Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:17]=[C:18]([F:21])[CH2:19][OH:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH3:6].C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:20][CH2:19][C:18]([F:21])=[CH:17][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH2:16][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(C2(C=C(F)CO)CC2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (2 ml), 1-(4-ethoxyphenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane (Example 10) (0.99 g), benzene (50 ml) and pyridine (0.38 ml) to yield the title compound (1.16 g, 99%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([O:20][CH3:21])[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:22][CH3:23])[C:10]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([NH:8][C:9]1[C:10]([F:24])=[C:11]([O:22][CH3:23])[C:12]([C:13]([OH:15])=[O:14])=[C:17]([O:20][CH3:21])[C:18]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OC)c(F)c(NCc2ccccc2)c(F)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(F)c(NCc2ccccc2)c(F)c(OC)c1C(=O)O
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate (24.0 g) was dissolved in ethanol (75 mL) and the solution stirred and cooled to 10° C. under a nitrogen atmosphere. Sodium hydroxide, 50% aqueous solution (12.5 g, 156 mmol) was added dropwise over 10 minutes at 10° C.–15° C. followed by ethanol (10 mL). The solution was stirred at 15° C.–25° C. A thick precipitate formed. Stirring was continued for a total of 2 hours at 15° C.–25° C. The mixture was heated to 50° C.–55° C. where it was held for 1.5 hours. The mixture was allowed to cool to room temperature and held overnight. Water (100 mL) was added and the resulting solution cooled in an ice bath and acidified with 37% HCl (13.5 mL) to pH 2. The mixture was extracted with toluene (100 mL) and methyl tert-butyl ether (100 mL) and the organic extract washed with water (10 mL) and concentrated to an oil. This was triturated with toluene (20 mL) to give crystals which were collected and vacuum dried at 45° C. to give 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (19.4 g, 60 mmol): mp: 85° C.–86° C. (decomposition with gas evolution).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[C:33](#[N:37])[CH:34]([CH3:36])[CH3:35]>C1COCC1>[Br:11][C:12]1[C:13]([C:34]([C:33]#[N:37])([CH3:36])[CH3:35])=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: -70 °C
Reaction time: 1 h

Procedure:
KHMDS 1 M in THF (1.517 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 200 mg, 0.506 mmol) and isobutyronitrile (52 mg, 0.758 mmol) in THF (5 mL) at −78° C. under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane, isocratic 1:3) to afford 5-bromo-6-(2-cyanopropan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (122 mg, 0.285 mmol) together with pyrimidine-5-boronic acid (53 mg, 0.427 mmol), Na2CO3 (0.427 mL, 0.855 mmol), PdCl2(dppf) (11 mg, 0.014 mmol) and dioxane (1.6 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 90° C. for 3 h, cooled to RT, treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, MeOH/DCM, isocratic 5:95) to afford the title product as a yellow solid. UPLC-MS (Condition 2) tR=1.05 min, m/z=428.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (s, 6H) 7.38 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, 2H) 8.26 (d, J=1.96 Hz, 1H) 8.96 (d, J=0.78 Hz, 2H) 9.18 (d, J=1.95 Hz, 1H) 9.30 (s, 1H) 10.64 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CC(=O)C(C)Br
Reactant: Nc1cc(Br)cnc1N
Solvent: CCO
Product: Cc1nc2c(N)cc(Br)cn2c1C
Temperature: 25 °C

Procedure:
A solution of 2,3-diamino-5-bromopyridine (4.0 g, 21.29 mmol) and 3-bromo-2-butanone (3.7 g, 24.48 mmol) in ethanol (40 ml) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. Yield 2.3 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>C(OCCO)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:24]([F:23])[CH:30]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc12
Temperature: 100 °C
Yield: 87.7 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloroaniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127° C. (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:17][CH2:18][C:19]#[N:20])[CH2:6][CH2:7][N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])#[N:2].[H][H]>O1CCOCC1>[NH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCN(CCCN)CCCN
Yield: 96.1 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)ethylenediamine, 0.50 g of Raney Co and 50 mL of dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 100° C. for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated to dryness to give 5.09 g of the title compound as a pale red oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[C:10](Cl)(=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C1C=CC=CC=1>[C:10]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][CH:5]=1)(=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution (5 ml) of 1.25 g (10 mmol) of methyl pyrrole-2-carboxylate in benzene was added 2.71 g (11 mmol) of tetradecanoyl chloride under ice-cooling, followed by adding 1.73 ml (15 mmol) of stannic chloride dropwise thereto. The mixture was stirred for 2 hours at room temperature, treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the product was purified by subjecting it to column chromatography over silica gel (ethyl acetate/hexane=1/7) to obtain 1.80 g (54% yield) of methyl 4-tetradecanoylpyrrole-2-carboxylate.
Reaction SMILES: O[C:2]1([CH2:17][C:18]#[N:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Cl>C(O)(C)C>[C:18]([CH:17]=[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)#[N:19]
Reactant: N#CCC1(O)c2ccccc2C=Cc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: N#CC=C1c2ccccc2C=Cc2ccccc21
Reaction time: 1 h

Procedure:
10 g. 5-hydroxy-5-cyanomethyl-5H-dibenzo-[a,d]-cycloheptene (0.0405 mol), prepared according to A, are heated to boiling for 1 hour in 150 ml. isopropanol saturated with hydrogen chloride. Subsequently, one evaporates the reaction mixture (residue 9.0 g., m.p. 137° - 138° ) and recrystallises the product from a petroleum fraction boiling at 100° - 140°. The analytically pure crystals melt at 143° - 144°, the yield amounts to 7.2 g. (79% of theory).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2)[N:14]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[Cl:41])[C:13]=1[C:42]([O:44]CC)=O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH2:33][N:14]1[C:13]2[C:42](=[O:44])[N:2]([CH3:1])[C:3](=[S:4])[NH:11][C:12]=2[C:16]([C:17]#[N:18])=[C:15]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:20]1
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 130 °C

Procedure:
Methyl isothiocyanate (7.36 ml) and potassium carbonate (14.86 g) were added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (27.96 g) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 13 hours. After the reaction solution was cooled to 25° C., toluene (50 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and the solid precipitated was collected by filtration and washed with water and then hexane. The solid thus obtained was dried at 45° C. under reduced pressure to obtain the title compound (28.56 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:12]=[C:13]1[CH2:18][CH2:17][C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:19]#[N:20])[CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2([OH:12])[CH2:18][CH2:17][C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:19]#[N:20])[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1F
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 15 ml of 3-fluoro-4-methoxyphenylmagnesium bromide solution (0.5 M in THF) were dissolved in 15 ml of dry THF in a dried two-necked flask equipped with a reflux condenser, and subsequently 1.5 g of 4-oxo-1-phenylcyclohexanecarbonitrile in the form of a suspension in 10 ml of THF were slowly added dropwise at room temperature. A precipitate was formed in the course of this. The reaction solution was heated under reflux for 2 h, subsequently added to ice water, treated with saturated ammonium chloride solution and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified chromatographically (HEP/EA 2:1) on silica gel. 950 mg of the title compound were obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([OH:3])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C:1]([C:4]2[C:5]3[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Reactant: COc1ccc(N)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-carboxy-2-oxindole (200 mg, 1.13 mmol) and 3-chloro-4-methoxyphenylamine (178 mg, 1.13 mmol) in dimethylformamide (15 mL) at room temperature was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 997 mg, 2.26 mmol) followed by 4-dimethylaminopyridine (206 mg, 1.69 mmol). The mixture was stirred at room temperature for 72 hours. The reaction was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (100 mL), water, 2N hydrochloric acid (100 mL), water (3×200 mL) and brine. It was then dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate to give 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)-amide as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:8][C:6]2[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ncc(Cl)nc1N
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.16 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.23 g). Yield 0.15 g.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>CC(C)=O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: NC(=O)CCl
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred solution containing 5 g (0.022 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of acetone, 0.024 mole of chloroacetamide was added in one portion. The stirred reaction mixture was heated at 56°-60° C. for 22 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air dried at 25°-30° C. A product with a melting point of 139°-141° C. (determined after recrystallization from 6:1 mixture of heptane and isopropyl alcohol) was obtained with a 32% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to a dry solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide (50 ml). The reaction was exothermic, immediately precipitating, triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first remove a small amount of ethylene glycol monobenzoate then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[C:18]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:19]([OH:35])[C:18]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(-c3ccccc3)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1cc(-c1ccccc1)c(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-5-phenyl-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.031 g, 0.056 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-5-phenyl-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.023 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(O)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[N:10][CH:11]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl)C(F)(F)F
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(Cl)c(NC(=O)C(F)(F)F)c2)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
N-{2-Chloro-5-[(5-nitropyridin-2-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (13 g, 35.9 mmol) was dissolved in acetic acid (200 mL), reduced iron (10 g, 179 mmol) was added, and the mixture was stirred at 60° C. for 3 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate (150 mL), aqueous sodium hydrogen carbonate solution (200 mL) was gradually added, and the mixture was filtered through celite. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oily substance was dissolved in toluene, and purified by silica gel column chromatography (ethyl acetate/hexane=20/80→80/20) to give the title compound (10.9 g, 91%) as a brownish-red oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
Methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 1) (2.90 g, 6.91 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (12 mL). 4N NaOH (4.3 mL, 17.27 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH-2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (2.36 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 8.01 (dt, J=1.41, 7.65 Hz, 1H), 7.76 (app t, J=1.68 Hz, 1H), 7.69-7.53 (m, 3H), 7.36-7.14 (m, 2H), 6.69 (s, 1H), 5.32 (s, 2H), 1.93 (s, 3H). ES-HRMS m/z 406.0662 (M+H C20H14ClF2NO4 requires 406.0652).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](O)(=[O:39])[C:30]1[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=1.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>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), isophthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid (19.5 mg, 34.2%). HRMS (ES+) m/z Calcd for C30H26Cl2F2N2O3+H [(M+H): 571.1362; Found: 571.1364.