Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(Cl)(Cl)[Cl:22]>O1CCOCC1>[ClH:22].[CH3:16][N:15]([CH3:17])[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:18]
Reactant: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1
Product: Cl
Yield: 71 %

Procedure:
General procedure B was followed using tert-butyl-4-(dimethylcarbamoyl)piperidine-1-carboxylate 2 (0.16 g, 0.60 mmol), MeOH (2.5 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (2.5 mL) to furnish the title compound as a pale yellow oil (67 mg, 71%), umax (CHCl3)/cm−1 3003, 2947, 1625, 1497, 1401, 1320, 1240, 1137, 1105; m/z (ESI) C8H17N2O requires 157.1335, found [M+H]+ 157.1338.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]F)=[CH:25][CH:24]=3)[C:12]2=[O:35])=[CH:4][CH:3]=1.[CH3:37][NH:38][CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[C:12](=[O:35])[N:13]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:38]([CH3:37])[CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42])=[CH:27][CH:28]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CNCCS(=O)(=O)O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCF)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCN(C)CCS(=O)(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate were then added. The mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product (50 mg) as an oil.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:25](O)=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=[N:43]C2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:30])=[O:31])[C:25]([NH2:43])=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid (61 mg, 0.11 mol), HOAt (18 mg, 0.12 mmol), i-Pr2NEt (60. mL, 0.45 mmol), NH4Cl (25 mg, 0.45 mmol), and EDCI (24 mg, 0.12 mmol) in 5 mL DMF was stirred for 24 h at RT. The reaction mixture was concentrated, taken up in H2O, and the white solid was filtered and air-dried to afford the title compound. MS (m/z, m+1): 539.4.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]([CH3:9])[CH:7]=[O:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[C:15]([C:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[C:25](C(O)=O)[C:20]2=[CH:19][N:18]=1)=[O:16].CNC>ClCCl.O1CCCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[C:15]([C:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:7]([N:6]([CH3:9])[CH3:5])=[O:8])[C:20]2=[CH:19][N:18]=1)=[O:16]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)c2ncc3c(C(=O)O)cccn23)ccc1[N+](=O)[O-]
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)c2ncc3c(C(=O)N(C)C)cccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.17 ml (2.36 mmol) of thionyl chloride and then 30 μl of N,N-dimethylformamide are added to 0.318 g (0.88 mmol) of 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-8-carboxylic acid obtained in example 183 in 10 ml of dichloromethane. The mixture is heated at reflux for 2 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is added to 5 ml of a 2N solution of dimethylamine in tetrahydrofuran. After stirring at ambient temperature for 18 h, the reaction medium is concentrated under reduced pressure. The residue is taken up in dichloromethane. The organic phase is washed with a 1N aqueous hydrochloric acid solution and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane and then a dichloromethane/methanol (99/1) mixture. 0.19 g of a yellow solid is collected. Melting point: 176° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.39 (1H, t), 7.53 (1H, d), 7.83 (1H, s), 8.0-8.12 (3H, m), 9.75 (1H, d)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:27])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With a 4.82 g (18.3 mmols) portion of t-butyl 3-[4-(3-hydroxypropyl)phenyl]propionate were admixed 5.09 ml (36.6 mmols) of triethylamine, 2.84 ml (36.6 mmols) of methanesulfonyl chloride and 50 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, concentrated and then diluted with benzene. The benzene layer was washed with saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated, giving 6.29 g (yield 100%) of t-butyl 3-[4-(3-mesyloxypropyl)phenyl]propionate in the form of an oil. This product was used for the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:64][CH2:65][O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.O>CN(C)C(=O)C>[CH2:67]([O:66][CH2:65][CH2:64][N:19]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[CH3:60])[C:17]([O:24][C@@H:25]2[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:48])[CH3:47])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]2[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCOCc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2 g) in N,N-dimethylacetoamide (36 mL) were added sodium hydride (55%, 0.26 g) and benzyl 2-bromoethyl ether (0.76 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (0.89 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]1[NH:34][CH2:33][CH2:32][N:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH:30]12>>[CH2:29]1[N:34]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:33][CH2:32][N:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH:30]12
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C1CCN2CCNCC2C1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN4CCCCC4C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with octahydro-1H-pyrido[1,2-a]pyrazine via General Procedure E to give 24 mg of 284 following reverse phase purification. MS (Q1) 502.3 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl[CH2:15][C:16]#[N:17]>O1CCCC1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:15][C:16]#[N:17])=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc2c(CCN)c[nH]c2c1
Reactant: N#CCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc2c(CCNCC#N)c[nH]c2c1
Reaction time: 15 h

Procedure:
17 g of 6-methyltryptamine were dissolved at 40° C. under inert atmosphere in 500 ml of tetrahydrofuran, and the solution was allowed to return to ambient temperature. 14.6 ml of 1,5-diaza[5,4,0]undec-5-ene were added followed by 6.2 ml of chloroacetonitrile and stirring for 15 hours. The solvent was eliminated under reduced pressure and the residue was taken up in 250 ml of methylene chloride, washed with water, dried and concentrated to dryness. The 25 g of crude product was purified by chromatography on silica (eluent: methylene chloride-ethyl acetate 3-7) to obtain 13.2 g of the expected product melting at 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][C:16](=[NH:18])[NH2:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:19])=[C:16]([NH2:17])[NH:18][C:16]=1[NH2:17])=[O:19])[CH3:12]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1OC
Yield: 72 %

Procedure:
Upon boiling a solution of 6.8 g 2-methoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 147°C (ethanol) is obtained. Yield: 72% of theory.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)\[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyrate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyric acid (425 mg, yield 87%) as colorless crystals. m.p. 116-117° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)CCC.N[C:33]1[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][C:34]=1[C:41]#[N:42].C1(C)C=CC=CC=1>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:41]([C:34]1[CH:35]=[N:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:33]=1[C:6]1[N:7]=[C:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=3[O:12][CH2:11][CH2:10][N:9]2[CH:23]=1)#[N:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reactant: CC(C)n1ncc(C#N)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCCn1cc(-c3c(C#N)cnn3C(C)C)nc1-2

Procedure:
A mixture of methyl 2-(tributylstannyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (155 mg, 0.291 mmol), 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (133 mg, 0.509 mmol) and Tetrakis(triphenylphosphine)palladium(0) (16.8 mg, 0.0145 mmol) in Toluene (6.0 mL, 56 mmol) was heated for 18 hours. The mixture was concentrated in vacuum, the residue purified on 4 g silica column eluting with 30% ethyl acetate in heptane. Yield 65 mg (59%). MS(ESI+): 378.2
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:25]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])[N:34]=[CH:35][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28]4[N:33]([C:36]5[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=5[F:43])[N:34]=[CH:35][C:27]=4[CH:26]=3)[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1ccc(NC(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Product: Cc1ccc(NC(=O)NC2CC2)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O

Procedure:
The title compound was prepared by a method similar to that described in Example 1, step 5 (Method A), starting from the 1-cyclopropyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one. MS (ESI, pos.ion) m/z: 317.2 (M+1).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:12]=[CH:13][C:14](=[O:17])[CH:15]=[CH:16]1
Reactant: O=c1ccn(CCCOC2CCCCO2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1ccn(CCCO)cc1
Yield: 99.2 %

Procedure:
A solution of 1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro4-pyridone (0.75 g, 3.16 mmol) in acetic acid (8 ml), THF (4 ml) and water (4 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation to give 1-(3-hydroxypropyl)-l,4-dihydro-4-pyridone (480 mg, 99%) as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.O1CCCC1>O>[C:1]([NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH:11]=[CH:10][N:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reaction time: 1 h

Procedure:
Butyroyl chloride (0.93 ml) was added dropwise to a stirred solution of 2-amino-4-(4-nitrophenoxy)pyridine (1.0 g), triethylamine (1.8 ml) and tetrahydrofuran (20 ml) at room temperature. After stirring for 1 hour, water was added, extraction was performed with ethyl acetate, the extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 0.6 g of the target substance as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:12](O)[CH2:13][OH:14].CCCCCC>C1COCC1>[B:9]([O:11][CH2:12][CH2:13][OH:14])([OH:10])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: OCCO
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccc(B(O)OCCO)c1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
3-Cyanophenyl boronic acid (1 g, 6.8 mmol) was dissolved in dry THF (10 mL) under nitrogen. Ethylene glycol (379 μL, 422 mg, 6.8 mmol) was added and the reaction was heated to reflux for 4 hours then cooled to room temperature. THF was removed by rotary evaporator to give a white solid. Cold hexane was added and the product was collected by filtration giving a white solid (1.18 g, quant. yield). 1H-NMR (300.058 MHz, DMSO-d6) δ ppm 7.92-8.01 (3H, m), 7.50-7.64 (1H, m), 4.35 (4H, s)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[S:10]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (39.4 g), 1-mesylpiperazine hydrochloride (55.7 g) and triethylamine (116 ml) in ethanol (500 ml) was stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, slurry washed with ethanol (2×80 ml, 160 ml) then with diethyl ether (150 ml), and dried to give 1-(6-chloropyrimidin-4-yl)-4-mesylpiperazine as a cream solid (71.9 g). mp 200-202° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27])#[CH:23]>C(O)(C)C>[ClH:1].[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:31])=[C:24]([C:22]#[CH:23])[CH:25]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cc(N)ccc1F
Solvent: CC(C)O
Product: C#Cc1cc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)ccc1F
Product: Cl
Yield: 58.1 %

Procedure:
4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (140 mg, 0.446 mmol) and 3-ethynyl-4-fluoroaniline (66 mg, 0.452 mmol) were reacted in refluxing isopropanol (3 mL) under an atmosphere of N2 for 16 hours. The solvent was removed in vacuo and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 116 mg of the pure title product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether and titrated with 1M HCl in ether to precipitate the title product as a white solid (99 mg; 50%; M.P. 170°-190° C. (dec); LC-MS: 412 (MH+); anal. RP18-HPLC RT: 4.33 min.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[N:22]=[C:23]=[O:24].CN(C)C=O>ClCCCl.O>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[C:16]=1[NH:22][C:23]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[N:4][N:3]=1)=[O:24]
Reactant: Nc1nnnn1Cc1ccccc1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)Nc1nnnn1Cc1ccccc1

Procedure:
5-Amino-1-benzyltetrazole (3.25 g, 0.0186 mol) was suspended in 15 mL of 1,2-dichloroethane after which 2,6-dimethylphenylisocyanate (3.5 mL, 0.025 mol) was added. The mixture was refluxed for 6 hours, 10 mL of dimethylformamide was added, and the mixture was refluxed for an additional 6 hours. The reaction mixture was diluted twice with 50 mL water and the water decanted from the precipitate then concentrated in vacuo adding ethanol as the azeotropic solvent. The precipitate was washed with ether, dried in a vacuum oven, washed with hot water and hot ethyl acetate, extracted with hot 9:1 methanol/methylene chloride, and concentrated to give the title compound, m.p. 220-230° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a mixture of 2-Amino-4-methylpyridine (21.6 g, 0.2 mol) and phthalic anhydride (29.6 g, 0.2 mol) in toluene (160 ml), was added triethylamine (2.8 ml, 0.02 mol). The mixture was refluxed for 5 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was suspended in acetic anhydride (250 ml). The mixture was then heated to reflux for 4 hr until the solid dissolves completely. After cooling to room temperature, white precipitate was collected by filtration and washed with acetic anhydride and hexane, and dried in high vacuo to give 26.6 g (56%) of 2-(4-methyl-pyridin-2-yl)-isoindole-1,3-dione as a white solid. 1H NMR (200 MHz, CDCl3) δ 2.45 (3H, s), 7.18 (1H, d, J=5.0 Hz), 7.25 (1H, s), 7.76-7.99 (4H, m), 8.53 (1H, d, J=5.0 Hz). m/z (EI) 238 (M+).