Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:27][CH:26]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(C(F)(F)F)cc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-trifluoromethylbenzylamine (88 mg, 0.5 mmol). The title product was obtained as an off-white solid (38.6 mg, 88% yield). 1HNMR (500 MHz, CDCl3) δ: 12.18 (1H, s), 7.88 (1H, t, J=4.58), 7.60 (2H, d, J=8.24 Hz), 7.53–7.47 (1H, m), 7.43 (2H, d J=8.24 Hz), 7.05 (2H, dd, J=8.24, 7.32 Hz), 4.65 (2H, d, J=6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C20H13F5N3O3 (M−H): 438.0877; found: 438.0878.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[C:15]([CH3:16])([CH3:18])[CH3:17])[O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(O)cc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Yield: 85.2 %

Procedure:
3-(Benzyloxy)-4-tert-butylphenol (4.9 g, 19.2 mmol), potassium carbonate (8.0 g, 57.6 mmol) and ethyl bromoacetate (2.6 ml, 23.0 mmol) were treated in the same procedure described in Example 13(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (29/1 to 19/1) to furnish 5.6 g (85% yield) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CN1C(=O)CCC1.CO>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccncn3)cc(Cl)nn12
Solvent: CO
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccncn3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 120 °C

Procedure:
A solution of 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 0.033 mmol) in NMP (1 mL) was treated with (trans)-cyclohexane-1,4-diamine (37.4 mg, 0.327 mmol) and heated to 120° C. for 4 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=19.202 minutes) was isolated and lyophilized to dryness to afford 6-((trans-4-aminocyclohexyl)amino)-N-4-pyridinyl-8-(4-pyrimidinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.1 mg, 8.59%). 1H NMR (500 MHz, DMSO) δ ppm 8.87 (1H, s), 8.65-8.74 (3H, m), 8.51 (1H, d, J=10.45 Hz), 8.25 (2H, d, J=6.60 Hz), 8.21 (2H, s), 7.25 (1H, d, J=6.05 Hz), 3.82-3.93 (1H, m), 3.16-3.24 (1H, m), 2.39 (2H, d, J=14.57 Hz), 2.11-2.22 (3H, m), 1.45-1.68 (4H, m). HPLC Rt=1.888 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=445.0.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:49]([OH:50])[CH:41]6[CH:42]([O:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:51]([CH3:53])[CH3:52])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:51]([CH3:52])[CH3:53])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:49]([OH:50])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)=CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.1 %

Procedure:
30 mg of compound (43) was dissolved in 4.3 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 50 minutes. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×21 cm) and eluted with n-hexane-ethyl acetate (3:1) to give 16.5 mg of compound (44) as a colorless oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21]O)[CH3:19])[CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:21][CH2:20][CH:18]([CH3:19])[CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])=[O:6])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOC(=O)c1ccccc1C=O
Reaction time: 0.25 h
Yield: 15.6 %

Procedure:
A solution of 7.50 g (50.0 mmol) 2-formylbenzoic acid, 4.88 g (40.0 mmol) 4-dimethyl aminopyridine (DMAP) and 15.60 g (100.0 mmol) citronellol in 75 ml dichloromethane was cooled in an ice bath before addition of a solution of 11.35 g (55.0 mmol) dicyclohexylcarbodiimide (DCC) in 25 ml dichloromethane for 15 min. The reaction medium was maintained with stirring at 0° for 15 min, then at 20° for 48 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried over Na2SO4, concentrated and chromatographed twice (SiO2, ethyl toluene/ethyl acetate 19:1 and SiO2, toluene) to give 2.25 g (16%) 3,7 dimethyl-6-octenyl 2-formylbenzoate in the pure state in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:38]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:23][N:38]=[C:24]3[S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.83 h
Yield: 70.1 %

Procedure:
A suspension of 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (2.36 g, 4.57 mmol) in ethanol and 1.0 N hydrochloric acid (85 mL) was heated to aid dissolution. The reaction mixture was treated slowly with sodium nitrite (0.549 g, 7.96 mmol) in water, stirred at ambient temperatures for 50 minutes, basified with solid sodium carbonate, stirred at ambient temperatures for 30 minutes and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified twice by flash chromatography with 2% methanol in chloroform and with 1.5-10% methanol in chloroform to afford 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff-colored foam, 1.69 g (70.1% yield), Mass spectrum (+EI, [M+H]+) m/z 528. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.72-8.75 (m, 1H), 8.55 (d, 1H, J=7.44 Hz), 8.17-8.27 (m, 1H), 7.98-8.03 (m, 1H), 7.52-7.74 (m, 4H), 7.19-7.34 (m, 6H), 7.06 (d, 1H, J=8.78 Hz), 4.99-5.09 (m, 3H), 3.61-3.70 (m, 1H), 3.34-3.55 (m, 3H), 2.11-2.28 (m, 1H), 1.99-2.07 ppm (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])#[CH:23]>C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.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.[Cu]I>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:23]#[C:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ncnc(C#Cc3ccccc3C(F)(F)F)c2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
1-{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.317 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol) and copper(I)iodide (5 mg, 0.026 mmol) were dissolved in diisopropylethylamine and stirred for 2 min. o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and the mixture stirred under N2 at 70° C. for 18 hours. The yellow suspension turned black. After cooling to room temperature, the reaction mixture was diluted with chloroform (12 ml), passed through a celite plug and concentrated under vacuo. Purification by Flash Chromatography (0-30% Ethyl acetate/Hexanes) gave Compound Dl. Yield 35%. 1H NMR 400 MHz CDCl3 δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7.56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[S:23]1(=[O:29])(=[O:28])[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:21][C:20]1[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH2:27][S:23]4(=[O:29])=[O:28])[S:6][CH:5]=3)=[O:8])[CH2:10][CH2:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3csc(N4CCCS4(=O)=O)c3)CC2)c(C)c1
Yield: 50.7 %

Procedure:
Using (5-bromothiophen-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 244 and isothiazolidine 1,1-dioxide (41 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)[C:29](=[O:31])[CH3:30]>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:29](=[O:31])[CH3:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Product: CC(=O)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Yield: 24 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazole (50 mg, 0.134 mmol) and N,N-dimethylacetamide following General Procedure K. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (14 mg, 24%): 1H NMR (CDCl3, 600 MHz) δ 7.69 (s, 1H), 7.27-7.25 (m, 2H), 7.17-7.15 (m, 3H), 4.83 (t, 1H, J=7.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 2.48 (s, 3H), 1.91-1.84 (m, 2H), 1.61-1.57 (m, 2H), 1.43-1.32 (m, 6H), 0.87 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 186.7, 169.5, 150.5, 143.6, 134.2, 129.2, 129.1, 126.5, 69.5, 37.2, 36.8, 32.2, 30.0, 30.0, 27.6, 26.5, 25.8, 19.1, −4.2, −4.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]#[N:18])[CH:11]=1.[OH-].[Na+]>CO>[C:17](/[C:16](/[C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[CH:6]\[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#C/C(=C\c1ccc(O)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmoles), 3-pyridylacetonitrile (0.54 ml, 4.1 mmoles) and 50% w/v of aqueous NaOH (3.3 ml) in methanol (10 ml) was stirred at room temperature for 30 minutes. The yellow precipitate that formed was filtered, washed with cooled methanol (1 ml), cooled CH2Cl2 (10 ml), and dried under vacuum over P2O5 to yield 0.6 g (66%) of the title compound. 1H-NMR (CD3OD) 8.8 (d, 1H), 8.4 (m, 1H), 8.05 (m, 1H), 7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 1H), 6.6 (m, 2H). 13C-NMR (DMSO) 177.52, 175.57, 146.59, 145.06, 144.78, 133.15, 132.73, 130.97, 123.8, 120.8, 120.3, 114.3, 88.5; Mass Spectrum m/e (M+1) 223.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][N:6]1[C:15](=[O:16])[C:14]2[CH2:13][C:12]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:11][CH2:10][C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH2:27][CH2:26]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH2:19]1[CH2:18][O:17][C:12]2([CH2:11][CH2:10][C:9]3[N:8]=[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([C:31]5[CH:40]=[CH:39][C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=5)[CH2:29][CH2:30]4)[N:6]([N:5]=[C:2]([CH3:4])[CH3:1])[C:15](=[O:16])[C:14]=3[CH2:13]2)[O:20]1
Reactant: CC(C)=O
Reactant: Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CC1(CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: CC(C)=Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CC1(CC2)OCCO1
Yield: 78 %

Procedure:
To a mixed solution of 29 ml of acetone and 1 ml of water, 229 mg of 3-amino-6,6-ethylenedioxy-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one as synthesized in Example 4-66 and 59 mg of pyridinium p-toluenesulfonate were added and heated under reflux for 112 hours. After cooling, the reaction mixture was extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purifying the residue on silica gel column chromatography (methanol:methylene chloride=1:9) to provide 194 mg (78%) of 6,6-ethylenedioxy-3-isopropylideneamino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(OC(C)C)(C)C.Cl[C:14]([C:16]([F:27])([F:26])[CH:17]([O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:18][CH3:19])=[O:15]>>[C:1]([NH:5][C:14]([C:16]([F:26])([F:27])[CH:17]([O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:18][CH3:19])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Solvent: CC(C)OC(C)C
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)NC(C)(C)C
Yield: 112.7 %

Procedure:
In a 50-mL glass flask with a dropping funnel, 3.0 g (41.6 mmol/2.0 eq) of tertiary butylamine and 5.0 g of diisopropyl ether were added and stirred. Subsequently, 5.0 g (20.8 mmol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester was dropped into the glass flask. The resulting solution was stirred for 10 minutes at room temperature. The completion of the reaction was confirmed by 19F NMR. After that, the solution was separated into an organic layer and an aqueous layer with the addition of 10 mL of water and 5 mL of diisopropyl ether. The thus-obtained organic layer was concentrated under a reduced pressure. With this, 6.5 g of methacrylic acid 1-tert-butylaminocarbonyl-1,1-difluoro-2-butyl ester was obtained as a white crystalline substance (yield: 99%, purity: 88%).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.ClC1C=CC=C(C(OO)=O)C=1.CS(C1N=NC(C#N)=C(N2CCC3C=CC=CC=3CC2)N=1)(=O)=O.[NH2:56][CH2:57][CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1>ClCCl.O1CCOCC1>[N:61]1[CH:62]=[CH:63][CH:64]=[C:59]([CH2:58][CH2:57][NH:56][C:3]2[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[N:8]=2)[CH:60]=1
Reactant: NCCc1cccnc1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Agent: CS(=O)(=O)c1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1nnc(NCCc2cccnc2)nc1N1CCc2ccccc2CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 120 mg (0.40 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 5 ml of dichloromethane was treated at room temperature with 109 mg (0.44 mmol) of 3-chloro-perbenzoic acid (70%). After 2 hours the reaction mixture was evaporated under reduced pressure, and, without working-up and characterization, the resulting crude 3-methanesulfonyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was directly treated with a solution of 108 mg (0.88 mmol) of 3-(2-aminoethyl)pyridine in 10 ml of dioxane. The reaction mixture was then stirred at 80° C. overnight. The reaction mixture was then evaporated under reduced pressure and the residue obtained directly chromatographed on silica gel with a 95:5:0.1 v/v/v mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. There were obtained 55 mg (37% of theory) of 3-(2-pyridin-3-yl-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white amorphous solid; MS: 372 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22]O)=[C:15]([CH3:24])[CH:14]=1)=[N:7]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:22][CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[NH:5][C:4](=[O:25])[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)=[CH:14][C:15]=1[CH3:24]
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one (1.54 g, 4.44 mmol), PPh3 (1.52 g, 5.78 mmol), and CBr4 (1.92 g, 5.78 mmol) in anhydrous DMF (30 mL) was stirred at room temperature for 36 hours. DMF was evaporated under vacuum, water (100 mL) was added, and stirred for 30 minutes. The solid separated was filtered, washed with water, then ether, and dried under vacuum to give 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-one as pale yellow solid. Yield: 1.38 g (crude). This product was used in the next step without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.C(N(CC)CC)C.[NH2:28][C:29](C)([CH3:33])[C:30](O)=O>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:28][CH:29]([CH3:33])[CH3:30])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CC(C)(N)C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)Nc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol), triethylamine (0.43 mL; 3.1 mmol) and 2-aminoisobutyric acid (320 mg; 3.1 mmol) under microwave irradiation for 6 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-isopropylamino-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (28 mg, 29%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O (M+H+) 317.2336, found 317.2334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.55 mmol) (from Example 13, Step A, supra) and NH4Cl (0.24 g, 4.43 mmol) in a mixture of MeOH, H2O and CHCl3 (50 mL, 2:1:12) was added Zn powder (0.72 g, 11 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired N4-(4-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as a pale yellow gum. (Yield 0.16 g, 88%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH:18]([C:28]([NH2:30])=[O:29])[C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH3:17])[CH2:6][CH2:5]1.Cl>C(O)C>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH:18]([C:28]([NH2:30])=[O:29])[C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH3:17])[CH2:8][CH2:9]1
Reactant: CC(c1ccccc1N1CCC(=O)CC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1N1CCC(O)CC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An amount of 0.224 gm (5.92 m mol) of sodium borohydride was added in portions with stirring to a solution of 1 gm (2.63 m mol) of 4-[(1-(2-(4-oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 20 ml of absolute ethanol. After stirring for 1.5 hours at room temperature, the reaction mixture was adjusted acidic by means of 2N hydrochloric acid, evaporated in vacuo, mixed with water and ethyl acetate, and adjusted to a pH of 6 by means of 2N sodium hydroxide solution. After extraction several times with ethyl acetate, the organic phase was dried and filtered, and the extract was evaporated in vacuo. The evaporated in vacuo. The evaporation residue was recrystallized from petroleum ether.