Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[N:16]=[C:17]([O:29][CH2:30][CH2:31][CH3:32])[C:18]2[N:23]=[C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[O:21][C:19]=2[N:20]=1.[Br:33][C:34]1[O:38][C:37]([C:39]2[O:40][C:41]3[N:42]=[C:43]([CH2:52]Br)[N:44]=[C:45]([O:48][CH2:49][CH2:50][CH3:51])[C:46]=3[N:47]=2)=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C.O>[Br:33][C:34]1[O:38][C:37]([C:39]2[O:40][C:41]3[N:42]=[C:43]([CH2:52][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:44]=[C:45]([O:48][CH2:49][CH2:50][CH3:51])[C:46]=3[N:47]=2)=[CH:36][CH:35]=1.[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:22]1[O:21][C:19]2[N:20]=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[C:17]([O:29][CH2:30][CH2:31][CH3:32])[C:18]=2[N:23]=1
Reactant: CCCOc1nc(CBr)nc2oc(-c3ccco3)nc12
Reactant: CCCOc1nc(CBr)nc2oc(-c3ccc(Br)o3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1nc(CN2CCOCC2)nc2oc(-c3ccc(Br)o3)nc12
Product: CCCOc1nc(CN2CCOCC2)nc2oc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
91.5 mg of morpholine and 207 mg of potassium carbonate were added to a solution of 169 mg of the mixture of 5-bromomethyl-2-furan-2-yl-7-propoxy-oxazolo[5,4-d]pyrimidine and 2-(5-bromo-furan-2-yl)-5-bromomethyl-7-propoxy-oxazolo[5,4-d]pyrimidine obtained in step (a) in 3 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 48 h. Then 50 ml each of water and ethyl acetate were added, the mixture was filtered through a Varian ChemElut cartridge, the cartridge washed with 10 ml of ethyl acetate, and the combined filtrates were evaporated to dryness in vacuo. Preparative HPLC (method HPLC1) of the residue yielded 41 mg of 2-(5-bromo-furan-2-yl)-5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidine (example 3) and 25 mg of the title compound in the form of 2-furan-2-yl-5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidine trifluoroacetic acid salt.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:17][C:11]2=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].C(OC(=O)C)(=[O:21])C>O>[S:5]([C:8]1[S:17][C:11]2[NH:12][C:13](=[O:21])[CH:14]=[CH:15][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C=NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Solvent: O
Product: NS(=O)(=O)c1cc2ccc(=O)[nH]c2s1
Yield: 60 %

Procedure:
A mixture of the product from Step A (10.75 g, 0.038 mol) and 50 ml of acetic anhydride was heated at reflux for 16 hours. After removal of the acetic anhydride in vacuo, the residue was heated in 6 N hydrochloric acid (50 ml) for 3 hours. The cooled reaction mixture was diluted with water (400 ml), chilled and the resulting solid was filtered, washed with water and dried, 5.25 g (60% yield). Recrystallization from water gave 2-sulfamoylthieno[2,3-b]pyridin-6(7H)-one; m.p. 306°-308° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Na+].[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.Cl>O.C(OCC)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=S(=O)([O-])c1ccc(NCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(O)c1ccc(N(Cc2ccc(F)cc2)Cc2ccc(Cl)cc2)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A mixture of 16.0 g (0.053 mole) of sodium 4-(((4-fluorophenyl)methyl)amino)benzenesulfonate in 200 ml of water, 4.5 g (0.053 mole) of 50 percent sodium hydroxide and 9.75 g (0.06 mole) of 4-chlorobenzyl chloride was stirred at about 85° C. for 20 hours. The reaction mixture was cooled and then treated with diethyl ether. The aqueous layer was heated and acidified with concentrated hydrochloric acid. A light tan powder precipitated. Recrystallization gave the product 4-(((4-chlorophenyl)methyl)((4-fluorophenyl)-methyl)amino)benzenesulfonic acid having a melting point greater than 250° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:21][C:22]1[C:23]([C:32]2[N:37]3[N:38]=[CH:39][N:40]=[C:36]3[N:35]=[C:34]([CH3:41])[CH:33]=2)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:41][C:34]1[CH:33]=[C:32]([C:23]2[C:22]([Cl:21])=[CH:27][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:25][N:24]=2)[N:37]2[N:38]=[CH:39][N:40]=[C:36]2[N:35]=1
Reactant: Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cnc(-c2cc(CBr)nc3ncnn23)c(Cl)c1
Reaction time: 8 h
Yield: 13.7 %

Procedure:
312 mg of N-bromosuccinimide and 13 mg of azobisisobutylonitrile (AIBN) were added to a solution having 500 mg of 7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine dissolved in 3 mL of carbon tetrachloride, followed by stirring overnight under reflux with heating. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/3) to obtain 86 mg of the desired product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)O1.[CH:21]([N:25]1[CH:29]=[C:28](I)[C:27]([C:31]2[S:32][CH:33]=[C:34]([Cl:36])[CH:35]=2)=[N:26]1)([CH2:23][CH3:24])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH:21]([N:25]1[CH:29]=[C:28]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)[C:27]([C:31]2[S:32][CH:33]=[C:34]([Cl:36])[CH:35]=2)=[N:26]1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2cn(C(C)CC)nc2-c2cc(Cl)cs2)ccn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide (0.48 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.04 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (0.40 mmol) in 3.0 mL degassed dioxane and 1.0 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 12 min. After cooling to room temperature, the reaction mixture was diluted with dioxane and filtered through a short pad of silica. The filtered solid was washed thoroughly with dioxane, ethyl acetate and dichloromethane. The combined filtrates were concentrated in vacuum. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 97:3 to 0:100) to afford 155 mg N-{4-[1-sec-butyl-3-(4-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridin-2-yl}propanamide (99% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][N:4]2[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
5-Bromo-2-butyl-3H-imidazole-4-carbaldehyde (38 g, 160 mmol) was dissolved in DMF (400 mL, 5 mol). Potassium carbonate (27 g, 200 mmol) was added followed by methyl 4-bromomethylbenzoate (38 g, 160 mmol) and the solution was stirred at room temperature overnight. The mixture was then concentrated and purified by silica gel chromatography (0-50% EtOAc:hexanes) to yield intermediate (9a) (32.2 g, 62.2 mmol). MS m/z: [M+H+] calcd for C17H19N2O3Br, 379.3; found 379.1. 1H-NMR (400 Mz, CD3OD) δ (ppm): 0.82 (t, 3H, J=5 Hz), 1.28 (m, 2H), 1.54 (q, 2H, J=5 Hz), 2.70 (t, 2H, J=5 Hz), 5.69 (s, 2H), 7.15 (d, 2H, J=5 Hz), 7.96 (d, 2H, J=5 Hz), 9.66 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1([O:36][CH2:35]1)[CH3:34]>CN(C)C=O>[OH:36][C:33]([CH3:35])([CH3:34])[CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCC(C)(C)O)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
Methyl 4-[1-[4-hydroxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (2.00 g) and potassium carbonate (1.62 g) are dissolved and suspended in dimethylformamide (20 ml) and thereto is added isobutylene oxide (1.06 ml). The mixture is stirred at 80° C. for 17 hours and thereto is added isobutylene oxide (1.06 ml), and the mixture is further heated with stirring for 5 hours. The reaction mixture is concentrated under reduced pressure and thereto is added water. The insoluble material is collected by filtration, washed with water and recrystallized from about 30% aqueous methanol to give the desired product (2.15 g), m.p. 89.5°-90.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=4)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:34]/[C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[CH:23]=[N:24][C:19]([N:16]4[CH2:17][CH2:18][O:13][CH2:14][CH2:15]4)=[CH:20][CH:21]=3)=[N:26][N:27]2[CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Temperature: 60 °C
Yield: 62.9 %

Procedure:
A round bottom flask was charged with 5-methoxyoxindole (100 mg, 0.61 mmol), 3-(6-Morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (266 mg, 0.61 mmol), piperidine (6 uL, 0.06 mmol) and MeOH (4 mL). The reaction was then heated to 60° C. for 4 h. An orange precipitate formed which was further precipitated by cooling to room temperature. The orange powder was then filtered and washed with MeOH to give the title compound (224 mg, 63%). 1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 8.79 (d, J=1.5 Hz, 1H), 8.20 (d, J=8.5, 1H), 8.17-8.13 (m, 2H), 7.77 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.82 (s, 2H), 3.73 (t, J=4.3 Hz, 4H), 3.62-3.53 (m, 9H), 0.82 (t, J=8.2 Hz, 2H), −0.12 (s, 9H); MS ESI 584.3 [M+H]+, calcd for [C32H37N5O4Si+H]+ 584.26.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[CH2:6].[P:12]([S-:25])([SH:24])([S:14][CH2:15][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=S>>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][S:14][PH:12]([S:25][CH2:2][NH:3][C:4](=[O:11])[CH:5]([CH2:6][S:25][PH:12]([S:14][CH2:15][CH2:16][CH:17]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])=[S:24])[CH2:7][CH:8]([CH3:10])[CH3:9])=[S:24])[CH3:23]
Reactant: CCOC(CCSP(=S)([S-])S)OCC
Reactant: C=C(CC(C)C)C(=O)NCO
Product: CCOC(CCS[PH](=S)SCNC(=O)C(CS[PH](=S)SCCC(OCC)OCC)CC(C)C)OCC

Procedure:
Following the procedure of Example 1, 0.4 mole of N-hydroxymethyl-2-isobutylacrylamide is reacted with 0.8 mole of diethoxypropyl hydrogen phosphorotetrathioate to yield N-(diethoxypropylthiophosphinothioylthiomethyl) 2-(diethoxypropylthiophosphinothioylthiomethyl)-4-methylvaleramide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[NH:27][CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(NCCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(NCCC(=O)O)nccc34)no2)cc1Cl
Temperature: 50 °C
Yield: 209.6 %

Procedure:
1,1-Dimethylethyl N-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]-β-alaninate (D9; 20 mg, 0.039 mmol) and 0.5M HCl in 1,4-dioxane (10 ml) were stirred at room temperature for 2.5 h. The reaction mixture was then heated to 50° C. for a further 30 minutes, cooled and evaporated to dryness. The resulting solid was triturated with ether and 1,4-dioxane to yield the title compound (20 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:24]([NH:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>CS(C)=O>[CH2:24]([N:28]([CH2:29][CH3:30])[C:2]1[C:3]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Cc1cc(C)c(N2C(=O)C(C)Cc3c(Cl)nc(C)nc32)c(C)c1
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc2c1CC(C)C(=O)N2c1c(C)cc(C)cc1C
Temperature: 135 °C
Yield: 55.8 %

Procedure:
A mixture of 4-chloro-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (75 mg, 0.227 mmol) and N-butyl-ethyl-amine (65 mg, 0.682 mmol) in DMSO (1 ml) was heated in an oil bath of 135° C. for 15 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 114 mg of the crude material. Silica gel column purification using 5% ethyl acetate in hexane as eluent provided 50 mg of the title compound as a colorless oil. 1H NMR (CDCl3) δ 6.95 (s,1H), 6.94(s,1H), 3.2-3.55(m,4H), 2.88-3.05(dd,1H), 2.70-2.85(m,1H), 2.55-2.70(m,1H), 2.35(s,3H), 2.25(s,3H), 2.05(s,3H), 1.97(s,3H), 1.5-1.65(m,2H), 1.3-1.5(m,2H), 1.35(d,3H), 1.2(t,3H), 0.98(t,3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=[C:20]1[CH:24]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][S:22][CH2:21]1>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:20]2[CH2:21][S:22][CH2:23][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: COC(=O)C1CSCC1=O
Product: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CSC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and methyl 3-oxotetrahydrothiophene-4-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[4-(methoxycarbonyl)-2,5-dihydro-thien-3-yl]ureido}-benzoate,
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:25]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 1.9 g (2.35 mL, 25.6 mmol, 1.01 eq) of 1-butanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to a brown oil. The oil was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 9.5 g (22.8 mmol, 90%) of the product as a clear light brown oil with an HPLC purity of 94.5 A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.77 (dd, J=2.36, 8.8 Hz, 1H), 4.05 (t, J=6.76 Hz, 2 H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.1 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 2H), 0.89 (t, J=4.56 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccc(F)cc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccc(F)cc3F)cc2=O)n1
Yield: 64 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,4-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 45) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,4-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.77 g, 64%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2259. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.1, J=10.9 Hz, 1H), 5.90 (d, J=2.6 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 7.24 (m, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.53-7.66 (m, 2H), 8.20 (d, J=2.6 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O.[NH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH2:35])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(N)(=O)=O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Through a 0° C. solution of the product from Example 1, Step C (96 mg, 0.21 mmols) in 5 mL of CH2Cl2, ammonia gas was bubbled for 3 minutes. The reaction was sealed, stirred for 30 minutes, warmed to room temperature and stirred 20 minutes more. This was poured into EtOAc and washed with water and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+MS: 443 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (100 mg, 0.329 mmol) obtained in step C of Example 1-1 was dissolved in benzene (2 ml). Thereafter, chloroacetic acid chloride (29 μl, 0.362 mmol) and pyridine (80 μl, 0.986 mmol) were added to the solution, and the obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the reaction solution was washed with 1 N hydrochloric acid, and was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was suspended in and washed with cold ethyl acetate, and a solid was collected by filtration, so as to obtain 2-chloro-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (70 mg, 56%).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(C)cccc2c1=O
Product: CCCC(=O)c1cnc2c(C)cccc2c1Cl

Procedure:
3-Butyryl-8-methyl-4(1H)-quinolone (20 g) and phosphoryl chloride (80 ml) were heated under reflux for 45 minutes. Excess phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and neutralised with sodium hydrogen carbonate. Extraction with dichloromethane, drying and evaporation gave 3-butyryl-4-chloro-8-methylquinoline (20 g) as a brown oil, which solidified at -15° C. but melted below room temperature. This was used without further purification.