Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([F:28])[CH:30]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)c(F)c3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 3-fluoro-4-chlorophenylboronic acid (133 mg, 0.76 mmol). Yield 103 mg (54%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(#N)C.ClCCl>[CH:24]([NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Reactant: CC(C)N
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 140 °C

Procedure:
Ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (1.4 g) in acetonitrile (10 mL) was treated with isopropylamine (8 mL, 89 mmol). The mixture was stirred at 140° C. (sealed tube) for 15 h. The mixture was dissolved in 100 mL dichloromethane and was washed with water (20 mL), brine (20 mL), then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 50% ethyl acetate/DCM to give ethyl 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:4].N#N.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)(C)C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.35 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (79 mg, 0.38 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 112 mg (69%) of 3-[tert-Butyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.50 ppm (m, 2H, Haro); 7.44-7.34 ppm (m, 3H, Haro); 7.27 ppm (s, 1H, Haro); 7.18 ppm (dl, 1H, Haro); 7.14 ppm (d, 1H, Haro); 7.00 ppm (dd, 1H, Haro); 3.93 ppm (s, 3H); 1.56 ppm (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28]>CC(C)=O.O>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[O:20][CH2:27][CH3:28]
Reactant: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(4-bromo-3-hydroxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-106, 1.61 g, 4.77 mmol), potassium carbonate (1.97 g, 14.31 mmol) and ethyl iodide (3.8 mL, 47.7 mmol) in acetone (50 mL) was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow oil. The material was used in the next step without further purification.
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].Cl[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:11]1[CH2:10][CH2:9][S:7][CH2:6][CH2:5][S:4][CH2:3][CH2:2][S:1][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: ClCCOCCOCCCl
Reactant: SCCSCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C1COCCSCCSCCSCCO1

Procedure:
This compound is obtained by reacting 1,5-dimercapto-3-thiapentane with 1,8-dichloro-3,6-dioxaoctane in the presence of cesium carbonate in dimethylformamide (DMF): ##STR2##
Reaction SMILES: [CH3:1]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.O[CH2:24][C:25]1([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.S(=O)(O)[O-].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH:24]([C:25]1([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]1)=[CH2:1]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(COCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.38 g, 3.3 mmol) was added to a solution of 1,1-dimethylethyl 4-(hydroxymethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate (Description 95, 1.06 g, 3 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 4 hours. Aqueous sodium bisulfite (10%, 10 mL) was added and the mixture was stirred at room temperature for 5 minutes. Saturated aqueous sodium hydrogen carbonate (20 mL) was added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and added to a stirred, cooled (0° C.) solution of triphenylphosphoranylidine (0.1M, 50 mL). The mixture was stirred at room temperature for 16 hours, then the solvent was evaporated under reduced pressure. Ethyl acetate (40 mL) and aqueous sodium hydrogen carbonate (10%, 40 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25) give the title compound (1.01 g, 99%). m/z (ES+) 332 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3]1.[C:15]([NH:25][CH2:26][C:27](O)=[O:28])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:19]1([CH2:18][O:17][C:15](=[O:16])[NH:25][CH2:26][C:27]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([C:7](=[O:8])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:3]2)=[O:28])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1ccc(C(=O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1-amino-1H-pyrrol-3-yl)phenylmethanone (5.96 g) and N-carbobenzyloxyglycine (6.69 g) in 70 ml of anhydrous DCM and 30 ml of anhydrous dimethylformamide was added DCC (7.22 g). The reaction mixture was stirred at room temperature for 4 hours and filtered. The filter cake was washed with ethyl acetate, and the combined filtrates were evaporated in vacuo. The residual oil was purified by preparative HPLC (silica gel, DCM/ethyl acetate 3:1). Evaporation of the desired fractions afforded a colorless oil, which was crystallized from DCM/ethyl ether yielding the product as colorless crystals (5.96 g), m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7]1)[CH:2]=[CH2:3].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>CC(N(C)C)=O.[Cu]=O>[O:12]=[C:8]1[NH:7][C:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[C:10](=[O:11])[N:9]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:25]=1
Reactant: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)NC1=O
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: O=[Cu]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 4-[(2-propenyloxy)methyl]-4-(3-trifluoromethylphenyl)imidazolidin-2,5-dione (1.45 g) and 4-bromo-2-(trifluoromethyl)benzonitrile (1.15 g) in DMAC (7 mL) is added copper oxide (528 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:33](=[O:34])[CH2:32][N:16]3[CH2:17][CH2:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]3=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)piperazine (0.034 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction mixture was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.27-7.38 (m, 8H), 7.18-7.25 (m, 2H), 6.94-7.01 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 3.73 (t, J=4.9 Hz, 2H), 3.54-3.60 (m, 2H), 3.54 (t, J=6.5 Hz, 2H), 3.02 (t, J=5.0 Hz, 2H), 2.89 (t, J=5.2 Hz, 2H), 2.82 (t, J=6.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:16])[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC>[O:13]=[C:5]1[C:4]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:16])=[CH:3][C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:7][N:6]1[CH2:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C(Cc1cc(Br)cn(CC(F)(F)F)c1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C(Cc1cc(-c2ccccc2)cn(CC(F)(F)F)c1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 85 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
1,1′-Bis(diphenylphospino)ferrocene palladium(II)dichloride dichloromethane complex (5 mg, 0.006 mmol) was added to a solution of 1-(1-{[5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg, 0.097 mmol), phenyl boronic acid (14 mg, 0.117 mmol), and potassium phosphate (45 mg, 0.214 mmol), in DME (2 mL) and heated to 85° C. After 24 h, water was added and the mixture was extracted with ethyl acetate (3×). The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [99%-85% dichloromethane/methanol] gave the title compound (25 mg). MS 512.1861 (M+1).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4]1.O.[C:11]([C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[CH:14]=1)#[N:12]>CN1CCCC1=O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]#[N:12])[CH:18]=[C:17]([O:9][CH2:8][C:5]2[CH:6]=[CH:7][S:3][CH:4]=2)[N:16]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(Cl)nc(OCc2ccsc2)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.24 g (ca.60% in mineral oil), 0.006×1.0 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, and 3-thiophenemethanol (0.69 g, 0.006×1.0 mol) was added thereto and the resultant solution was stirred for about 30 minutes at room temperature. The resultant mixture was cooled to 4° C. with iced water, then 4-cyano-2,6-dichloropyridine (1.04 g, 0.006 mol) was added thereto and stirred for about 1.5 hour while cooling with iced water.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH:13]=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][O:3]1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CCc1ccc2c(=O)occc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(=O)occc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1-oxo-1H-isochromen-6-yl) acetaldehyde (240 mg, 1.275 mmol) and tert-butyl piperazine-1-carboxylate (238 mg, 1.275 mmol) were dissolved in dichloroethane (10 mL) and added sodium triacetoxyborohydride (811 mg, 3.83 mmol) then stirred at RT for 16 hrs. LC-MS showed product peak. The reaction was washed with NaHCO3, brine, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed through a 80 g. ISCO Redi-Sep column and eluted with 0-100% ethyl acetate/hexane to yield tert-butyl 4-[2-(1-oxo-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate. 1H-NMR (500 MHz, CDCl3) δ ppm 8.25 (d, J=8 Hz, 1H), 7.42 (d, J=9.4 Hz, 2H), 6.49 (d, J=5.7 Hz, 1H), 3.49 (s, 4H), 2.96 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.3 Hz, 2H), 2.51 (s, 4H), 1.50 (s, 9H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:49].O>O1CCCC1>[Si:3]([O:10][C@H:11]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:34])[N:25]([CH3:49])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)[N:13]1[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1ccccn1)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
NaH (8.38 mg of a 60 wt % dispersion in mineral oil, 0.210 mmol) was added to a stirred, room temperature mixture of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-{[2-(pyridine-2-yl)ethyl]carbamoyl}benzyl)pyrrolidine-1-carboxylate (120 mg, 0.191 mmol) in tetrahydrofuran (1.9 mL), and the mixture was stirred for 30 minutes. After 30 minutes, iodomethane (0.014 mL, 0.23 mmol) was added and the mixture was stirred for 12 hours. Water was then added and the mixture was partitioned with EtOAc. The aqueous extracts were extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product as an orange oil that was used directly in the next step. LC-MS=644.3 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1)([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:54][C:53]4[CH:55]=[CH:56][C:50]([CH:47]([CH3:49])[CH3:48])=[CH:51][CH:52]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C(C)C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-isopropylaniline (Aldrich) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:14]=[CH:13][CH2:12][O:11]1)([O-])=O.[N+](C1C=CC=CC=1C1CC=CO1)([O-])=O.CCN(CC)CC>[Pd].CO>[O:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1C1C=CCO1
Agent: [Pd]
Agent: O=[N+]([O-])c1ccccc1C1CC=CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1ccccc1C1CCCO1
Yield: 84 %

Procedure:
5% Palladium on carbon (16.3 g, 50% wet, 3.83 mmol, Aldrich 330116) was placed in a Parr bottle under nitrogen, followed by MeOH (100 mL, JT-Baker 909333). The crude mixture of 2-(2-nitrophenyl)-2,5-dihydrofuran and 2-(2-nitrophenyl)-2,3-dihydrofuran (3a & 3b) (163 g) dissolved in MeOH (389 mL) was added to the Parr bottle, followed by NEt3 (237.6 mL, 1.705 mol, Sigma-Aldrich 471283). The bottle was placed on a Parr shaker and saturated with H2. 30 psi H2 was added and the bottle was shaken until starting material was completely consumed (LCMS and NMR showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving a brown oil. The reaction was repeated three more times on the same scale and the batches were combined for purification. The crude product was vacuum distilled (ca. 15 torr) collecting the distillate at 108-129° C. to give (4) as a clear faint yellow oil (427.9 g, average yield was 84%; 98% GCMS purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 163.95 (1.46 min). 1H NMR (300 MHz, CDCl3) δ 7.15-7.04 (m, 2H), 6.77-6.62 (m, 2H), 4.85-4.77 (m, 1H), 4.18 (s, 2H), 4.12-4.02 (m, 1H), 3.94-3.85 (m, 1H), 2.25-1.95 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([N:24]2[CH2:25][CH2:26][N:27]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:23]2=[O:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)cc3F)ccn2)cn1
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A 0° C. mixture of 3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.528 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with DCM, sonicated and allowed to evaporate overnight. The residue was treated with Et2O, sonicated and the resulting solid collected via filtration to afford N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (154 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 7.95 (s, 1 H), 7.74 (dd, J=12.9, 2.2 Hz, 1 H), 7.36-7.28 (m, 2 H), 7.22 (d, J=2.5 Hz, 1 H), 6.62 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.82 (m, 6 H), 3.79 (m, 2 H), 3.45 (m, 2 H), 3.37 (m, 2 H), 1.72 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 481.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
tert-Butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 1.24 mmol) was dissolved in CH2Cl2 (15 mL) followed by the addition of TFA (8 mL). The reaction was stirred for 1.5 h, and the solvents were evaporated to an oily liquid which was diluted with CH2Cl2 and neutralized with a 1 M aqueous NaOH solution. The organic layer was separated, and the aqueous layer was washed two times with CH2Cl2. After drying the combined organic phases over MgSO4, they were filtered, and concentrated to afford 2-(4-((R)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as a solid (0.354 g, 85%). LC/MS: m/z 335.7 (M+H)+ at 1.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).