Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1)=O.Cl.[NH2:32][OH:33].C(O)C.[OH-].[K+]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4](=[N:32][OH:33])[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3F)CC1)CCCC2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
To a solution of 7.0 g (0.0143 mole) of 3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 70 ml of pyridine, 5.4 g (0.0777 mole) of hydroxylamine hydrochloride and 100 ml of ethanol 1.6 g (0.0286 mole) of potassium hydroxide are added. The reaction mixture is heated to boiling for 10 hours, cooled to room temperature and the solvent is removed in vacuo. To the residue 100 ml of water are added and the mixture is extracted with 100 ml of dichloromethane. The organic phase is washed twice with 50 ml of water each, dried over anhydrous magnesium sulfate and evaporated. The residual crude product is recrystallized from ethyl acetate. Thus 4.2 g of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one are obtained. Yield 65.1%. According to HPLC analysis the purity of the product is 97.2%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[CH:39]>C(N(CC)CC)C.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>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[C:39][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: C#CCCCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C#CCCCCl)cc1)C(F)(F)F
Temperature: 55 °C

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-iodophenyl)acetamide (3.2 g, 10 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821), dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.2 mmol), triphenylphosphine (19 mg, 0.07 mmol), and copper (I) iodide (0.019 g, 0.1 mmol) in triethylamine (50 mL) was degassed under Argon for 10 minutes while stirring in a 55° C. oil bath. The mixture was then treated with 5-chloropentyne (1.1 mL, 10 mmol). After four hours of heating, the mixture was allowed to cool to room temperature and was then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the crude title compound, which was carried forward without further purification. ES/MS calcd. for C14H14ClF3NO+ : 290.1. found m/z=290.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:6][CH:7]=1.[NH:18]([C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[C:19]([NH2:21])=[NH:20].[OH-].[Na+]>CO.O>[N:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[NH:23][C:22]=1[N:18]=[C:19]1[NH:21][C:9]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:21][C:19](=[N:18][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[NH:20][C:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:20]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1cccc(Cl)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccc2)NC(=Nc2nc4ccccc4[nH]2)N3)c1

Procedure:
Following the procedure of Example 1, 1-(3-chlorophenyl)-2-phenylethanedione (0.25 g, 1.0 mmol) and 2-guanidinobenzimidazole (0.215 g, 1.2 mmol) in methanol (12 mL) was treated with a solution of sodium hydroxide (48 mg, 1.2 mmol) in 1.2 mL of water. The title compound was isolated as pale yellow crystals (130 mg, 39% yield). MS (ESI) m/z 559 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2OC)[C:3]=1[NH2:21].[C:22](=[O:25])([O-])[O-].[K+].[K+].Cl[C:29](OC1C=CC([N+]([O-])=O)=CC=1)=[O:30]>C(#N)C>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:21][C:22](=[O:25])[N:9]2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[C:15]([O:30][CH3:29])[CH:16]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: COc1ccc(CNc2nc(N)nc(Cl)c2N)c(OC)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)[nH]c3c(Cl)nc(N)nc32)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 6-Chloro-N4-[(2,4-dimethoxyphenyl)methyl]pyrimidine-2,4,5-triamine (8.4 g, 27.11 mmol), acetonitrile (400 ml), potassium carbonate (11.2 g, 81.33 mmol) and p-nitrophenyl chloroformate (11.0 g, 54.22 mmol) were stirred at 25° C. for 48 hours. Reaction mixture was cooled to room temperature and filtered through celite bed, washed with cold acetonitrile and evaporated to dryness to obtain pure 2-Amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7H-purin-8-one (9.0 g, 98%)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:13]([CH3:32])[C:14]([N:16]([CH3:31])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:35])([CH3:32])[C:14]([N:16]([CH3:31])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C(=O)N(C)c1ccccc1N(C)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1N(C)c1ccccc1

Procedure:
To a solution of 52 mg (0.11 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide in 0.5 ml N,N-dimethylformamide at 0° C. were added 32 mg (0.16 mmol) potassium hexamethyldisilazide. Stirring was continued for 1 h at this temperature and 30 mg (0.16 mmol) methyl iodide were added. After stirring for 3 h at room temperature, ethyl acetate was added. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 54 mg (quantitative) of the title compound as colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CCOC(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[N:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nnc2ccc(I)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(I)cc2c1O

Procedure:
A solution of ethyl 4-hydroxy-6-iodo-3-cinnolinecarboxylate (0.27 g, 0.79 mmol) and 4-chlorobenzylamine (3.50 mL, 28.77 mmol) is heated at 90° C. for 30 minutes. The reaction is cooled slightly and poured into 25 mL EtOAc. Hexanes are added to precipitate the product and the resulting solid is filtered and dried. The product is further purified by trituration with CH2Cl2/hexanes (0.29 g, 0.67 nmmol, 85%). Physical characteristics are as follows: m.p. 307-308° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.99, 8.47, 8.15, 7.57, 7.40, 4.55; IR (drift) 2972, 2958, 2901, 2846, 1645, 1601, 1557, 1488, 1458, 1356, 933, 922, 822, 806, 722 cm−1; MS (ESI) m/z 439.8 (M+H)+, 437.8 (M—H)−; Anal. Calcd for C16H11ClIN3O2: C, 43.71; H, 2.52; N, 9.56; Found: C, 43.94; H, 2.50; N, 9.43.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].ICCCCI.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: [Li]CCCC
Agent: ICCCCI
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N,N′N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dilute HCl (pH 1) and water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J7.5, 1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C@@H:39]2[CH3:44])[C:31]2[CH2:36][N:35]([CH3:37])[CH2:34][C:32]=2[N:33]=1>>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:28]3[N:29]=[C:30]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][C@@H:39]4[CH3:44])[C:31]4[CH2:36][N:35]([CH3:37])[CH2:34][C:32]=4[N:33]=3)=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(O)n3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3cccc(O)n3)cc2)nc2c1CN(C)C2
Yield: 9.2 %

Procedure:
Method as described for example 47 using 1-(6-hydroxypyridin-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and reduced in vacuo. The residue was purified by prep LCMS (high pH), to yield the title compound (7.9 mg, 0.017 mmol, 9.2%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([OH:42])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(N)ncnc2Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Oc3cc(O)cc(NS(C)(=O)=O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Yield: 31 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.27 mmol), 3-hydroxy-5-(methylsulfonamido)phenyl 4-amino-6-chloropyrimidine-5-carboxylate (104 mg, 0.29 mmol), DIEA (323 μl, 1.85 mmol) and cesium fluoride (121 mg, 0.80 mmol) were suspended in tert-butanol (8 ml) and the mixture was heated at 70° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 50 mg (31% yield) as a solid. Purity 97%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]CC)=O)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH2:14]([NH2:16])[CH3:15].C1COCC1>C(O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:16][CH2:14][CH3:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: CCN
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)c1nc(Br)ccc1N
Temperature: 120 °C
Yield: 70 %

Procedure:
A stirred suspension of ethyl 3-amino-6-bromopyridine-2-carboxylate (5 g, 20.3 mmol) in ethanol (40 mL) in a steel bomb was treated with a 2M solution of ethylamine in THF (220 mL, 440 mmol) and heated to 120° C. for 2 days. The reaction mixture was cooled to RT, the solvents were evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, 0.5% methanol in dichloromethane) to give 3.5 g (70%) of the required material as white solid 1H NMR (400 MHz, CDCl3) δ 7.77 (brs, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 5.99 (brs, 2H), 3.4 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11](C=O)[CH:12]=[O:13])=[N:6][C:5]=1[Cl:16].O.C(O)=O>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[Cl:16]
Reactant: COC(=O)c1ccc(CN(C=O)C=O)nc1Cl
Solvent: O
Solvent: O=CO
Solvent: CO
Product: COC(=O)c1ccc(CNC=O)nc1Cl

Procedure:
To a solution of 2-chloro-6-diformylaminomethylnicotinic acid methyl ester (53.0 g, 0.21 mol) in methanol (300 mL) was added water (3.72 mL, 0.21 mol) and formic acid (15.6 mL, 0.42 mol) before the reaction mixture was heated at reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL). The resultant solution was washed with water (200 mL) and the aqueous layer extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as an orange oil which solidified on standing (42.6 g, 90%). 1H NMR (CDCl3, 400 MHz) 8.34 (1H, s), 8.17 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=7.8 Hz), 6.63 (1H, br s), 4.63 (2H, d, J=5.6 Hz), 3.96 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3Cl)ccc2sc1=O

Procedure:
6-(2-Chloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-chloro-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.412 (s, 1H), 7.697 (d, 1H), 7.490-7.305 (m, 5H), 4.018 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]>C(Cl)Cl>[Br:24][CH2:20][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CCBr
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Triphenylphosphine (39.2 g, 0.150 mol) and carbon tetrabromide (49.5 g, 0.150 mol) were added sequentially to a solution of 2-(2-hydroxyethyl)-nitrobenzene (25.0 g, 0.150 mol) in methylene chloride (400 mL) at 0° C. The reaction was stirred overnight and quenched with saturated sodium bicarbonate solution. The methylene chloride phase was washed with saturated brine and dried over magnesium sulfate. The crude product was treated with ethyl acetate, and the precipitated triphenylphosphine oxide removed by filtration. Further purification by flash chromatography by (silica gel, 0–10% ethyl acetate in hexane gradient elution) produced the title compound (27.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=O)[CH:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(O)(=O)C.CO>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1
Reactant: C1COCCN1
Reactant: O=CCC(c1ccccc1)n1cc(Br)cn1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnn(C(CCN2CCOCC2)c2ccccc2)c1

Procedure:
A suspension of EXAMPLE 77C (150 mg), morpholine (0.117 mL), acetic acid (0.062 mL) and solid-supported MP-CNBH3 (Argonaut Technologies, 885 mg, 2.63 mmol/g) in dichloromethane (4 mL) and methanol (2 mL) was shaken at room temperature for 18 hours. The reaction mixture was filtered, concentrated and purified by RP HPLC (30-100% CH3CN/water/0.1% TFA) to provide the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1(=[O:19])[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][NH:9]1.Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(O)C>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:29]=[CH:30][C:21]=1[N:16]1[CH2:17][CH2:18][C:13]2([C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: O=C1NCCCC12CCNCC2
Reactant: Clc1cnc2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 160 °C
Yield: 78.1 %

Procedure:
The mixture of 2,9-diazaspiro[5.5]undecan-1-one TFA salt ([1190586-22-1], 1.0 g, 3.5 mmol), 2-chloroquinoxaline ([1448-87-9], 0.77 g, 4.6 mmol), DIPEA (3.7 ml, 21 mmol) and DMAP (22 mg, 0.18 mmol) in ethanol (10 ml) was placed in a microwave tube. The tube was sealed and the suspension was heated at 160° C. for 2 h under microwave conditions. The mixture was filtered and the residue washed with ethanol. The filtrate was concentrated and the precipitate filtered and washed with ethanol. The combined solid material was dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.81 g (77%) of the title compound as a pale yellow solid which was not further purified. [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.79 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.53-7.58 (m, 2H), 7.31-7.39 (m, 2H), 4.22 (dt, J=13.5, 4.4 Hz, 2H), 3.37-3.49 (m, 2H), 3.06-3.15 (m, 2H), 1.91-2.05 (m, 2H), 1.75-1.83 (m, 2H), 1.65-1.75 (m, 2H), 1.44-1.55 (m, 2H); LCMS RtB=2.80 min, [M+H]+=297.2].
Reaction SMILES: [NH2:1][OH:2].[C:3](Cl)(=[O:7])[C:4]([CH3:6])=[CH2:5].Cl.NO.Cl>N1C=CC=CC=1>[C:3]([NH:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: NO
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)NOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,O-dimethacryloylhydroxylamine was prepared by the reaction of hydroxylamine with methacryloyl chloride in pyridine medium. Hydroxylamine hydrochloride (10 g; 0.144 mol) was dissolved in 50 ml pyridine (0.632 mol) and 25.4 g (0.243 mol) methacryloyl chloride was dropwise added. Temperature of the reaction mixture was kept below 45° C. After completed addition of methacryloyl chloride, the mixture was stirred at ambient temperature for 2 hours. Then, the mixture was diluted with 100 ml dropwise added in order to transfer pyridine to its hydrochloride. The organic layer was separated, washed four-times with 100 ml water, and then dried over MgSO4. Chloroform was evaporated in vacuum and the oily residue was dried in vacuum of an oil pump. The product crystallized during drying, the crystals were filtered and twice recrystallized from the mixture diethyl ether - light petroleum. The yield was 7.0 g (34%) N,O-dimethacryloylhydroxylamine, m.p. 55° C., elemental analysis; calculated C- 56.70, H - 6.55, N - 8.28%; found C - 56.74, H - 6.22, N - 8.34%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH:34]5[CH2:39][CH2:38][N:37]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(CC(F)(F)F)CC1
Yield: 11 %

Procedure:
The title compound was prepared as described in Example 103C, using 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea (0.213 g, 0.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at room temperature for 4 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC (C18 column and 60-90% MeCN/H2O with 0.05% AcOH) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]quinazolin-4-yloxy}phenyl)urea as a solid (0.027 g, 11%). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 8.61 (s, 1H), 7.66 (t, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.31 (m, 2H), 7.02 (d, 1H), 5.83 (s, 1H), 4.60 (m, 1H), 4.04 (s, 3H), 3.04 (q, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.15 (m, 2H), 2.02 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 615 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2].C[I:19].[I-].[NH+]1C=CC=C[CH:22]=1>CC(C)=O>[I-:19].[CH:1]([NH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:22])=[O:2]
Reactant: CI
Reactant: O=CNc1ccccc1CCc1ccccn1
Reactant: c1cc[nH+]cc1
Agent: [I-]
Solvent: CC(C)=O
Product: C[n+]1ccccc1CCc1ccccc1NC=O
Temperature: 5 °C

Procedure:
A solution of 2-(o-formamidophenethyl)pyridine (55 g., 0.243 mole) and methyl iodide (38 g., 0.268 mole) in 500 ml. of acetone is refluxed for 20 hours. The mixture is cooled at 5°C. and filtered to provide 82 g. (92%) of the pyridinium iodide having melting point of 199.5°-201.5°C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]=1[CH3:12]>C(Cl)Cl.N1C=CC=CC=1.O>[Cl:3][CH2:6][C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)oc2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(CCl)oc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (1.48 g, 12.4 mmole) was added dropwise to a solution of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmole) in methylene chloride (10 ml) and pyridine (2 drops) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with water, the organic phase separated, and the aqueous phase re-extracted with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate, dried (Na2SO4) and the solvent evaporated to leave the title compound, 0.93 g. A portion was recrystallised from ethanol, m.p. 141°-142°.