Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl.[CH2:32](O)C.C(=O)([O-])O.[Na+]>C(O)C>[ClH:16].[Cl:16][C:15]1[C:10]([N:7]2[C:8]([CH3:9])=[C:4](/[CH:1]=[CH:2]/[CH2:32][N:28]3[CH2:29][CH2:30][N:25]([C:20]4[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=4)[CH2:26][CH2:27]3)[CH:5]=[N:6]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(/C=C/CN2CCN(c3cc(F)cc(F)c3)CC2)cnn1-c1ncccc1Cl
Reaction time: 21 h

Procedure:
In 40 ml of absolute ethanol was dissolved 0.72 g of 4-acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole, and 1.38 g of 1-(3,5-difluorophenyl)piperazine, 7 ml of a 1N hydrochloric acid/ethanol solution, and 0.917 g of p-formaldehyde were added thereto, followed by refluxing for 20 hours. To the reaction mixture was further added 0.917 g of p-formaldehyde, followed by refluxing for 50 hours. After the reaction mixture was allowed to stand at room temperature for 21 hours, a saturated aqeous solution of sodium hydrogencarbonate was added thereto, and the mixture was extracted with chloroform three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was subjected to silica gel column chromatography using a mixture of chloroform-methanol (50:1 by volume) as a developing solvent. The fraction containing the desired compound was concentrated to yield 0.72 g of the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25][C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:28]=4[N:27]=3)[C:19]=2[Cl:37])[CH2:14][CH2:13]1.N>ClCCl>[O:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:28]=4[N:27]=3)=[O:9])[C:19]=2[Cl:37])[CH2:16][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3Cl)nc2c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCOCC4)c3Cl)nc2c1
Reaction time: 1 h

Procedure:
A solution of m-chloroperbenzoic acid (1.61 g) in dichloromethane (75 ml) was added dropwise to a stirred solution of 2 -(4 -morpholino-3 -chloro-2 -pyridylmethylthio)-5 -methoxy- (1H)-benzimidazole (3.35 g) in dichloromethane (150 ml) cooled to -35°. After 1 hour, ammonia was passed through the solution for 5 minutes and the precipitate filtered off. The solution was evaporated under reduced pressure and the residue chromatographed (silica gel, 2 % CHCl3 /MEOH-NH3 ) to give an oil which was crystallised from ethanol to give 2 -(4 -morpholino-3 -chloro-2 -pyridylmethylsulphinyl)-5 -methoxy-(1H)-benzimidazole. (2.6 g).
Reaction SMILES: [C:1]1([C:7]2([C:11](Cl)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:22][C:11]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:9][CH2:8]2)=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Reactant: COc1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccccc3)CCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phenylcyclobutanecarbonyl chloride (129 g) in dichloromethane (500 ml) was added under nitrogen over 1.5 hours to a stirred mixture of 4-methoxyphenethylamine (99.5 g), dichloromethane (500 ml) and triethylamine (110 ml). The mixture was stirred at 20°-25° C. for one hour and allowed to stand for 16 hours. The reaction mixture was washed with 2N hydrochloric acid, water and 2N aqueous sodium hydroxide solution, dried and evaporated to give N-[2-(4-methoxyphenyl)ethy]-1-phenylcyclobutane carboxamide.
Reaction SMILES: N([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:8](O)[CH2:9][CH2:10][CH3:11].N(O[CH3:16])=O>CO>[C:6]1([CH2:5][C:4](=[O:3])[CH3:16])[CH:7]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCO
Reactant: CON=O
Reactant: CCCCON=O
Solvent: CO
Product: CC(=O)Cc1ccccc1

Procedure:
Phenylacetone was prepared in the same manner as in Example 1, except that n-butyl nitrite and n-butyl alcohol were used in lieu of methyl nitrite and methyl alcohol and that the reaction temperature was changed to 55° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[C:36]([NH2:41])[CH:37]=[CH:38][C:39]=1[Cl:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)c(Cl)c4)cc3)c(C#N)cc21
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoic acid (17 mg, 0.0481 mmol) was diluted with CH2Cl2 (1 mL) followed by the addition of oxalyl chloride in CH2Cl2 (2M in CH2Cl2) (0.0289 mL, 0.0577 mmol) and 1 drop of DMF. The reaction was stirred for 20 minutes, and then 3,4-dichlorobenzenamine (15.6 mg, 0.0962 mmol) and N,N-diisopropylethylamine (0.0210 mL, 0.120 mmol) were added. After stirring for 30 minutes the reaction was loaded directly onto a Biotage 12i eluting with hexane:ethyl acetate (1:1) to yield the title compound (17 mg, 71.0% yield) as a clear oil.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].O>CO.CN(C)C=O>[C:1]([O:6][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: OCCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)OCCCCCCO
Reaction time: 0.5 h

Procedure:
Methacrylate acid (43.0 g=0.5 mole) was dissolved in 50 mL methanol. Tetrabutylammonium hydroxide (25% in methanol, 519 gm=0.5 mole) was added to the latter solution. The solution was stirred for 30 minutes, and then freed of solvent on a rotary evaporator. The residue was dissolved in 100 mL of N,N-dimethylformamide (DMF) and a solution of 6-chloro-1-hexanol (68.3 gm+0.5 mole) in 200 mL DMF was added. This was stirred at 50° C. for 4 hours, the heat was discontinued, and the solution was stirred at room temperature overnight. An equal volume of H2O was combined and the solution was extracted with three portions of ethyl acetate. The combined ethyl acetate layers were back-extracted with three portions of H2O, dried over MgSO4, and the mixture evaporated to an amber oil. 1H NMR (CDCl3): δ (ppm) 4.1 (2H, t). Elemental Analysis: C10H18O3, mol. wt. 186. Calcd.: C, 61.5; H, 9.7; O, 25.8. Found: C, 61.7; H, 9.7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27](I)([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: CC(C)I
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.95 g) in dimethylformamide (20 ml), there was added anhydrous potassium carbonate (0.8 g) while stirring at room temperature. After stirring for 10 minutes at about 40° C., isopropyl iodide (1.7 g) was added thereto, and the resultant mixture was stirred for 3 hours at 70°-80° C. After being allowed to col to room temperature, the mixture was poured into water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 1.2 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][Cl:15].O>CCCCC.CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: ClCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: O
Product: ClCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
NaH (0.253 g; 0.11 mole of 60% NaH in suspension in mineral oil, previously washed with pentane) is added to a solution of indole (1.17 g; 0.1 mole) in 10 mL of DMF placed under a nitrogen atmosphere, then the reaction mixture is stirred for 30 minutes at ambient temperature. 1-bromo 2-chloroethane is then added. After reaction for 2 hours, the reaction mixture is treated by the slow addition of water and extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on silica gel. The 1-(2-chloroethyl)indole is obtained pure with a yield of 80%.
Reaction SMILES: [K:1].CC(C)([O-:5])C.[O:7]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[K:1].[O:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O-:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K]
Solvent: CS(C)=O
Product: [O-]c1ccccc1Oc1ccccc1
Temperature: 0 °C

Procedure:
13.2 g of potassium-tert.-butoxide is added portionwise, with slight external cooling (ice water) and with the introduction of nitrogen, to a solution of 20.4 g of 4-phenoxyphenol in 200 ml of dimethylsulphoxide. After potassium-phenoxy-phenolate has formed, with complete dissolving of the potassium-tert.-butoxide, there is added dropwise to the phenolate within 30 minutes at 20°-22° C, with stirring, 21.5 g of 1-bromo-3-phenoxypropane, and the whole is stirred at 30° C for a further 16 hours. In further processing, the reaction mixture is poured, with stirring, into 800 ml of ice water, and the mixture is repeatedly extracted with dichloromethane. The combined dichloromethane phases are thereupon repeatedly washed with ice-cold 10% potassium hydroxide solution, water and saturated sodium chloride solution; they are then dried over sodium sulphate and the solvent is completely removed in vacuo. The 1-phenoxy-4-(3-phenoxy)-1-propoxy-benzene then solidifying in crystalline form is further purified by recrystallisation in isopropanol; m.p. 69°-71° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([O:19]C)=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C@H:6]([OH:32])[CH2:5]1.Cl>O.C1COCC1>[Cl:3][C@H:4]1[C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[C@@H:7](/[CH:21]=[CH:22]/[C@@H:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C@H:6]([OH:32])[CH2:5]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCCC[C@@H](C)O)[C@H](O)C[C@H]2Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)CCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Reaction time: 24 h
Yield: 83.6 %

Procedure:
Lithium hydroxide (1.2 mL of a 0.5N solution in H2O, 0.605 mmol) was added to a solution of the ester 31 (111 mg, 0.242 mmol) in THF (0.5 mL) at 23° C. After stirring for 24 h the reaction mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 4:1 CH2Cl2/MeOH) provided 90 mg (84%) of the free acid 33 (see Scheme 5).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28]([OH:30])=O)=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:17])[CH3:16])[C:9]3=[N:8][C:7]=2[CH:31]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:62](CC)CC.[NH4+].[Cl-]>CN(C=O)C.O>[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:37])=[O:30])=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1.[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:62])=[O:30])=[CH:20][N:19]=4)[C@@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)CC
Reactant: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Product: CC(C)[C@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %
Yield: 10.8 %

Procedure:
To a solution of (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (100 mg, 0.19 mmol, partially racemized) in DMF (2 mL) was added HATU (97 mg, 0.25 mmol) and Et3N (52 mg, 0.51 mmol). The mixture was stirred at rt for 1 h. NH4Cl (19 mg, 0.34 mmol) was added in one portion. The mixture was stirred at rt for 16 h. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were washed with water (3×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC and SFC separation to afford (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (55.2 mg, 56.7% yield, isomer 1) as a white solid and (S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (10.5 mg, 10.8% yield, isomer 2) as white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH3:16][N:17]([CH3:29])[C:18]1([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(B)#N.[Na].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH3:16][N:17]([CH3:29])[C:18]1([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:20][CH2:19]1
Reactant: CN(C)C1(c2cccs2)CCNCC1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(CCCN1CCC(c2cccs2)(N(C)C)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
6.4 g (1.3 eq) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 7.5 g (1 eq) N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride in 75 ml methanol at 0° C. and the reaction mixture was stirred for 15 min at 0° C. 4.9 g (3 eq) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 90 min at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). As the conversion was not yet complete, the pH of the reaction mixture was adjusted to 5-6 with acetic acid and the mixture was stirred for 12 h at room temperature. Once the conversion was complete, the methanol was distilled off, water was added, the mixture obtained was extracted with IPA/chloroform (2×100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCl3). 8.5 g (84%) of product were obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([N:14]3[CH2:19][CH2:18][C:17]([CH2:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(O)[CH2:16][CH2:15]3)[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:43])CC.[Cl:46]CCl>>[ClH:46].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([N:14]3[CH2:19][CH2:18][C:17]([CH2:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([F:43])[CH2:16][CH2:15]3)[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(c1ccc(N2CCCC2)cc1)N1CCC(O)(CC(=O)c2ccccc2)CC1
Agent: O=C=O
Solvent: CC(C)=O
Product: CC(c1ccc(N2CCCC2)cc1)N1CCC(F)(CC(=O)c2ccccc2)CC1
Product: Cl
Temperature: -75 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
N-(1-(4-(1-pyrrolidinyl)phenyl)ethyl)-4-benzoylmethyl-4-piperidinol (III-25) is firstly prepared according to the method of synthesis and post-treatment in Example 2. 1.57 g (4.0 mmol) of N-(1-(4-(1-pyrrolidinyl) phenyl)ethyl)-4-benzoylmethyl-4-piperidinol is dissolved into 20 ml of anhydrous dichloromethane and cooled with dry ice-acetone with temperature controlled at below <−70° C. The reaction solution is added dropwise a dichloromethane solution (8 mol, 25 ml) of DAST under protecting of nitrogen gas. After completion of addition, the temperature is maintained at −75° C. and reacting for 1 hour, and the temperature is raised slowly and maintained at −10° C. and reacting for 2 hours. Then operating according to the post-treatment method in General Method six obtains 0.78 g of a white crystal, with yield of 40.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccc(OC)nc12)C(=O)OCC
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 2-methoxy-quinolin-8-ol (commercial; 1.75 g, 10 mmol) and diethyl bromomalonate (1.85 mL, 10 mmol) in DMF (35 mL) was added Cs2CO3 (6.52 g, 20 mmol). The reaction mixture was heated at 80° C. for 1.5 h then allowed to cool to rt. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by CC (EA-Hept 1:3 to 1:1) to give the title compound as a yellowish oil (2.50 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH2:26][OH:27])/[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[C:20](\[CH2:26][O:27][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])/[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Reaction time: 24 h
Yield: 97 %

Procedure:
42 g of 4-methylbenzenesulfonyl chloride are added to a solution of 45.8 g of Z-1-(4-chlorophenyl)-2-hydroxymethyl-4,4-dimethylpent-1-ene in 200 ml of methylene chloride and 59 g of triethylamine at room temperature. After 24 hours, the reaction mixture is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue gives 73.1 g (98%) of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[N+:13]=[N-:14]>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2=[N:11][C:17](=[O:19])[C:16]3[C:15]([N:12]2[NH:13][N:14]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: N#CCc1ccccc1F
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Agent: [Na]
Solvent: CCO
Product: O=c1nc2c(-c3ccccc3F)n[nH]n2c2ccccc12
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
Sodium (0.55 g, 24 mmol) was dissolved in dry ethanol (25 ml) at room temperature under nitrogen. 2-Fluorophenylacetonitrile (1.9 ml, 15 mmol) was added and the orange solution was stirred for 15 min, followed by dropwise addition of a solution of 2-azidobenzoic acid (1.97 g, 12.1 mmol) in diy ethanol (20 ml). The thick, white gel was stirred at room temperature for 45 min then refluxed for 18 h. Solvent was removed by evaporation and water (40 ml) was added. The yellow suspension was acidified with aqueous citric acid (1 M). The precipitate was collected, washed with water and dried in vacuo at room temperature to give 3-(2-fluorophenyl)-1,2,3-triazolo[1,5-α]quinazolin-5-one (3.38 g, 100%) as an off-white powder, m.p. 238-241° C. (DMF). Found: C, 64.33; H, 3.06; N, 20.29. C15H9FN4O requires C, 64.28; H, 3.24; N, 19.99%. δH (360 MHz; DMSO) 7.33-7.38 (2H, m), 7.46-7.55 (1H, m), 7.69-7.73 (2H, m), 8.02 (1H, ddd, J=9, 9 and 1), 8.24 (1H, dd, J=8 and 1), 8.38 (1H, d, J=8) and 12.40 (1H, br s); m/z (ES+) 821 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(C=O)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(4-methoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with p-anisaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.91-1.94 (m, 2H), 2.13-2.23 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.47 (s, 2H), 3.74 (s, 3H), 4.74-4.80 (m, 1H), 6.89-6.91 (m, 2H), 7.24-7.26 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.36 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=494.