Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.C(N(CC)CC)C.O.Br[C:28](Br)([CH3:30])[CH3:29]>>[CH3:1][N:2]1[CH2:30][CH2:28][CH2:29][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]2[CH2:3]1
Reactant: CNCC1Nc2ccccc2Cc2ccccc21
Reactant: CC(C)(Br)Br
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCCN2c3ccccc3Cc3ccccc3C2C1
Reaction time: 2 h

Procedure:
4.76 g 5,6-dihydro-6-methylaminomethyl-11H-dibenzo[b,e]azepine is dissolved in 125 ml dibromopropane and 5 ml triethylamine is added to the solution. The mixture is boiled under reflux with stirring for 2 hours, after which it is cooled. 150 ml Water is then added and the whole is shaken for a little while, after which the aqueous layer is separated from the dibromopropane layer. The organic layer is subsequently dried over sodium sulphate and evaporated to dryness under vacuum. The residue is further purified chromatographically on a silica gel column with methanol:acetone (9:1) as eluent.
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CCCCCl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Reaction time: 3 h

Procedure:
To n-butyllithium (7.28 mL of a 2.5 M solution in hexane, 18.2 mmol) at −5° C. was added dry THF (80 mL) dropwise, maintaining the temperature below 5° C. 5-Chloro-1-pentyne (7.75 mL , 73.1 mmol) was added at 5° C., and the solution was stirred for 3 hours. The reaction was quenched by the addition of tri-n-butyltin chloride (21.0 mL, 77.4 mmol), and was allowed to stir for an additional 10 min. The solution was poured into saturated aqueous NaHCO3 (500 mL) and hexane (500 mL). The hexane layer was washed with H2O (200 mL), then brine (200 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:13]([F:23])[C:8]2=[N:9][O:10][C:11]([CH3:12])=[C:7]2[CH:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[C:8]([C:13]=1[F:23])=[N:9][O:10][C:11]=2[CH3:12]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc2c(F)c(Nc3ccccc3Cl)c(C(=O)O)cc12
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylic acid methyl ester (55) (100 mg, 0.299 mmol) in 6:1 THF:water (3.5 mL) was added LiOH (0.60 ml of a 1 M solution in water). After 1 hour, the reaction was acidified to pH 1 with 1 N HCl, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated to give the desired product (56) (87 mg, 91%). MS APCI (−) m/z 319, 321 (M+, Cl pattern) detected: 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.38 (dd, 1H), 7.20 (m, 1H), 6.91 (m, 2H), 2.88 (s, 3H): 19F NMR (376 MHz, CD3OD) −136.40 (s, 1F).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: ClCc1nc2cccnc2s1
Reactant: CSc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-[2-(methylthio)phenyl]piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H) 2.75 (m, 4H) 2.97 (m, 4H) 4.06 (s, 2H) 7.13 (m, 3H) 7.56 (dd, J=8.31, 4.58 Hz, 2H) 8.33 (dd, J=8.14, 1.36 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 357 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:10]2[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[CH:24][CH:23]=1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Solvent: CC(=O)O
Product: CC(C)(C)Cn1c(Cc2ccc(-n3cccc3)cc2)cc2cnc(C#N)nc21
Yield: 60.2 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.32 mmol) in acetic acid (1 ml) is slowly added 2,5-dimethoxy-tetrahydro-furan (0.35 mmol). The reaction mixture is refluxed for 2 h and cooled. The mixture is quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with saturated ammonium chloride and brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane:AcOEt=6:1 (v/v) and n-hexane:AcOEt=4:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 60.2%, Rf=0.55 (n-hexane:AcOEt=2:1). 1H-NMR (400 MHz, CDCl3) δ 1.06(s, 9H), 4.09(s, 2H), 4.24(s, 2H), 6.27(s, 1H), 6.35-6.36(m, 2H), 7.16-7.17(m, 2H), 7.21(d, 2H), 7.38(d, 2H), 8.84(s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(OC)c1N
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a solution of methyl 2-amino-3-methoxybenzoate (13.0 g, 71.8 mmol) in DMF (30 mL) was added NBS (14.38 g, 80.8 mmol) at room temperature and the resulting reaction mixture was stirred for 17 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-bromo-3-methoxybenzoate (13.7 g, 73%). 1H NMR consistent.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH:2]1[C:7]([OH:9])=O.[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][CH2:11]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:7]([CH:2]5[CH2:1][NH:6][C:4](=[O:5])[NH:3]5)=[O:9])[CH2:31][CH2:32]4)(=[O:24])=[O:25])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][CH2:12]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: O=C1NCC(C(=O)O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(C(=O)C4CNC(=O)N4)CC3)ccc2n1CC1CC1
Reaction time: 15 h

Procedure:
To a solution of 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) in dichloromethane (1 mL) was added 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazole (STEP D of Example 5, 25 mg, 0.062 mmol), triethylamine (13 microL, 0.093 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.093 mmol) at room temperature, then stirred. After 15 h, 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) was added to the mixture and stirred at room temperature. After 2 days, the mixture was washed with water (0.5 mL). The organic layer was mounted to a strong cationic exchange column (SCX) which was preconditioning with methanol (4 mL). SCX was washed with methanol (4 mL). Finally SCX was washed with 1 mol/L ammonia in methanol (5 mL), the product was collected a collection tube and concentrated at under reduced pressure by centrifugal concentrator. The residue (25 mg) was purified by prep-LC-MS(“process A”).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([O:8][CH3:9])[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]([O:8][CH3:9])[CH2:5][CH2:6][O:7][S:18]([CH3:17])(=[O:20])=[O:19])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CON(CCO)CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[(2-hydroxy-ethyl)-methoxy-amino]-ethanol (20.0 g, 148.0 mmol) and triethylamine (41.3 ml, 30.0 g, 296.3 mmol) in tetrahydrofuran (855 ml) under argon was added methanesulfonyl chloride (25.2 ml, 37.3 g, 325.6 mmol) dropwise, keeping the temperature below 20° C. with an ice bath. The reaction mixture was stirred at room temperature for 4 hours, the resulting precipitate filtered off and the filtrate concentrated. The residue was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Yield: 40.0 g of methanesulfonic acid 2-[(2-methanesulfonyloxy-ethyl)-methoxy-amino]-ethyl ester as a pale yellow oil, this material was used without further purification.
Reaction SMILES: Cl[C:2]1C(Cl)=CC(C(Cl)(Cl)Cl)=C[N:3]=1.Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.[C-]#N.[K+]>CS(C)=O>[Cl:20][C:19]1[C:14]([C:2]#[N:3])=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-Chloro-2-fluoro-5-(trifluoromethyl)pyridine (obtained as a by-product from the fluorine exchange reaction when converting 2,3-dichloro-5-trichloromethyl pyridine to 2,3-dichloro-5-(trifluoromethyl)pyridine) (40.0 g, 0.2 mole) was put into 270 ml of dimethyl sulfoxide and stirred while potassium cyanide (14.4 g, 0.221 mole) was spooned in over a 20-minute period. The mixture was then stirred for another 20 minutes. The temperature was held between 23° and 28° C. throughout the reaction. The mixture was poured into 600 ml of ice water and the product was extracted into hexane. The hexane was removed on a rotary evaporator. The product was treated with activated charcoal and distilled on a Vigreaux-Claisen still at 108°-110° C. at 30 mm Hg to yield 31.45 g of colorless oil with an analysis of, in percent by weight:
Reaction SMILES: [SH-:1].[Na+].[CH2:3]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13](Cl)[NH:12][C:11]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CN(C)C=O>[CH2:3]([N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([SH:1])[NH:12][C:11]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [SH-]
Reactant: Cc1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(S)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium hydrosulfide (119.8 g, 2,14 mole) was added to a cloudy solution of 3-benzyl-6-chloro-5-methyl-1H-pyrimidine-2,4-dione (178 g, 0.71 mole) in dimethylformamide (1 L) and heated to 60° C. 18 hours to give a dark green solution. The reaction solution was cooled and poured into 1 M HCl (6 L) and stirred at room temperature for 1 hour. The solid was collected by filtration and washed with water, dried under vacuum with P2O5 at 45° C. overnight to give 177.4 g. 1H-NMR (CDCl3) δ 10.45 (s, 1H), 7.41 (d, 2H), 7.23–7.30 (m, 3H), 5.07 (s, 2H), 3.59 (s, 1H), 1.96 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7].[I-:19].[Na+].CCCCCC>CC(C)=O>[I:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: [I-]
Reactant: O=C(CCCCCl)Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(CCCCI)Nc1ccc(C(F)(F)F)cc1

Procedure:
5--Chloro-N-[4--(trifluoromethyl)phenyl]-pentanamide (2.795 g) and sodium iodide (3.32 g) were stirred in acetone (20 ml) at 22° C. for 3d, then heated at reflux for 16h, all under nitrogen. The cooled reaction mixture was chromatographed with 50:50 ethyl acetate:hexane to isolate product with Rf =0.30 in 35:65 ethyl acetate:hexane by addition of hexane and evaporation of solvent under a stream of nitrogen afforded, after suction filtration, a white solid (2.8 87 g). The product iodide contained ca. 5% starting chloride and was used without further purification.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:3](=[O:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCc1cccnc1
Reactant: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 102 °C

Procedure:
21.6 g (131 mmol) 3-(3-pyridyl)-propionic acid methyl ester, 35.1 g ml (109 mmol) 4-(1-diphenylmethylpiperidine-4-yl)-butylamine and 9.8 g (54.5 mmol) 30% sodium methylate solution in methanol are heated to boiling in 480 ml toluene for five hours. Subsequently, 30 ml of solvent are distilled; thereby, sodium methylate precipitates and the temperature of the suspension increases to 102° C. under heavy foaming. The mixture is cooled to 70-80° C. and extracted twice with 45 ml and 30 ml of water. The organic phase is azeotropically dried on a moisture separator and cooled to ca. 0° C. The resulting precipitate is filtered off and crystallized from 190 ml toluol. Colorless crystals with a MP of 139° C. were recovered; yield: 46.3 g (93%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
4-Hydroxybenzoic acid (1.01 g, 7.31 mmol) and 4-aminophenol (1.19 g, 10.9 mmol) were dissolved in 15 mL of dry DMF. To the above solution EDCl (1.40 g, 7.31 mmoL) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using EtOAc in hexane as an eluent (10% to 20%) to give 580 mg (34% yield) of 4-hydroxy-N-(4-hydroxyphenyl)-benzamide. MS (ES) m/z: 230.04 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:28])=[C:17]([CH3:27])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:28])=[C:17]([CH3:27])[C:18]4[O:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(N2CCN(c3ccc(S(C)=O)cc3)CC2)c(C)c2c1OC(C)(C)C2
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To the THF/ethyl acetate (1:1, 6.0 mL) solution of 1-[4-(methylsulfanyl)phenyl]-4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (200 mg, 0.50 mmol) synthesized in Example 89, m-chloroperbenzoic acid (70%, 124 mg, 0.50 mmol) was added under ice cooling, followed by stirring for 2 hours. The reaction solution was added with an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) and the resulting solids were recrystallized from hexane-THF to obtain the title compound 94 mg (yield 46%). Melting point was 223 to 227° C. (hexane-THF).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:17])=O>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1

Procedure:
1.5 g of 4-fluoro-3-trifluoromethylbenzoic acid, 0.65 ml of thionyl chloride and two drops of DMF are heated under reflux for 12 h in 17 ml of toluene and the mixture is subsequently concentrated and used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([NH:35][C:36](=[O:47])[C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43](F)(F)F)[CH:38]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:49](F)(F)C1C=C(C=CC=1)C(Cl)=O>>[CH3:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[CH3:49])[C:36]([NH:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]([C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:12]=[CH:11][C:10]=2[NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])[CH:34]=1)=[O:47]
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1ccc(C(=O)Nc2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1C

Procedure:
This compound was prepared by the route used to prepare 3-((3-((4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzamido)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 73, substituting 3,4-dimethylbenzoyl chloride for 3-(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.71-8.65 (m, 2H), 7.96-7.84 (m, 3H), 7.77-7.70 (m, 3H), 7.55-7.41 (m, 4H), 7.33 (d, J=8.1 Hz, 1H), 2.63 (s, 2H), 2.60 (d, J=6.9 Hz, 4H), 2.63-2.58 (m, 2H), 2.52-2.46 (m, 2H), 2.38 (s, 6H), 1.90-1.74 (m, 6H). MS (ES, m/z): 623 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([N:30](C(C)C)CC)(C)C.CN>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([NH:30][CH3:27])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: CN
Solvent: C1CCOC1
Product: CCCn1c(NC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 50.6 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropyl ethyl amine (0.05 g, 0.407 mmol) and 1M methyl amine in THF (0.042 g, 1.36 mmol). The reaction mixture was heated at 50° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue obtained was purified by column chromatography to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one (0.025 g, 51%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>O1CCCC1>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:12])[C:9]([O:11][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC(CC(O)C(=O)O)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(CC(O)C(=O)OCc2ccccc2)N1

Procedure:
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.1 g), triethylamine (1.2 g), N-N-dimethylaminopyridine (1.5 g), and benzyl chloroformate (17 g) in 40 ml tetrahydrofuran is heated at reflux for 16 hours. After cooling and filtering off the triethylamine-hydrochloride, the solution was concentrated and chromatographed on SiO2 (elution with methanol:chloroform; 3:97) to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, benzyl ester mp 95°-96° C. NMR (CDCl3) and 7.37 (s, 5H), 7.93 (d, 1H), 5.40 (s, 1H), 1.70 (m, 2H). IR (KBr) 3330, 3200, 1733, 1691, 1497, 1456, 1389, 1351, 1287, 1216.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1([C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:15])[CH2:13][CH2:12]1.O>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:14]2([C:11]3([O:10][CH3:9])[CH2:13][CH2:12]3)[CH2:2][O:15]2)=[CH:18][CH:19]=1
Reactant: C[S+](C)(C)=O
Reactant: COC1(C(=O)Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC1(C2(Cc3ccc(F)cc3)CO2)CC1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
15 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. under a nitrogen atmosphere to a mixture of 2.2 g (10 mmol) of trimehylsulphoxonium iodide and 0.4 g (13 mmol) of sodium hydride (80% pure). After addition is complete, the mixture is allowed to warm to room temperature in the course of 10 minutes and a solution of 2 g (9.6 mmol) of 4-fluorobenzyl 1-methoxycyclopropyl ketone in 10 ml of absolute dimethyl sulphoxide is then added dropwise with stirring. The reaction mixture is then poured into water. The resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. 1.5 g (70% of theory) of 2-(4-fluoro-benzyl)-2-(1-methoxy-cyclopropyl)-oxirane are obtained in this manner in the form of an oil. ##STR33##