Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].[CH3:28]I.Cl>COCCOC>[CH3:28][N:3]1[C:4]([CH3:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1]
Reactant: CI
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1=C(C)N(C)C(C)=C(C(=O)OCC)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.78 g (0.008 mol) of diethyl 2,6-dimethyl-4-(4-fluorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate dissolved in 25 ml of 1,2-dimethoxyethane, and 0.30 g (0.01 mol) of 80% strength sodium hydride and, after 30 min, 1.43 g (0.01 mol) of methyl iodide are added. The mixture is stirred at room temperature for 3 hours, neutralized with dilute hydrochloric acid and evaporated in vacuo. The residue is purified by chromatography on silica gel (methylene chloride).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:9]2[C:14](=[O:15])[NH:13][CH:12]=[N:11][C:10]=2[NH:16][C:17]=1[CH3:18])=[O:6])([CH3:3])[CH3:2].[CH3:28][O+](C)C.F[B-](F)(F)F>ClCCCl>[CH:1]([O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:9]2[C:14]([O:15][CH3:28])=[N:13][CH:12]=[N:11][C:10]=2[NH:16][C:17]=1[CH3:18])=[O:6])([CH3:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)c2c(nc[nH]c2=O)N1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: COc1ncnc2c1C(c1cccc([N+](=O)[O-])c1)C(C(=O)OC(C)C)=C(C)N2
Reaction time: 3 h

Procedure:
Three and 0.7 g (10 mmol) (±)-3,4,5,8-tetrahydro-7-methyl-5-(3-nitrophenyl)-4-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid isopropyl ester and 3.0 g (20 mmol) trimethyloxonium-tetrafluoroborate are stirred in 150 ml 1,2-dichloroethane in nitrogen atmosphere and at room temperature for three hours. The product is extracted twice with 50 ml saturated sodium hydrogen carbonate solution, the organic phase is separated, dried over sodium sulfate and reduced under vacuum. Twice recrystallizing the residue from diisopropyl ether/isopropanol yields the product in the form of colorless crystals with a mp of 212°-213° C.
Reaction SMILES: C([O:3][C:4](=[O:26])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=[N:11][CH:12]=1)C.[OH-].[Na+]>CO.C1COCC1>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C@@H:14]([NH:13][C:10]2[N:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:26])=[O:3])=[CH:8][CH:9]=2)[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)O)cn2)C1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A mixture of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (600 mg) and 1N NaOH solution (3.3 ml) in MeOH (10 ml) and THF (10 ml) was stirred at 70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and H2O. The aqueous solution was adjusted to PH4.5 and extracted with AcOEt and THF. The organic layer was washed with brine and dried over MgSO4. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give (2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (0.45 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH:5]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[NH4+].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)([OH:11])[CH2:6][CH:5]2[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1
Reactant: CN1CCC(C2CC(=O)c3ccc(F)cc32)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2CC(O)(c3ccc(F)cc3)c3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
5-Fluoro-3-(1-methyl-4-piperidyl)indanone (100 g) (prepared according to standard methods--J. Med. Chem., 11, (1968), 1064-66) in dry tetrahydrofuran (500 ml) was added dropwise to 4-fluorophenylmagnesium bromide (from 95 g of 4-bromofluorobenzene and 20 g of Mg-turnings in 500 ml of dry tetrahydrofuran). The reaction mixture was poured into NH4Cl (100 g) and crushed ice (3 L) and extracted with ether (2×300 ml). The combined organic phases were extracted with 0.5M CH3COOH (2×500 ml). The acid H2O-phase was made alkaline with 2M NaOH solution and extracted with ether (2×200 ml). The combined ether-phases were worked up as above and the starting material removed by washing with light petroleum. The title compound crystallized from isopropylether. Yield: 16.5 g (11.7%). MP: 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([O:13]C)=O.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([OH:13])[NH:18][N:17]=1
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
970 g of methyl 3-(2,4-dichlorophenyl)-3-oxopropionate were initially charged in 4000 ml of ethanol. Over a period of 15 min, 201 g of hydrazine hydrate were added dropwise, the mixture was stirred at room temperature overnight, the precipitated solid was filtered off and the filtrate was concentrated to ⅓ of its original volume. The filtrate was stirred for another two nights, the resulting solid was filtered off with suction and the filtrate was again concentrated to ⅓ of its original volume. This gave a total of 714.2 g (79.4%) of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid. M.p.: 198° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:8][CH:9]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:23][CH:5]1[C:4](=[O:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)OC1=CCN(C(=O)OCc2ccccc2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl 4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate (800 g, 2.61 mol) in acetonitrile was added Selectfluor™ (932.8 g, 2.63 mol) in small portions under nitrogen at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc/petroleum ether=1:1) indicated the reaction was complete, and the solvent was removed in vacuo. The residue was triturated with ethyl acetate (5 L, 3 L) for 30 min and filtered. The filtrate was concentrated and the syrup was purified by column chromatography (EtOAc/petroleum ether=1:10 to 2:3) to afford benzyl 3-fluoro-4-oxopiperidine-1-carboxylate. 1H NMR (600 MHz, CDCl3-D6) 7.40-7.30 (m, 5H); 5.20 (s, 2H); 5.00-4.70 (d, 1H); 5.20-4.90 (d, 1H); 4.30-4.20 (m, 1H); 3.40-3.20 (m, 2H); 2.50 (s, 2H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:36](=[O:38])[CH3:37])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CC(=O)Cl
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(C)=O)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.28 g (4.6 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was suspended in dichloromethane (50 ml). Triethylamine (3.5 ml, 25.3 mmol) was added followed by the addition of acetyl chloride (0.49 ml, 6.9 mmol). The reaction mixture was stirred for 24 hours at room temperature. The precipitate was filtered, washed with water and purified using column chromatography to give the title compound (1.39 g, 70%), MS (EI): 430.2 (MH+); 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.89-0.96 m (2H); 1.06-1.35 m (3H); 1.55-1.82 m (6H); 1.79 s (3H); 2.76 (3H); 2.98-3.18 m (4H); 3.37-3.58 m (5H); 4.16-4.29 m (2H); 7.90 br (residual NH); 11.35 br (residual NH).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[CH3:15][CH:16]1[CH2:21][C:20](=[O:22])[O:19][C:17]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([C:20](=[O:22])[CH2:21][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1CC(=O)OC1=O
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 37.7 g (0.2 mole) of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene and 22.82 g (0.2 mole) of methylsuccinic anhydride in 250 cm3 of anhydrous 1,2-dichloroethane, there are added, by portions, over a period of about 1 hour, 53.3 g (0.4 mole) of anhydrous aluminum chloride in a manner to maintain the temperature lower than or equal to 30° C. After stirring for 3 hours at ambient temperature, the reaction mixture is poured into 200 cm3 of ice water. The organic phase is decanted. The aqueous phase is again extracted twice with 100 cm3 of dichloromethane. The dichloroethane and dichloromethane phases are combined, washed with water, dried on sodium sulfate and concentrated under reduced pressure. The residue is taken up in 300 cm3 of hexane, filtered, successively washed three times with 200 cm3 of toluene and then recrystallized in isopropyl ether. After drying, 20.7 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- 2-naphthyl)-4-oxo-2-methyl butyric acid in the form of a white solid whose melting point is 165° C. are obtained.
Reaction SMILES: [OH:1]O.[CH:3]([C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4]>CC(O)=O>[CH:3]([C:6]1[C:7]([CH3:12])=[N+:8]([O-:1])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: Cc1ncccc1C(C)C
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(C(C)C)ccc[n+]1[O-]
Temperature: 70 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A 50% solution of hydrogen peroxide (24.89 mL) was slowly added to a solution of 3-isopropyl-2-methyl-pyridine (24.5 g, 183 mmol) (Ishiguro et al. Yakugaku Zasshi 1958, 78, 220) in HOAc (280 mL). The mixture was warmed to 70° C. and stirred for 18 h, then cooled to room temperature and concentrated in vacuo to remove the majority of HOAc. The mixture was basified with a saturated solution of NaHCO3 to pH 12 and extracted with CH2Cl2 (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 3-isopropyl-2-methyl-pyridine 1-oxide (26.05 g, 94%) as a yellow oil. 1H NMR (CDCl3) δ 1.24 (d, 6H, J=7.0 Hz), 2.56 (s, 3H), 3.13 (sep, 1H, J=7.0 Hz), 7.06-7.17 (m, 2H), 8.17 (d, 1H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]#[N:7])[CH3:2].[CH:16]([O:19][C:20](=[O:25])[CH2:21][C:22](=[NH:24])[NH2:23])([CH3:18])[CH3:17].CC[O-].[Na+]>C(O)C>[CH:16]([O:19][C:20]([C:21]1[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([NH2:7])[NH:24][C:22]=1[NH2:23])=[O:25])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Reactant: CC(C)OC(=O)CC(=N)N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OC(C)C)C1c1ccccc1
Yield: 54 %

Procedure:
Upon heating a solution of 10.1 g benzylidenecyanoacetic acid ethyl ester, 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for four hours, 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester of m.p. 170° is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:19][CH3:20])[C:11](F)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:21]2[CH2:23][CH2:22]2)[CH:7]=1)=[O:5])C.F[B-](F)(F)F.[H+].[N:30]1([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)[CH:34]=[CH:33][N:32]=[N:31]1>>[CH:21]1([N:8]2[C:9]3[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:37]4[CH2:38][CH2:39][CH:35]([N:30]5[CH:34]=[CH:33][N:32]=[N:31]5)[CH2:36]4)[C:10]=3[O:19][CH3:20])[C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7]2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: F[B-](F)(F)F
Agent: [H+]
Product: COc1c(N2CCC(n3ccnn3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Ethyl-6,7-difluoro-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate was complexed with fluoroboric acid according to the procedure described in Example 34, and then reacted with 3-(1,2,3-triazol-1-yl)pyrrolidine under the same reaction conditions, followed by hydrolysis to yield the desired product, m.p. 200°-201° C. 1H NMR (TFA) δ: 9.34 (s, 1H), 8.69 (d, 1H), 8.58 (d, 1H), 8.09 (d, 13.3HZ, 1H), 5.93-5.8 (m, 1H), 4.83-4.34 (m, 4H), 4.2-4.0 (m, 2H), 3.79 (s, 3H), 3.05-2.75 (m, 2H), 1.7-1.1 (m, 4H). Anal. calcd. for C20H20FN5O4 . 1/2 H2O: C, 56.87; H, 5.01; N, 16.58. Found: C, 56.86; H, 4.68; N, 16.24.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[O:22]=[C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=2[S:24]1>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH:4]([OH:21])[CH2:3][CH2:2][NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:26]3[NH:27][C:23](=[O:22])[S:24][C:25]=3[CH:31]=2)=[O:33])[CH2:11][CH2:10]1
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Reactant: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2[nH]c(=O)sc2c1

Procedure:
Prepared as described in Example 1 from 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.152 g). Title compound obtained as a white solid (0.105 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNC
Product: CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and dimethylamine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 3.35-3.8 (m, 12H), 2.98 (s, 6H); MS (DCI) m/z 380 (M+H)+;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[S:9])[NH2:8])[CH:2]=1.Br[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:9][CH:11]=[C:12]([OH:13])[N:8]=2)[CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine-3-carbothioamide (20 g, 0.145 mol) was dissolved in a mixture of toluene (145 ml) and DMF (116 ml). Ethyl bromoacetate (24.2 g, 0.145 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The precipitated yellow compound was filtered, washed with water and dried to give 2-(3-pyridyl)thiazol-4-ol as hybromide salt.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH:14]=1.[ClH:45].O1CCOCC1>O1CCOCC1>[ClH:45].[ClH:45].[NH2:19][CH:16]1[CH2:17][CH2:18][C:13]([C:12]#[C:11][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:27]=[CH:28][C:29]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[O:33])=[CH:30][C:2]=2[F:1])=[CH:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CC=C(C#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)CC1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
A solution of tert-butyl 4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (40 mg, 0.066 mol) in anhydrous 1,4-dioxane (2 mL) was cooled to −10° C. and treated with 4 M HCl/1,4-dioxane (4 mL). The mixture was stirred at −5° C. for 2.5 h then at rt for 1 h. The mixture was concentrated under vacuum without any heating to give the title compound (32 mg, 84%) as a yellow solid. 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 10.61 (s, 1H), 8.69 (s, 1H), 8.44 (d, 1H, J=6.1 Hz), 8.06 (d, 1H, J=2.0 Hz), 7.80 (dd, 1H, J=12.7, 2.0 Hz), 7.46-7.38 (m, 1H), 7.35 (dd, 1H, J=8.6, 5.6 Hz), 7.19-7.13 (m, 1H), 6.82 (d, 1H, J=5.6 Hz), 6.17 (s, 1H), 3.74 (s, 2H), 3.73-3.62 (m, 2H), 3.62-3.54 (m, 1H), 3.34-3.22 (m, 1H), 2.31 (s, 1H), 1.99-1.96 (m, 1H), 1.71-1.66 (m, 1H); MS(ESI+): m/z 503.12 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Product: O=C(C1=COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 76 %

Procedure:
That compound is obtained in a yield of 76% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCC1>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Temperature: 70 °C
Yield: 33.2 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (400 mg, 1.70 mmol) in EtOH was added hydantoin (186 mg, 1.86 mmol) and pyrrolidine (14 μL, 0.17 mmol). The reaction was stirred at 70° C. over weekend. Precipitate was filtered and air dried to yield 180 mg (33% yield) 5-((5-chloro-7-(cyclopropylamino)pyrazolo-[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=319)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reaction time: 2 h

Procedure:
A solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.03 g, 3.75 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in methylene chloride (15 mL) is cooled to 0° C., then MeSO2Cl is added dropwise. After 2 hrs, TLC indicated that the reaction is not complete, 10 mol % more of triethyl amine and MeSO2Cl are added. After additional 2 hrs, the reaction mixture is diluted with methylene chloride and washed with sodium bicarbonate, water and brine, dried over sodium sulfate. Concentration gave the crude title compound, which is used for the next step without further purification.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.Cl.C(O)(=[O:28])C>>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:16])=[O:28]
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reactant: CC(=O)O
Agent: Cl
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 70 %

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CC(C)=O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc(Cl)cc1N
Yield: 74.5 %

Procedure:
To a suspension of 2-Amino-4-chloro-phenol (1.43 g, 10 mmoles, 1 eq) and potassium carbonate (6.9 g, 50 mmoles, 5 eq) in acetone (25 ml) was added in one portion (2-Chloro-ethyl)-dimethyl-amine hydrochloride (2.16 g, 15 mmoles, 1.5 eq). The reaction mixture was refluxed under Nitrogen for 6 hours at which time the suspension was filtered and the solid washed with acetone. The combined filtrate was concentrated under vacuum and purified by flash chromatography (EtOAc/MeOH/NEt3: 87/9/3) to afford a beige solid (1.6 g, yield=72%).