Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 12.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenyl)amino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.249 g, 0.520 mmol) obtained in Example 106, step 2 and ethanesulfonamide (0.238 g, 2.60 mmol), the title compound (0.036 g, 11%) was obtained.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]=[O:41])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]([OH:41])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1
Reactant: CS(C)(=O)=O
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CS(=O)(=O)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
To a solution of methyl sulfone (65 mg, 0.68 mmol) in THF (1.5 mL) is added a solution of n-BuLi (0.27 mL, 0.68 mmol, 2.5 M solution in hexane) at −78° C. After stirring for 5 minutes, HMPA (0.1 mL) is added. After stirring for additional 10 minutes, a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (26 mg, 0.069 mmol) in THF (1 mL) is added. The resulting solution is stirred for 1.5 hours at −78° C. The reaction is quenched with saturated aqueous NH4Cl, warmed to room temperature, and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (3% MeOH in CH2Cl2) to give the crude desired product (31 mg, 96%) which is used directly without further purification: MS APCI (+) m/z 462, 464 (M+, Br pattern) detected.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[NH:6][C:5]=2[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:20])=O>C1COCC1>[Cl:20][C:7]1[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:15]([CH3:17])[CH3:16])[C:5]=2[N:6]=1
Reactant: Cc1nn(C(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nn(C(C)C)c2nc(Cl)cc(C(=O)O)c12
Temperature: 105 °C
Reaction time: 24 h

Procedure:
3-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1.5 g, 6.38 mmol) was added to a solution of THF (15 mL) followed by addition of phosphorous oxychloride (8.9 mL, 96 mmol), and the contents heated at 105° C. overnight. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatiles. The residual contents were slowly poured into a solution of iced water and 1N NaOH (10 mL), and the contents were stirred at room temperature for 24 h, during which time solid precipitation ensued. Additional 1N NaOH was added, upon which the solids went into solution. After stirring at room temperature for an additional 30 min., the contents were cooled in an ice bath and the mixture slowly acidified to pH=3-4 by slow addition of 6N HCl, to afford a heterogenous mixture. The mixture was filtered and a white solid set aside. The aq. layer was further extracted with EtOAc and DCM. The combined organic layers dried were dried over MgSO4, filtered and concentrated in vacuo. The resultant light brown solid was triturated in EtOAc/EtOH (1:1) and filtered to afford a first crop of white solid product, which was set aside. The filtrate was again concentrated in vacuo. The residue was diluted with EtOAc, sonicated, treated with hexanes, and filtered. The process was repeated. The isolated solid product crops were dried under vacuum (3 h) and collected as 1.33 g (80%). LCMS E-S (M+H): 254.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, 6 H), 2.60 (s, 3 H), 5.10 (quin, J=6.63 Hz, 1 H), 7.50 (s, 1 H), 14.17 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1

Procedure:
To a solution of N-(5-aminopyridin-2-yl)acetamide (1.00 g, 6.62 mmol) and pyridine (0.647 ml, 7.94 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.10 ml, 7.94 mmol), and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.47 g (68.1%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH3:1][Li].CC1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1>CCOCC.C(Cl)Cl.[Cu]I>[CH2:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To copper(I) iodide (1.25 g, 6.55 mmol) in Et2O (25 mL) was added methyllithium (8.2 mL, 13.1 mmol) at 0° C. A solution of phenylmethyl(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (0.85 g, 2.182 mmol) in CH2Cl2 (4 mL) was added next, and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (230 mg, 45%) as a colorless oil. LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[C:11]([C:18]#[N:19])=[C:10]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[Cl:3][C:12]1[C:11]([C:18]#[N:19])=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([Cl:6])[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Solvent: O
Product: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
POCl3 (1.64 g, 1 ml, 10.7 mmol, Eq: 30.1) was added to 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carbonitrile (100 mg, 356 μmol, Eq: 1.00) and the mixture was refluxed for 1 h. The reaction mixture was then allowed to cool to RT, poured onto cold water and extracted with DCM (3×). The combined organic layers were washed with brine, dried with Na2SO4 and evaporated to dryness. The remaining residue was purified by column chromatography (silica gel, DCM/heptane 1:1) to afford the title compound as white solid (81 mg). MS (ESI): 299.0 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=CC=CC=[C:14]12>>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1.[CH:2]1[CH:1]=[CH:6][C:5]2[C:7](=[O:8])[CH:9]=[CH:10][C:11](=[O:12])[C:4]=2[CH:3]=1.[C:16]1(=[O:17])[O:18][C:13](=[O:23])[CH:14]=[CH:15]1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C1C=CC(=O)c2ccccc21
Product: O=C1C=CC(=O)O1
Product: c1ccc2ccccc2c1

Procedure:
By the process according to the present invention it has surprisingly been possible to obtain a colorless, pure phthalic anhydride with a melting point of 131.2° C., a naphthoquinone content of less than 1 ppm, and a color value of less than 10 APHA. These surprising results have been obtained by heating crude phthalic anhydride produced from naphthalene containing 0.7-0.8% by weight of naphthoquinone and 0.04% by weight of maleic anhydride, for 20 hours with, for example, 0.2% by weight of commercial polybutadiene oils to about 240° C., followed by vacuum distillation. Similar results were obtained with the use of polyisoprene, polydimethylbutadiene, and poly-1,3-pentadiene.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:24])[CH:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.CO.[Li+].[OH-].Cl>O>[CH:13]1[C:12]2[C:11](=[CH:10][C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
5-(2-(9H-fluoren-9-ylidene)acetamido)pentanoic acid methyl ester (335 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (279 mg, 87% yield) as a white solid. LC-MS (m/z) 322 (M+1).
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[S:2].N1CC[CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15]C1>O1CCCC1>[NH2:8][C:1]([N:3]1[CH2:4][CH2:15][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:7]1)=[S:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
To a solution (200 mL) of 1,1′-thiocarbonyldiimidazole (15.0 g) in tetrahydrofuran was added ethyl piperidine-4-carboxylate (12.59 g) at room temperature, and the mixture was stirred at room temperature for 3 hrs and then at 55° C. for 1 hr. Tetrahydrofuran (ca. 100 mL) was distilled off under reduced pressure and 2M ammonia methanol solution (150 mL) was added. After stirring the reaction mixture at room temperature for 15 hrs, the mixture was concentrated. The residue was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v) to give ethyl 1-(aminocarbonothioyl)piperidine-4-carboxylate as colorless crystals (4.76 g, yield 27%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 97-98° C.
Reaction SMILES: C[NH:2][C:3](=O)[C:4]1C(=C[CH:10]=[CH:11][CH:12]=1)C(N)=O.C[N:15]([CH3:18])[CH:16]=[O:17].[C:19]([O-:22])(=O)[CH3:20].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[CH3:18][N:15]1[C:19](=[O:22])[C:20]2[C:3](=[CH:4][CH:12]=[CH:11][CH:10]=2)[NH:2][C:16]1=[O:17]
Reactant: CN(C)C=O
Reactant: CNC(=O)c1ccccc1C(N)=O
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Product: Cn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 2 h

Procedure:
A 50 ml. flask was charged with 1.0 g. N-methylphthalamide suspended in 11 ml. dimethylformamide. A 2.6 g. portion of lead tetra-acetate was added to the suspension, and the reaction mixture stirred at 40°-50° for 2 hours. The reaction mixture was diluted with 15 ml. water, cooled and filtered. The yield amounted to 0.89 g., melting point 230°-232°, representing 88 percent of theory based on the N-methylphthalamide. The structure was confirmed by infrared spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Br)n1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.84 mmol) and (S)-(−)-1-phenylethylamine (0.435 mL, 3.41 mmol) were heated at 100° C. for 12 hours. The mixture was cooled to room temperature, dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 6% ethyl acetate-hexane) afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][C@H:19]1[CH2:24][NH:23][CH2:22][C@@H:21]([CH3:25])[NH:20]1.C(N(C(C)C)CC)(C)C.Cl>C(#N)C.C(OCC)C>[CH3:18][C@H:19]1[NH:20][C@@H:21]([CH3:25])[CH2:22][N:23]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[CH2:24]1
Reactant: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOCC
Product: C[C@@H]1CN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)C[C@H](C)N1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 6-chloro-4-phenyl-3-trifluoromethyl-pyridazine (D3) (0.15 g, 0.58 mmol), 2,6-cis-dimethylpiperazine (0.097 g, 0.87 mmol) and diisopropylethylamine (0.202 ml, 1.16 mmol) in acetonitrile (3 ml) was stirred at 180° C. for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and then dichloromethane and a saturated solution of ammonium chloride were added. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 1-3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The product thus obtained was treated with a solution of hydrochloric acid in diethyl ether (2M) to yield the corresponding salt E4 (0.058 g, 27%; CIS) as a pale brown solid. C17H19F3N4.HCl; free base requires 336. Found 337 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[CH3:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1C
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(O)c([N+](=O)[O-])c1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 20 a) except for using 15.7 g (129 mmol) of 3,4-dimethylphenol, 130 ml of acetic acid, 8 ml of water and 12.2 g (135 mmol) of 70% nitric acid. 3,4-Dimethyl-2-nitrophenol was thus obtained in the yield of 7.01 g (26.0%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=O)[CH2:19]Br.CN(C)C=O.C(O)C>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[O:3][CH:19]=1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3C(F)(F)F)co2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-carbamoylbenzoate (896 mg), 2-trifluoromethylphenacyl bromide (2.22 g) and N,N-dimethylformamide (5 ml) was stirred at 130° C. for 2 hours. Hot ethanol was added to the reaction mixture, which was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to a silica gel column chromatography to obtain methyl 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoate as an oil from a fraction eluted with ethyl acetate-hexane. This oil was dissolved in a mixture of tetrahydrofuran (10 ml) and ethanol (10 ml), and hydrolyzed by adding a 1N aqueous solution of sodium hydroxide (10 ml). The reaction mixture was neutralized with 1N hydrochloric acid, and precipitated crystals were collected by filtration. The product was recrystallized from acetone-hexane to obtain 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoic acid (203 mg, yield: 12%). Colorless prisms. Melting Point: 264 to 265° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH2:32][CH3:33].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH2:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 22.1 %

Procedure:
A mixture of 1.1 g (3.481 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.746 g (4.525 mmole) of 4-amino-3-ethylbenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 18 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.3421 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) as off-white solid.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[N:20]=[CH:19][N:18]2CC2C=CC=CC=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:30]>CO.C(Cl)Cl.C(OCC)C>[ClH:30].[CH2:15]1[C:16]2([C:21](=[O:22])[NH:20][CH2:19][NH:18]2)[CH2:17][NH:14]1
Reactant: O=C1N=CN(Cc2ccccc2)C12CN(C(c1ccccc1)c1ccccc1)C2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1NCNC12CNC2
Reaction time: 0.17 h

Procedure:
To a solution of 2-benzhydryl-5-benzyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-3A-5a; 1.83 g, 4.80 mmol) in methanol/methylene chloride was added excess 1 M HCl in diethyl ether (10 ml). After stirring for 10 minutes, the solvent was removed, in vacuo, and the resultant hydrochloride salt dissolved in methanol (50 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 1.1 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 22 hours. The reaction was filtered through a 0.45 μM disk, and then concentrated, in vacuo, to give a gummy solid. This material was triturated from methanol to afford I-3A-5b (450 mg, 47%) as a tan solid: +APcI MS (M+1) 127.9; 1H NMR (400 MHz, CD3OD) δ 4.51 (s, 2H), 4.41-4.33 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[N:6][CH:7]=1.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:9]=[CH:10]2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: Fc1ccc(-c2c[nH]cn2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc(-c3ccc(F)cn3)c2)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
In a screw-cap vial, added 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g, 0.30 mmol), 3-Fluorobenzonitrile (0.04 ml, 0.36 mmol), potassium carbonate (0.21 g, 1.5 mmol) and dimethylformamide (1 ml). Stirred the resulting reaction mixture at 110° C. overnight. Cooled the reaction mixture to room temperature, diluted with chloroform (50 ml), sequentially washed with water (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was triturated with 10% diethyl ether in hexanes to yield the title compound (45 mg) as a dirty yellow colored solid. 1H-NMR (CDCl3), δ (ppm): 8.43 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 2H), 7.70 (m,4H), 7.48 (dt, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=O)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[NH2:28][NH2:29].C(OCC)(=O)C>CO.[O-2].[Mn+4].[O-2]>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:28]=[N:29][N:23]3[C:18]=2[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22]3)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:28]=[N:29][N:23]3[C:18]=2[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22]3)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(C(=O)c2ncnc3[nH]ccc23)CC1
Reactant: NN
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](c2nnn3cnc4[nH]ccc4c23)CC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
(4-{[(tert-Butyldimethylsilyl)oxy]methyl}cyclohexyl)(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (9.23 g, 24.7 mmol) in methanol (200 mL) was mixed with hydrazine monohydrate (38.0 mL, 618 mmol) and then stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and mixed with ethyl acetate, washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in chloroform (240 mL) and mixed with manganese(IV) oxide (10.7 g, 124 mmol). The reaction mixture was stirred at 70° C. for 1 day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1 (v/v)) to give 1-(cis-4-{[(tert-butyldimethylsilyl)oxy]methyl)}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (Reference Synthetic Examplea 135a; pale yellow solid, 670 mg, yield 7%) in a less polar fraction and 1-(trans-4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (Reference Synthetic Examplea 135b; pale yellow solid, 5.02 g, yield 52%) in a more polar fraction.