Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([F:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 31.5 %

Procedure:
The title compound was prepared from 2-bromo-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.08 mmol), cyclohexene, (0.27 mL, 3.58 mmol), and 1.0 M boron tribromide in dichloromethane (6.49 mL, 6.49 mmol) according to the procedure and in the same manner as described in Example 4, step b. The crude product was purified by re-crystallization from dichloromethane to yield 4-[(2-bromo-6-methylphenanthridin-5(6H)-yl)sulfonyl]-2-fluorophenol (0.15 g, 0.34 mmol, 31%) as an off-white solid, m.p. 203-206° C.;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[O:14])=[CH:2]1
Reactant: Cc1cc(N)no1
Reactant: O=C(O)CSc1c[nH]c2ccccc12
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)CSc2c[nH]c3ccccc23)no1
Yield: 71 %

Procedure:
2-((1H-indol-3-yl)thio)acetic acid (650 mg, 3.14 mmol) from Step B, 3-amino-5-methyl-isoxazole (616 mg, 6.28 mmol), PyClu (2.00 g, 6.28 mmol), and DIEA (1.36 mL, 7.85 mmol) were added to dichloroethane (25 mL) and microwave irradiated at 110° C. for 20 minutes. The solvent was removed in vacuo and the remaining residue purified on a silica gel column (0-70% ethyl acetate:hexanes over 33 min) to yield the desired product (642 mg, 2.23 mmol, 71% yield). LCMS>99% at 214 nm, RT=1.23 min, m/z=288 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13].OC1C2C(=CC=CC=2)[NH:26]C1=O.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.S(Cl)(Cl)(=O)=O>>[NH2:26][C:5]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[CH:3]=2)[N:7]([S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[C:6]1=[O:12].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13]
Reactant: O=C1Nc2ccccc2C1O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(Cl)cc21
Solvent: O=S(=O)(Cl)Cl
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccccc2)c2cc(F)c(Cl)cc21

Procedure:
The title compound was prepared in analogy to example 1.1 to 1.3 using 5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one as 3-hydroxy-1,3-dihydroindol-2-one IV and phenylsulfonyl chloride as sulfonyl chloride VII. 5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one was prepared in analogy to example a.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8]O)=[C:5]([Cl:7])[N:6]=1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[N:29]=[C:28]([SH:30])[N:27]=[C:26]([OH:31])[CH:25]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([CH:10]([CH3:12])[CH3:11])[C:4]([CH2:8][S:30][C:28]2[N:27]=[C:26]([OH:31])[CH:25]=[C:24]([CH3:23])[N:29]=2)=[C:5]([Cl:7])[N:6]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)n1c(Cl)nc(Cl)c1CO
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)nc(SCc2c(Cl)nc(Cl)n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methanol was dissolved in chloroform (40 mL), followed by addition of PBr3 (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The mixture was then stirred at room temperature for 2 hours. DMF was removed under vacuum and the crude residue was purified by column chromatography to provide 2-({[2,4-dichloro-1-(propan-2-yl)-1H-imidazol-5-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (700 mg, 21% overall yield); 1H NMR (400 MHz, CD3OD): δ 1.59 (d, 6H), 2.24 (s, 3H), 4.56 (s, 2H), 4.59 (m, 1H), 6.03 (bs, 1H); M+333.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[CH3:6].[OH:31][CH2:32][C:33]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C1CCCCC1>ClCCl>[C:46]1([C:33]2([CH2:32][O:31][CH:5]([C:7]3[CH:8]=[C:9]([C:24]([F:26])([F:27])[F:25])[CH:10]=[C:11]4[C:15]=3[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=[CH:12]4)[CH3:6])[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (290 mg, 0.576 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (184 mg, 0.633 mmol) in dichloromethane (2 mL) at 0° C. was added cyclohexane (2 ml) and fluoroboric acid diethyl ether complex (0.016 ml, 0.115 mmol). The reaction was stirred at 0° C. for 45 min and was judged complete by TLC. The reaction was quenched with aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 12% to 100%. The product (173 mg, 0.273 mmol, 47.5% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.77 (m, 1H), 7.39 (m, 1H), 7.14-7.29 (m, 5H), 7.07 (m, 1H), 6.54 (m, 1H), 5.15 (m, 1H), 3.32 (m, 2H), 3.21 (m, 2H), 3.00 m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.75 (m, 2H), −0.09 (s, 9H); LC/MS (HPLC method 4): tR=4.36 min, 655.20(MNa)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:12])[CH2:9][CH2:10][S:11][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl.O>[Br:18][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[S:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(C)c2c1SCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of 4.07 g (0.021 mol) of the title compound of Step B in 25 mL of methylene chloride was added dropwise to a mixture of 7.07 g (0.053 mol) of aluminum chloride (purchased from Aldrich Chemical Company) and 25 mL of methylene chloride. The suspension was stirred for approximately 15 minutes, 1.14 mL (0.022 mol) of bromine (purchased from Janssen) was added dropwise and the mixture was refluxed for 10 minutes. The hot mixture was poured into 10 mL of concentrated hydrochloric acid containing 75 g of ice, stirred for 10 minutes, diluted with 50 mL of water, and extracted with diethyl ether (2×200 mL). The organic layer was washed with water (2×200 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude product was chromatographed over silica gel eluting with ethyl acetate:hexane (5% 95%) to yield 2.62 g of the title compound of Step C as a solid melting at 87-88° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.6 (s,3H), 3.0 (m,2H), 3.2 (m,2H), 7.45 (s,1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>C1COCC1.N>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (3.63 mmol, 1.00 g) in dry THF (40 mL) at 0° C. was added trichloroacetylisocyanate (4.72 mmol, 0.889 mg; 563 μL) dropwise over 5 minutes. The resulting solution was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. The reaction was diluted with NH3 saturated CH3CN solution (40 mL) and stirred at room temperature over the weekend. The volatiles were removed in vacuo and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (1×100 mL), the combined organics washed with water (1×100 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2 :EtOAc) to afford the title compound as a white solid, mp=149°-150° C. (0.800 g, 70%).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl.C(O)(C)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloride acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 91.9 %

Procedure:
Piperazine (0.06 g, 0.74 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.15 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and filtered to give 0.17 g of the title compound as a solid, mp 206-208° C.
Reaction SMILES: [I:1]I.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:4].C(=O)(O)[O-].[Na+]>O.C(O)C>[I:1][C:19]1[N:18]=[CH:17][N:16]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: O=C(O)CCCCCc1cccc2cncn12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCc1cccc2c(I)ncn12
Reaction time: 0.75 h

Procedure:
Iodine crystals (1.9 g) are added to a well-stirred solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine and 1.68 g of sodium bicarbonate in 10 ml of water and 1 ml of ethanol. Additional 4 ml of ethanol are added to dissolve the bulk of the iodine and stirring is continued for 45 minutes. The reaction mixture is diluted with 125 ml of water and extracted twice with methylene chloride at pH 8 (NaHCO3 added if necessary). The aqueous phase is concentrated in vacuo, charcoaled and adjusted to pH 4.5 with 2 N HCl. The precipitate is collected, dried and recrystallized from methanol/ether to give 1-iodo-5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 163°-165°.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:10]1([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[C:20]3[CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC[C@@H]1Cc1cn(C(=O)c2ccccc2)c2ccc(OC3CCCCC3)cc12
Reaction time: 15 h
Yield: 20.1 %

Procedure:
Benzoyl chloride (0.10 mL, 0.86 mmol) was added to a solution of (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3g, ~75 mg, 0.24 mmol), triethylamine (0.20 mL, 1.4 mmol) and DMAP (23 mg, 0.19 mmol) in dichloromethane (2.5 mL). The mixture was stirred for 15 h. prior to quenching with water (25 mL) and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform (1.5-3.3%) yielded (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-benzoylindole (20.1 mg, 20%, HRMS-FAB+ for C27H32N2O2 : calculated MH+ :417.25421; found MH+ :417.25475).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(N(C)C)=O>[O:30]=[C:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C(CBr)CCc1ccccc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CCc1ccccc1)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.863 g, 1 eq.) was suspended in dimethylacetamide (DMA) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (360 mg, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 1-bromo-4-phenylbutan-2-one (1.1 g, 1.2 eq.) was added. The reaction was stirred at room temperature for 2 hours. The reaction was poured onto 100 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g) was used without purification. LCMS: 358 [M+H].
Reaction SMILES: N[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[C:3]=1[C:30]#[N:31].N(OCCC(C)C)=O.[ClH:40]>C(#N)C.[Cu](Cl)Cl>[Cl:40][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[C:3]=1[C:30]#[N:31]
Reactant: Cl
Reactant: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(F)c(F)c3)c2C#N)ccn1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccc(F)c(F)c3)c2C#N)ccn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Under argon, 0.86 g (1.97 mmol) of 4-({[6-amino-3,5-dicyano-4-(3,4-difluorophenyl)pyridin-2-yl]sulfanyl}methyl)-N-methylpyridine-2-carboxamide (Example 4), 0.46 g (3.93 mmol) of isopentyl nitrite and 0.53 g (3.93 mmol) of copper(II) chloride were initially charged in 20 ml of acetonitrile and the mixture was stirred at 65° C. overnight. After a reaction time of 3 h, another 0.23 g (1.97 mmol) of isopentyl nitrite and 0.26 g (1.97 mmol) of copper(II) chloride were added to the reaction mixture. After cooling to RT, 3.93 ml of 1N hydrochloric acid were added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxolan-4-one (15 g; 55 mmol) is dissolved in 50 ml of methanol. 4-(2-Aminoethyl)-2-methoxyphenol hydrochloride (14 g; 69 mmol) and triethylamine (7 g; 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. The remaining 2-(4-bromophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide is purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4) tR=4.18 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H) 2.58 (t, J=5.87 Hz, 1H) 3.39-3.47 (m, 4H) 3.69 (t, J=8.60 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33 (m, J=8.40, 2.50 Hz, 3H) 7.71 (dd, J=7.82, 2.35 Hz, 1H) 7.81-7.86 (m, 2H) 7.95 (d, J=2.35 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 1c (2 g, 4.12 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 94%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].Cl[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][N:7]2[C:8]3[C:3](=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[N:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCCl
Reactant: Cc1cc(C)c2ccc(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ccc(=O)n(CCN3C(=O)c4ccccc4C3=O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5,7-dimethyl-1,8-naphthyridin-2(1H)-one (3.5 g., 0.02 mole) in 25 ml. of dry dimethyl formamide under nitrogen atmosphere is added a 57% suspension of sodium hydride in mineral oil (0.84 g., 0.02 mole). This mixture is stirred at room temperature for 1/2 hour. A mixture of N-(2-chloroethyl) phthalimide (4.6 g., 0.022 mole) in 25 ml. of dry dimethylformamide is added to the first suspension. The mixture is stirred at steam bath temperature for 16 hours. On cooling, it is filtered to remove salt and the filtrate evaporated to dryness in vacuo to afford 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:12]([C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:30][NH2:31]>CO>[OH:29][C:26]1[CH:27]=[CH:28][C:23](/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])=[CH:6][CH:7]=2)=[C:12](/[C:15]2[CH:20]=[CH:19][N:18]([CH3:21])[C:17](=[O:22])[CH:16]=2)\[CH2:13][CH3:14])=[CH:24][CH:25]=1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccn(C)c(=O)c1
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccn(C)c(=O)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-1-(4-hydroxyphenyl)-but-1-en-2-yl)-1-methylpyridin-2(1H)-one (30 mg, 1.0 eq) in 10 mL MeOH was added 5 mL 30% CH3NH2 (aq), and the mixture was then heated at 85° C. for 36 h. Then the solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (3 mg, Z-isomer), E-isomer (2 mg), and Z/E mixture (230 mg, 49% yield) as well. 1H NMR (400 MHz, CDCl3) δ 6.96-6.98 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 6.47 (d, J=2.0 Hz, 1H), 5.78 (dd, J=6.8 Hz, 2.0 Hz, 1H), 3.98 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 2.96 (t, J=5.2 Hz, 2H), 2.52 (s, 3H), 2.36-2.38 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); m/z=405[M+1]+.