Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>N1C=CC=CC=1>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:1][C:17](=[O:20])[CH2:18][CH3:19])[S:7][C:8]=2[CH:14]=1
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)Nc1nc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise propionyl chloride (0.5 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.1 g) having the following physical properties.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.[Cl:35][C:36]1[S:37][C:38]([CH2:41]Cl)=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:41][C:38]2[S:37][C:36]([Cl:35])=[CH:40][CH:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-chloro-5-(chloromethyl)thiophene (2.39 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 45%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nnnc1CCl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS (m/e): 379.3 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9]4=[C:10]([C:19](=[O:23])[NH:20][C:21](=[O:22])[N:8]4[C:7]=2[CH:6]=1)[CH:11]=[CH:12][CH:13]=3.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:20]1[C:19](=[O:23])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[S:15][C:16]4[CH:17]=[CH:18][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][C:7]=4[N:8]([C:9]=23)[C:21]1=[O:22])[CH3:27]
Reactant: CCI
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cccc3c2n(c1=O)-c1cc(C(F)(F)F)ccc1S3
Reaction time: 1 h

Procedure:
57% Sodium hydride in mineral oil (4.2 g., 0.100 mol.) was added to a stirred solution of 28.0 g. (0.0834 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine -1,3(2H)-dione in 220 ml. of dry dimethylformamide. The mixture was stirred for 1 hour at 25°, then 16.8 g. (8.6 ml., 0.108 mol.) of ethyl iodide was added. The resulting greenish yellow, turbid mixture was stirred for 4.5 hours at 25°, then filtered to give a clear yellow solution. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with petroleum ether to remove the mineral oil. The crude solid product was precipitated from a methanol-water mixture to give the title compound, m.p. 150°-152° (ethanol).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:17]=[C:18]([C:33]([O:35]C)=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl>CO>[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:17]=[C:18]([C:33]([OH:35])=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 35.8 %

Procedure:
An aqueous NaOH 2N (0.622 mL, 1.24 mmol) solution was added to methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (195 mg, 0.41 mmol) in MeOH (2 mL) and the reaction mixture stirred at 40° C. for 6 h. The mixture was cooled to 0° C. and an aqueous HCl 2N (0.684 mL, 1.37 mmol) solution was added dropwise to the reaction mixture until pH ˜5. The solution was partially concentrated and a precipitate appeared. Water was added to the slurry and extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The formed precipitate was triturated with ether, filtered, washed with ether, dried under vacuum at 50° C. to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (67 mg, 35%) as a pale beige solid. Mass Spectrum: m/z [M+H]+=457.
Reaction SMILES: [Se](=O)=O.O.[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].CC[O:19]C(C)=O>O1CCOCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH:5]=[O:19])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1cccc([N+](=O)[O-])c1
Yield: 76 %

Procedure:
To a solution of Selenium dioxide (9.4 g, 85 mmol) in 1,4-Dioxane (50.0 mL) and Water (1.70 mL, 94.4 mmol), was added 3-Nitroacetophenone (12.0 g, 72.9 mmol). The reaction mixture was refluxed for 4 hours with stirring, then taken up with EtOAc (100 mL) and washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and conc. in vacuo. Purification was by ISCO column chromatography (20-70% EtOAc/Hex) to afford (3-Nitro-phenyl)-oxo-acetaldehyde (9.98 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[CH:9]=[CH2:10].FC(F)(F)C(NC1C=CC=CC=1)=O>>[CH2:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:8]
Reactant: Nc1ccccc1
Reactant: C=CCBr
Agent: O=C(Nc1ccccc1)C(F)(F)F
Product: C=CCNc1ccccc1

Procedure:
N-Allylaniline [NMR (200 MHz, DMSO-d6): δ3.68 (t, J=5.2 Hz, 2H); 5.10 (d, J=10.2 Hz, 1H); 5.23 (d, J=17.2 Hz, 1H); 5.78 (br s, 1H); 5.75-5.97 (m, 1H); 6.52 (t, J=7.3 Hz, 2H); 6.56 (d, J=7.8 Hz, 2H); 7.06 (t, J=7.3 Hz, 2H)] was prepared from aniline and allyl bromide via trifluoroacetanilide using the general method described by Hodge (Harland, Pa.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984, 941).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (760 mg) in dry THF (10 ml) containing potassium carbonate (386 mg) was treated dropwise with thiomorpholine (0.36 ml, 369 mg). The resulting mixture was stirred at room temperature under nitrogen for 20 h before filtering and concentrating in vacuo to give impure title compound which was purified by FCC eluting with dichloromethane to give the title compound as a crystalline white solid (634 mg). m.p. 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.[BH4-].[Na+]>CN(C=O)C.[Co](Cl)Cl>[NH2:33][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:19])=[CH:25][CH:24]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 72 h
Yield: 43.1 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (200 mg, 0.442 mmol, 1.0 equiv.), cobalt chloride (86 mg, 0.664 mmol, 1.5 equiv.) and sodium borohydride (50 mg, 1.33 mmol, 3.0 equiv.) in DMF (15 mL) was stirred at 0° C. to rt for 3 days. The reaction was quenched with ice cubes, diluted with DCM (100 mL) and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave {4-[2-(aminomethyl)phenyl]phenyl}-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (87 mg, 43%). MS found for C26H21C1N4O2 (M+H)+: 457.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH3:16])([CH3:15])[O:13][C:12](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:11]=2[C:22]#[N:23])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:24]([N:26]([CH2:35][CH3:36])[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[CH:34])=[CH:29][CH:28]=1)[CH3:25].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:22]([C:11]1[C:12](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[O:13][C:14]([CH3:15])([CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N:1]2[CH:34]=[C:33]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH2:35][CH3:36])[CH2:24][CH3:25])=[CH:28][CH:29]=3)[N:3]=[N:2]2)=[CH:9][CH:8]=1)#[N:23]
Reactant: C#Cc1ccc(N(CC)CC)cc1
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccc(-c2cn(-c3ccc(C4=C(C#N)C(=C(C#N)C#N)OC4(C)C)cc3)nn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 2-[4-(4-azidophenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (60 mg, 0.20 mmol) and diethyl-(4-ethynyl-phenyl) amine (35 mg, 0.20 mmol) in ethanol (10 mL) was stirred at 60° C. Sodium ascorbate (14 mg, 0.07 mmol in 1 mL water) solution was added followed by copper sulfate (8 mg, 0.03 mmol in 1 mL water) solution. The mixture was stirred at 60° C. for 24 h, cooled, poured into cold water and was stirred at room temperature for 1 h. The precipitate formed was filtered off and air dried. The product was further purified by silica gel column chromatography using hexane/EAC 30-50% and finally recrystallized from dichloromethane/methanol. Yield: 70 mg (73%) Mp: 275° C. IR (neat) 3022, 2230, 1620 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 3.40 (q, 4H), 1.83 (s, 6H), 1.18 (t, 6.8 Hz, 6H); 13CNMR (CDCl3) δ 175.44, 174.40, 149.64, 147.93, 140.30, 129.83, 128.81, 126.91, 126.14, 120.32, 115.77, 114.36, 110.77, 110.79, 109.99, 102.25, 98.91, 59.89, 44.11, 26.07, 12.30. Anal. Calcd for C28H25N7O: C, 70.72; H, 5.30; N, 20.62. Found: C, 69.83; H, 5.63; N, 20.87. UV-Vis (CH2Cl2): λmax=319 nm ε=3.562×104 L·mol−1 cm−1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:12][S-:13].[Na+]>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:11][C:4]1[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([S:13][CH3:12])[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.250 g, 1.32 mmol) and sodium thiomethoxide (0.093 g, 1.32 mmol) in THF (10 mL) was stirred at rt for 6 h. After this time, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.210 g, 84%) as an off-white solid. MW=200.69. 1H NMR (DMSO-d6, 300 MHz) δ 2.90 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.56 (s, 3H), 2.10 (quin, J=7.6 Hz, 2H); APCI MS m/z 201 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1([CH2:26][C:27]([OH:29])=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:30]1([O:36][CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>>[CH3:37][O:36][C:30]1[CH:35]=[CH:34][C:33]([C:27](=[O:29])[CH2:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A mixture of methanesulfonic acid (100 g) and P2O5 (10 g) was stirred at 50°-60° C. until solution was complete, then cooled to room temperature. To this was added phenylacetic acid (2.0 g) and anisole (4.00 g). The mixture was stirred at 50°-60° C. for 90 minutes, cooled to room temperature and poured into ice water (1.2 L). The solution was made basic by gradual addition of solid sodium bicarbonate, then extracted into ethyl acetate (800 mL). The ethyl acetate was dried over magnesium sulfate and evaporated to give 3.88 grams of crude product. This crude product was chromatographed on silica gel eluting with 2% ethyl acetate in hexane, to obtain 2.92 grams of 1-(4-methoxyphenyl)-2-phenylethanone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][NH:12][CH3:13])=[CH:5][NH:6]2.CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:32][CH:31]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([N:12]([CH2:11][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH3:13])=[O:40])=[CH:32][CH:31]=1
Reactant: CNCc1c[nH]c2cccc(F)c12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1c[nH]c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 35.4 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.285 g, 1.74 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.2 g, 36%) was prepared as a white powder: MS (ES) m/e 325 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:30])[N:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:31]([O:33]C)=[O:32])=[CH:7][C@@H:6]1[OH:35])(=[O:3])[CH3:2]>C(N(CC)CC)C>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:30])[N:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:31]([OH:33])=[O:32])=[CH:7][C@@H:6]1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)OC)=C[C@H](O)[C@H]1NC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](O)[C@H]1NC(C)=O
Temperature: 50 °C

Procedure:
A mixture of (4S,5R,6R)-5-acetylamino-4-hydroxy-6-[(2-biphenyl-4-yl-ethyl)propylcarbamoyl]-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (0.89 g) water (5 ml) and triethylamine (5 ml) was heated at 50° C. for 6 hours. The solvent was then removed in vacuo and the residue was co-evaporated with dioxane (×3) to afford the title compound as an off white solid (0.87 g). 1H NMR (250 MHz, D6 -DMSO rotamers) 7.96 (1H, d, J=8 Hz), 7.60 (4H, m), 7.45 (2H, m), 7.33 (3H, m), 5.72 (1H, m), 5.15 (1H, m), 4.90 (1H, m), 4.25 (1H, m), 3.87 (1H, m), 3.60-2.95 (8H, m), 1.80+1.75 (3H, 2×s), 1.55 (1H, m), 1.46 (1H, m), 0.83 (3H, m). Mass analysis: C26H30N2O6. 1.0 H2O. 0.6 C6H15N Required: C, 65.20; H, 7.58; N, 6.68. Found: C, 65.40; H, 7.59; N, 6.44.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([O:31]C)=O)[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]>>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH:27]([C:29]([NH:3][CH3:2])=[O:31])[CH2:26][C:25]=4[CH:33]=3)[N:14]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1
Reactant: CN
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)c(Cl)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N4-(3,4-dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine gave (±)-N4-(3,4-dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.09 (s, 1H), 8.08 (m, 3H), 7.76 (bd, 1H, J=9.3 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.43 (bs, 1H), 7.24 (bd, 1H, J=8.7 Hz), 6.73 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.3 and 6.6 Hz), 3.39 (dd, 1H, J=10.5 Hz), 3.15 (dd, 1H, J=6.3 Hz), 2.60 (d, 3H, J=4.8 Hz); LCMS: purity: 99%; MS (m/e): 450 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH:11][C:12]1[C:13]([CH2:21][CH2:22][CH3:23])=[N:14][N:15]([CH3:20])[C:16]=1[C:17]([NH2:19])=[O:18])=O)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[NH:19][C:17](=[O:18])[C:16]2[N:15]([CH3:20])[N:14]=[C:13]([CH2:21][CH2:22][CH3:23])[C:12]=2[N:11]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1sccc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3sccc3OCC)nc12
Temperature: 80 °C
Yield: 57.4 %

Procedure:
A mixture of 3 (1.15 g, 3.42 mmol), NaOH (284 mg, 7.1 mmol) in ethanol (11 mL) and water (34 mL) was heated at 80° C. for 65 h. After cooling to r.t. a white precipitate was formed. Filtration and drying under vacuum gave 0.625 g of the product. The filtrate was extracted with CH2Cl2, and the organic phase was washed with 1N HCl and brine, dried with MgSO4. Evaporation of the solvent gave additional product; mp: 151-152° C.; 1H NMR (CDCl3) δ 1.00 (t, J=7 Hz, 3 H), 1.54 (t, J=7 Hz, 3 H), 1.82 (sxt, J=7 Hz, 2 H), 2.86 (t, J=7 Hz, 2 H), 4.23 (s, 3 H), 4.34 (q, J=7 Hz, 2 H), 6.87 (d, J=6 Hz, 1 H), 7.37 (d, J=6 Hz, 1 H); MS (m/z): 319 (MH+).
Reaction SMILES: O.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:2][C:14](=[O:16])[CH3:15])=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c2ccccc12
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(O)c2ccccc12
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 4-amino1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling, and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(4-hydroxy-1-naphthyl)acetamide (20 g, 79% yield) formed.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20](ON2C(=O)CCC2=O)=[O:21])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:21])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(OCCOC(=O)C1CCCCC1)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: O=C(NC1(C(=O)O)CC1)OCCOC(=O)C1CCCCC1
Yield: 16.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (426 mg, 4.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (1.1 g, 3.5 mmol) were reacted to provide 172 mg (16% yield) of the title compound (10) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 123.6-125.3° C. 1H NMR (CDCl3, 400 MHz): δ=9.92 (br s, 1H), 6.76 (q, 1H), 6.34 (br s, 0.3H), 5.59 (s, 0.7H), 2.27 (m, 1H), 1.10-1.95 (m, 17H). MS (ESI) m/z 317.15 (M+NH4)+; 322.13 (M+Na)+; 298.15 (M−H)−.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.CO.[OH-].[Li+]>O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2ccccc2)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetate (2c) (48 mg, 0.11 mmol) in a 1/1 mixture of tetrahydrofurane/methanol (2 mL) was added a solution of lithium hydroxide (11 mg, 0.44 mmol) in water (0.25 mL). The mixture was stirred at 65° C. for 2 hours. TLC analysis showed no more starting material. The mixture was concentrated under reduced pressure. Water (0.5 mL) and ethyl acetate (2 mL) were added to the residue. The aqueous layer was acidified with 1M hydrochloric acid until pH 5 and extracted with ethyl acetate (3×2 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetic acid (example 2) (40 mg, 0.095 mmol, 85%) as a white solid.