Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(C[N:41]([C:43]3[CH:51]=CC(C(O)=O)=C[CH:44]=3)C)N=2)N=1.O.O.C([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])#N.CCN(C(C)C)C(C)C.C(OP(CCCN)(=O)OCC)C>CN(C=O)C>[CH2:58]([O:57][P:56]([CH2:51][CH:43]([NH:41][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[CH3:44])(=[O:63])[O:60][CH2:61][CH3:62])[CH3:59]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(CCCN)OCC
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 3 hours, when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added. The solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product (65.5 mg) collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount (32.8 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 31.9; MS (m/z) 503.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH2:18](O)[C:19]([F:22])([F:21])[F:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Reactant: OCC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAS Registry No. 862111-61-3) (5.0 g, 16 mmol) was dissolved in tetrahydrofuran (80 mL). To the solution were added trifluoroethanol (1.37 mL, 19 mmol), triphenylphosphine (5.0 g, 19 mmol) and diethyl azodicarboxylate (3.7 mL, 19 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and for 6 h at room temperature. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with water. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel with dichloromethane:heptane 1:2 to yield the product as white solid, MS (ISP) 397 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](OC(C)=O)=[O:35].OS([O-])(=O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][C:34](=[O:35])[CH3:33])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A solution of 214e (287 mg, 0.65 mmol) in pyridine (5 mL) was treated with Ac2O (0.4 mL, 3.62 mmol). After 6 hours, the reaction mixture was poured into 5% NaHSO4 and extracted 3 times with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (SiO2, EtOAc) afforded 119 mg of 2100h, 1HNMR (CDCl3, mixture of four diastereoisomers) δ1.80-2.05(m), 2.12(s), 2.13(s), 2.19(s), 2.22(d), 2.67-2.75(m), 2.80-2.95(m), 3.00-3.20(m), 3.21-3.33(m), 3.50-3.95(four discrete multiplets), 4.19(m), 4.55(m), 4.57-4.65(m), 4.69(m), 4.85-4.95(m), 5.04(m), 5.10(s), 5.10-5.22(m), 6.46(d), 6.03(s), 6.50(d), 6.58(d), 6.75(d), 6.95-7.05(m), 7.22(m), 7.30(m), 7.71(d), 7.75-7.83(m).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1cccc(F)c1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1cccc(F)c1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 31.6 %

Procedure:
Using Method G, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (372 mg, 1.00 mmol) and 2-fluoro-6-methoxyphenylboronic acid (1.40 g, 8.24 mmol) were reacted. After purification the title compound (117 mg, 33% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.50 (bm, 1H), 7.94 (dd, J=5.2, 9.2 Hz, 1H), 7.53 (a t, J=8.7 Hz, 1H), 7.40 (apparent q, J=7.8 Hz, 1H), 6.86 (m, 2H), 3.72 (s, 3H), 2.96 (m, 1H), 0.88 (m, 2H), 0.62 (m, 2H). MS APCI, m/z=371.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[NH:13][C:12]1=[O:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34]Br)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH2:34][N:13]1[C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([CH:18]([CH3:19])[CH3:20])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:9])[C:12]1=[O:25])(=[O:28])[CH3:27]
Reactant: CC(C)C1=NC(NC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Reactant: CC(=O)c1sccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(C(C)C)c2ccccc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a suspension of sodium hydride (0.065 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1, 4-benzodiazepin-2-one (0.508 g) in dry N,N-dimethylformamide (5 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature for 2 hours. To the mixture was added dropwise a solution of 2-acetyl-3-bromomethylthiophene (0.420 g) in dry N,N-dimethylformamide under cooling in an ice-bath. After completion of the addition, the mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnight. The resultant mixture was concentrated in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (50 ml) and dried over anhydrous sodium sulfate. Filtration and evaporation gave a crude product. The product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1) to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (0.380 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[CH:12]=[C:7]12.O=P(Cl)(Cl)Cl.[CH2:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH3:25]>ClCCCl>[CH2:24]([C:26]1[N:27]=[CH:28][N:29]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=4)[CH:30]=1)[CH3:25]
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Reactant: CCc1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
111-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (440 mg, 1.24 mmol) in dry DCE (10 mL) was treated with POCl3 (0.23 mL, 2.49 mmol) and heated to 100° C. for 1 h. The mixture was allowed to cool to RT and then poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (10 mL) and 4-ethyl-1H-imidazole (597 mg, 6.21 mmol) was added. The mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O, extracted with DCM and the combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to give the title compound (523 mg) as a brown oil. UPLC-MS: MS 433.1 (M+H+); UPLC rt 0.93 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.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>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
6.74 g (29.3 mmol) of ethyl 5-bromonicotinate, 8.35 g (43.9 mmol) of 4-trifluoromethylphenylboronic acid, 0.17 g (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0) and 6.21 g (58.6 mmol) of sodium carbonate were dissolved in a mixture of 75 ml of 1,2-dimethoxyethane, 15 ml of water and 184 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by flash chromatography (dichloromethane/acetonitrile 100:2→100:5). Yield: 6.22 g (72% of theory)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([CH:24]([F:26])[F:25])[CH2:23][O:22]2)[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:26][CH:24]([F:25])[C:21]([OH:22])([CH2:20][C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Reactant: Oc1ccnc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)F
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a solution of the 4-hydroxyquinoline and 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane in DMSO (1.0 mL) stirred under nitrogen was added NaHMDS (1.2 mL, 1.0M in THF) dropwise. The mixture was stirred at room temperature for 15 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Trituration of the residue with diethyl ether gave the product 1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one as a crystalline solid that was collected by filtration and air dried (77.7 mg, 20%).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1cccc(F)n1
Reactant: CN
Product: CNc1cccc(S(N)(=O)=O)n1

Procedure:
To 10 ml of condensed methylamine was added 1.86 g (10 mmol) of 6-fluoropyridine-2-sulfonamide. The mixture was allowed to reflux under a dry-ice condenser for 4 hr, then excess amine was allowed to evaporate overnight. The residue was crystallized with water to yield 1.64 g of tan solid, m.p. 124° C. to 126° C. NMR (CDCl3): δ 2.64 (s, 3H), 6.12 (br s, 2H), 6.30 (d, 1H), 6.86 (d, 1H), 7.23 (dd, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19]Br>O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]=1[Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: BrBr
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Br

Procedure:
37.5 g (0.15 mole) of p-octyloxy benzoic acid are put in suspension in 108 ml of deionized water. The temperature of the reaction medium is brought to between 50° C. and 55° C. and 8.7 ml (0.17 mole) of bromine are added at this temperature over a period of 7 hours 30 minutes.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C(O[C:10](OCC)(OCC)[CH2:11][CH3:12])C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C>[CH2:11]([C:12]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[C:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5])[CH3:10]
Reactant: N#CCC(N)=O
Reactant: CCOC(CC)(OCC)OCC
Reactant: C1COCCN1
Solvent: CC#N
Product: CCC(=C(C#N)C(N)=O)N1CCOCC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A stirred mixture of cyanoacetamide (84 g.), triethylorthopropionate (193 g.) and morpholine (108 g.) was heated under reflux for 3 hours. The initial reflux temperature was 121° C. and the final reflux temperature was 91° C. At the end of the reflux period acetonitrile (50 ml.) was added, the mixture was cooled to 25° C., the crystalline precipitate was collected, and washed with 2 × 100 ml. of cold ethanol. Weight = 87 g. Yield = 42%. A sample was recrystallized from ethanol as white needles m.p. 158° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>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.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:36]5[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 14.3 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.147 mmol, 1 eq), 2-aminopyrimidine-5-boronic acid pinacol ester (48 mg, 0.22 mmol, 1.5 eq), 1,4-dioxane (4 mL), K2CO3 (61 mg, 0.441 mmol, 3 eq), H2O (1.6 ml) and Pd(PPh3)2Cl2 (10 mg, 0.0147 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was purified in an Isolute Flash Si II column (0-3% MeOH in DCM). The product obtained was triturated with EtOAc and filtered. The filtrate was evaporated and the residue was triturated with acetone. The filtrate was evaporated. The residue was purified by column chromatography (EtOAc) to give the desired product (11 mg, 14%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.90 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 2H), 7.43 (m, 2H), 7.36 (dd, J=8.3, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 4.53 (m, 1H), 3.93 (s, 3H), 3.75 (m, 2H), 3.29 (m, 2H), 1.93 (m, 2H), 1.81 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH2:24]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:26]5[CH2:27][CH2:28][CH2:29][CH:25]5[CH2:24][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: C1CNC(CN2CCCC2)C1
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3CN3CCCC3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (150 mg, 0.454 mmol), TEA (0.500 mL), and 1,2′-methylenedipyrrolidine (420 mg, 2.73 mmol) in NMP (0.500 mL) was stirred at 150° C. for 24 hr under nitrogen atmosphere. The resultant mixture was purified by reverse phase combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to afford 105 (81 mg, 40% yield) as white solid. LCMS (ESI): RT=4.54 min, m/z: 449.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 5.98-5.93 (m, 2H), 4.52-4.47 (m, 4H), 4.14 (s, 1H), 3.47 (s, 1H), 3.27 (s, 1H), 2.58-2.56 (m, 2H), 2.50-2.46 (m, 4H), 2.06-1.93 (m, 2H), 1.92-1.87 (m, 2H), 1.70-1.67 (m, 4H), 1.48 (s, 6H)
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1>>[C:39]([NH:38][C:34]1[CH:33]=[C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][NH:22][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:27][CH2:28]2)[CH:37]=[CH:36][CH:35]=1)(=[O:43])[CH:40]([CH3:42])[CH3:41]
Reactant: CCCCCC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCCCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 11 was prepared from 2,2-diphenyl heptanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.40 (m, 1H), 7.37–7.19 (m, 11H), 6.88 (d, 1H, J=7.3 Hz), 6.34 (t, 1H, J=4.5 Hz), 3.34–3.27 (m, 3H), 2.94–2.87 (m, 2H), 2.52 (septet, 1H, J=6.9 Hz), 2.46–2.34 (m, 4H), 2.27 (t, 2H, J=6.9 Hz), 2.00–1.91 (m, 2H), 1.77–1.69 (m, 2H), 1.69–1.52, (m, 5H), 1.30–1.20 (m, 12H); ESMS m/e: 568.4 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[CH:33]([C:35]1[N:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]2[O:47][CH:48]([CH3:50])[CH3:49])=O.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:33][C:35]2[N:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][C:39]([C:45]#[N:46])=[C:38]3[O:47][CH:48]([CH3:50])[CH3:49])[C:14](=[O:16])[N:13]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3NC(NCc4ccc(C(F)(F)F)cc4C(F)(F)F)=NC3=O)nc12
Temperature: 25 °C

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (82.7 mg, 0.18 mmol) (prepared as described in C-H Kwon et al. J. Med. Chem. 1991, 34, 1845-1849), 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (45.6 mg, 0.19 mmol) (see Example 1) and iPrOH (5 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 5 h to give a brown solution. The reaction mixture was cooled to r.t. and concentrated to give a light yellow solid, 66.3 mg, which was purified by flash column purification to give 6-[2-(2,4-bis-trifluoromethyl-benzylamino)-5-oxo-3,5-dihydro-imidazol-4-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile, as a light yellow solid, 20.6 mg (20.9%). HR-ES (+) m/e calcd for C25H18F6N6O2 (M+H)+ 549.1468. found 549.1472.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[C:15](Cl)[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH:23]1[CH:24]=[CH:25][C:26]2[N:31]([OH:32])[N:30]=[N:29][C:27]=2[CH:28]=1.CC[N:35]=C=NCCCN(C)C.Cl.N.O1CCOCC1>CN(C=O)C.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[C:18]([C:19]([NH2:35])=[O:21])=[CH:17][N:16]=[C:15]([O:32][N:31]4[C:26]5[CH:25]=[CH:24][CH:23]=[CH:28][C:27]=5[N:29]=[N:30]4)[N:14]=3)=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)c1cnc(Cl)nc1Nc1ccc(-n2cncn2)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-n2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(4-(1H-1,2,4-triazol-1-yl)phenylamino)-2-chloropyrimidine-5-carboxylic acid (iii) (730 mg, 2.305 mmol) in DMF (15 mL), at room temperature, was added HOBt (470 mg, 3.478 mmol, 1.508 equiv), and EDC.HCl (690 mg, 3.599 mmol, 1.561 equiv), and the mixture was stirred for 45 minutes. Then cooled it to 0° C., and treated with 0.5 M NH3 in dioxane (14.0 ml, 7.0 mmol, 3.0 equiv), and stirred the mixture at room temperature for 18 h. Then diluted it with water (7×) to precipitate iv. Collected it by filtration, rinsed with water, and air dried; yield 841 mg (88%). MS: 415.1 (M+H), and 437.1 (M+Na).