Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCC(O)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to piperidin-4-ol via General Procedure B. The product was purified via reverse phase HPLC to give 12.9 mg of 251. MS (Q1) 464.8 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9](C)[C:10]([C:12]3[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([O:27][CH2:28][C:29]1[C:30]([C:36]2[N:40]([CH3:41])[C:39]3[CH:42]=[CH:43][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:45][C:38]=3[N:37]=2)=[N:31][CH:32]=[CH:33][C:34]=1[Cl:35])(=O)C.[OH-].[Na+]>C(O)C.O>[C:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH2:18][OH:19])=[C:16]([Cl:20])[CH:15]=[CH:14][N:13]=3)[N:11]([CH3:24])[C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4].[C:46]([C:44]1[CH:43]=[CH:42][C:39]2[N:40]([CH3:41])[C:36]([C:30]3[C:29]([CH2:28][OH:27])=[C:34]([Cl:35])[CH:33]=[CH:32][N:31]=3)=[N:37][C:38]=2[CH:45]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(Cl)ccnc1-c1nc2cc(C(C)(C)C)ccc2n1C
Agent: Cn1c(-c2nccc(Cl)c2CO)nc2cc(C(C)(C)C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2nccc(Cl)c2CO)nc2ccc(C(C)(C)C)cc21
Temperature: 19 °C
Reaction time: 2 h

Procedure:
A mixture of 160l and 160j (480 mg, 1.3 mmol), and sodium hydroxide (104 mg, 2.6 mmol) in ethanol (20 mL) and water (20 mL) was stirred at 19° C. for 2 h. See FIG. 5. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×2). The organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford (2-(6-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methanol 160k and (2-(5-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methanol 160l as a mixture of regioisomers (400 mg, 94%). MS-ESI: [M+H]+ 330.2.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21](Cl)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(N)CCCC1>[Cl:23][C:19]1[CH:20]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:16]2[N:15]=[C:14]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: NC1CCCC1
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 154.6 %

Procedure:
N-Cyclopentyl-4-[5,7-dichloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (80 mg, 0.18 mmol) in cyclopentylamine was treated as described for Example 13 to give 70 mg (80%) of N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine as a solid. 1H NMR (CDCl3): δ 7.96 (d, 1H), 7.85 (s, 1H), 7.54 (d, 2H), 6.98 (d, 2H), 6.27 (d, 1H), 6.08 (d, 1H), 5.97 (d, 1H), 5.13 (d, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.87 (s, 3H), 2.2-2.0 (m, 4H), 1.4-1.9 (m, 12H); MS m/z 503 (M+1).
Reaction SMILES: [C:1]([O:5][C@H:6]([CH3:11])[C:7]([O:9]C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C(OCC)(=O)C.C1COCC1>[Cl:12][CH2:13][C:7](=[O:9])[C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:11]
Reactant: COC(=O)[C@@H](C)OC(C)(C)C
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)C(=O)CCl
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A mixture of 8.00 g (50 mmol) of methyl (R)-2-(tert-butyloxy)propionate, 8.74 g (75 mmol) of sodium chloroacetate, 7.53 g (75 mmol) of triethylamine, and 200 mL of THF was cooled in ice, and 93.8 g (150 mmol) of a 1.6 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 2 hours. After the completion of the dropwise addition, the reaction was performed at room temperature for another 2 hours, the reaction solution was cooled in ice again. Then, 20 mL of concentrated hydrochloric acid was added thereto, and subsequently 100 mL of ethyl acetate was added. Stirring was performed at room temperature for 1 hour. Then, the resulting organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7.35 g of a crude product. The resulting product was purified by column on silica gel to obtain 6.66 g of the title compound (yield: 80%). 1H-NMR (400 MHz, CDCl3) δ: 1.21 (s, 9H), 1.35 (d, 3H, J=6.6 Hz), 4.20 (q, 1H, J=6.6 Hz), 5.50 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.CCCCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOCC>[OH:33][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccccc1CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
A stirred solution of N-[(2-methyl)phenyl]-2,2-dimethyl-propanamide (95.6 g, 0.5 mol) in THF (500 ml) was cooled to 0° C. and treated with 1.6 M n-butyllithium in hexane (628 ml, 0.1 mol). The addition of n-butyllithium was complete after 45 minutes. During the addition, the temperature of the mixture was maintained below 10° C. with external cooling. The resultant dianion solution was aged for 2 hours at 0° C. until the homogeneous orange solution became a yellow heterogeneous slurry. The dianion was then quenched with benzaldehyde (63.6 g, 0.6 mol) and aged for 15 minutes at about 24° C. The reaction mixture was diluted with ether (200 ml), treated with crushed ice (200 g), and stirred for 5 minutes. The organic phase was separated, washed with saturated sodium chloride (250 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual oil was crystallized from hexane, filtered and recrystallized from dichloromethane (500 ml reflux) to give N-[2-(2-hydroxy-2-phenylethyl)-phenyl]-2,2-dimethylpropanamide (87 g, 0.29 mol) in 58% yield. The product had a melting point of 183°-184° C.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1>>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:5]
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cncc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cncc(C2CCN(CCCNC(=O)C(O)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 176 was prepared from hydroxy(diphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 515.4 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:16][C:17](=[O:39])[N:18]([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][C:27]=2[OH:38])[CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:38][C:27]1[CH:28]=[C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([N:18]([CH3:19])[C:17]([NH:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:39])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccccc2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 300 μL (2.5 mmol, 2.7 eq) of benzyl bromide and 400 mg (0.93 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.9 eq) of potassium carbonate at 90° C. for 3 hours, methyl 3-[2-benzyloxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Br[C:24]([CH3:33])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]>>[CH3:33][C:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:17][CH:18]=1)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]
Reactant: [H][H]
Reactant: COC(=O)C(C)(Br)C(=O)OC
Reactant: Oc1ccc(Oc2cnc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C)(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)OC
Temperature: 70 °C

Procedure:
In a nitrogen atmosphere, add a solution of 4.8 g (0.02 mole) 2-(4-hydroxyphenoxy)quinoxaline in 30 cc dimethylfornmamide to 0.8 (0.02 mole) 57% sodium hydride. When the evolution of hydrogen ceases, add 4.8 g (0.021 mole) dimethyl 2-bromo-2-methylpropanedioate dropwise. When the addition is complete, heat at approximately 70° C. until the reaction is complete. Pour the mixture into ice-water and extract with ether. Concentration of the dry ethereal extracts yield the title compound.
Reaction SMILES: [C:1]1([O:7][Si](CC2C=CC=CC=2C2C3C(=CC=CC=3)C=CC=2)(C)C)CCCC[CH:2]=1.C1(=O)CCCCC1.C([N-]C(C)C)(C)C.[Li+].C1(C2C=CC=CC=2C[Si](Cl)(C)C)C2C(=CC=CC=2)C=CC=1.[H][H].[C:66]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)(=[O:73])C1C=CC=CC=1>CC(C)=O>[C:1]([O:73][CH2:66][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)(=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(Cc1ccccc1-c1cccc2ccccc12)OC1=CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(Cl)Cc1ccccc1-c1cccc2ccccc12
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O=C1CCCCC1
Product: CC(=O)OCc1ccccc1

Procedure:
For example, 1-cyclohexenyloxy-[((1-naphthyl)phenyl)methyl]dimethylsilane, which is a silyl enol ether form of cyclohexanone, may be formed by treating cyclohexanone with lithium diisopropylamide at low temperature (e.g. −78° C.) so as to generate a lithium enolate, and capturing this with [((1-naphthyl)phenyl)methyl]dimethylsilyl chloride. By the same method, a ketone having an active hydrogen such as acetone or benzophenone may be derivatized to the corresponding silyl enol ether. Furthermore, a silyl ketene acetal form of benzyl acetate may be formed by treating benzyl acetate with lithium diisopropylamide at low temperature (e.g. −78° C.) so as to generate a lithium enolate, and capturing this with [((1-naphthyl)phenyl)methyl]dimethylsilyl chloride. By the same method, a carboxylic acid ester having an active hydrogen may be derivatized to the corresponding silyl ketene acetal.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=O)=[CH:40]2>C1COCC1>[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:40]2
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of pentyl triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-hex-1-enyl-1H-indole was purified by column chromatography.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]=[CH:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH2:8][N:7]1C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[C].[Pd]>[CH2:12]([O:11][C@H:9]1[CH2:8][NH:7][C@H:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: C=C(C)CO[C@@H]1C[C@@H](C=CCC(C)C)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCC[C@@H]1C[C@@H](OCC(C)C)CN1
Yield: 97.6 %

Procedure:
In 5.8 ml of ethanol is dissolved 0.29 g of benzyl (2S,4R)-2-(4-methyl-1-pentenyl)-4-[(2-methyl-2-propenyl)oxy]-1-pyrrolidinecarboxylate. After adding 0.06 g of 5% palladium-carbon, the mixture is stirred at ambient temperature for 1.5 hours in a stream of hydrogen. The reaction mixture is filtered with Celite, and the solvent is distilled off from the filtrate under reduced pressure. Thus, 0.18 g of (2R,4R)-4-isobutoxy-2-(4-methylpentyl)-pyrrolidine is obtained as a yellow oily product.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]2[NH:21][C:20](=[O:22])[C@@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[CH2:14][C:13]=2[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:33]>>[ClH:33].[O:22]=[C:20]1[C@@H:19]2[N:15]([CH2:16][CH2:17][CH2:18]2)[CH2:14][C:13]2[CH:23]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])[CH:10]=[N:11][C:12]=2[NH:21]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (R)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid tert-butyl ester (2.53 g, 7.68 mmol) in CH2Cl2 (15 mL) was treated with TFA (15 mL). After stirring at room temperature under N2 for 45 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (30 mL of a 4.0 M solution in dioxane, 120 mmol). The resulting mixture was sonicated for 10 min, stirred under N2 for 20 min, diluted with Et2O (100 mL), sonicated for 20 min and stirred for 20 min. The solid was isolated by filtration, washed with Et2O, and dried under vacuum at 50° C. overnight to give the title compound (2.66 g, quantitative) as an off-white solid: MS (ESI) m/e 274 (M+H)+.
Reaction SMILES: ON1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[OH2:9].[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[CH3:3][C:14]1[CH:13]=[CH:12][C:11]([C:10]([OH:18])=[O:17])=[CH:16][CH:15]=1.[C:10]([OH:18])(=[O:17])[C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Reactant: O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 5 h
Yield: 6.68 %
Yield: 28.9 %

Procedure:
Into an air-flow pressure reactor (or air-flow pressurizable reactor) equipped with a dehydrator similar to Dean-Stark apparatus, 300 g (2.8 mol) of p-xylene, 0.20 g (1.1 mmol) of cobalt acetate (bivalent), and 0.20 g (1.2 mmol) of manganese acetate (bivalent) were charged. Nitrogen was introduced into the reactor to raise the reactor pressure to 0.5 MPa. The mixture was heated to 150° C., and the reactor was ventilated with a mixed gas of air and nitrogen to adjust the oxygen concentration contained in off-gas to 5%. A separately prepared mixture of 0.25 g (2.2 mmol) of N-hydroxysuccinimide and 2 g of water was continuously fed in the reactor over 5 hours. Incidentally, it was assumed that the reaction was started at the time the addition of the catalyst was started, and that the reaction was completed at the time the addition of the catalyst was completed. Moreover, the reaction was carried out with trapping the produced water. After the reaction was completed, the reactor was cooled and the pressure was released. The reaction mixture was analyzed by a high-performance liquid chromatography (HPLC) to determine the conversion of the substrate and the amount and yield of the product. The conversion of p-xylene was 35.7%, and 110 g of p-toluic acid (yield 28.9%), 31 g of terephthalic acid (yield 6.68%), and 0.32 g of benzoic acid as a by-product (yield 0.094%) were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:5][CH2:6]1)=[O:32]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: O=C1NCc2ccccc2N1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (680 mg, 1.40 mmol) from Step 5 in DCM (15 mL) was added DIEA (0.366 mL, 2.1 mmol) followed by 2,4-dimethoxybenzoyl chloride (309 mg, 1.54 mmol). The reaction was stirred for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (50 mL) and saturated aqueous NaHCO3 (2×50 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting first with 95:5 EtOAc:CHCl3 and then with 95:3:2 EtOAc:CHCl3 :MeOH. The title compound was obtained as a white solid (77% yield).
Reaction SMILES: [NH2:1][C:2]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(CC)CC.[C:26]1([C:32]#[C:33][C:34]2[O:38][C:37]([C:39](ON3C(=O)CCC3=O)=[O:40])=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:2]1([NH:1][C:39]([C:37]2[O:38][C:34]([C:33]#[C:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:36]=2)=[O:40])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:3]1)[CH3:18]
Reactant: CCOC(=O)CC1(N)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A stirred solution of tert-butyl 3-amino-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (130 mg, 0.503 mmol) in DMF (3 mL) was treated with NEt3 (0.19 mL, 1.37 mmol), and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate, prepared as described in Preparation 5 (141 mg, 0.457 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the crude product purified by column chromatography to obtain the title compound (168 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.40 (m, 3H), 7.12 (s, 1H), 7.04 (s, 1H), 6.70 (s, 1H), 4.17 (m, 4H), 4.03 (d, 2H, J=9.6 Hz), 3.17 (s, 2H), 1.45 (s, 9H), 1.26 (t, 3H, J=7.2 Hz); MS ESI 453.2 [M+H]+, calcd for [C25H28N2O6+H]+ 453.51.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13](C(F)(F)F)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:42])C(=O)C1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([Cl:42])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc3c(Cl)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate (140 mg, 0.34 mmol) and NCS (90 mg, 0.68 mmol, 2.0 eq.) were dissolved in MeCN (5 mL). Then CF3COOH (12 mg, 0.1 mmol, 0.3 eq.) was added to the mixture at 0° C. The mixture was warmed to r.t. and stirred for 1 h. Then the pH of the solution was adjusted to 7 with saturated Na2CO3, concentrated and the mixture was extracted by EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (6/1) to give product methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylate (65 mg, 43%) as a slight yellow oil. EDI-MS (M+1)+: 444.0. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 1H), 7.69-7.66 (m, 2H), 7.50-7.47 (m, 1H), 7.28-7.27 (m, 1H), 4.25-4.19 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.59-3.58 (m, 2H), 3.38-3.37 (m, 3H), 2.23-2.20 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.52 (m, 2H), 1.12-1.07 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][CH:20]([CH3:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][C:4]=3[CH3:23])[N:12]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1-c1noc(-c2ccc(CC(C)C)cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)ccc1-c1noc(-c2ccc(CC(C)C)cc2)n1

Procedure:
A solution of 2.3 g (6.2 mmol) of 3-(4-bromo-2-methylphenyl)-5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazole (from Step A), 1.46 g (12.4 mmol) of zinc cyanide and 2.15 g (1.86 mmol) of Pd(PPh3)4 in 20 mL of DMF was stirred at 100° C. for 20 h. The reaction was cooled and quenched with 10 mL of sat'd NaHCO3. The quenched mixture was extracted with 100 mL of dichloromethane. The extract was dried and concentrated to afford 1.40 g of the title compound which was used without further purification: ESI-MS 318 (M+H); LC-1: 4.8 min.