Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[H-].[Na+].Br[CH2:30][C:31]([NH2:33])=[O:32]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:22]3[CH:23]=[N:24][N:25]([CH2:30][C:31]([NH2:33])=[O:32])[CH:26]=3)=[CH:15]4)=[N:9][N:10]=2)[N:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cn[nH]c5)cc4c3)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CC(N)=O)c5)cc4c3)n2n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
6-(6-Methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1H-pyrazol-4-yl)-quinoline (65 mg, 0.19 mmol, 1 equiv) was dissolved in dimethylformamide (0.5 mL) and NaH (60% in oil, 1.2 equiv, 0.228 mmol, 9 mg) was added. The solution was stirred under nitrogen for 30 min and then 2-bromoacetamide (26 mg, 0.19 mmol, 1 equiv) was added and the solution heated at 90° C. for 18 h. The product was extracted into dichloromethane and washed with water. The organic phase was concentrated to dryness to afford the title compound (40 mg, 52% yield). Analytical data presented in Table 2.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2cnc3ccccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-hydroxyphenoxy)quinoline (2.4 g), ethyl 2-bromopropionate (2.1 g), anhydrous potassium carbonate (3.3 g) and dimethylformamide (50 ml) was stirred and heated at 80° C. for 4 hours. The mixture was poured into water (500 ml) and extracted with diethyl ether (2×100 ml). The ether extracts were dried, evaporated to dryness and then chromatographed on silica gel (100 g) with dichloromethane elution. Ethyl 2-[4-(3-quinolinyloxy)phenoxy]propionate was obtained as a pale yellow oil (1.9 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.75 (1H, d); 8.1 (1H, bd); 7.7-7.3 (4H, m); 7.0 (4H, s, phenoxy protons); 4.75 (1H, q, CH-CH3); 4.25 (2H, q, OCH2 -CH3); 1.65 (3H, d, CH-CH3); 1.25 (3H, t, OCH2 -CH3).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.CCOCC.C(OCC)(=O)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccnc4)ccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
A stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-(tributylstannyl)-benzimidazol-1-yl]pyrimidine (27 mg), 3-bromopyridine (44 μL) and tetrakis(triphenylphosphine)palladium(0) (0.5 mg) in DMF (4 mL) was heated and maintained at 100° C. overnight. The reaction mixture was cooled and transferred to a separatory funnel containing 100 mL ether plus 25 mL ethyl acetate. The organic layer was washed 3× with water and 1× with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with methanol in dichloromethane to give 9.1 mg of the title compound. Mass spectrum (ESI): 393.2 (M+1).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NCCCCCCOc1ccc(OCCN2CCOCC2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2ccc(OCCN3CCOCC3)cc2)c(Nc2ccncc2)c1=O
Yield: 64 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-[4-(2-morpholin-4-yl-ethoxy)-phenoxy]-hexylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C1CCNCC1
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCCCC2)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
To a suspension of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (76 mg, 0.18 mmol) in dimethylformamide (2 mL) was added under nitrogen at 0° C. piperidine (30 mg, 0.35 mmol) and triethyl amine (36 mg, 0.35 mmol). The reaction was stirred at room temperature over night. Piperidine (30 mg, 0.35 mmol) was added and the reaction stirred at room temperature for 3 hours. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (19:1:0.2 v/v/v) as eluent to yield the title compound (13 mg, 18%) as an orange solid. MS ISP (m/e): 334.3 (27), 419.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.60 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.60 (d, 1H), 7.19 (d, 1H), 7.03 (s, 1H), 3.80 (s, 3H), 3.63 (m, 1H), 3.05 (m, 1H), 2.55-2.80 (m, 2H), 2.25 (m, 2H), 2.14 (s, 3H), 1.89 (m, 2H), 1.38-1.68 (m, 8H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][CH:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[C:16]4[N:17]([N:38]=[CH:39][CH:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 52%).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[CH2:9][CH2:10][CH2:11][CH2:12]Br.O>CN(C)C=O>[C:5]([C:4]1([C:3]#[N:7])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[N:6]
Reactant: N#CCC#N
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(C#N)CCCC1
Reaction time: 8 h

Procedure:
Sodium hydride (37.8 g; 0.94 moles) was suspended in dimethylformamide (250 mL) under an atmosphere of N2. A solution of malononitrile (30 g; 0.45 moles) and 1,4-dibromobutane 99.7 g; 0.45 moles) in dimethylformamide (150 mL) was added dropwise at such a rate so as not to exceed 30° C. The mixture was stirred for overnight, poured into H2O (500 mL), and then washed with two portions of ethyl ether. The organics were combined, washed with brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo, leaving a bilayered liquid. The lower portion was separated (28.8 g) and identified as the desired product.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][CH:21]([CH3:23])[C:20](=[O:24])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CN(C)C=O>[CH2:7]([S:14][C:15]1[N:16]=[C:17]2[S:22][C:21]([CH3:23])=[C:20]([O:24][CH3:1])[N:18]2[N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1Sc2nc(SCc3ccccc3)nn2C1=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1c(C)sc2nc(SCc3ccccc3)nn12
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide (2.6 g) was added to a solution of the product of stage (b) in dimethylformamide (30 ml) with stirring and cooling. After 10 minutes, this solution was treated with dimethyl sulphate (2.8 g) and stirring was continued for 4 hours. Addition to ice/water/ether and filtration gave 2.3 g of desired product, mp 101°-103° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([SH:23])[CH:20]=[CH:21][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[S:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([OH:16])[CH:18]=1
Reactant: Oc1cccc(S)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Sc3cccc(O)c3)c2cc1OC
Temperature: 40 °C
Yield: 92.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol), (prepared as described for the starting material in Example 1), was added to a solution of 3-hydroxybenzenethiol (168 mg, 1.3 mmol) and N,N-diisopropylethylamine (233 μl, 1.3 mmol) in DMF (5 ml). After heating at 40° C. for 10 minutes, the reaction mixture was allowed to cool, diluted with water, acidified to pH3 and the mixture extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was recrystallised from a mixture of ethanol and ether to give 6,7-dimethoxy-4-(3-hydroxyphenylthio)quinazoline (259 mg, 93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].C(O)C.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>O>[Br:1][C:2]1[C:10]2[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13]
Reactant: NCc1ccccn1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1sc2nc(Cl)nc(NCc3ccccn3)c2c1Br
Temperature: 60 °C
Yield: 79.9 %

Procedure:
A stirred mixture of 5-bromo-2,4-dichloro-6-methylthieno[2,3-d]pyrimidine (1.0 g, 3.35 mmol), ethanol (40 ml), 2-aminomethylpyridine (0.40 ml, 3.69 mmol) and triethylamine (0.50 ml, 3.69 mmol) was heated at a temperature of 60° C. for 1 hour. The reaction mixture was then cooled to ambient temperature, diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by flash chromatography (silica) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane gave (5-bromo-2-chloro-6-methylthieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a white solid (0.99 g).
Reaction SMILES: I[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)CC)C.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:22]([OH:26])([C:24]#[C:25][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7])[CH3:23]
Reactant: C#CC(C)(C)O
Reactant: Cc1onc(-c2ccccc2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#CC(C)(C)O
Temperature: 90 °C
Reaction time: 1.75 h
Yield: 77.7 %

Procedure:
A mixture of 4-iodo-5-methyl-3-phenylisoxazole (5.73 g, 20.1 mmol), palladium(II) acetate (135 mg, 0.60 mmol), 1,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol) and 2-methyl-3-butyn-2-ol (3.0 mL, 30.7 mmol) in N,N-dimethylformamide (40 mL) was evaporated and flushed with argon. Cuprous iodide (77 mg, 0.40 mmol) was added and the reaction mixture was stirred for 23 h at 90° C. (after 1.75 h and 4.5 h, respectively, further palladium(II) acetate (135 mg, 0.60 mmol), 1,3-bis(diphenylphosphino)propane (249 mg, 0.60 mmol), triethylamine (7.0 mL, 50.2 mmol), 2-methyl-3-butyn-2-ol (3.0 mL, 30.7 mmol) and cuprous iodide (77 mg, 0.40 mmol) were added) before cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 600 mL) and ethyl acetate (1000 mL). The aqueous layer was extracted with ethyl acetate (1000 mL) and washed with aqueous sodium hydroxide (1 M, 600 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=67:33) afforded the title compound (3.77 g, 78%) as a yellow oil. MS: m/e=242.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH3:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:18][Mg]Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][C:17]([CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-methyl-2-phenylpropylmagnesium chloride.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[F:36])=[O:28]>CC#N>[Cl-:25].[F:36][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:30]=1[NH:29][C:27]([CH2:26][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2)=[O:28]
Reactant: O=C(CCl)Nc1ccncc1F
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccncc1F
Product: [Cl-]

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N-(3-fluoro-pyridin-4-yl)-acetamide (Example 54a) ( mmol) in MeCN (1.5 mL) were stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeH/dichloromethane to give the title compound a white solid (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 4.26 g of 3,4-dichlorobenzaldehyde and 3.0 g of 2,4-pentanedione. Yield 1.3 g, mp 73° C.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[CH2:36]([NH2:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(OCC)(=O)C>CO>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:48][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:6]=1
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCNc1nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
Following the procedure of Example 1, 2,4-bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (5.2 g) was reacted with dodecylamine (2.8 g) to afford an oily product. It was treated with alumina column chromatography (eluent=ethyl acetate:methanol=10:1) and the resulting crystals were recrystallized from n-hexane to afford the desired product as white crystals melting at 107°-109° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C[O:23][CH:24]=[C:25]([C:30](OC)=O)[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[O:23]=[C:24]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:30]=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.05 g) and dimethyl methoxymethylenepropanedioate (6.48 g) in N,N-dimethylformamide (28 ml) was stirred at 100° C. for 1 hour and 10 minutes. After cooling to ambient temperature, water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol, treated with activated charcoal, and evaporated under reduced pressure until crystallizaton began. After cooling, the resulting solid was collected, washed with methanol and with dichloromethane, and dried. There was obtained crystalline methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.16 g). The filtrate was evaporated under reduced pressure to give a residue which was chromatographed on silica gel with 1% methanol-dichloromethane. The first fractions contained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.9 g). The second fractions contained dimethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (5.16 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].ClCCl.CCN(C(C)C)C(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[CH3:27][S:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(CCO)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cccc(CCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
Ethyl 3-(2-hydroxyethyl)benzoate (824 mg) was mixed with dichloromethane (10 ml), DIPEA (1.5 ml) was added thereto, and methanesulfonyl chloride (972 mg) was added dropwise thereto at 0° C., followed by stirring for 1.5 hours while slowly warming to room temperature. Water was added to the reaction mixture, followed by stirring for 10 minutes, and then the organic layer was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (1.12 g).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:14][C:15]1[N:20]=[C:19]([Cl:21])[C:18]([NH2:22])=[CH:17][CH:16]=1.O>CC(C)=O>[Br:14][C:15]1[N:20]=[C:19]([Cl:21])[C:18]([NH:22][C:2]([NH:3][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:1])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Br)nc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccc(Br)nc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of ammonium thiocyanate (0.4 g, 5.0 mmol) in acetone (5 mL) was slowly added benzoyl chloride (0.6 mL, 5.0 mmol) and the suspension was heated to reflux for ten minutes. A solution of 6-bromo-2-chloro-3-pyridinamine (1.0 g, 4.8 mmol) in acetone (10 mL) was then added and the reaction mixture was refluxed for one hour. After cooling to room temperature the mixture was poured into water and partitioned with ethyl acetate (250 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (2×, 100 mL). The combined organic layers were washed with brine (2×, 100 mL), dried over sodium sulfate, filtered and concentrated until a suspension formed. The white solid was collected by filtration to give N-(6-bromo-2-chloropyridin-3-ylcarbamothioyl)benzamide (1.6 g, 89%). 1H NMR (400 MHz, d6-DMSO): 12.62 (br s, 1H), 12.00 (br s, 1H), 8.37 (d, 1H), 8.00 (2d, 2H), 7.79 (d, 1H), 7.69 (t, 1H), 7.57 (t, 2H). MS (EI) for C13H9BrClN3OS: 370 (MH+).