Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CN1C(=O)CCC1.CS(O)(=O)=O>C(O)(C)C.O>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:18][C:6]=2[CH:7]=1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2s1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2s1
Temperature: 65 °C
Yield: 86.6 %

Procedure:
The product from Example 165E (0.4 g), 4-cyanophenylboronic acid(0.45 g, 2.5 eq), triphenylphosphine (65 mg, 0.2 eq), and bistriphenylphosphine palladium dichloride (87 mg, 0.1 eq) in isopropanol (8 mL) was treated with potassium phosphate (0.52 g, 2 eq) in 8 mL of water. The mixture was heated at 65° C. under nitrogen for 25 hours, allowed to cool to room temperature, and treated with H2O:NMP:MeSO3H (70:20:10, 10 mL). The mixture was extracted with toluene (2×10 mL) and the acidic aqueous phase was basified to pH 10 using 50% NaOH. The basified solution was extracted with methylene chloride (10 mL), washed with water (2×10 mL), and concentrated to a brown oil. The brown oil was dissolved in EtOAc (20 mL), washed with water (2×10 mL), and concentrated. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound (0.37 g). MS m/z 347(M+H)+. The free base was dissolved in 5 mL of MeOH and added to L-tartaric acid (0.16 g, 1 eq) in 5 mL of MeOH. The mixture was concentrated to dryness, and crystallized from EtOAc/EtOH to give the tartrate salt (0.33 g). 1H NMR(DMSO-d6) δ 1.17 (doublet), 1.41-1.49(multiplet), 1.74-1.82(multiplet), 1.97-2.03(multiplet), 2.55-2.59(multiplet), 2.80 (multiplet), 3.12-3.37(multiplet), 4.11(singlet), 7.33 (singlet), 7.66 (doublet), 7.93(singlet), 8.02(doublet), 8.13(doublet).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][NH:6][CH:7]=1)=[O:2].F[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:19]1[C:14]([N:6]2[CH:7]=[C:3]([CH:1]=[O:2])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1n[nH]cc1C=O
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1C=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
A mixture of ethyl 4-formyl-1H-pyrazole-3-carboxylate (1.6 g, 9.52 mmol), 2,3-difluorpyridine (1.20 g) and potassium carbonate (1.97 g) in dimethylformamide (8 mL) is heated and stirred at 100° C. for 1.5 h. Then, the reaction mixture is stirred at room temperature overnight. Water is added, and the organic phase is extracted with ethyl acetate, decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. Crude is purified by normal phase Isco chromatography using ethyl acetate and hexane to give 711 mg of the title compound. MS (m/z): 264 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].CN(C)[CH:14]=[O:15]>C1COCC1.BrCCBr>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1)[CH:14]=[O:15]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
3,5-Dichloroanisole (74.0 g, 419 mmol) in THF (200 mL) was added dropwise to magnesium metal (14.2 g, 585 mmol, pre-washed with 0.5 N HCl) in THF (100 mL) at 25° C. After the addition, 1,2-dibromoethane (3.9 g, 20.8 mmol) was added dropwise. The resultant dark brown mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., and N,N-dimethylformamide (60 mL) was added in one portion. The mixture was partitioned with diethyl ether (3×400 mL) and 6N HCl (500 mL). The combined organic extracts were washed with brine (300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography (2×) on silica get eluting with Hex:EtOAc (4:1) afforded the sub-title compound (38.9 g, 54%) as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9]1([CH3:21])[C:17]([O:19][CH3:20])=[O:18])(OC(C)(C)C)=O.[ClH:22]>>[ClH:22].[CH3:21][C:9]1([C:17]([O:19][CH3:20])=[O:18])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: COC(=O)C1(C)C2CCCCC2CN1C(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)C1(C)NCC2CCCCC21

Procedure:
N-BOC-1-methyl-octahydroisoindole-1-carboxylic acid, methyl ester was treated with HCl according to the procedure described in Example 1, Step A to afford 1-methyl-octahydroisoindole-1-carboxylic acid, methyl ester hydrochloride which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=1.[CH3:22]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:22])[CH:5]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COC(=O)c1cc(OCCCO)cc(N2CCCC2=O)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 3 h
Yield: 57.5 %

Procedure:
3-(3-Hydroxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B15) (127 mg, 0.43 mmol, 1 equiv) in CH2Cl2 (2 ml) was treated with proton sponge (279 mg, 1.30 mmol, 3 equiv) and trimethyloxonium tetrafluoroborate (192 mg, 1.30 mmol, 3 equiv). After 3 hrs, further quantities of proton sponge (93 mg, 0.43 mmol, 1 equiv) and trimethyloxonium tetrafluoroborate (65 mg, 0.43 mmol, 1 equiv) were added and stirring was continued for a further 2 h. The mixture was then partitioned between AcOEt and 2N aqueous HCl solution. The two layers were separated and the aqueous phase extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaHCO3 solution, 2N aqueous HCl solution and brine and then dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/iso-hexane: 1/4 to 1/3) gave 3-(3-methoxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B17) (76 mg, 58%). [M+H]+=308.1
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:26])[C:14]2[C:19]([NH:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:26][N:13]([CH:10]1[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1)[C:14]1[C:19]([NH:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH3:23])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCC(C)(C)Nc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCC(C)(C)Nc1cccnc1N(C)C1CCNCC1
Reaction time: 1.5 h

Procedure:
To a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[N-methyl-N-(3-(1,1-dimethylpropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 63, 2.39 g) in dry methylene chloride (30 ml) under nitrogen at 0° is added trifluoroacetic acid (6.37 ml) over 1 min. The resulting mixture is warmed to 20°-25°, stirred for 1.5 hrs, and then added to a mixture of sodium hydroxide (3.31 g) in water (40 ml) at 0°. The layers are separated, the aqueous phase is extracted with methylene chloride (4×40 ml), and the combined organic phases are washed with saline (40 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 7.66, 7.02, 6.84, 4.86, 3.39, 3.13, 2.63, 1.81-1.52, 1.31 and 0.87δ.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: CCCN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])O
Product: CCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
N-propylphthalimide (50 g) was nitrated in 500 g 99% nitric acid to produce 4-nitro-N-propylph thalimide under conditions described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19]C(OC(C)(C)C)=O)[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[CH:40]=[N:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:19][C@@H:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[C:4]([O:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:40]=[N:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=3)[C:29]([F:32])([F:30])[F:31])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:13][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccccc3-c3ccc(C#N)nc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
80 mg of (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid was dissolved in the solution of 30% trifluoro acetic acid in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by preparative HPLC to give 12.6 mg of (S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano-pyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 8.86(s, 1H), 8.17(d, J=2 Hz, 1H), 8.15(d, J=2 Hz, 1H), 7.96(m,2H), 7.59(m,1H), 7.36(m, 3H), 6.7(s, 1H), 6.65(d, J=6.8 Hz, 1H), 4.25(m, 1H), 3.47(m, 1H), 3.23(m, 1H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]=2[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([NH2:53])[CH:45]=[C:46]2[C:50]=1[C:49]([CH3:52])([CH3:51])[CH2:48][CH2:47]2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:41][C:42]1[CH:43]=[C:44]([NH:53][C:38]([CH:27]2[N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]2=3)=[O:40])[CH:45]=[C:46]2[C:50]=1[C:49]([CH3:51])([CH3:52])[CH2:48][CH2:47]2
Reactant: CC1(C)CCc2cc(N)cc(F)c21
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 65 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
T3P (4.89 mL, 8.22 mmol) was added to a solution of 6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylic acid (1.69 g, 5.48 mmol), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.982 g, 5.48 mmol), DIEA (4.77 mL, 27.41 mmol) and DMAP (0.737 g, 6.03 mmol) in ethyl acetate (40 mL) at room temperature. The mixture was stirred at 65° C. for 15 hr, the reaction mixture was poured into water (150 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained precipitate was washed with hexane to give tert-butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.09 g, 4.45 mmol, 81%) as an off-white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:29])[C:24]=2[O:25][CH2:26][O:27][CH3:28])=[CH:21][CH:20]=[C:19]([O:30][CH2:31][O:32][CH3:33])[CH:18]=3)=[CH:11][C:10]=1[O:34][CH2:35][O:36][CH3:37])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:29])[C:24]=2[O:25][CH2:26][O:27][CH3:28])=[CH:21][CH:20]=[C:19]([O:30][CH2:31][O:32][CH3:33])[CH:18]=3)=[CH:11][C:10]=1[O:34][CH2:35][O:36][CH3:37]
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(O)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (55 mg, 0.108 mmol) in 10 mL MeOH was added Palladium on activated carbon (20 mg). The mixture was stirred at rt under H2 atmosphere for 2 h. Solid was filtered off and the filtrate was concentrated to afford 2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one as a yellow solid (45 mg, 99%). This material was used directly for the next reaction without purification. MS (ESI) m/z 419 (M+H+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1C(Cl)=O.Cl>C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][C:23]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 40 °C

Procedure:
Potassium ethyl malonate (10.2 g, 60 mmol), MgCl2(6.3 g, 66 mmol), and triethylamnine (28 ml, 200 mmol) were suspended in dry ethyl acetate (200 ml) and heated to 40° C. for 15 hr. A solution of 2-fluoro-5-trifluoromethylbenzoyl chloride (10 g, 44.1 mmol) in ethyl acetate (40 ml) was dropped in slowly (in about one hour). After another hour, the mixture was treated with 2N HCl (200 ml). The organic layer was washed with 0.5 N HCl 2×, 5% K2CO3 2×, brine 2×, and dried over Na2SO4. Evaporation of the solvent and vacuum drying afforded ethyl 3-[2-fluoro-5-(trifluoromethyl)phenyl]-3-oxopropanoate as a pale yellow oil. NMR (500 MHz, CDCl3) δ: 1.25 (t, J=7.4 Hz, 3H); 1.32*; 4.00 (d, JF-H=3 Hz, 2H); 4.21 (q, J=7.4 Hz, 2H); 5.8*; 7.22*; 7.29 (t, J=10.3 Hz, 1H); 7.66*; 7.82 (br, 1H); 8.14*; 8.24 (d, J=6.4 Hz, 1H). Enol form* exists in about 35%.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]S(C)(=O)=O)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][N:29]3[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]3=[O:33])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Reactant: CN1C(=O)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(CC[C@@H]2C[C@H]2c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-{(1R,2S)-2-[2-(methylsulfonyl)ethyl]-cyclopropyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-5, 39 mg, 0.10 mmol, 1.0 equiv) was added to anhydrous DMF (0.50 mL) and cooled to 0° C. 3-Methylimidazolidine-2,4-dione (31-6, 58 mg, 0.51 mmol, 5.0 equiv) and NaH (20 mg, 0.51 mmol, 5.0 equiv, 60% dispersion in oil) were added sequentially and the resulting mixture was warmed to RT. After 18 h, LCMS showed complete consumption of 32-5. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) afforded 32-6 as a colorless oil. MS m/z (M+H): calculated=400.2343; observed=400.2342.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:40]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.9 %

Procedure:
To a solution of Intermediate A (116 mg, 0.714 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol) and the mixture stirred at RT for 20 min. A solution of Intermediate 63b (280 mg, 0.714 mmol) in DMF (3 mL) was added and the mixture was stirred at 60° C. for 25 min, and up to 150° C. over 20 min. The cooled mixture was diluted with water and extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified twice by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (141 mg, 37%). LCMS (Method 3): Rt 3.12 min, m/z 536 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[S:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:9]=2[CH:8]=1)C.Cl>C(O)C.[OH-].[Na+]>[Cl:20][C:19]1[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=3[S:11][C:10]=2[C:18]=1[Cl:21]
Reactant: CCOC(=O)COc1cc2c3c(sc2c(Cl)c1Cl)CCCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2c3c(sc2c(Cl)c1Cl)CCCC3
Yield: 81.7 %

Procedure:
A suspension of 3.2 g of ethyl[ (3,4-dichloro-6,7,8,9-tetrahydro dibenzothien-2-yl)oxy]acetate in 30 ml of 95% ethanol and 300 ml of 20% sodium hydroxide solution is stirred at reflux for 2 hours. The mixture is cooled, acidified with conc. hydrochloric acid and the resultant suspension is stirred in the cold for 30 minutes before filtration. The air dried product is recrystallized from 70 or 95% ethanol to give 2.41 g of [(3,4-dichloro-6,7,8,9-tetrahydodibenzothien-2-yl)oxy]acetic acid as fine needles, mp 257°-259°.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:31][S:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>C(O)CCC.C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][S:32][CH3:31])[CH:35]=2)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSCc1cccc(N)c1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCO
Product: CSCc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.34 mL; 1.35 mmol) was added to a stirred solution of 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (450 mg; 1.35 mmol) and 3-[(methylsulfanyl)methyl]aniline (311 mg; 2.03 mmol) in 1-butanol (3.00 mL). The batch was stirred at 140° C. for 16 hours. After cooling the batch was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (167 mg; 0.37 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:24])=[CH:18][C:19]([NH:23][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[CH:20][C:21]=1[CH3:22]
Reactant: COc1cc2nccc(Oc3c(C)cc(N)cc3C)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3c(C)cc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=180-182° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.65 (s, 1H), 8.41 (d, 1H, J=5 Hz), 7.60 (s, 1H), 7.58 (s, 2H), 7.45-7.33 (m, 5H), 6.19 (d, 1H, J=7 Hz), 4.18 (p, 1H, J=7 Hz), 3.95 (d, 6H, J=6 Hz), 2.05 (s, 6H), 1.45 (d, 6H, J=7 Hz).
Reaction SMILES: Cl.[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH2:13])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C:7]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:6]1=2)(=[O:4])[CH3:3].[C:34]([N:41]([CH3:47])[C@H:42]([C:44](O)=[O:45])[CH3:43])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH:13][C:44](=[O:45])[C@@H:42]([N:41]([CH3:47])[C:34](=[O:35])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[CH3:43])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C:7]2[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:6]1=2)(=[O:4])[CH3:3]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a 0° C. solution of (3S,4S)-5-acetyl-3-amino-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (216 mg, 465 μmol) in DMF (1.55 ml) was added Boc-N-methyl-L-alanine (104 mg, 511 μmol), N,N-diisopropylethylamine (322 μl, 1.86 mmol), and HBTU (194 mg, 511 μmol). The reaction was stirred at rt for 30 min, then diluted with H2O and the solids were collected by vacuum filtration, taken up in EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (255 mg, 89%) as a white solid. MS m/z 636 (MNa)+.