Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:14][C:15](Cl)=[N:16][C:17]=1[CH3:18].C(N(CC)CC)C.C(O)C(O)C>ClCCl>[CH3:11][C:12]1[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:14][C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[N:16][C:17]=1[CH3:18]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: COc1cc(F)ccc1N
Solvent: CC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Temperature: 140 °C
Yield: 74.9 %

Procedure:
A reaction mixture of 4-fluoro-2-methoxy-aniline(0.155 g, 1.10 mmol), 5,6-dimethyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.24 lg, 0.84 mmol), triethylamine(0.15 ml, 1.1 mmol) and propyleneglycol (2 ml) was heated to 140° C. for 5 hours, cooled to a room temperature, diluted with dichloromethane(10 ml), and then washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/N-hexane=1/1) to give 0.247 g of the titled compound. (Yield 75.2%)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl.Cl>ClCCl>[CH:18]([C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=2[O:6][C:2]=1[CH3:1])=[O:19]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methyl-7-nitrobenzo[b]furan (1.77 g) and aluminum chloride (2.66 g) in dichloromethane (40 ml) was added dropwise a solution of dichloromethyl methyl ether (3.6 ml) in dichloromethane (10 ml). The mixture was stirred at ambient temperature for 30 minutes and the reaction mixture was poured into a mixture of ice and 1N-hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, aqueous saturated sodium bicarbonate and brine. Then, the solution was dried over sodium sulfate and evaporated in vacuo. The obtained oil was crystallized from diethyl ether to give 3-formyl-2-methyl-7-nitrobenzo[b]furan (1.83 g).
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:11][C@H:10]2[O:25][CH3:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.[C:32](O)(=[O:34])[CH3:33].[C:36](OC(=O)C)(=[O:38])[CH3:37].[OH-].[NH4+]>O>[OH2:7].[C:32]([NH:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](=[O:24])[N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:11][C@H:10]2[O:25][CH3:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1)(=[O:34])[CH3:33].[C:36]([NH:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:24])[CH2:11][C@H:10]2[O:25][CH3:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1)(=[O:38])[CH3:37]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1OC
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCCC2)C[C@H]1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a stirred solution of 4 parts of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide in 20 parts of acetic acid were added 0,89 parts of acetic acid anhydride. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into water and the whole was treated with ammonium hydroxide while cooling. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was solidified in a mixture of 2,2'-oxybispropane and a few drops of acetonitrile. The solid product was filtered off and crystallized from acetonitrile. After cooling to 0° C., the product was filtered off and dried in vacuo at 40° C., yielding 1.9 parts (42.8%) of cis-4-(acetylamino)-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide hemihydrate; mp. 149.7° C. (compound 114).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.Cl.[N:15]1([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:1]([N:18]1[CH2:19][CH2:20][N:15]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:16][CH2:17]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)c1ccc(CN2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(Cc2ccc(C(=O)O)cc2)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(Cc2ccc(C(=O)OC)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and methyl 4-[1-piperazinylmethyl)benzoate dihydrochloride as starting raw materials, to produce methyl 4[[4-((E)-2-decenoyl)piperazin-1-yl]methyl]benzoate (methyl ester of Compound 48).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[N:7]([N:8]=[C:9]([C:15]([NH2:17])=[O:16])[CH:10]=3)[C:6]=2[CH:18]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>O1CCOCC1>[CH3:21][N:22]([CH3:24])[CH:23]=[N:17][C:15]([C:9]1[CH:10]=[C:11]2[N:7]([N:8]=1)[C:6]1[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:14][CH2:13][CH2:12]2)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Solvent: C1COCCO1
Product: CN(C)C=NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 97.1 %

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid amide (1.11 g, 3.60 mmol) and dimethylformamide dimethylacetal (1.44 mL, 10.8 mmol) in dry 1,4-dioxane (25 mL) was heated at 100° C. for 2 h, then concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide as a yellow solid (1.27 g, 97%). LCMS: RT=3.27 min, M+H+=363/365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH:28]2[CH2:30][CH2:29]2)[N:25]=[C:24]([O:31][C:32]2[CH:41]=[C:40]([CH3:42])[C:35]3[NH:36][C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:28]1([C:26]2[N:25]=[C:24]([O:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)[CH:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[N:27]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(Oc2cc(Cl)nc(C3CC3)n2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)nc(C4CC4)n3)CC1)C(=O)N2

Procedure:
39 mg (0.14 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 39 mg (0.12 mmol) 6-(6-chloro-2-cyclopropylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL (0.57 mmol) DIPEA in 1.0 mL DMF were stirred for 2 h at 90° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C@H:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C@@H:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC[C@@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC[C@@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-4-methoxybutan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.82 Hz, 3H) 1.67-1.77 (m, 1H) 1.77-1.89 (m, 1H) 2.44 (s, 3H) 3.39 (t, J=6.57 Hz, 2H) 4.05-4.20 (m, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.17 (br. s., 1H) 8.43 (d, J=7.07 Hz, 3H) 8.87-8.95 (m, 1H) 12.98-13.34 (m, 1H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: CN(C)CCN[C:6]1[C:18]2[C:17](=[O:19])[C:16]3C=CN=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:8]=2[N:7]=1.Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][SH:32].[CH2:34]([N:36](CC)[CH2:37]C)C.[H-].[Na+]>CN(C=O)C.ClCCl>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][S:32][C:6]1[C:18]2[C:17](=[O:19])[C:16]3[CH:37]=[N:36][CH:34]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:8]=2[N:7]=1
Reactant: CN(C)CCS
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccncc1-3
Reactant: CCN(CC)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c3c(c(SCCN(C)C)nc2c1)C(=O)c1cnccc1-3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-chloro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one (Example 1c-2) (20 mg) was dissolved in DMF (2 ml). To the solution were added 2-dimethylaminoethanethiol hydrochloride (21 mg), triethylamine (0.04 ml) and 60% NaH in paraffin liquid (Kanto Chemical Co. Inc.: 15 mg). The mixture was stirred at room temperature for 5 hours. The reaction mixture was dissolved in dichloromethane and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel TLC developed by dichloromethane-MeOH-ammonia water (25%)=100:10:1. The desired product (19 mg) was obtained as a yellow solid. ESI−MS: m/z 366 (MH+); 1H-NMR (CDCl3): δ2.41 (6H, s), 2.75 (2H, m), 3.51 (2H, m), 3.99 (3H, s), 7.20 (1H, dd, J=9 Hz, 2.5 Hz), 7.25 (1H, d, J=2.5 Hz), 7.86 (1H, dd, J=5 Hz, 1 Hz), 8.13 (1H, d, J=9 Hz), 8.85 (1H, d, 5 Hz), 8.90 (1H, d, J=1 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:59][CH2:60][CH3:61])[CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])[CH2:50][CH3:51]>CN(C=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:56][CH2:55][C:54]([CH3:57])([CH3:58])[CH2:53][N:52]([CH2:49][CH2:50][CH3:51])[CH2:59][CH2:60][CH3:61])=[O:20])=[CH:22][CH:23]=1)[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: CCCN(CCC)CC(C)(C)CN
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(C)(C)CNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (100 mg) obtained in Example 2-2 was dissolved in DMF (2.0 ml) and then added with DCC (55.4 mg), HOBt (36.3 mg), and the compound (50.0 mg) obtained in Example 23-3, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. Then, the solution was added with 1 mol/l hydrochloric acid to separate the solution into layers. After the aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution to make the solution basic, the solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. After that, the residue was subjected to purification through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.5 mg) of the subject compound as a white solid.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.[CH3:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9]=1[CH:14]=[O:15].[CH2:16]=O>C(O)(=O)C.O>[C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][N:3]([CH2:16][C:12]1[C:8]([CH3:7])=[C:9]([CH:14]=[O:15])[NH:10][C:11]=1[CH3:13])[CH2:2]2
Reactant: C=O
Reactant: C1NC[C@H]2C[C@@H]12
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C=O)c(C)c1CN1C[C@H]2C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,5S)-3-aza-bicyclo[3.1.0]hexane (10 mmoles) in acetic acid (10 ml) there are added 10 mmoles of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde and formaldehyde (11 mmoles) 37% in water. The reaction mixture is stirred overnight at ambient temperature and then evaporated to dryness. Purification by flash chromatography on silica gel (SiO2; heptane/AcOEt) and then trituration in heptane to yield the title product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[CH2:12][CH2:13]Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(OCC)C>O1CCOCC1>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[N:4][C:3]=2[CH2:12][CH2:13]1
Reactant: ClCCc1nnc2ccccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccccc1N1CCc2nnc3ccccc3c21

Procedure:
4-Chloro-3-(2-chloroethyl)cinnoline (1.52 g, 0.0067 mol) and o-toluidine (1.43 g, 0.0134 mol) in 1,4 dioxan (20 ml) were heated under reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The aqueous layer was extracted with chloroform (6×50 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a brown oil. The oil was purified by chromatography using chloroform (1 litre), chloroform/methanol (20:I) as eluant. The fractions containing the product were combined and evaporated under reduced pressure to give an oil. On trituration with diethyl ether a solid was obtained. The solid was collected by filtration and dried, 0.76 g. Recrystallization from ethyl acetate gave the title compound, 0.48 g, m.p. 140-142°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])[S:8][C:4]=2[CH:3]=1.C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>ClCCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:11][C:21]([OH:22])=[N:13][N:12]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NNC(=O)Cc1nc2ccc(Br)cc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Oc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a suspension of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (500 mg, 1.75 mmol) (described in WO 2011/074560) in 1,2-dichloroethane (15 mL) at 0° C. was added CDI (340 mg, 2.10 mmol) then the reaction mixture allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified on silica gel chromatography eluting with 0 to 10% MeOH/DCM to give Compound 51a (296 mg, 54% yield) as a white solid. LCMS=0.84 min using analytical method (M), 502.0 (M+H). 1H NMR (400 MHz, CDCl3 containing CD3OD) δ 8.02 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.7, 1.9 Hz, 1H), 4.38 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CO.[Pd]>[C:11]1([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)c1ccccc1

Procedure:
Chalcone (compound 1) (37.6 mmol) was dissolved in 250 ml of toluene (in some cases 25 ml of MeOH was added to insure a complete dissolution) and 400 mg of 10% Pd/C (0.01 eq) was added to the mixture. The compound was hydrogenated at 45 psi in a Parr apparatus for 40 min to 3 hrs to form 1,3-diphenylpropan-1-one (compound 2), during which time the reaction mixture was periodically checked for the starting material by TLC (Hex:EtOAc=1:1) to prevent over-reduction. Upon completion of reduction the reaction mixture was filtered through a short pad (2-3 inch) of silica gel and solvent was removed in vacuo to afford a crude product, which was either sufficiently pure to use in the next step or was purified by recrystallization from MeOH or Hex:EtOAc=3:1 or, in the case where over-reduction has occurred, by silica gel column chromatography using Hex:EtOAc=5:1 as an eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:30])=[CH:23][C:24]([N:27]([CH3:29])[CH3:28])=[N:25][CH:26]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[CH:26]=[N:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: Cc1cc(N(C)C)ncc1N=C=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2cnc(N(C)C)cc2C)c1NCCCO
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (4.00 g, 15.5 mmol) and 5-isothiocyanato-N,N,4-trimethylpyridin-2-amine (8.96 g, 46.4 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 7 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-({[6-(dimethylamino)-4-methylpyridin-3-yl]carbamothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate as a brown amorphous (3.01 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]#[N:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:11]#[N:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cc2nc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc2nc(Cl)ccc2n1Cc1ccccc1

Procedure:
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonitrile (0.10 g, 0.56 mmol, from Step 2) in DMF (1.3 mL) was treated with K2CO3 (0.12 g, 0.84 mmol) and benzyl bromide (74 μL, 0.62 mmol, Aldrich) overnight. The reaction mixture was diluted with EtOAc and washed three times with water and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded purified product. Yield: (0.12 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)C=C)n2oc(=O)nc2n1

Procedure:
6.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 120 ml. of methylene chloride and 8 ml. of triethylamine. 3 ml. of acrylyl chloride in 35 ml. of methylene chloride are added dropwise at 0° C. while stirring. The mixture is then stirred for 2 hours, diluted with 100 ml. of water and adjusted to pH 4 with 2-N hydrochloric acid. The two phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using methylene chloride and methanol for the elution and the desired substance is recrystallized from methylene chloride and diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}acrylamide having a melting point of 157°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: FC(F)(F)c1ccc(Cl)cc1CCl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-chloro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (48% yield).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:14][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
Triethylamine (7 mL, 50 mmol) was added to a solution of β-alanine methyl ester hydrochloride (5.25 g, 37.5 mmol) in methylene chloride (100 mL). The solution was cooled to 0° C. and t-butyl bromoacetate (4.88 g, 25 mmol) in methylene chloride (100 mL) was then added. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo; 0.80 g (14% yield).