Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:16])[CH:5]=1.[CH2:18]([O:25][CH2:26][CH2:27][CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:28][CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: OCCCOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCCOCc2ccccc2)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoic acid methyl ester (D37) (300 mg, 1.28 mmol, 1 equiv), 3-benzyloxypropan-1-ol (0.28 ml, 1.79 mmol, 1.4 equiv) and triphenyl phosphine (470 mg, 1.79 mmol, 1.4 equiv) in THF (10 ml) at room temperature was treated dropwise with DEAD (0.282 ml, 1.79 mmol, 1.4 equiv). The mixture was stirred for 16 h at room temperature then concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/iso-hexane: 1/4 to 1/1) gave 3-(3-benzyloxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D38).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][N:9]=2)=[O:27])=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Product: O=C(COc1ccc(OCc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 10 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 2-(4-(benzyloxy)phenoxy)acetic acid (commercially available) using General Procedure B. Column chromatography (SiO2, 2.5×6 cm, 20-40% EtOAc-hexanes gradient) followed by PTLC (SiO2, 50% EtOAc-hexanes) afforded 11b (35 mg, 0.09 mmol, 10%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.70 (app d, 1H, J=4.0 Hz), 8.04 (d, 1H, J=8.1 Hz), 7.86 (td, 1H, J=7.7, 1.5 Hz), 7.55-7.52 (m, 1H), 7.44-7.33 (m, 6H), 6.94-6.89 (m, 4H), 5.45 (s, 2H), 5.03 (s, 2H); ESI-TOF m/z 387.1343 (C23H19N2O4+H+ requires 387.1345).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=1.Cl>C1COCC1>[OH:3][CH2:2][CH2:1][O:4][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: OCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCCO)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylene glycol (34 μl) was added to a suspension of sodium hydride (24 mg) in anhydrous THF (2 ml) at 0° C. After 30 min stirring at 0° C., 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (47 mg) dissolved in THF (1.2 ml) was added. The mixture was allowed to warm to RT and stirred overnight. A 1M HCl solution was added and the resulting mixture was extracted with EA. The org. phases were dried (Na2SO4) and evaporated off.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[CH2:24]([O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
500 mg of 5-formylfuran-2-carboxylic acid was dissolved in 10 mL of tetrahydrofuran, added with 990 μl of triethylamine, cooled to 0° C., and then added with 374 μl of ethyl chloroformate. After stirring at this temperature for 30 minutes, 406 μl of benzylalcohol was added and stirred at room temperature overnight. Adding water to stop the reaction, the solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and purified by silica gel column chromatography, to afford 508 mg of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:19])([CH3:18])[C@@H:15]4[O:17][C@@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1.O.[NH3:21]>C(O)C>[NH2:21][C@H:16]1[C:6]2[C:7](=[CH:8][C:9]3[C:10]([CH3:12])=[CH:11][C:2]([Cl:1])=[N:3][C:4]=3[CH:5]=2)[O:13][C:14]([CH3:19])([CH3:18])[C@@H:15]1[OH:17]
Reactant: N
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@@H]1O[C@H]31
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Temperature: 90 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of (3R*,4R*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (2.0 g, 7.25 mmol) in ethanol (20 mL), ammonia water (10 mL) was added, and the resulting mixture was stirred in a sealed tube at 90° C. for 3 hours. Upon the completion of the reaction, the reaction solution was concentrated, and ethyl acetate was added thereto, The resulting solution was washed with water and then with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/2) to obtain the aimed product (yield: 86%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][CH:23]([CH3:25])[CH3:24])[N:16]=3)[O:12][N:11]=2)[CH:7]=[C:6]([CH3:26])[C:5]=1[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:63]([NH:70][CH2:71][CH2:72][NH2:73])([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64]>CN(C=O)C.CCOC(C)=O>[C:66]([O:65][C:63](=[O:64])[NH:70][CH2:71][CH2:72][NH:73][C:29](=[O:30])[CH2:28][CH2:27][C:5]1[C:6]([CH3:26])=[CH:7][C:8]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][CH:23]([CH3:25])[CH3:24])[N:16]=3)[O:12][N:11]=2)=[CH:9][C:4]=1[CH2:2][CH3:3])([CH3:67])([CH3:68])[CH3:69]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a suspension of Intermediate 10 (25 mg, 0.061 mmol) in DMF is added DIPEA (16 μL, 0.092 mmol) followed by TBTU (23.5 mg, 0.073 mmol). The reaction mixture is stirred for 5 min before adding N-Boc-ethylenediamine (12 μL, 0.073 mmol) and stirring is continued for 2 h. The reaction mixture is diluted with EtOAc (20 mL) and is washed with sat. aq. NaHCO3 (15 mL). The org. phase is then dried over Na2SO4, filtered, and evaporated to give a yellow oil that is purified by prep. TLC (eluting with DCM/MeOH 95:5) to afford [2-(3-{2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-ethyl]-carbamic acid tert-butyl ester (27 mg) as a white solid; LC-MS: tR=1.09 min; [M+1]+=552.30.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=O.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:12][N:13]([CH2:1][C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)[CH3:14]
Reactant: CNC
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 5-formyl-2-thiopheneboronic acid (500 mg, 3.2 mmol) in DCE (30 mL) was added dimethylamine hydrochloride (520 mg, 6.3 mmol) followed by triethylamine (0.9 mL, 6.5 mmol). The reaction mixture was stirred for 10 min before sodium triacetoxyborohydride (1.36 g, 6.3 mmol) was added in one portion. After the reaction mixture was stirred at room temperature for 5 h, it was quenched with 30 mL of MeOH, stirred briefly, then concentrated under vacuum. Introduction of a CH2Cl2/Et2O mixture to this residue revealed a solid, which was filtered and washed with Et2O. The resulting organic filtrate was concentrated to a viscous oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Nc1cc(Cl)ccc1C(=O)O
Reaction time: 2 h
Yield: 78 %

Procedure:
2-Amino-4-chloro-benzoic acid (515 mg, 3.0 mmol) was suspended in dry THF (5 ml) and phenylisocyanate (429 mg, 3.6 mmol) was added. Triethylamine (303 mg, 3.0 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with 75 ml ethyl acetate and extracted into 150 ml 1 M aqueous NaOH, and washed once with 50 ml ethyl acetate. The aqueous phase was then acidified with 4 M aqueous HCl and the product extracted with 2×100 ml ethyl acetate. The organic solvent was dried (Na2SO4) and reduced under vacuum, and the product recrystallised from acetone/water to yield 680 mg (78%) of off-white crystals (m.p. 186-188° C.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([N:7]([CH2:20][C:21]2[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CCCNc1nc(-c2ccccc2)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)c(C)o1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a solution of 5-methyl-4-phenyl-N-propyl-1,3-oxazole-2-amine (407 mg, 1.88 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 82 mg, 2.04 mmol) at room temperature and the mixture was stirred for 30 min. Methyl 3-[4-[[4-(chloromethyl)benzyl]oxy]phenyl]propanoate (500 mg, 1.57 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (251 mg, yield 32%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2C(OC)=O)[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[OH-].[K+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([CH:15]=2)[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c2n1CCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)cn3c2CCC3)cc1

Procedure:
Methyl 2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate (0.4 g, 0.96 mmol) is heated under reflux for 1 h in methanolic KOH (2 N, 9 ml, 1.01 g of KOH, 18 mmol). After cooling, water (20 ml) is added and the alkaline phase is rendered weakly acidic (pH 3) using HCl (conc. 25%). The deposited substance is extracted with ethyl acetate, and the ethyl acetate extract is dried using Na2SO4 sicc. and concentrated after filtering. After the removal of the solvent in vacuo, 0.4 g (75% GC) of residue remains. The CC purification is carried out on SiO2 using ethyl acetate as an eluent. The main fractions are concentrated in vacuo and the residue is recrystallized from diisopropyl ether:
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=12.S(OC)(O[CH3:23])(=O)=O.O>CS(C)=O>[CH3:23][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:6]2[CH2:5][C:4]3[C:15]([C:7]1=2)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c2c(c3ccccc31)Cc1ccccc1-2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (375 mq, 15.6 mmol) was added to dimethylsulfoxide (DMSO) (13 cm3) under an atmosphere of nitrogen. The solution was then heated to 70° C. until no more gas (H2) evolved. The solution was cooled to room temperature and 5,10-dihydroindeno[1,2-b]indole (2.69 g, 13.1 mmol) dissolved in a minimum amount of DMSO was added. After stirring at room temperature for 1 hour, dimethyl sulphate (1.5 cm3, 15 mmol) was introduced, and stirring continued for a further 1 hour. Water (3 cm3) was cautiously added, and the reaction then poured into ice/water. The solid thus formed was collected by suction filtration, washed firstly with water, dried on the water pump, and then washed with petrol (60°-80° C.). Crystallization from ethanol yielded colourless needles of the title compound. Yield: 1.52 g (53%). M.p. 152° C. 1H NMR (CDCl3) δ: 3.55 (2H, s,), 3.85 (3H, s,), 6.8-7.4 (8H, m, arom.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([C:38]([CH:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[O:39])[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C(=O)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (50 mL) at room temperature. To the resulting mixture was then added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (332 mg, 1.45 mmol, 1.00 equiv), in portions at room temperature, followed by BOP (767 mg, 1.74 mmol, 1.20 equiv), in portions at room temperature. To the resulting mixture was added DIPEA (280 mg, 2.17 mmol, 1.50 equiv), in portions at room temperature. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was washed with water (1×50 mL). The resulting solution was extracted with DCM (3×50 mL), the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carbonyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.[O:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH2:35])[CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.O.C(Cl)CCl>[O:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]([NH:35][C:22](=[O:24])/[CH:21]=[CH:20]/[C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NC1CCOc2ccccc21
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NC2CCOc3ccccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a DMF (4 mL) solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (70 mg) obtained in Example 121, chroman-4-ylamine (CAS#53981-38-7) (49 mg), EDC (62 mg) and HOBT (44 mg) were added at room temperature under nitrogen atmosphere, and the reaction solution was agitated at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system), and (E)-N-(chroman-4-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide racemate (90 mg) was obtained. This compound (50 mg) was separated by CHIRALPAK™ AD-H (2 cm×25 cm: mobile phase; hexane-ethanol 20%) available from Daicel Chemical Industries, Ltd., and the title optically-active substance with a retention time of 22 minutes (16 mg; >99% ee) and the title optically-active substance with a retention time of 28 minutes (19 mg; >98% ee) were obtained. The physical properties of the title optically-active substance with a retention time of 22 minutes (Example 413) are as follows.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Na+].Cl.Cl.[F:28][C:29]([F:40])([F:39])[C:30]1[N:35]=[CH:34][C:33]([C@H:36]([NH2:38])[CH3:37])=[CH:32][N:31]=1.CN1CCOCC1.Cl.CN(C)CCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:21]([NH:38][C@@H:36]([C:33]3[CH:32]=[N:31][C:30]([C:29]([F:40])([F:39])[F:28])=[N:35][CH:34]=3)[CH3:37])=[O:22])=[CH:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc2cc(C(=O)O)cc(-c3ccc(F)cc3)c2o1
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Agent: CCN=C=NCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2)c2oc(C(C)(C)C)nc2c1)c1cnc(C(F)(F)F)nc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert-butyl-7-(4-fluorophenyl)-1,3-benzoxazole-5-carboxylic acid with three equivalents of sodium chloride (30 mg, 74.0 μmol), (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine dihydrochloride (19.5 mg, 74.0 μmol) and N-methylmorpholine (33.7 μL, 0.307 mmol) in N,N-dimethylformamide (0.409 mL) were added N[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (20.6 mg, 107 μmol), 1-hydroxy-7-azabenzotriazole (4.2 mg, 31.0 μmol). The mixture was stirred at 40° C. for 1 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (22.6 mg). HRMS [M+1] found=487.1766. 1H NMR (500 MHz, DMSO-d 6): δ 9.15 (2H, s), 8.20 (1H, s), 8.14 (1H, s), 8.02 (2H, t, J=6.70 Hz), 7.45 (2H, t, J=8.65 Hz), 5.33 (1H, m, J=7.09 Hz), 1.63 (3H, d, J=7.07 Hz), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][O:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][O:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:24][CH:25]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3COCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCOC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 14.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (R)-4-(8-amino-3-(morpholin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 47) and 2-butynoic acid, to afford the title compound (4.9 mg, 14.1%). Data: UPLC(C) Rt: 1.38 min; m/z 482.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=2)[C:12]([OH:14])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.O>CN1C(=O)CCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH:44][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=[C:9]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:10]=2)=[CH:38][CH:37]=1
Reactant: COc1cccnc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Reactant: NCCc1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccnc1-c1cc(C(=O)NCCc2ccc(F)cc2)cc(-n2cnnn2)c1
Reaction time: 0.67 h
Yield: 7.6 %

Procedure:
3-(3-Methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid (140 mg) and dissolved in dry NMP (15 mL), and CDI (80 mg, 0.49 mmol) was added. The reaction mixture was stirred for 40 minutes, and then 2-(4-fluorophenyl)-ethylamine (0.16 mL, 1.22 mmol) was added. The reaction mixture was stirred for 24 hours at room temperature, and then poured into 30 mL water. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc/hexanes (30%-100%) to give 15 mg of N-[2-(4-fluoro-phenyl)-ethyl]-3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzamide, MS (M+H)=419.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:22](O)[C:23]#[CH:24].S(=O)(=O)(O)O>O>[CH2:24]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14])[C:23]#[CH:22]
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C#CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: C#CCOC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 41 %

Procedure:
A mixture of 21.2 grams of 4,4-bis(4-hydroxyphenyl)pentanoic acid, 50 ml. of propargyl alcohol and 0.3 ml. of concentrated sulfuric acid was stirred at room temperature for 40 hours. The mixture was then poured into 500 ml. of water, with stirring. The oily layer was allowed to settle and the aqueous layer was removed by decantation. The oily layer was washed with water two additional times. Finally, 500 ml. of water containing 10 grams of sodium bicarbonate was added to the oily layer, the product was extracted from the mixture into ether and chromatographed on a silica column (using 10/90 acetone/toluene, by volume, eluent) to give 96.9 grams (41%) of white solid, m.p. 99.5°-101.0° C.