Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2ncnc(Oc3ccc(N)cc3F)c12
Reaction time: 7 h
Yield: 92.1 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.04 g, 10.55 mmol) in anhydrous methanol (60 mL) and anhydrous tetrahydrofuran (40 mL), at ambient temperature under nitrogen atmosphere, was added zinc dust (6.90 g, 105 mmol) and ammonium chloride (5.64 g, 105 mmol). The mixture was stirred for 7 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to a pale yellow solid which was partitioned between chloroform and water. The aqueous layer was then extracted twice with chloroform. The combined chloroform layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (2.51 g, 92%) as a solid. 1H NMR (CDCl3) δ 7.86 (s, 1H), 7.64 (d, 1H, J=2.6 Hz); 7.08–7.03 (m, 1H), 6.61 (d, 1H, J=2.4 Hz), 6.55–6.45 (m, 2H), 3.78 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 259.0995 (M+H)+ calc, 259.0997 (M+H)+ found.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:20]([O:27][CH2:28][CH:29]1[CH2:34][CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([C:32]2[CH2:33][CH2:34][CH:29]([CH2:28][O:27][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:30][CH:31]=2)=[CH:6][N:7]=1
Reactant: CC1(C)OB(C2=CCC(COCc3ccccc3)CC2)OC1(C)C
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(C3=CCC(COCc4ccccc4)CC3)cnc2N)cc1F
Temperature: 115 °C
Yield: 81 %

Procedure:
Methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (343 mg, 1.051 mmol), 2-(4-((benzyloxy)methyl)cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (414 mg, 1.261 mmol) PdCl2(dppf)-CH2Cl2 adduct (86 mg, 0.105 mmol) were placed in a microwave vial and then DME (3.5 mL) was added. Then 2.0 M Na2CO3 (1261 μL, 2.52 mmol) was added and the mixture was degassed and purged with nitrogen and then heated at 115° C. for 30 min upon which the reaction was complete. The reaction mixture was diluted with EtOAc and washed with water and the organic layer was separated and dried (MgSO4), filtered and concentrated and the residue purified by flash chromatography (0-100% EtOAc/heptane) to afford 381 mg the desired product as a yellow solid (81%). LCMS (m/z): 448.2 (MH+), 1.16 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: NC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(N3CCC(Nc4ncccn4)CC3)nc3ccccc32)cc1

Procedure:
A mixture of 1.71 g (0.005 mole) of 1-{1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl}-4-piperidinamine, 0.57 g (0.005 mole) of 2-chloropyrimidine, 0.43 g (0.052 mole) of sodium bicarbonate and 19 ml of ethanol is brought to reflux temperature for 2 days and 2 nights. The mixture is evaporated to dryness, and water and 2N sodium hydroxide are added. The product is taken up with methylene chloride, decanted and washed with water. The product is chromatographed on a silica column (eluent: dichloromethane/methanol, 47:3).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@H:18]([OH:19])[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:35])[CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC[C@@H]2CNCC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CN(C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol (0.117 mmol, 0.06 g) in DCM (1 mL) was added formaldehyde solution (1 mL) followed by sodium triacetoxyborohydride (0.3 g) and continued stirring the reaction mixture for 3 h at room temperature. The reaction mixture was diluted with DCM (10 mL), washed the organic layer with water, dried the organic layer, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with DCM (200 mL) followed 10% methanolic solution of ammonia (2 M solution of NH3 in methanol) in DCM to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol which was treated with 4 N HCl in dioxane. The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and dried under high vacuum to provide the title compound (0.058 g). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.81 (1H, s), 7.47 (2H, d), 7.13 (2H, d), 4.6-4.76 (2H, m), 4.42-4.48 (1H, m), 3.52-3.85 (3H, m), 3.12-3.22 (4H, m), 2.92 (3H, s), 2.21-2.36 (2H, m), 1.84-2.04 (4H, m), 1.23-1.64 (11H, m), 0.82 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[CH:39]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccc(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 63 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (3 mL), 3-fluorophenyl boronicacid (27.132 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) dissolved in 1.06 mL water] was added at room temperature. The reaction mixture was de-gassed with argon by purging for 30 min. Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added and the reaction mixture was further degassed for another 10 min. The reaction mixture was heated for 30 min at 80° C. (while progress of the reaction was monitored by LC-MS). The reaction was filtered and diluted with water (5 mL) and extract with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(5-chloro-3′-fluoro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (383) (65 mg, 63.04%) as an off-white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8](=[O:20])[N:7]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:5]>CO.[Pd]>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8](=[O:20])[N:7]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@@H](CC=Cc2ccccc2)C(=O)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@@H](CCCc2ccccc2)C(=O)N1C(=O)OC(C)(C)C

Procedure:
A solution of the compound obtained from Step A (6.0 g) and Pd/C (10%, 620 mg) in methanol (150 mL) was hydrogenated at 40 psi in a par-shaker for 3.0 h. Pd/C was removed by filtration through a pad of celite. Removal of solvent under reduced pressure gave practically pure product as a viscous oil. 1HNMR (300 MHz, CDCl3) δ 7.29–7.14 (m, 5H), 4.53 (d, J=9.5 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 2.60 (m, 3H), 2.20 (m, 1 H), 1.98 (m, 2H), 1.64 (m, 2H), 1.50 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(F)ccc2C1=O
Yield: 90.2 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 250 mg, 1.5146 mmol) was reacted with 3-iodo-4-methyl-pyridine (365 mg, 1.66 mmol), 1,4-dioxane (10 mL), copper iodide (29 mg, 0.151 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (21.5 mg, 0.151 mmol) and potassium phosphate (965 mg, 4.54 mmol) for 14 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 350 mg of the product (90.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21]
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccc(Cl)c2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 75.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (200 mg, 0.589 mmol), 6-mercaptopurine monohydrate (124 mg, 0.726 mmol), K2CO3 (100 mg, 0.726 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 202 mg of a white solid (75%), mp 211.9-212.7© (decomposes). 1H NMR (DMSO-d6) δ: 13.54 (br s, 1H); 8.47 (s, 1H); 8.44 (s, 1H); 8.12 (d, J=7.9 Hz, 1H); 8.07 (d, J=7.6 Hz, 1H); 7.78 (d, J=7.5 Hz, 1H); 7.67 (d, J=7.1 Hz, 1H); 7.58 (t, J=7.9 Hz, 1H); 7.42-7.54 (m, 2H); 4.52 (s, 2H). 13C NMR (DMSO-d6) ppm: 160.3, 156.9, 153.9, 151.5, 149.7, 143.5, 135.7, 134.0, 132.1, 131.8, 131.4, 131.1, 130.5, 130.3, 128.9, 128.3, 126.1, 122.4, 32.5. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS: C, 52.76; H, 2.66; Cl, 15.57; N, 18.46; S, 7.04. Found: C, 52.65; H, 2.79; Cl, 15.32; N, 18.47; S, 7.18.
Reaction SMILES: Cl.[Cl:2][C:3]([Cl:51])([Cl:50])[C:4]([O:7][C:8]([N:10]1[C@H:15]2[C:16]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]4[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=4[Cl:37])=[CH:23][CH:24]=3)[CH2:18][C@@H:11]1[CH2:12][N:13]([C:43]([O:45]C(C)(C)C)=O)[CH2:14]2)=[O:9])([CH3:6])[CH3:5].[CH3:52]CN(C(C)C)C(C)C.C(Cl)(C)=O>C(Cl)Cl>[Cl:51][C:3]([Cl:50])([Cl:2])[C:4]([O:7][C:8]([N:10]1[C@H:15]2[C:16]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]4[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=4[Cl:37])=[CH:23][CH:24]=3)[CH2:18][C@@H:11]1[CH2:12][N:13]([C:43](=[O:45])[CH3:52])[CH2:14]2)=[O:9])([CH3:6])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(C)=O)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
HCl (4M in dioxane, 30 mL) was added to a sol. of compound C5 (3.34 g, 4.20 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred for 1 h at 0° C., then for 1 h at rt. The solvents were removed under reduced pressure, and the residue was dried under high vacuum. The residue was dissolved in CH2Cl2 (30 mL), and DIPEA (2.88 mL, 16.8 mmol) was added. The mixture was cooled to −20° C., and AcCl (0.315 mL, 4.41 mmol) was added carefully. The mixture was stirred for 20 min at −20° C., and CH2Cl2 was added. The mixture was washed with aq. 1M HCl and aq. 1M NaOH. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:3→1:2) yielded the title compound (3.03 g, 98%). LC-MS: tR=1.18 min; ES+: 738.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[CH2:11]([O:13][C:14](=[O:42])[C:15]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])([CH3:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH:26]2[CH2:30][NH:29][C:28](=[O:31])[N:27]2[CH3:32])=[CH:19][CH:18]=1)[CH3:12].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:42])[C:15]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])([CH3:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH:26]2[CH2:30][N:29]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:28](=[O:31])[N:27]2[CH3:32])=[CH:19][CH:18]=1)[CH3:12]
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzyl bromide (0.02 mL, 0.172 mmol, d=1.436) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.051 g, 0.115 mmol) and sodium hydride (0.011 g, 0.287 mmol, 60% suspension on mineral oil), and pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed with 1N HCl, water, and brine. The organic layer is dried over MgSO4, concentrated in vacuo, and carried into the next step. MS [EI+] 565 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21]N=C[C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CC1C([N+]([O-])=O)=C2C(=CC=1)C=[N:37][CH:36]=C2>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:36]=[N:37][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Product: O=c1c2cc(Cc3ccc(Cl)nc3)c3ncccc3c2ncn1[C@H]1CCCC[C@@H]1O

Procedure:
6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[2,3-h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one in Example 1, substituting 6-methyl-5-nitroquinoline for 6-methyl-5-nitroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Oc1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1Oc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6-chloro-pyridin-3-yloxy)-benzaldehyde (250 mg, 1.07 mmol) in methanol at ambient temperature was added sodium borohydride (49 mg, 1.3 mmol). The resulting reaction was stirred for 30 minutes, then quenched with saturated NaHCO3. The methanol was removed in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to an oil. The crude was purified by flash chromatography (eluting with 25% ethyl acetate/hexane) to give the above named compound as an oil (250 mg, 100%).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:16]=O)=[CH:9]2.[O-]S([O-])(=O)=O.[Mg+2]>C(O)C.C(Cl)Cl>[Br:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:16]=[N:2][CH3:1])=[CH:9]2
Reactant: COc1ccc2cc(C=O)ccc2c1Br
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: CN=Cc1ccc2c(Br)c(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methylamine (2.35 mL of an 8.03 M solution in ethanol, 18.8 mmol) in 5 mL of methylene chloride was added under nitrogen dropwise over 5 minutes to a mixture of 5-bromo-6-methoxy-naphthalene-2-carbaldehyde (1.00 g, 3.77 mmol), prepared in the previous step, and 3 g of anhydrous MgSO4 in 20 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 21 h (overnight). The reaction was filtered and the filtrate concentrated under reduced pressure to give (5-bromo-6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (1.05 g, 100%) as a light tan solid, mp 105-107° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)(C)N=Cc1ccc(F)cc1F

Procedure:
To a solution of 2,4-difluorobenzaldehyde (431.6 mg, 3.04 mmol) in toluene (5 ml) was added t-butylamine (0.63 ml, 6.00 mmol) and stirred under reflux using a Dean-Stark trap to remove water for 1 hour. Then t-butylamine (0.63 ml, 6.00 mmol) was added to the mixture and stirred for 5 hours. The solvent was evaporated to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28]>>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3cccs3)CC1)O2

Procedure:
Compound 78 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, thiophene-2-sulfonyl chloride and conditions outlined in procedure P. M.p.=245-248° C.; 400 MHz 1H NMR (CDCl3) δ: 8.02-8.05 (m, 1H), 7.70-7.67 (m, 1H), 7.61-7.59 (m, 1H), 7.48-7.44 (m, 2H), 7.27-7.22 (m, 1H), 7.22-7.18 (m, 1H), 3.79-3.72 (m, 2H), 2.94 (s, 2H), 2.91-2.84 (m, 2H), 2.26-2.18 (m, 2H), 2.02-1.91 (m, 2H); LCMS: 448 [M+H].
Reaction SMILES: BrC1C=CC(C(N)=O)=CC=1.O=CC(Cl)(Cl)[Cl:14].[Br:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25](O)[C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1COCC1.C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][CH:25]([Cl:14])[C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NC(=O)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1

Procedure:
A mixture of 4-bromoaniline 118 (5.0 g, 24.2 mmol) and chloral (4.7 mL, 48.2 mmol) in THF (4 mL) was heated for 30 minutes. Solvent was removed under vacuum. 4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide 121 (1.26 g, 3.62 mmol) in chloroform (15 mL) and PCl5 (0.8 g, 3.65 mmol) was heated at 50° C. for 30 minutes. The product was isolated from a standard aqueous work-up and extraction to produce 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide. 4-Bromo-N-(1,2,2,2-tetrachloroethyl)benzamide (1.21 mmol) in ether (50 mL) was reacted with 6-chloropyridin-3-amine (0.32 g, 2.44 mmol) at room temperature for 18 hours. The mixture was subjected to a standard aqueous work-up and extraction. Chromatography on silica gel (7:3 hexanes:CH2Cl2) gave 4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide (Compound-42, 0.36 g, 65%). 1H NMR (300 MHz, d4-methanol): δ=7.99 (dd, J=3.0, 0.6 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.36 (dd, J=9.0, 3.3 Hz, 1H), 7.26 (dd, J=8.7, 0.6 Hz, 1H), 6.36 (s, 1H).
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[O:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[CH2:48][NH2:49]>CC(N(C)C)=O>[O:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[CH2:48][NH:49][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:10]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCC1CCCO1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added C-(tetrahydro-furan-2-yl)-methylamine (32 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.