Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCCn1ncc(C(=O)O)c1Cl
Yield: 88.2 %

Procedure:
To a solution of 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.71 g, 7.0 mmol) in methanol (7 mL) and water (7 mL) was added lithium hydroxide (235 mg, 9.8 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid as an orange solid (1.35 g, 88%). Mass spectrum: m/z: 219.3 (M+1).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=C[NH:16][N:15]=1>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[N:16]3[N:15]=[CH:14][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]3[N:2]=[CH:3][CH:4]=2)=[CH:8]1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccoc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of ethyl 3-aminopyrazole-4-carboxylate in glacial acetic acid is heated at reflux temperature for 6 hours. The product is isolated as described for Example 1 to give the product of the example.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([N+:19]([O-])=O)[CH:6]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[C:7]([NH2:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Tert-butoxycarbonylamino-3-nitro-benzoic acid ethyl ester (3.5 g, 11.3 mmol) was dissolved in ethanol (300 mL) and 10% palladium on carbon was added (0.45 g, 0.42 mmol). The mixture was evacuated and filled with hydrogen, then stirred at room temperature for 1 hour. The catalyst was filtered, washing with ethanol, and the solvent was evaporated. The crude 3-amino-4-tert-butoxycarbonylamino-benzoic acid ethyl ester thus obtained [3.1 g, 95%, MS (ISP): m/e=279.3 (M−H)] was used as such in the following reaction.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CC(N(C)C)=O>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CC(=O)N(C)C
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DMA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH:52]C(OCC1C=CC=CC=1)=O)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O.[Pd]>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH2:52])[OH:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 250 mg of 2,3,4,5,6-penta-O-acetyl-D-gluconic acid (benzyl 3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide in 20 ml of dioxan and 2 ml water was hydrogenated at room temperature in the presence of palladium on charcoal (10%). After 2 hours, the catalyst was filtered off over a filter aid and the filtrate was concentrated. The residue was crystallized from ethyl acetate/ether and gave 2,3,4,5,6-penta-O-acetyl-D-gluconic acid (benzyl 3,4-di-O-acetyl-2-amino-2,6-didesoxy-a-D-glucopyranosid-6-yl)-amide, [a]+96.0° (c 0.2; dioxan), MS: m/z 741.1 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][C:18]2[S:19][C:20]([C:28]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[N:22]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:19][C:20]=1[C:28]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCNCC1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
Compound 560 (428 mg, 0.849 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with diethyl ether to afford the entitled Compound 561 (263 mg, 77%).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:1]([O:3][CH2:4][CH2:5][O:6][N:27]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37])=[CH2:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=COCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 53 %

Procedure:
Ethylene glycol vinyl ether (9.88 g, 112 mmol), triphenylphosphine (29.4 g, 112 mmol), and N-hydroxyphthalimide (18.22 g, 111.7 mmol) were combined in 300 mL of anhydrous tetrahydrofuran and cooled to 0° C. (ice bath). Diethylazodicarboxylate (18.0 mL, 114 mmol) was added dropwise over 15 min and the resultant reaction mixture was allowed to warm to ambient temperature over 18 h. The reaction mixture was concentrated to a paste and the solids were filtered and washed with chloroform. The filtrate was further concentrated and filtered again, washing the solids with chloroform. The remaining chloroform solution was concentrated to an oil. The oil was dissolved in absolute ethanol (75 mL). Scratching with a glass rod induced crystallization. The crystals were collected and recrystallized from hot ethanol to afford colorless needles of 2-(2-vinyloxy-ethoxy)-isoindole-1,3-dione (13.8 g, 53% yield): 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2 H), 7.75 (m, 2 H), 6.46 (dd, J=14.3, 6.7 Hz, 1 H), 4.45 (m, 2H), 4.16 (dd, J=14.4, 2.2 Hz), 4.02 (m 3 H).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=1)=O.O.[NH2:15]N>C(O)C>[CH3:12][C:10]1[CH:11]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[S:8][CH:9]=1
Reactant: NN
Reactant: Cc1csc(C(=O)C=CN(C)C)c1
Solvent: O
Solvent: CCO
Product: Cc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-(4-methyl-2-thienyl)prop-2-en-1-one (72 mmol) and hydrazine hydrate (144 mmol) in 80 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated to afford 11.58 g (98% yield) 3-(4-methyl-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([CH3:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:7]=3)[C:9](=[O:21])[N:10]2[CH2:19][CH3:20])=[CH:15][N:14]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with phenyl isocyanate (0.066 mL, 0.603 mmol and stirred at RT overnight. The resulting solid was collected via filtration and dried to afford 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (211 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.77 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.01-7.98 (m, 2H), 7.73 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.25 (dd, J=8.5, 7.3 Hz, 2H), 7.17 (d, J=12.2 Hz, 1H), 6.97-6.90 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 451.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24](Cl)=[O:25])[N:23]=1>>[CH3:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])[N:23]=1
Reactant: Cc1nc(C(=O)Cl)c(C)s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1nc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c(C)s1

Procedure:
Beginning with 0.34 gm (1.6 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.44 gm (2.50 mMol) 2,5-dimethyl-4-thiazolecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 4.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C1(N2[CH2:38][CH2:37][CH:36]([O:39]C3C=CC(N)=CC=3)[CH2:35][CH2:34]2)CCC1>>[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:26]2[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@@H]1CCCN1CCCOc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The entitled compound was obtained as a brown oily substance, according to the same method as in Reference Example 21 or according to a method similar to it but using 4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}aniline 4-methylbenzenesulfonate produced according to a method described in a patent (WO2005/077905), as the starting compound in place of 4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)cc(CCC(=O)O)n4C)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
Sodium hydroxide (63 mg) was added to a solution of methyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D116) (72 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoic acid (E91) (12 mg). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.71 (2H, t), 3.03 (2H, t), 3.75 (3H, s), 5.46 (1H, m), 6.40 (1H, s), 7.60 (1H, d), 7.82 (1H, dd), 8.24 (1H, d), 8.56 (1H, d), 8.93 (1H, d), 12.33 (1H, s); MS (ES): C22H21ClN4O4 requires 440; found 441.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1C(=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][OH:33])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CO)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 2.8 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 mL) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL l) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloromethane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was suspended in water (0.5 mL) and DMSO (2.0 mL) and the reaction mixture was stirred for 18 h at 60° C. the resulting solution was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate. Drying over sodium sulfate and urification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20) afforded the title compound (57 mg, 33%) as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:11](=[O:13])/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][CH:7]=2)\[CH3:14])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C/C(=C\C(=O)O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: C/C(=C\C(=O)N1CCC[C@H]1CN1CCCCC1)c1ccc(C(F)(F)F)cc1

Procedure:
110 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(trifluoromethyl)phenyl)but-2-enoic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21]O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.BrC1C=CC(N2C(C(F)(F)F)=CC(C(O)=O)=N2)=NC=1.C(Cl)(=O)C(Cl)=O.NC(C)(C)CO>C(Cl)Cl.O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[O:18][CH2:23][C:20]([CH3:21])([CH3:24])[N:19]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(CO)NC(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Agent: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COC(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Step-1: 1-(5-Bromopyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide: To (0° C.) cooled solution of 1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (500 mg, 1.48 mmol), in DCM (20 mL) was added oxalyl chloride (391 μL, 4.46 mmol) followed by catalytic amount of DMF. The resulting mixture was stirred at room temperature for 3 h. The solvent and excess of oxalyl chloride was then removed under vacuum and the resulting residue was dissloved in DCM (10 mL). A solution of 2-amino-2-methylpropan-1-ol (0.35 mL, 3.72 mmol) in DCM (5 mL) was then added to the above solution drop-wise at 0° C. and the resulting mixture was warmed to room temperature and then continued stirring at the same temperature for 18 h. Water (10 mL) was added to the above reaction followed by DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with bine (10 mL), dried (anhydrous Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography to afford 600 mg (99%) of the title compound as white solid. 1HNMR (400 MHz, CDCl3) δ 8.61 (d, J=2.0 Hz, 1H), 8.04 (dd, J=2.0 & 8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 6.96 (s, 1H, D2O exchangeable), 3.73 (s, 2H), 1.44 (s, 6H) ; ESI-MS (m/z) 407, 409 [(MH)+, Br79,81].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Yield: 39.2 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 39%). MS (ISP) 356.9 [(M+H)+]; mp 206° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:17].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][C:13]([OH:17])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.0 g of 2-phenyl-4-hydroxyethyl5-methyloxazole in 20 ml of acetone was added a solution consisting of 1 g of chromium trioxide, 0.9 ml of concentrated sulfuric acid and 4 ml of water and the reaction stirred at room temperature for 40 minutes. The reaction mixture was poured into water (60 ml) and the product extracted with 150 ml of ethyl acetate. The organic layer was washed with water (2×50 ml) and dried over sodium sulfate. Removal of the solvent gave the crude product as an oil. The residue was dissolved in 80 ml of ethyl acetate and the product extracted with 100 ml of 0.25N aqueous sodium hydroxide. The aqueous layer was separated, acidified with 1N hydrochloric acid and the product extracted with 150 ml of ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated to give a yellow solid, 500 mg.
Reaction SMILES: Cl.[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([NH:13][CH:14](O)[C:15]([OH:17])=[O:16])=[O:12]>C(O)(=O)C>[Cl:9][CH2:10][C:11]([N:13]([C:5]1[CH:6]=[CH:7][C:2]([OH:8])=[CH:3][CH:4]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:12]
Reactant: Oc1ccccc1
Reactant: O=C(CCl)NC(O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN(C(=O)CCl)c1ccc(O)cc1
Reaction time: 8 h
Yield: 52.5 %

Procedure:
18 g of gaseous hydrochloric acid at 5° C are dissolved in a solution of 94 g (1 mole) of phenol and 83.8 g (0.5 mole) of chloracetamidoglycolic acid in 120 g of glacial acetic acid. After 8 hours at this temperature and then 16 hours at ambient temperature, the hydrochloric and acetic acids are distilled off at 25 mm of mercury, then the excess phenol at 2 mm of mercury at a temperature below 50° C, 200 ml of nitromethane are added, it is filtered, washed with ethyl ether and dried. 64 g of product are obtained (yield 53% with respect to the chloracetamidoglycolic acid). The product recrystallised in water melts at 187° C.