Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO.C1CCCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]1[N:28]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:29][C:11](=[O:13])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(=Cc1ccc(Cl)cc1Cl)C(=O)OCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2Cl)nc(-c2ccccc2)[nH]c1=O
Reaction time: 1 h
Yield: 105 %

Procedure:
A solution of diethyl 2-(2,4-dichlorobenzylidene)malonate (300 mg, 0.91 mmol) and benzamidine (134 mg, 0.91 mmol) in EtOH (3 mL) was heated to 60° C. for 2 hrs. The reaction was concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (4 mL) and DDQ (238 mg, 1.05 mmol) was added. After 1 hr, The reaction was diluted with cyclohexane/EtOAc solution (4:1, 100 mL) and the organic layer was extracted with saturated NaHCO3 solution (2×60 mL), brine (50 mL). The organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give ethyl 4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (372 mg, 100%) as a yellow solid. This product was moved onto next step without further purification.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(-c2ccccc2C)c1
Temperature: 77.5 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of dimethyl iodoterephthalate (2.41 kg, 7.53 mol), ortho-tolylboronic acid (1.23 kg, 9.04 mol), palladium(II) acetate (16.9 g, 0.08 mol), and triphenylphosphine (79.0 g, 0.30 mol) in deoxygenated toluene (19 L) and 2M Na2CO3 (19 L) was vigorously mechanically stirred for 4 hours at 75-80° C. and cooled to room temperature to provide two distinct layers. The layers were separated, and the organic layer was filtered through a pad of silica gel 60 (4.79 kg of silica gel slurried with 2×10 L of MTBE) with a 40 L MTBE rinse, concentrated to 40 L, stored at 2-8° C. for 18 hours, filtered through a pad of diatomaceous earth (4.91 kg of Celite® 521 slurried in 20 L of MTBE) with a 40 L MTBE rinse to provide a solution of 2.12 kg (99%) of the desired product in MTBE.
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[F:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][C:27]=1[C:28]#[N:29].C(N(CC)CC)C>ClCCl>[F:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]=[C:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[C:9](=[O:16])[O:8]2)=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 1B (3.05 g) in dichloromethane (30 mL) was added 2-fluoro-5-formylbenzonitrile (1.08 g) and triethylamine (1.02 mL). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and brine. The organic layer was washed with brine and concentrated. The concentrate was purified by flash chromatography on silica gel with 50% ethyl acetate in hexane.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH2:23][C:24]#[N:25])[CH:22]=1)([CH3:16])([CH3:15])[CH3:14].[Cl:28][CH2:29][CH2:30][CH2:31]I.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>CCCCCC.C1COCC1.O.C(OCC)(=O)C>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:23]([CH2:31][CH2:30][CH2:29][Cl:28])[C:24]#[N:25])[CH:22]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(C(C)(C)C)cc1CC#N
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(C)C)cc1C(C#N)CCCCl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium in hexane (2.69 M, 3.0 mL) was added to a solution of N,N-diisopropylamine (1.2 mL) in THF (15 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. The solution was cooled to −78° C. and a solution of (5-tert-butyl-2-methoxyphenyl)acetonitrile (1.5 g) in THF (6.5 mL) was added dropwise. The solution was stirred at −30° C. for 25 minutes and then cooled again to −78° C. 1-Chloro-3-iodopropane (1.2 mL) was added dropwise to the solution, and then the reaction solution was gradually heated to room temperature. After ice-cooling the reaction solution, a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 4.4 mL) was added to the reaction solution. Then, a lithium diisopropylamide solution prepared from N,N-diisopropylamine (0.6 mL) and a solution of n-butyllithium in hexane (2.69 M, 1.5 mL) was added to the reaction solution. A saturated ammonium chloride aqueous solution was added to the reaction solution. Then, ethyl acetate and water were added and the organic layer was separated. The resulting organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Merck silica gel 60 (230-400 mesh); elution solvent:heptane:ethyl acetate=1:49) to obtain 864 mg of a 1:7 mixture of (5-tert-butyl-2-methoxyphenyl)acetonitrile and the title compound. The property values of the title compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (300 mg, 1.0 mmol), toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester (386 mg, 1.06 mmol) and Cs2CO3 (423 mg, 1.3 mmol) were combined in anhydrous DMF (7 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0-20% ethyl acetate in hexanes) to provide the ethyl ether compound as a colorless oil (177 mg, 28%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Br[CH2:17][CH2:18][Si:19]([CH2:22][CH2:23]Br)([CH3:21])[CH3:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CCBr)CCBr
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[Si]1(C)CCN(Cc2ccccc2)CC1
Yield: 53.7 %

Procedure:
Benzylamine (20 mL, 182 mmol) and Et3N (15.2 mL, 109 mmol) are added to a solution of bis-(bromomethyl) dimethylsilane 2 (10 g, 36.5 mmol) in chloroform (100 mL). The mixture is then refluxed for 16 h. 5% sodiumhydroxide solution (150 mL) is then added and the aqueous layer is extracted with dichloromethane (DCM, 2×100 mL). It is then washed with brine (200 mL), dried and concentrated. The product is purified by column chromatography on silica gel using hexane-EtOAc mixtures to obtain the product 3 as a light yellow liquid (4.3 g) in 54% yield.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C(OC)(C)(C)C>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methyl t-butyl ether (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in methyl t-butyl ether was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:25]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Product: COC(=O)CC(=O)Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-4,5-dichloro-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOC(=O)C1CCC(=O)CC1
Yield: 94.5 %

Procedure:
To a vigorously stirring suspension of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol, Aldrich) and activated 4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. was sequentially added 4-methylmorpholine-N-oxide (2.0 g, 17 mmol) and tetrapropylammonium perruthenate (410 mg, 1.2 mmol). After stirring the resulting black suspension for 30 min, the mixture was concentrated in vacuo, and the resulting residue was filtered through a plug of silica gel (30% ethyl acetate in hexanes) to provide ethyl 4-oxocyclohexanecarboxylate as a clear oil (1.93 g, 98%). MS (AP CI) 171 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)=O)(C)(C)C.[ClH:21].CCOCC>O1CCOCC1>[ClH:21].[NH2:8][CH2:9][C:10]1([C:18]([OH:20])=[O:19])[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC1(C(=O)O)CC12CCCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid (200 mg, 0.706 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3 mL). The reaction was stirred for 18 hours at room temperature. Ether (20 mL) was added and the precipitate was isolated by vacuum filtration. The solid was dried in a vacuum oven at 48° C. to give 133 mg (86%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid hydrochloride as a white solid: mp 240-242° C.; 1H NMR (300 MHz, D2O) δ 0.92 (d, J=5.2 Hz, 1H), 1.40 (d, J=5.2 Hz, 1H), 1.4-1.6 (m, 10H), 3.12 (d, J=14.0 Hz, 0.1H), 3.61 (d, J=14.0 Hz, 1H); MS (APCI) m/z 184 [M+H]+. Anal. Calc'd For C10H17NO2—HCl: C, 54.67; H, 8.26; N, 6.38; Cl, 16.14. Found: C, 54.91; H, 8.36; N, 6.25; Cl, 15.99.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:4]=1
Reactant: CSc1ccccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccccc1-c1cc(Br)ccc1F
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 57 %

Procedure:
To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 ml) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C. before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 ml) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 ml) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 ml) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (4×35 ml). The combined organics were washed with 1M aqueous sodium sulphite solution (30 ml), then saturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16](OS(C(F)(F)F)(=O)=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccn(Cc3ccccc3)c2c(=O)n1C
Reactant: OB(O)c1ccc(Cl)cc1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of methyl 1-benzyl-6-methyl-7-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.5 g, 16.9 mmol), 4-chlorophenylboronic acid (3.89 g, 23.64 mmol) and Na2CO3 (7.52 g, 70.9 mmol) in 1,4-Dioxane (100 mL) and Water (20 mL) degassed with N2 for 15 minutes. The mixture was treated with palladium tetrakis (1.024 g, 0.887 mmol) and then stirred at 90° C. under N2 atmosphere overnight. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-40% ethyl acetate/hexanes) to afford methyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (6.4 g, 15.7 mmol, 93% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.40 (s, 2H) 7.31-7.37 (m, 4H) 7.23-7.27 (m, 2H) 7.05 (d, J=2.93 Hz, 1H) 6.12 (d, J=2.93 Hz, 1H) 5.87 (s, 2H) 3.62 (s, 3H) 3.61 (s, 3H); LCMS (m/z) ES+=407 (M+1).
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:19][CH2:18][CH2:17][O:16]2)[CH:10]=1)([CH3:8])[C:4]([O:6]C)=[O:5].[OH-].[K+]>[Zn].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[C:20]1([C:15]2([C:11]3[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=3)[O:19][CH2:18][CH2:17][O:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C(=O)O)c1cccc(C2(c3ccccc3)OCCO2)c1

Procedure:
To 456 mg of methyl α-methylthio-α-(m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl)propionate were added 2.00 g of potassium hydroxide and 10 ml of water. The mixture was heated under reflux with stirring. A mixture of 100 mg of zinc powder and 10 mg of copper sulfate pentahydrate was added three times at 30 minute intervals, and the mixture was further heated under reflux for 24 hours with stirring. After cooling, 20 ml of water was added. The insoluble matter was separated by filtration, and washed with 20 ml of water. The filtrate and the washing were combined, and extracted with 10 ml of diethyl ether. The organic layer was adjusted to pH 1 with 3.5 ml of conc. hydrochloric acid, and extracted four times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and concentrated under reduced pressure to afford α-(m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl)propionic acid as colorless crystals.
Reaction SMILES: Cl.[C:2](=[NH:13])([O:9][CH:10]([CH3:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:22][N:23]([CH3:38])[C:24](=[O:37])[O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:38][N:23]([C:24]([O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:37])[S:22][N:13]=[C:2]([O:9][CH:10]([CH3:11])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(SCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CC(C)OC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=NSN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)c1ccccc1

Procedure:
To a solution of isopropyl benzimidate hydrochloride (18.0 g, 90 mmoles) in methylene chloride (100 ml) at 0° under an atmosphere of dry nitrogen is added a solution of triethylamine (28 ml, 200 mmoles) in a small stream with stirring. To this mixture is added a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chlorothio(methyl)carbamate (26 g, 90 mmoles) in methylene chloride (80 ml) in a dropwise fashion. The reaction mixture is stirred for two hours at 0° and then washed in turn with water, 2N hydrochloric acid and saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is poured onto a column of silica gel. Elution of the column with a solvent consisting of 15 parts ether and 85 parts Skellysolve B gives from the appropriate fraction isopropyl N-[[methyl[[[2,3-dihydro-2,2-dimethyl-7-benzofuranyl]oxy]carbonyl]amino]thio]benzimidate as a yellow oil.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].IC>C1COCC1>[CH3:1][C:9]1[C:8]([F:14])=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: [Li]CCCC
Reactant: Fc1ccc(Br)c(F)c1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisoproplylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of TBF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of TBF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1)[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([C:19]1[CH:24]=[N:23][C:22]([C:25]([OH:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=1)[CH2:15][CH:16]1[CH2:18][CH2:17]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(O)c1ccc(C(CN)CC2CC2)cn1
Product: CC(C)(O)c1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(5-(1-amino-3-cyclopropylpropan-2-yl)pyridin-2-yl)propan-2-ol was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=407.1, tR (minutes, Method F)=1.98. [α]D20=+23.89 (c=3.0 mg/mL,CHCl3)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>C(Cl)Cl>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride, under nitrogen, while cooling to 0° C. is added dropwise 30 ml of triethylamine followed by a solution of 4'-(propyl)[1,1'-biphenyl]-4-carbonyl chloride in 10 ml of methylene dichloride. The reactants are stirred at room temperature for 16 hours. The reaction mixture is poured in ice water and extracted with methylene chloride (3×50 ml) The organic layer is, washed with water, 2N citric acid, saturated aqueous NaHCO3, water and dried (MgSO4) and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel with ethyl acetate-hexane to give 1.4 g of the desired product as a crystalline solid, m.p. 118°-120° C. MS(M+H=407.3; M+Na=429.3)