Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N:7]1[C:14](=[O:15])[CH2:13][C:11](=O)[N:10]([CH3:16])[C:8]1=[O:9].CN(C)[CH:19]=[O:20]>>[Cl:3][C:11]1[N:10]([CH3:16])[C:8](=[O:9])[N:7]([CH3:6])[C:14](=[O:15])[C:13]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
Phosphorous oxychloride (690 ml) was added slowly to dry N,N-dimethyl formamide (180 ml) at 0° C. The mixture was then allowed to warm to room temperature. 1,3-Dimethylbarbituric acid (60 g, 384.27 mmol) was added portion wise and refluxed for 45 min. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure and the viscous residue was poured into ice-cold water (2000 ml). The reaction mixture was allowed to room temperature and extracted with chloroform (3×500 ml).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4]C=[CH:6][CH:7]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]3[CH2:29][NH:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:13]1)[CH:9]([CH3:11])[CH3:10].[NH:30]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:10][CH:9]([CH3:11])[CH2:8][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]3[CH2:27][N:28]([C:7]4[CH:2]=[CH:3][N:4]=[N:30][CH:6]=4)[CH2:29]3)=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: Brc1cccnc1
Reactant: CC(C)Cn1cc(-c2ccc(NC(=O)C3CNC3)cc2)cn1
Product: CC(C)Cn1cc(-c2ccc(NC(=O)C3CN(c4ccnnc4)C3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 4-bromopyridazine for 3-bromopyridine and N-(4-(1-isobutyl-1H-pyrazol-4-yl)phenyl)azetidine-3-carboxamide for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.51 (d, J=3.0 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.64-7.56 (m, 2H), 7.55-7.48 (m, 2H), 6.55 (dd, J=6.0, 3.0 Hz, 1H), 4.31-3.96 (m, 4H), 3.91 (d, J=7.1 Hz, 2H), 3.74 (s, 1H), 2.12 (dd, J=13.3, 6.5 Hz, 1H), 0.86 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 377 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: CC1=NN(C)C(C(=O)O)C1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)C1
Yield: 71.7 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (120 mg, 0.87 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol), N,N-diisopropylethylamine (240 mg, 1.8 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (199 mg, 72%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([OH:12])=O)[CH2:2]1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:28][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:10]([CH:3]2[CH2:2][C@H:1]([CH3:13])[CH2:6][CH2:5][C@H:4]2[CH:7]([CH3:8])[CH3:9])=[O:12])=[CH:20][CH:21]=1
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Reactant: NC(=O)Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)CC1C(=O)Nc1ccc(CC(N)=O)cc1
Temperature: 25 °C

Procedure:
The p-Menthane-3-carboxylic acid (obtained according to publication: Desmond Cunningham, Eva T. Gallagher, David H. Grayson, Patrick J. McArdle, Christina B. Storey, Deborah J. Wilcock; J. Chem. Soc., Perkin Trans. 1, 2002, 2692-2698), (2.5 g, 13.5 mmol) was heated under reflux with thionyl chloride (Alfa Aesar) (7 mL) for three hours. Then the excess of thionyl chloride was distilled off in vacuo. Residue was dissolved in CH2Cl2 (30 mL). This solution was added drop wise to the mixture of 4-aminophenylacetamide (2.2 g, 13.5 mmol) and triethylamine (1.8 g, 17.8 mmol) at 0° C. After ten minutes the solution was allowed to warm to room temperature. After 1 hour GC showed that reaction is completed. CH2Cl2 (50 mL) was added to the reaction and this mixture was washed by 0.1 N HCl aq, water, 0.1 N NaOH aq, by brine and dried over MgSO4. The mixture was then filtrated and evaporated give white solid which was crystallized from hot ethyl acetate providing 3 g (65%) product as white solid. C19H28N2O2 (MW 316.22); 1H NMR (500 MHz, DMSO-d6) δ: 9.79 (s, 1H), 7.51 (d, 2H, J=8.41), 7.36 (br s, 1H), 7.15 (d, 2H, J=8.41 Hz), 6.82 (br s, 1H), 3.30 (s, 2H), 2.30 (t, 1H, J=11.43 Hz of d, J=3.19 Hz), 1.70-1.77 (m, 2H), 1.61-1.68 (m, 2H), 1.51 (t, 1H, J=11.5 Hz, of t, J=2.8 Hz), 1.33-1.38 (brs, 1H), 1.17 (q, 1H, J=12.16 Hz), 1.02 (q, 1H, J=12.7 Hz, of d, J=2.7 Hz) 0.89-0.96 (m, 1H), 0.88 (d, 3H, J=6.5 Hz), 0.85 (d, 3H, J=6.9 Hz), 0.79 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:35][NH:36][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2Cc3ccccc3C2=O)ccc1OC
Yield: 75.1 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.78 g, 5.00 mmol), N,N′-carbonyldiimidazole (850 mg, 5.24 mmol) and O-benzylhydroxylamine hydrochloride (940 mg, 5.89 mmol) in tetrahydrofuran (10 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (1.73 g, 75% yield): mp, 132.0-133.0° C.; 1H NMR (DMSO-d6) δ1.29 (t, J=6.9 Hz, 3H, CH3), 2.83 (d, J=7.8 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.93-4.02 (m, 2H, CH2), 4.09 (d, J=17.5 Hz, 1H, NCHH), 4.51 (d, J=17.5 Hz, 1H, NCHH), 4.59 (d, J=11.3 Hz, 1H, PhCHH), 4.66 (d, J=11.2 Hz, 1H, PhCHH), 5.74 (t, J=7.8 Hz, 1H, NCH), 6.83-6.93 (m, 3H, Ar), 7.21-7.29 & 7.45-7.59 (m, 8H, Ar), 7.68 (d, J=7.4 Hz, 1H, Ar), 11.17 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 35.08, 46.18, 51.29, 55.43, 63.71, 76.69, 111.82, 112.11, 119.25, 122.82, 123.44, 127.85, 128.17, 128.75, 131.31, 131.61, 132.17, 135.86, 141.68, 147.88, 148.45, 166.26, 166.88. Anal. Calcd for C27H28N2O5: C, 70.42; H, 6.13; N, 6.08. Found: C, 70.31; H, 6.07; N, 5.88.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
50 g (0.247 mol) of 1-chloro-2,4-dinitrobenzene, 73.5 g (0.74 mol) of cyclohexylamine, 68 g (0.5 mol) of potassium carbonate and 20 ml of water were heated in 400 ml of dimethylformamide at 80°-90° C. for 3 h. The mixture was then concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure to yield 63.9 g (98%) of the product. Melting point 155° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([O:1][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
A mixture of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (53 mg, 0.23 mmol), ethyl 2-bromoisobutyrate (69 uL, 0.47 mmol), cesium carbonate (166.8 mg, 0.5119 mmol), and 1,4-dioxane (2.0 mL, 26 mmol) was heated in a sealed vial at 100° C. for 22 hours. The reaction mixture was poured into ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 63.4 mg (80%) of ethyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)-2-methylpropanoate which was carried forward without purification. LCMS (ESI): M+H=343.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1cnc2ccccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cnc3ccccc3n2)n1
Reaction time: 0.25 h

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (104 mg, 0.55 mmol) and 2-but-3-ynyl-quinoxaline (100 mg, 0.55 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 116 mg (0.40° mmol, 72%) of 2-(6(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as an orange solid (M.P.: 136° C. dec.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:7]3[C:6]4[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:28][CH:27]=2)=[O:25])=[CH:34][CH:35]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 3-methylxanthine (1.06 g) in DMF (26 ml) were added potassium carbonate (1.06 g) and 4-(4-chlorobenzoyl)benzyl bromide (1.98 g) and the mixture was stirred at room temperature for 24 hours. To this reaction mixture were added water and ethyl acetate and the floating matter was filtered off and the filtrate aqueous solution was diluted with 1N-hydrochloric acid and extracted with chloroform. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ethyl acetate to provide the title compound as colorless powder (239 mg, 10%). 1H-NMR (CDC13) 8: 3.54(3H,s), 3.57(3H,s), 7.41-7.52(4H,m), 7.68-7.81(5H,m).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[CH3:20][N:21]([CH3:31])[C:22]([CH2:24][C:25]1[S:26][C:27]([SH:30])=[N:28][N:29]=1)=[O:23].P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:30][C:27]3[S:26][C:25]([CH2:24][C:22]([N:21]([CH3:20])[CH3:31])=[O:23])=[N:29][N:28]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN(C)C(=O)Cc1nnc(S)s1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 10 °C
Yield: 87.7 %

Procedure:
Mixed were 1.36 g of 7-ACA, 0.36 g of water and 1.32 g of 2-dimethylaminocarbonylmethyl-5-mercapto-1,3,4-thiadiazole, and 6.5 ml of acetonitrile was added. 5.04 g of diphosphoryl tetrachloride was added through a dropping funnel to the mixture at -20° to -30° C., followed by rinsing the funnel with 1.5 ml of acetonitrile. The reaction mixture was warmed at 10° C. over a period of 5 minutes with stirring, placed in a warm water bath of 40° C. and stirred at the same temperature for 20 minutes. The reaction solution was cooled with ice and adjusted to pH 4.1 with aqueous concentrated ammonia after the addition of 10 ml of cold water. The precipitate was recovered by filtration, washed with water and dried, thereby affording 1.82 g (87.6%) of 7-amino-3-(2-dimethylaminocarbonylmethyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26]2)=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26]4)=[CH:23][N:24]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Reactant: Nc1ccc(N2CCNC(=O)C2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNC(=O)C4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (22 mg, 0.1 mmol), 4-(6-aminopyridin-3-yl)piperazin-2-one 141-4 (19 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (40 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (52 μL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(3-oxopiperazin-1-yl)pyridin-2-yl)acetamide 141. MS m/z 402.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.53 (s, 1H), 8.49 (d, 1H), 8.05-8.01 (m, 2H), 7.94 (d, 1H), 7.75 (d, 2H), 7.57 (s, 1H), 7.48-7.48 (m, 3H), 7.41 (dd, 1H), 3.74 (s, 1H), 3.71 (s, 2H), 2.54-2.50 (m, 7H), 1.24 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[B-](Br)(Br)(Br)[S+](C)C.C(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CNc1nc2c(OCc3ccccc3)cccc2n1C
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNc1nc2c(O)cccc2n1C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a suspension of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (150 mg) in dichloromethane (2 ml) was added boron tribromide-methyl sulfide complex (211 mg) in dryice-aceton bath, and the mixture was stirred for 1 hour under ice-cooling and then at ambient temperature overnight. To the reaction mixture were added chloroform-methanol (3:1, v/v) and saturated sodium bicarbonate solution, and insoluble material was filtered off. The separated organic layer was concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=8:1, v/v) to give 4-hydroxy-1-methyl-2-methylamino-1H-benzimidazole (49 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)N=2)=[CH:6][CH:5]=1)[CH3:2].ClC1N=C(N[C:37]2[CH:42]=CC(OCCCCCC)=[CH:39][CH:38]=2)C(F)=CN=1.[CH2:51]1COC2C=CC(N)=CC=2O1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[CH:51]=2)=[CH:6][CH:5]=1)[CH2:2][CH2:42][CH2:37][CH2:38][CH3:39]
Reactant: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CCCCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Product: CCCCCCOc1ccc(Nc2cc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparartion of N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyrimidineamine with 3,4-ethylenedioxyaniline gave N4-(4-n-hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine. The crude product was purified by chromatography (2:1 CHCl3/EtOAc) (0.22 g, 69%) as a tan solid: Rf 0.54 (4:1 CHCl3/EtOAc); mp 124.0-125.2° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=3.2 Hz, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.18 (d, J=2.4 Hz, 1H), 6.91-6.86 (m, 3H), 6.78-6.74 (m, 2H), 6.62 (d, J=1.8 Hz, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J=6.5, 2H), 1.83-1.74 (m, 2H), 1.51-1.42 (m, 2H), 1.36-1.32 (m, 4H), 0.93-0.89 (t, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.5, 143.5, 143.0, 142.8, 140.2, 139.9, 139.5, 139.2, 133.9, 130.7, 123.1, 117.1, 115.0, 113.5, 109.3, 68.5, 64.7, 64.5, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR) 3378 cm−1; ESI MS m/z 439 [C24H27FN4O3+H]+; HPLC (Method A) >99% (AUC), tR=14.6 min. Anal. Calcd for C24H27FN4O3: C, 65.74; H, 6.21; N, 12.78. Found: C, 65.52; H, 6.23; N, 12.66.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:19]=[CH:18]2>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:27])=[O:26])[CH:19]=[CH:18]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Product: Cl
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Yield: 58 %

Procedure:
Using analogous procedures to those described in two of the paragraphs of the portion of Example 50 which is concerned with the preparation of starting materials, 1-tert-butoxycarbonylpiperazine was reacted with 6-chloronaphth-2-ylsulphonyl chloride to give 1-(6 -chloronaphth-2-ylsulphonyl)piperazine hydrochloride salt in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:16]=3)=[C:4]2[CH:3]=1.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[C:13]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[CH:31][CH:32]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[N:16]=3)=[C:4]2[CH:3]=1
Reactant: BrCC1CC1
Reactant: Oc1ccc(-c2nn3c(NC4CC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1cc(NC2CC2)n2nc(-c3ccc(OCC4CC4)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 4-[5-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol (110 mg, 0.24 mmol) in acetonitrile was added bromomethyl cyclopropane (96 mg, 0.72 mmol) and cesium carbonate (85 mg, 0.26 mmol). The reaction mixture was heated at reflux for 6 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (2:5 hexanes/ethyl acetate), gave 5-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (75 mg, 61%) as a yellow solid. 1H NMR (CDCl3) δ 7.97 (d, 1H), 7.90 (s, 1H), 7.50 (d, 2H), 6.95 (d, 2H), 6.38 (s, 1H), 6.32 (d, 1H), 6.28 (d, 1H), 5.13 (d, 1H), 4.36 (m, 1H), 3.85 (d, 2H), 2.64 (m, 1H), 2.10 (m, 2H), 1.80–1.66 (m, 4H), 1.55 (m, 2H), 1.30 (m, 1H), 0.88 (m, 2H), 0.74 (m, 2H), 0.66 (m, 2H), 0.39 (m, 2H). MS m/z 515 (M+1).
Reaction SMILES: C(OC([NH:11][C:12]([CH3:28])([CH3:27])[CH:13]=[C:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15](OC)=[O:16])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:27][C:12]1([CH3:28])[NH:11][C:15](=[O:16])[CH:14]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13]1
Reactant: COC(=O)C(=CC(C)(C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(NC(=O)OC(C)(C)C)C(=O)N1
Yield: 89.9 %

Procedure:
A solution of methyl 4-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate (which may be prepared as described in Description 35) (2499 mg, 6.37 mmol) in methanol (125 mL) was passed over a 10% Pd/C cartridge on an H-Cube under full hydrogen flow at 25° C. The methanol solution evaporated to give tert-butyl N-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)carbamate (D36) (1307 mg, 5.7252 mmol, 89.9% yield);
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH:9]([CH3:10])[C:8](=[O:11])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrBr
Reactant: CCOC(=O)C(C)C(=O)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-methyl-3-oxopentanoate (5.0 g, 34.7 mmol) in chloroform at 0° C. was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, and concentrated to give the title compound. 1HNMR (500 MHz, CDCl3), δ4.781-4.740 (dd, J=6.6 Hz, 1H), 4.140-4.098(dd, J=7.0 Hz, 1H), 3.770 (s, 3H), 1.797-1.783(d, J=6.6 Hz, 3H), 1.455-1.442 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:7][C:8](=[S:11])[NH:9][N:10]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: COc1ccc(Cc2n[nH]c(=S)[nH]2)c(OC)c1
Reactant: BrCc1ccccn1
Agent: Br
Product: COc1ccc(Cc2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Yield: 34 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,4-dimethoxybenzyl)-2H-1,2,4-triazole-3(4H)-thione (example 9a) and 2-(bromomethyl)pyridine hydrobromide. Yield 34%. 1H NMR (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.79 (s, 3H), 4.0 (s, 2H), 4.34 (s,2H), 6.35-6.45 (m, 2H), 7.1 (d, 1H), 7.15 (t, 1H), 7.3 (d, 1H), 7.7 (t, 1H), 8.5 (s, 1H). MS(M+H, 343).