Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH2:17][CH:19]1[O:21][CH2:20]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrCC1CO1
Reactant: CCCCc1c(C)[nH]c(C(=O)OCC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C)[nH]c(C(=O)OCC)c1OCC1CO1
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Using the method described in Example V, 35 g of 2-carboethoxy-3-hydroxy-4-butyl-5-methyl-pyrrole, 32 g of epibromohydrin and 41 g of dry potassium carbonate in 100 ml of N,N-dimethylformamide, when heated at 50° C. for 8 hours, give 41 g of 1-(2-carboethoxy-4-butyl-5-methyl-pyrrol-3-oxy)-2,3-epoxypropane, of melting point 125°-127° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:18]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)c2ccc(OC)c(OC)c2)n1
Yield: 72.9 %

Procedure:
In 100 ml of methylene chloride, 21.3 g of 2-amino-4-ethoxycarbonyl-1,3-thiazole was suspended, followed by the addition of 24.8 g of 3,4-dimethoxybenzoyl chloride, 25.3 g of triethylamine and 0.15 g of 4-dimethylaminopyridine. The resulting mixture was refluxed for 2 hours. After the reaction mixture was allowed to cool down, methylene chloride was distilled off under reduced pressure. To the residue, 1000 ml of water was added. Crystals so precipitated were collected by filtration and then recrystallized from ethanol, whereby 30.3 g of the title compound was obtained. Yield: 73%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and bromomethyl-4-trifluoromethyl-benzene as described in Example 49 and isolated as yellow solid (0.075 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 2H), 7.70 (d, J=4 Hz, 1H), 7.61 (d, J=8 Hz, 2H), 7.44 (d, J=4 Hz, 1H), 7.26-7.36 (m, 3H), 6.88 (d, J=2 Hz, 1H), 6.13 (t, J=5 Hz, 1H), 5.41 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=458.1; Rt=1.35 min; HRMS (M+H)+=458.13.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[C:32]2[O:33][CH2:34][O:35][C:31]=2[C:30]([C:36]#[C:37][CH2:38][NH:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:29][C:28]=1[Cl:45].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:45][C:28]1[CH:29]=[C:30]([C:36]#[C:37][CH2:38][NH:39][C:40](=[O:44])[N:41]([CH3:42])[CH3:43])[C:31]2[O:35][CH2:34][O:33][C:32]=2[C:27]=1[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)CC1=O
Yield: 81.4 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (140 mg, 0.38 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (125 mg, 0.42 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.81 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (193 mg, 81%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.03 (quintet, 2H), 2.20 (s, 3H), 2.59 (t, 2H), 2.81 (s, 6H), 2.91 (s, 2H), 3.33 (t, 2H), 3.48 (t, 2H), 3.94 (s, 3H), 4.10 (d, 2H), 4.14 (t, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.16 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 624/626.
Reaction SMILES: N#N.O.[CH3:4][NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][N:7]=1.NN>C(O)C.[Pd]>[CH3:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Agent: NN
Solvent: CCO
Solvent: O
Product: CNc1ncccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Palladium (0.924 g, 0.868 mmol) was added to a three necked 1 L round bottom flask equipped with a condenser and flow of N2, and it was wet by adding a few mL of water. Then, N-methyl-3-nitropyridin-2-amine (19.0 g, 124 mmol) dissolved in ethanol (130 mL) was added. Hydrazine (15.41 ml, 496 mmol) was added to the above solution dropwise over a period of 20 minutes with continuous stirring. The reaction was exothermic, and H2 gas evolved during the reaction. The reaction mixture was stirred at room temperature for about 2 h. The color of the reaction changed from yellow to colorless. Completion of the reaction was checked by TLC. Pd was filtered on a tightly packed Celite® plug. The Celite® was first washed with DCM, and Pd was filtered off. A little bit of Celite®was placed on the top of Pd for safety, and it was washed with DCM until all the product was washed off of the Celite®. Combined solvent was concentrated and residue was taken in EtOAc washed with H2O. NaCl solid was added to remove any left over hydrazine. EtOAc was dried on Na2SO4, filtered and concentrated to give a dark brown solid (11.95 g; 78.25%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:17]=[CH:18][C:10]([C:7]5([N:3]6[CH2:4][CH2:5][CH2:6][S:2]6(=[O:19])=[O:1])[CH2:9][CH2:8]5)=[CH:11][CH:12]=4)=[O:15])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C3(N4CCCS4(=O)=O)CC3)cc2)CC1
Yield: 32.8 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)cyclopropyl]benzoic acid (141 mg) described in Preparation Example 31 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (114 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (79 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].C(Cl)Cl.CO.O1CCOCC1>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH:12][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(N)cc1CN1CCC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1nc(Nc2cc(Br)cn(C)c2=O)cc1CN1CCC1
Temperature: 100 °C
Yield: 97.9 %

Procedure:
Following Example 156g, 200b (350 mg, 2 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (0.54 g, 2 mmol), cesium carbonate (1.3 g, 4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.2 mmol), Xantphos (0.23 g, 0.4 mmol) and 1,4-dioxane (20 mL) were heated at 100° C. for 8 hours. Work-up and flash column chromatography (silica, 3:1 methylene chloride/methanol) give a 98% yield (0.69 g) of 3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 200c as a yellow solid. MS (ESI+) m/z 354.1 (M+H).
Reaction SMILES: [CH:1]1([CH2:10][CH:11]=[N:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.[NH4+].[OH-]>CO.O>[CH:1]1([CH2:10][CH2:11][NH:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ON=CCC1C=Cc2ccccc21
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: ONCCC1C=Cc2ccccc21

Procedure:
2-(1H-indene-1-yl)acetaldoxime (50 mg, 0.29 mmol) was dissolved in methanol (15 ml) and treated with sodium cyanoborohydride (34 mg, 0.54 mmol). Methyl orange indicator (ca 1 mg) was added, and the pH of the mixture adjusted by addition of 1:1 conc. HCl:MeOH to maintain the indicator color slightly to the red side of the turning point. After ca 1 ml of the acid mixture had been added, the indicator remained red. The reaction was made basic with conc. NH4OH, and water was added. The mixture was extracted with ether and the ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to provide N-(2-(1H-indene-1-yl)-ethyl)hydroxylamine.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](Br)=[C:12]([CH3:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46]([O:50][CH3:51])(=[O:49])[CH:47]=[CH2:48]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[N:11]=[C:12]([CH3:20])[C:13](/[CH:48]=[CH:47]/[C:46]([O:50][CH3:51])=[O:49])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc1Br)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Temperature: 120 °C
Yield: 24.3 %

Procedure:
To a suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd(OAc)2 (0.70 mg, 0.003 mmol), Ph3P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120° C. in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by prep-HPLC provided methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH+: 412.3, Rη=0.26 (1:1 EtOAc:Hex).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[C:14]([CH2:15][C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>>[O:18]=[C:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8][C:7]2[CH:19]=[CH:20][C:4]([CH2:3][C:1]([NH2:2])=[O:21])=[CH:5][C:6]1=2
Reactant: [OH-]
Reactant: N#CCc1ccc(Oc2ncccc2CC(=O)O)cc1
Agent: [Na+]
Product: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
To 1 g of 2-(4-cyanomethylphenoxy)-3-pyridylacetic acid was added 20 g of polyphosphoric acid, and the mixture was stirred in an oil bath at 151°-152° C. for 2.5 hours. After cooling, to this was ice water to decompose excess polyphosphoric acid, and the mixture was basified with a 10% sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a solid, which was chromatographed over 20 g of silica gel and eluted with n-hexane/acetone (2/1-1/1) to obtain crystals. These were recrystallized from acetone to give 300 mg (yield: 30%) of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetamide as white needle crystals having a melting point of 214°-217° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23]1.C(N(C(C)C)C(C)C)C>C(#N)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[CH:3]=[C:2]([N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[O:28])[CH2:30][CH2:31]2)[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=1
Reactant: O=C(c1ccoc1)N1CCNCC1
Reactant: Clc1cc(-c2ccco2)nc2cc(-c3ccccc3)nn12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccoc1)N1CCN(c2cc(-c3ccco3)nc3cc(-c4ccccc4)nn23)CC1
Temperature: 100 °C
Yield: 99.2 %

Procedure:
A mixture of 7-chloro-5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidine (0.148 g, 0.5 mmol, 1.0 eq), furan-3-yl(piperazin-1-yl)methanone (0.180 g, 1.0 mmol, 2.0 eq,) and N-ethyl-N-isopropylpropan-2-amine (0.129 g, 1.0 mmol, 2.0 eq) in acetonitrile (5.0 mL) was heated at 100° C. for 3 hr. The completed reaction was purified by chromatography (Biotage 25 g, EtOAc/Hexane) to afford (4-(5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)(furan-3-yl)methanone (0.218 g, 99%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.83 (m, 1H), 7.62 (m, 1H), 7.52-7.47 (m, 3H), 7.45-7.41 (m, 1H), 7.23 (dd, J=3.5, 0.7 Hz, 1H), 6.93 (s, 1H), 6.65 (m, 1H), 6.62 (dd, J=3.5, 1.8 Hz, 1H), 6.60 (s, 1H), 4.08 (b, 4H), 3.92 (b, 4H). 13C NMR (125 MHz, CDCl3) δ 164.1, 155.4, 152.4, 151.8, 150.1, 148.5, 144.3, 143.8, 143.2, 132.9, 129.0, 128.7, 126.4, 120.6, 112.6, 110.9, 110.1, 92.9, 88.9, 48.3. LCMS retention time: 3.20 min; purity at 215 nm=100%. HRMS m/z calculated for C24H27N5O2 ([M+H]+): 440.1717. found 440.1715.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=O)[CH2:19][O:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([C:30]=2[NH2:31])=[N:28][C:27]([O:32][CH3:33])=[CH:26][CH:25]=3)=[CH:16][CH:17]=1)([CH3:8])([CH3:7])[CH3:6].C([BH3-])#N.[Na+].ClCCl>CO>[C:5]([O:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[N:14][C:15]([CH:18]2[NH:31][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[N:28]=4)[N:23]=[CH:22][C:21]=3[O:20][CH2:19]2)=[CH:16][CH:17]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1ccc2ncc(OCC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c(N)c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2n1)NC(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetic acid (110 mg, 1.83 mmol, 1.7 eq) is added at room temperature to a stirred solution of {6-[2-(4-amino-6-methoxy-[1,5]naphthyridin-3-yloxy)-acetyl]-pyridin-3-yl}-carbamic acid tert-butyl ester (470 mg, 1.10 mmol 1.0 eq) in methanol (20 mL) and the resulting mixture is stirred at room temperature for 1 hour before the addition of sodium cyanoborohydride (370 mg, 5.89 mmol, 5.3 eq). After 4 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 200:1 to 50:1, v/v) to afford [6-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow solid (222 mg, 49% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:2].C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)=[CH:15][N:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1cncn1
Product: CCOC(=O)C(=CN(C)C)n1cncn1

Procedure:
1.9 g (9.8 mmol) [1,2,4]-triazol-1-ylacetic acid ethyl ester [Ainsworth et al., J. Am. Chem. Soc. 1955, 77, 621-623] and 3.6 ml (2.9 g, 19.6 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 12 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [OH-].[K+:2].[Br:3][C:4]1[N:5]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:6]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[N:7][N:8]=1>C(O)C>[Br:3][C:4]1[N:5]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:6]([S:9][CH2:10][C:11]([O-:13])=[O:12])=[N:7][N:8]=1.[K+:2]
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
Aqueous potassium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10° C. The mixture was stirred at 10° C. for a further 10 mins. Volatile solvents were removed in vacuo to dryness to provide potassium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a solid, (884 mg, 100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=[O:15])=[N:3][CH:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:15]=[C:14]1[N:3]2[CH:2]=[N:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]2=[N:11][CH:12]=[C:13]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c3ccccc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To diethyl [(4-quinazolinylamino)methylene]propanedioate (16.0 g) was added diphenylether (70 ml) which had been heated at 250° C. in advance. The reaction mixture was stirred at 250°-260° C. for 20 minutes and cooled to ambient temperature. To the resultant mixture was added hexane. The mixture was stirred to give crystals, which was washed with hexane and dried. The crude crystals were dissolved in ethyl acetate under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to a volume of 200 ml. To the concentrate was added hexane and the mixture was allowed to stand at ambient temperature to precipitate crystals, which were separated by filtration, washed with a mixture of ethyl acetate and hexane and dried to give crystalline ethyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (12.4 g).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:17])[C:8](=[O:9])[C:7]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH3:17])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:16]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2=O
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Bromine (12.3 mL, 241 mmol) was added dropwise to a solution of acetic acid (400 mL) containing 2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (40.9 g, 200 mmol) synthesized in Reference Example 35, and then it was stirred at room temperature. After stirring for 1 hour, the reaction solution was poured into 5% aqueous solution of sodium sulfite. The generated crystals were collected by filtration, and recrystallized from methanol to give 47.4 g of the title compound (yield: 84%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([N:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[CH:39][CH:38]=2)=[N:29][N:28]=[N:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.O>C1(C)C=CC=CC=1>[OH:47][CH2:46][C@@H:45]([N:44]([CH2:43][C:40]1[CH:39]=[CH:38][C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]2[N:26]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:27]=[N:28][N:29]=2)=[CH:42][CH:41]=1)[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH3:48]
Reactant: CCCC(=O)Cl
Reactant: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Butyryl chloride (258 μL, 2.5 mmol) was added to a solution of intermediate (5a) (1.1 g, 2.1 mmol), and DIPEA (504 μL, 2.9 mmol) in toluene (20 mL) at 0° C. The solution was stirred at room temperature for 30 minutes. Water was added (20 mL), and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5b) as a white solid (942 mg).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[C:17](O)=[O:18])[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][N:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1
Reactant: O=C(O)c1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylic acid (155 mg, 0.52 mmol) and triethylamine (0.072 mL, 0.52 mmol) in tetrahydrofuran (3 mL) at 0° C. was added isopropyl chloroformate (0.52 mL, 0.52 mmol). A white solid was seen to precipitate. The mixture was stirred at 0° C. for approximately 1 hour and then filtered into a stirring solution of sodium borohydride (25 mg, 0.67 mmol) in water at 0° C. The solution was stirred at 0° C. for approximately 30 minutes and the allowed to warm to ambient temperature. The solution was concentrated and water was added. The solution was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford [5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (83 mg, 56%). 1H-NMR (400 MHz, CDCl3) δ 8.62 (s, 2H), 4.44 (s, 2H), 2.20-2.14 (m, 1H), 1.30-1.44 (m, 4H).