Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:9][NH2:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:12]([CH2:18][C:19](=O)[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[CH3:20][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(CCc2ccccc2)n1

Procedure:
The title compound was prepared from phenethyl hydrazine (3.92 g, 0.029M)(obtained by the method of J. H. Biel U.S. Pat. No. 3,000,903) and ethyl 2,4-dioxovalerate (4.55 g, 0.029M) as described in Example 1, Preparation 1 as a yellow oil (3.84 g, 52%); νmax (CH2Cl2) 1720 cm-1 ;
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][C:20]3[NH:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>C(O)(=O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[NH:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)[nH]1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)[nH]1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A mixture of methyl 5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate (593 mg, 1.5 mmol) and platinum oxide (68 mg) in glacial acetic acid (200 mL) was stirred overnight under hydrogen (50 psi). The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The solid was recrystallized from methanol to give methyl 5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-2-carboxylate as an off-white solid (505 mg, 84%), mp 246-248° C.: 1H NMR (DMSO-d6) δ 11.67 (s, I H), 10.90 (br s, 1H), 10.60 (br s, 1H), 6.66 (s, 1H), 6.45 (s, 1H), 5.91 (s, 1H), 3.72 (s, 3H), 3.22 (brd, 1H, J=10.5 Hz), 2.81 (m, 1H), 2.64 (m, 2H), 2.52 (brd, 1H, J=15.2 Hz), 1.88 (dd, 1H, J=15.2, 7.9 Hz), 1.68-1.50 (m, 3H), 1.21 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14]
Reactant: O=C(O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 690.9 %

Procedure:
(2,5-dichloro-4-nitrophenyl)acetic acid (22) (Valerie K. Chamberlain and R. L. Wain. Ann. appl. Biol. (1971), 69, 65-72.) (500 mg, 2.0 mmol) was dissolved in ethanol (10 ml), and after adding p-toluenesulfonic acid monohydrate (50 mg, 0.26.mmol), the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and concentrated and exsiccated under reduced pressure. To the resulting residue was added a saturated solution of sodiumbicarbonate (30 ml), and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using silica gel, and from the eluate of chloroform was obtained the title compound (505 mg, 91%) as a pale yellow crystal powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(O)c1
Product: CN(C)C=CC(=O)c1cccc(O)c1
Temperature: 100 °C
Yield: 36.7 %

Procedure:
A mixture of 3-hydroxyacetophenone (20.0 g, 146.9 mmol) and N,N-dimethylformamide dimethyl acetal (26.26 g, 220.4 mmol) is heated over night at 100° C. The excess of the acetal is removed under reduced pressure and 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (10.32 g, 37%) is obtained after chromatography on silica gel with dichloromethane/ethanol 9:1. This intermediate enone is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 5.02 g of the title epoxide (78%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]([CH3:31])[CH:21]=1>CN(C=O)C>[CH3:31][N:22]1[CH:21]=[C:20]([C:11]2[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:30]
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCOC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 mL) was added NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) at 0° C. and then stirred at 0° C. for 0.5 hrs. 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (110.0 mg, 0.33 mmol) was added. The mixture was stirred at 0° C. for 0.5 h and then at r.t. for 3 hrs. It was then quenched with aqueous sat. NH4Cl (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure to afford a crude product which was purified by prep-HPLC to give the title compound (62.0 mg, 39.7%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J=7.6 Hz, 1H), 8.00 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.58-7.51 (m, 2H), 7.11-7.03 (m, 3H), 5.01-4.98 (m, 1H), 3.97 (dd, J1=10.4 Hz, J2=4.8 Hz, 1H), 3.76-3.70 (m, 2H), 3.67 (s, 3H), 3.61-3.42 (m, 1H), 3.11 (s, 3H), 2.18-1.88 (m, 2H). LCMS (M+H)+=400.0 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH2:13][C:14](OCC)=[O:15])([O-:12])=[O:11].N1CCCCC1>C1(C)C(C)=CC=CC=1>[N+:10]([C:13]1[C:14](=[O:15])[NH:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:12])=[O:11]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Nc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50.8 %

Procedure:
2-Aminobenzaldehyde (1.75 g, 14.5 mmol) was dissolved in xylene (87.5 mL). To this, ethyl 2-nitroacetate (6.43 mL, 58.0 mmol) and piperidine (1.58 mL, 16.0 mmol) were added and the mixture was stirred with heat at 150° C. for 1.5 hours and successively stirred with cooling in an ice bath for 0.5 hour. The precipitate was collected by filtration and dried under reduced pressure. Thus, 3-nitroquinolin-2(1H)-one (1.40 g, yield: 51%) was obtained.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:8][C:7]=1[O:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:7]([O:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:6]([CH:11]=1)[C:5]([OH:41])=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)O)c1
Yield: 84 %

Procedure:
Sodium hydroxide hydrolysis of 5-(octadecyloxy)-2-(3-phenylpropoxy)benzoic acid methyl ester under conditions described in Example 60 gave 5-(octadecyloxy)-2-(3-phenylpropoxy)benzoic acid (84% yield, mp 68°-70°).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:24](=O)[CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:22][C:20]1[CH:21]=[C:12]([N:11]([CH2:24][CH3:25])[CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[C:13]([CH3:23])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a stirred solution of methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)-5-chloro-2-methylbenzoate (6.6 g, 19 mmol) and acetaldehyde (2.56 g, 58.4 mmol) in dichloroethane (70 mL) was added acetic acid (7.0 g, 120 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (12 g, 57 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (4.0 g, 56%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[C:41]([N:38]1[CH2:37][CH2:36][N:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:2]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:16])[N:8]4[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1)(=[O:43])[CH3:42]
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 30.7 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (95 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 52 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:41]1(=[O:50])[N:40]([CH2:39][CH2:38][CH2:37][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]12
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c3ncccc23)c1
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.43 mmol) and N-(3-bromopropyl)phthalimide (133 mg, 0.50 mmol) in DMF (10 ml) was added potassium carbonate (114 mg, 0.83 mmol), and the mixture was stirred at 50°-60° C. for one hour. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from hexane to give the title compound (229 mg, 0.35 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])=[CH2:13].[H-].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[C:3]([CH2:2][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])[C:21](=[O:23])[CH3:22])=[CH:8][C:7]([F:9])=[C:6]([Cl:10])[N:5]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Reactant: C=Cc1ccccc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred mixture of 1B (0.5 g, 1.93 mmol) and N-(2-vinyl-phenyl)-acetamide bb (0.314 g, 1.95 mmol) in DMF (5 mL) was added NaH (47 mg, 1.95 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at room temperature, then poured into H2O (50 mL) and extracted with Et2O (20 mL). The Et2O layer was washed with H2O (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1C (0.63 g, 96%). HPLC Rt=3.212 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: Cc1ccccc1
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(Cl)cc2)C(=O)OC1=O

Procedure:
3,5-Diacetyl-4,6-dihydroxy-2H-pyran-2-one (5.3 g.) is dissolved in 200 ml. of boiling toluene and an equimolar amount of p-chloroaniline is added. The mixture is refluxed for 12 hours, cooled and filtered to yield 5-acetyl-3-[1-(p-chlorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 205°-206° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C@H:38]([OH:41])[CH2:39][OH:40])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C@H:38]([OH:41])[CH2:39][OH:40])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1ccn(C[C@H](O)CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (5 mL) and then added dropwise to a separate reaction flask containing a mixture of (S)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US 20080021032, Example 34, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 100% ethyl acetate to 5% methanol/ethyl acetate) to afford (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (99 mg, 69%) as a white foam: [α]28D=−12.0°, (c=0.15, methanol); HR-ES(+) m/e calcd for C23H27N4O4F3 [M+H]+ 481.2057, observed 481.2057; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 7.94-8.05 (m, 2H), 7.73-7.80 (m, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H), 4.98-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.75 (m, 2H), 4.09 (dd, J=4.05, 13.64 Hz, 1H), 3.81-3.91 (m, 1H), 3.77 (br. s., 1H), 3.24-3.30 (m, 2H), 1.99-2.09 (m, 1H), 1.06-1.95 (m, 10H).
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:22]1([C:28](Cl)(Cl)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].[K+].[OH-].[Na+]>CN1CCCC1=O>[C:1]([NH:4][CH:5]([CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution (1.25 M) of diethyl acetamidomalonate (13.33 g, 61.8 mmol) in N-methyl-2-pyrrolidone (40 mL) was added potassium t-butoxide (7.20 g, 64.3 mmol), and the mixture was stirred at room temperature for 1 hour. Diphenylmethylene chloride (10.0 g, 49.3 mmol) and potassium iodide (4.10 g, 24.7 mol) were added, and the mixture was stirred at 70° C. for 6 hours. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture, and the mixture was stirred for 5 hours at 60° C. After cooling to room temperature, the mixture was partitioned. The aqueous layer was adjusted to pH 7.0 with concentrated hydrochloric acid (4.4 mL), ethyl acetate (30 mL) and then concentrated hydrochloric acid (6.9 mL) were added, and the aqueous layer was extracted. The aqueous layer was further extracted with ethyl acetate (40 mL). The organic layers were combined, washed 3 times with 2M hydrochloric acid (20 mL), washed with saturated brine (10 mL), and concentrated. Toluene (30 mL) was added to the concentrate, and the mixture was concentrated at 50° C. Toluene (30 mL) was further added, and the mixture was stirred for 30 minutes. The mixture was cooled to 0° C. over 5 hours to allow precipitation of white crystals. The crystals were collected by filtration and dried under reduced pressure to give the title compound (11.69 g). The powder X-ray (Cu—Kα ray) of the dry crystals showed characteristic peaks at 5.8°, 11.5°, 21.6°, 23.2°, and 28.7°.
Reaction SMILES: [C:1](=O)([O:7]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:6][CH2:5]1.[C:18]([CH2:20][C:21]1([N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[N:34][N:33]4[C:36]([C:39]5[CH:40]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])[CH:42]=[CH:43][CH:44]=5)=[CH:37][N:38]=[C:32]4[CH:31]=3)[CH:27]=[N:26]2)[CH2:24][NH:23][CH2:22]1)#[N:19].C(N(CC)CC)C>CN(C)C=O.CO>[C:18]([CH2:20][C:21]1([N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[N:34][N:33]4[C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:52])([F:53])[F:51])=[O:47])[CH:40]=5)=[CH:37][N:38]=[C:32]4[CH:31]=3)[CH:27]=[N:26]2)[CH2:22][N:23]([C:1]([O:2][CH2:3][CH:4]2[CH2:6][CH2:5]2)=[O:7])[CH2:24]1)#[N:19]
Reactant: O=C(OCC1CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)OCC2CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropylmethyl 4-nitrophenyl carbonate (11 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.O>O1CCCC1>[F:40][C:2]1[S:1][C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sc(F)cc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo [2,2,1]heptane-2-carboxamide (200 mg, 0.67 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamide (1.67 mL, 3.35 mmol). The mixture was stirred at this temperature for 1 hour before N-fluorobenzene sulfonimide (2.3 mL, 3.35 mmol) was added. The mixture was stirred for another 10 minutes at this temperature before it was allowed to warm to room temperature. After 1 hour, water was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL) and the extracts were washed with water (2×10 mL) dried over magnesium sulphate and evaporated in-vacuo. Column chromatography with 20% ethyl acetate in hexane provided (1S,2R,3S,4R)-3-(2-fluoro-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and o-anisaldehyde (77 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (107 mg, 39%). 1H NMR (CDCl3): 8.03 (d, J=15.9 Hz, 1H), 7.61 (dd, J=1.4, 7.7 Hz, 1H), 7.44 (d, J=16.2 Hz, 1H), 7.40-7.34 (m, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.09 (dd, J=3.0, 8.7 Hz, 1H), 7.00-6.94 (m, 2H), 6.92 (d, J=9.3 Hz, 1H), 4.42-4.32 (m, 4H), 3.86 (s, 3H).