Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(Cl)Cl>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:27]([F:26])([F:37])[F:38])[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.100 g, 0.275 mmol), 2-(trifluoromethyl)benzoyl chloride (0.049 ml, 0.330 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (0.600 g, 1.376 mmol) in DCM (2 ml) was stirred at rt for 17 h. The mixture was filtered, evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (0.053 g, 36%). 1H NMR (500 MHz CDCl3): δ 7.68 (t, 1H), 7.61-7.42 (m, 6 h), 7.26 (d, 1H), 7.18 (d, 1H), 5.21 (d, 1H), 4.61-4.46 (m, 1 h), 3.24-3.10 (m, 2H), 2.54-2.38 (m, 2H), 1.88-1.78 (m, 1H), 1.76-1.48 (10H), 1.44-1.32 (m, 1H), 1.26-1.10 (m, 1H); 13C NMR (125 MHz CDCl3): δ 167.4, 167.3, 159.8, 159.7, 134.8, 133.9, 133.8, 132.5, 132.3, 131.9, 131.7, 130.4, 130.2, 129.5, 129.0, 128.9, 127.3, 127.0, 126.9, 125.3, 125.1, 107.8, 107.5, 61.9, 50.3, 50.1, 45.7, 45.5, 41.2, 40.3, 40.1, 32.5, 32.1, 31.9, 31.8, 27.8; Mass Spectrum: M−H+ 534
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25]1.CO>CCO>[CH:24]1([CH2:28][NH:29][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CCC1
Solvent: CCO
Solvent: CO
Product: O=C(c1ccc(NCC2CCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (237 mg, 0.680 mmol) and cyclobutylmethyl amine (0.205 mL of a 4M/MeOH solution, 0.816 mmol) in 3 mL of EtOH containing TEA (0.140 mL, 1.02 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 262 mg (93%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.83 (m, 2H), 1.97 (m, 1H), 2.02 (m, 1H), 2.20 (m, 2H), 2.73 (m, 1H), 3.37 (m, 2H), 4.27 (m, 4H), 6.93 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.79 Hz, 1H), 8.24 (m, 1H), 8.30 (m, 1H); MS (ESI) 413.95 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH:15]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH2:16]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:31]1[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=[C:30]1[CH3:29])=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C)c2n1
Temperature: 150 °C
Yield: 74.6 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine (112 mg, 0.28 mmol), 2-methylbenzimidazole (44 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.01 mmol), Xphos (26 mg, 0.06 mmol) and Cs2CO3 (179 mg, 0.55 mmol) in dioxane (3 mL) was purged with argon then heated at 150° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 467 as a cream solid (105 mg, 75%). LCMS (Method I): RT 2.46 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.67 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.97 (dd, J=11.4, 4.1 Hz, 2 H); 3.89-3.82 (m, 9 H); 3.54 (m, 2 H); 3.37 (td, J=11.4, 2.0 Hz, 2 H); 3.06 (m, 2 H); 2.94 (s, 3 H); 2.38-2.27 (m, 1 H); 1.54 (m, 2 H) and 1.32-1.14 (m, 3 H)
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[N:24]1[NH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:27][CH:28]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(#N)C.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>[Cl:1][C:2]1[C:3]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[NH:25][N:24]=[CH:28][CH:27]=3)=[CH:34][CH:33]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1
Reactant: OB(O)c1ccc(-c2ccn[nH]2)cc1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
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: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)c(Cl)cc21
Temperature: 130 °C

Procedure:
A 5 mL Biotage™ microwave vial was charged with 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 73.2 mg, 0.150 mmol), 4-(2H-pyrazol-3-yl)-phenylboronic acid (33.9 mg, 0.180 mmol) and Pd(PPh3)4 (8.7 mg, 5 mol %) followed by dioxane (1.5 mL) and 1M aqueous K2CO3 (180 uL). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 130° C. for 10 min. The suspension was then diluted with EtOAc (5 mL) and washed with 1M aqueous K2CO3 (twice, 1 mL) and water (twice, 1 mL). The organic layer was evaporated to dryness in vacuo to give yellow oil. The oil was dissolved in ACN and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The solvent was evaporated to dryness in vacuo to give the crude product as pale yellow solid. LR-MS (API-ES): calculated for C23H27ClN4O3SSi 502.1, observed m/e 503.0 (M+H)+ (Rt 3.30 min).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=CC=C[CH:15]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.CC(O)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C1COCC1>[CH:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])([CH3:19])[CH3:15]
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
Under an atmosphere of nitrogen a mixture of 4-hydroxy-3-(trifluoromethyl)benzonitrile (5.89 g, 31.5 mmol) and triphenylphosphine (13.21 g, 50.4 mmol) in anhydrous THF (200 mL) was stirred for 5 min. at ambient temperature. To the solution DBAD (11.60 g, 50.4 mmol) was added, stirred 5 min before the addition of 2-propanol (3.03 mL, 39.3 mmol). The mixture was stirred at ambient temperature for 72 hr. The solvent was removed under reduced pressure. The resulting oil was triturated with 30-60° C. pet/ether (200 mL), filtered to remove phosphine oxide and the crude product was purified further by elution through silica with heptane/ethyl acetate (4:1). The isolated oil was dissolved in dichloromethane (200 mL) and stirred with TFA (4.85 mL, 63.0 mmol) for 90 min. at ambient temperature. The solution was basified with 2.5N NaOH (30 mL) and the product was partitioned between DCM and the basic aqueous phase to give the crude 4-isopropoxy-3-(trifluoromethyl)benzonitrile (6.56, 91%). LCMS (Table 1, Method a) Rt=2.32 min, 1H NMR (400 MHz, CDCl3) 7.85 (d, 1H), 7.75 (dd, 1H), 7.06 (d, 1H), 4.73 (m, 1H), 1.41 (dd, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=O.[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][C:17]([C:31]([F:32])([F:34])[F:33])([OH:35])[CH2:16][NH:15][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([CH2:3][OH:2])=[N:6]3)=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)cc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 200 mg (0.39 mmol) of 5-[4-(4-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid methyl ester is dissolved in 5.0 ml of methanol and mixed with 60 mg (1.56 mmol) of sodium borohydride. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 70 mg (37% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH:14]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24])([CH2:16][CH3:17])[CH3:15].C(N(CC)CC)C>O1CCCC1.O>[CH:14]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:11]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8])=[O:12])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)[C@@H]1CCCC[C@H]1N
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)[C@@H]1CCCC[C@H]1NC(=O)c1sc(C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
At 0° C., 3.4 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic chloride is dripped into a solution of 2.3 g of trans-2-sec.-butylcyclohexylamine and 1.5 g of triethylamine in 15 ml of tetrahydrofuran, and the mixture is stirred for 2 hours at 25° C. The batch is diluted with 300 ml of water, extracted twice with tert-butyl methyl ether and dried, the solvent is evaporated off, and the residue is made into a paste with a small amount of pentane. There is isolated 2.3 g of 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid-trans-2-sec-butylcyclohexylamide of m.p. 112°-113° C.
Reaction SMILES: [CH:1]1([CH2:7]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:16]2[CH:20]=[C:19]([CH2:21][O-:22])[N:18]=[CH:17]2)C=CC=CC=1.[Na+]>>[NH:16]1[CH:20]=[C:19]([CH2:21][O:22][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=[CH:17]1
Reactant: [O-]Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: ClCC1CCCCC1
Agent: [Na+]
Product: c1nc(COCC2CCCCC2)c[nH]1

Procedure:
The preparation is carried out as in Example 36 with cyclohexylmethyl chloride and sodium [1-(triphenylmethyl)imidazol-4-yl]methoxide. The title compound is crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-])=O)[C:4]=1[OH:25].[OH-].[Na+].C(S(O)=O)(N)=N.Cl>O.C(O)C>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]3=[N:22]2)[C:4]=1[OH:25]
Reactant: Cc1cc(CO)c(O)c(N=Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 80 °C

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, addition funnel, powder addition funnel, and nitrogen inlet was added 26.0 g (73.2 mmol) 2-(hydroxymethyl)-4-methyl-6-((2-nitro-4-(trifluoromethyl)phenyl)-diazenyl)phenol and 300 ml ethanol. Sodium hydroxide (17.6 g, 441 mmol) was dissolved in 100 ml deionized water and approximately one fourth was added dropwise to the azo mixture. The reaction mixture was heated to 80° C. and 23.9 g (221 mmol) formamidinesulfinic acid and the remaining sodium hydroxide solution were added to the azo mixture over 30 minutes. The reaction mixture was heated at 80° C. for 3 hours, poured in 3 L deionized water, and acidified to pH 4 using 1N HCl. The solid was collected by vacuum filtration, washed with ample amounts of water, and then dried for 20 hours under vacuum (0.1 mm Hg) at 42° C. to give 18.6 g (79%) of an off white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([O:10][CH3:11])=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=[N:6][N:5]2[CH:15]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:11][O:10][C:9]1[C:4]2[N:5]([CH:15]=[C:2]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:12]([NH2:14])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(C(N)=O)cnn2cc(Br)cc12
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: [K+]
Solvent: COCCOC
Product: COc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 92.5 °C
Yield: 80.4 %

Procedure:
Nitrogen was bubbled through a mixture of 6-bromo-4-methoxypyrrolo[1,2-b]pyridazine-3-carboxamide (77 mg, 0.285 mmol), phenyl boronic acid (104 mg, 0.855 mmol), tetrakis(triphenylphosphine)palladium (32.9 mg, 0.029 mmol) and 2M aq. potassium carbonate, (0.570 mL, 1.140 mmol) in DME (0.75 mL) for ˜1 minute. The reaction mixture was then heated to 90-95° C. for 1 hr. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried (MgSO4) and concentrated to afford a yellow solid that was chromatographed on a 12 g silica gel cartridge, eluting with a 0-100% EtOAc/hexanes gradient. The pure fractions were concentrated to a tan solid that was contaminated with a small amount of triphenylphosphine oxide. The material was triturated with ethyl ether to afford the title compound (62 mg, 0.229 mmol, 80% yield) as a tan solid. HPLC (condition M): retention time=2.36 min.; LCMS (ES+) m/z: 268.11 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 4.52 (s, 3 H), 5.73 (s, 1 H), 7.20 (d, J=1.8 Hz, 1 H), 7.27-7.35 (m, 2 H), 7.41-7.47 (m, 2 H), 7.63-7.68 (m, 2 H), 8.10 (d, J=1.8 Hz, 1 H), 8.69 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.[C:23](OCCC)(=[O:26])[C:24]#[CH:25]>C(O)CC>[F:21][C:19]([F:22])([F:20])[C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:25]=[CH:24][C:23](=[O:26])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]=2[CH:15]=1
Reactant: C#CC(=O)OCCC
Reactant: NC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Solvent: CCCO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-trifluromethyl-5-phenyl-3H-1,4-benzodiazepine, propyl propiolate and propanol were refluxed. The mixture was chromatographed to give 9-trifluoromethyl-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:18][C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)CN(CCc1cccc(OCc2ccccc2)c1)C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)CN(CCc1cccc(O)c1)C1CCOC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 0.61 g (1.59 mmol) of 2-[[2-(3-Benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amino]-N,N-dimethyl-acetamide and 60 mg of Pd/C 10% in 10 ml of ethanol was hydrogenated for 2 hours at 40 psi. The catalyst was filtered off and the solvent was removed under vacuum. The crude residue was triturated with diethyl ether and filtered. 0.45 g (96% yield) of a yellow solid were isolated.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH3:10].CCOCC>C1(C)C=CC=CC=1>[N:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc2nccnc2c1

Procedure:
1,2-phenylenediamine (2.3 g) and acetic acid (1 ml) were added to a solution of the compound mentioned above (7.54 g) in toluene (50 ml), and the mixture was heated under reflux for an hour. The solid formed upon addition of ether to the reaction mixture at 0° C. was filtered to give a quinoxaline derivative (1.91 g). The compound was dissolved in tetrahydrofuran (500 ml), and sodium hydride (60%, 1.0 g) and 2-trimethylsilylethoxymethyl chloride (8.6 ml) were added to the solution at room temperature. The mixture was stirred for an hour. Aqueous ammonium chloride was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with water and aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a compound protected by the SEM group.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[CH3:26]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]3[CH:33]=[CH:34][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:30][CH:31]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 151.0 mg (76%) of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CCCON=C(C)C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CCCON=C(C)C
Temperature: 100 °C
Yield: 96.7 %

Procedure:
In a pressure vessel under a nitrogen atmosphere, acetone O-{3-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}oxime (2.50 g, 5.74 mmol), phenylboronic acid (1.05 g, 8.61 mmol), palladium (II) acetate (13 mg, 0.057 mmol), triphenylphosphine (45 mg, 0.17 mmol), and 2 M aqueous sodium carbonate (3.45 mL, 6.89 mmol) were combined in 5:1 n-propanol:water (12 mL). The solution was placed under vacuum and back-filled with nitrogen three times. The pressure vessel was sealed and heated at 100° C. for 2 days, then was allowed to cool to ambient temperature. Chloroform (200 mL) was added and the mixture was washed with water (40 mL) and brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-25% CMA in chloroform) to yield 2.4 g of acetone O-{3-[4-amino-2-(ethoxymethyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}oxime as a yellow powder, mp 134.0-136.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][Cl:18])[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(CCCCl)CC1
Yield: 64.7 %

Procedure:
A mixture of 35.2 g (0.2 mole) of 1-(2-methyl-phenyl)-piperazine, 31.4 g (0.2 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 100 ml of tetrahydrofurane is refluxed for five hours. After cooling it is filtered, the filtrate is concentrated and the residue is fractionally distilled under vacuum. There are obtained 32.7 g of 3-[4-(2-methyl-phenyl)-piperazino]-propyl chloride (65% of theory) of boiling point 138°-140° C/0.1 mm Hg.
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(C2C=CC(O)=CC=2)C=1.Cl.ClCCN1CCCCC1.C[O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67]C)=[CH:63][CH:62]=2)=[C:42]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:46][CH:45]=2)[CH:43]=1>>[OH:67][C:64]1[CH:65]=[CH:66][C:61]([CH2:60][CH2:59][C:41]2[C:42]([C:44]3[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[CH:46][CH:45]=3)=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=2)=[CH:62][CH:63]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2-c2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc(CCc2ccc(O)cc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 41.8 %

Procedure:
Synthesized from 5′-methoxy-2′-[2-(4-methoxyphenyl)ethyl]biphenyl-4-ol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{5′-methoxy-2′-[2-(4-methoxyphenyl)ethyl]biphenyl-4-yloxy}ethyl}piperidine (250 mg) was used according to an analogous synthetic method to Example 779 to provide the title compound (98 mg).