48.1 %

Procedure:
A solution of 7 g (30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic acid was dissolved in dry dichloromethane (200 mL) and treated with oxalyl chloride (3.2 mL, 36 mmol) and dimethylformamide (0.5 mL) for 18.5 h. The solvents were removed in vacuo and the residual brown oil was passed through silica gel (2 inches in a 350 mL scintered-glass Büchner funnel) and eluted with 700 mL of hexanes:ethyl acetate 9/1 (v:v). The elutate was concentrated in vacuo and the oil dissolved in dry dichloromethane (200 mL). This solution was treated with pyridine (12 mL, 150 mmol) and dry isopropanol (60 mL, 750 mmol) for 4 h at room temperature. The solvents were removed in vacuo and the residue partioned between dichloromethane (100 mL) and water (200 mL). The aqueous layers were extracted with dichloromethane (2×30 mL). The combined organic layers were extracted with sodium bicarbonate (2×30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. Purification by column chromatography on silica gel (250 g) eluting with hexanes:ethyl acetate 95/5 (v:v) gave isopropyl 2-ethyl-3-bromo-thiophene-5-carboxylate (4 g, 48%) as a yellow oil. 1H-NMR (DMSO-d6; 300 MHz) δ7.66 (s, 1H), 5.89 (septet, 1H, J=6.2 Hz), 2.80 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.0 Hz), 1.24 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[OH:11])=[O:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+]>C(O)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[O:11])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A solution of 4,4'-dibromobenzoin (20.2 g, 0.055 mol), ammonium nitrate (4.6 g, 0.0575 mol) and copper(II) acetate (0.100 g, 0.0005 mol) in 80 percent aqueous acetic acid (200 mL) is heated at reflux for three hours. The reaction mixture is cooled to room temperature and the product which crystallizes out is filtered off, washed with ethanol and dried, giving 13.0 g (64 percent) of product as a light yellow solid, mp 226° C. to 228° C. 1H NMR (CDCl3) δ 7.83 (d, J=8.5 Hz, 4H), 7.66 (d, J=8.5 Hz, 4H); 13C NMR (CDCl3) δ 192.25, 132.44, 131.45, 131.22, 130.7.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:7])C.CO.C1COCC1.O[Li].O>O>[C:15]1([C:12]2[N:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:21])=[O:3])=[CH:14][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of 5-amino-2-phenyl-pyridine (4.0 g, 0.0235 mol) in dichloromethane (40 mL) was added ethyl malonyl chloride (5.307 g, 0.035 mol) dropwise. The resulting mixture was stirred for 1 hour. The mixture was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over Na2SO4 and evaporated to afford 5.46 g (80%) of N-(6-phenyl-pyridin-3-yl)-malonamic acid ethyl ester. To a solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid ethyl ester (5.46 g, 0.019 mol) in the mixture of methanol (27.5 mL), THF (55 mL) and H2O (16.5 mL) was added LiOH.H2O (1.212 g, 0.0288 mol). The resulting reaction mixture was stirred for 1 hour at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 4.0 g (82%) of N-(6-phenyl-pyridin-3-yl)-malonamic acid.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[CH2:36]Br.Cl>CC(N(C)C)=O>[CH3:42][O:41][C:39]1[CH:38]=[C:35]([CH2:36][N:9]2[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:24])[CH:34]=[C:33]([O:32][CH3:31])[CH:40]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: COc1cc(CBr)cc(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)cc(OC)c1
Reaction time: 8 h
Yield: 41.2 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (1.5 g, 11 mmoles) and 3,5-dimethoxybenzyl bromide (300 mg, 1.3 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from toluene gave the title compound (190 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (s, 1 H), 10.15 (s, 1 H), 6.40 (s, 3 H), 4.92 (s, 2 H), 4.64 (t, J=11.87 Hz, 1 H), 4.09-4.17 (m, 2 H), 3.70 (s, 6 H), 2.26 (s, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.62 (d, J=11.62 Hz, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.06-1.17 (m, 1 H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])#[CH:15].CCCCCC>COCCOC.[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.C(OCC)(=O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: C#Cc1ccccc1F
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccccc1C#Cc1nccs1
Yield: 41.5 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 13 mmol) and CuI (316 mg, 1.6 mmol) were combined in DME (25 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (5.8 mL, 42 mmol) and PdCl2(PPh3)2 (580 mg, 0.83 mmol) were added and 1-ethynyl-2-fluorobenzene (1.0 g, 8.3 mmol) was added dropwise. The reaction was heated under reflux for 4 h at which time GC/MS showed the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 98:2 hexane:ethyl acetate to afford 2-[(2-fluorophenyl)ethynyl]-1,3-thiazole (700 mg, 41% yield) as a yellow oil that was impure by 1H NMR analysis. The compound (140 mg) was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 50:50 water:acetonitrile to 100% acetonitrile to afford 2-[(2-fluorophenyl)ethynyl]-1,3-thiazole (53.2 mg, 75% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.88 (d, J=3.0 Hz, 1H), 7.59–7.53 (m, 1H), 7.42–7.35 (m, 2H), 7.18–7.09 (m, 2H). MS (ESI) 204 (M++H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[CH:19]=3)=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[C:19]=3[CH:21]([OH:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Reactant: CCOC(=O)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-imidazo[1,2-a]pyridine (19b) (50 mg, 0.2 mmol), ethyl glyoxylate 50% in toluene (0.20 mL, 1.0 mmol) and p-toluenesulfonic acid (6 mg, 0.03 mmol) in ethanol (1 mL) was heated at 80° C. for 1 hour. Ethyl glyoxylate 50% in toluene (0.10 mL, 0.5 mmol) was added and the heating was maintained for one supplementary hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogencarbonate (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired hydroxyl-ester (19c) (56 mg, 0.159 mmol, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@H:3]([CH3:14])[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][NH:58][CH2:57]3)[CH2:50][CH2:49]1>CN(C=O)C>[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C@@H:3]([CH3:14])[C:2]([F:1])([F:16])[F:15])=[O:9])[CH2:57]3)[CH2:50][CH2:49]1
Reactant: c1cc2c(cc1C1CCOCC1)CNC2
Reactant: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccccc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 0.9 g (3.8 mmol) 2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid in 9 ml DMF under argon at room temperature, was added 1.4 g (4.2 mmol) TBTU, 3.3 ml (19.2 mmol) N-ethyldiisopropylamine and finally 0.8 g (3.8 mmol) 5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole (CAS: 905274-50-2). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water and twice with sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 1.5 g (93%) of the title compound as a yellow oil. MS (m/e): 420.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:9][CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1(c2ccc(Br)cc2)CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 4-(4-bromophenyl)-4-methylpiperidine (285) (4.1 g, 16 mmol) in DCM (20 mL) was added (BOC)2O (5.7 g, 26 mmol). The resulting mixture was stirred at RT for 30 min before being diluted with water (10 mL). The mixture was extracted with DCM (10 mL×2). The combine organic layers were washed with brine, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 20% EtOAc in PE to give tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (5 g, 88%) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][N:23]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][N:23]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC(N(CCN(C(=O)OC(C)(C)C)c2ccccn2)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCN(C(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1)c1ccccn1
Reaction time: 2.25 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl-[2-[tert-butoxycarbonyl(2-pyridyl)amino]ethyl]amino]cyclohexyl]acetate (968 mg, 1.91 mmol) in THF (3 mL); methanol (3 mL) and water (6 mL) was added lithium hydroxide monohydrate (397 mg, 9.7 mmol). The resulting solution was stirred for 2.25 hr, then acidified to pH 3 with 1N HCl. The resulting mixture was extracted with dichloromethane (4 times). The combined organic extract was dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (10 g silica; eluted with 40-100% ethyl acetate in hexanes) to give the title compound as a 6:1 mixture of trans:cis isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: ClCCl
Solvent: COCCOC
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)ccn1
Temperature: 80 °C
Yield: 35.3 %

Procedure:
N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (55 mg, 0.36 mmol), 0.3 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (31 mg, 35%). ESI-MS m/z calc. 439.1. found 440.3 (M+1)+. Retention time 2.12 minutes.