Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[C:11]1([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>>[C:11]1([C:17]2[O:18][C:19]([CH:3]=[O:4])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ccco2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
To a 0° C. solution of N,N-dimethylformamide (1.9 mL, 24.97 mmol) in a three-neck flask equipped with a condenser was added POCl3 (0.65 mL, 6.94 mmol) dropwise via syringe with stirring. When the heat of the reaction subsided, 2-phenylfuran (1.0 g, 6.94 mmol) was added. The reaction was warmed to 80° C. and stirred overnight. The solution was cooled to room temperature and then neutralized to pH 8 with aqueous saturated sodium acetate. The mixture was extracted with ether (3×30 mL), dried over MgSO4, filtered and evaporated. Chromatography (silica gel, 20% ether/hexanes) yielded 1.0 g (83%) of 5-phenyl-2-furaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([CH:11]([OH:15])[C:12]#[C:13][CH3:14])=[C:6]2[CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11](=[O:15])[C:12]#[C:13][CH3:14])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC#CC(O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-ol (1.04 g, 3.30 mmol) in chloroform (50 mL) was added manganese dioxide (5.70 g, 65.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The suspension was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (950 mg, 91%). Rf 0.44 (3:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.49 (d, 1H), 7.73 (m, 2H), 7.50 (t, 1H), 7.19 (m, 3H), 1.71 (3H); 19F NMR (CDCl3) δ −112.58; mp 182–183° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:19].[C:20]1([CH2:26][C:27](=[NH:31])OCC)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[ClH:19].[CH3:18][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c(COc2cccnc2NC(=N)Cc2ccccc2)c(C)c1
Yield: 24.6 %

Procedure:
A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (4.84 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.95 g), m.p. 173°-178° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1.CCOCC>[F:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(CO)c1
Temperature: 0 °C

Procedure:
To a 1M solution of lithium aluminum hydride in THF (57 mL) at 0° C. is added a solution of 2-fluoro-5-methylbenzoic acid (8.0 g, 52 mmol) in 160 mL of ether drop-wise. The reaction is then heated at reflux for 1.5 hr. The reaction is then cooled to 0° C. and is quenched with H2O (4 mL), aqueous 40% NaOH (4 mL) and H2O (4 mL). The resultant slurry is then filtered through celite and MgSO4. The filtrate is then concentrated and purified by silica gel flash column chromatography to provide the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([OH:32])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C@H:37]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=[O:35])C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([O:32][C:33]([O:36][CH3:37])=[O:35])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:17][CH3:18])[O:19][CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](OC(C)=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C(OC)OC)CC[C@H]3[C@H]12
Yield: 77 %

Procedure:
The procedure of Example 12 was repeated except that 45.0 mg (0.1 mmole) of 1α,2α-epoxy-7α-hydroxy-21,21-dimethoxy-20-methylpregn-5-en-3β-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate to give 39.0 mg of 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate (yield: 77%).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][N:35]=[CH:34]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14]([C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][N:35]=[CH:34]5)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc3[nH]ncc3c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 24.1 %

Procedure:
3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (0.085 g, 0.203 mmol) and 5-bromo-1H-indazole (0.048 g, 0.244 mmol, 1.2 eq) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.128, 0.929 mmol, 4.6 eq) was added and the solution was degassed with Argon. PdCl2(dppf) (0.023 g, 0.032 mmol, 0.16 eq) was added and the reaction was heated in a microwave at 100° C. for 20 min. Solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. 0.020 g (24%) product obtained.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([O:16][CH2:17]C)=[O:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)=[O:2].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](OC2C=CC=CC=2)=[O:31])[N:22]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([O:20][CH3:19])[N:22]=[C:23]([NH:29][C:30]([NH:13][S:10]([C:8]2[CH:9]=[C:4]([NH:3][CH:1]=[O:2])[CH:5]=[CH:6][C:7]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:12])=[O:31])[N:24]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOC(=O)c1ccc(NC=O)cc1S(N)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
1.00 g of 5-formylamino-2-ethoxycarbonylbenzenesulfonamide, 1.11 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine and 0.82 ml of DBU in acetonitrile are reacted analogously to Chemical Example A.1; Yield: 1.00 g, M.p.: 113° to 118° C. (dec.), Mass spectrum (CI):(M+l) =454
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:12]([C:33]([O:35]CC)=[O:34])=[C:11]2[C:38]1[CH:43]=[CH:42][C:41]2[O:44][CH2:45][O:46][C:40]=2[CH:39]=1)([O:3]CC)=[O:2].C(COC1C=C(OC)C=CC=1CN1C2C(=CC(O)=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O)(OCC)=O.BrCC(OCC)=O>>[C:1]([CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:12]([C:33]([OH:35])=[O:34])=[C:11]2[C:38]1[CH:43]=[CH:42][C:41]2[O:44][CH2:45][O:46][C:40]=2[CH:39]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)COc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OCC)n2Cc1ccc(OC)cc1OCC(=O)OCC
Agent: CCOC(=O)CBr
Agent: CCOC(=O)COc1cc(OC)ccc1Cn1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2cc(O)ccc21
Product: COc1ccc(Cn2c(C(=O)O)c(-c3ccc4c(c3)OCO4)c3cc(OCC(=O)O)ccc32)c(OCC(=O)O)c1

Procedure:
Ethyl 5-carboethoxymethoxy-1-(2-carboethoxymethoxy-4-methoxybenzyl)-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate. The title compound was prepared from ethyl 1-(2-carboethoxymethoxy-4-methoxybenzyl)-5-hydroxy-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate (150 mg, 0.26 mmol) and ethyl bromoacetate (55 mg, 0.33 mmol) by the method given in example 7b (119 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=537.98 (M+H+); retention time=0.54 minutes.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15]3[C:20]([CH:21]=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][CH:5]=1>ClCCl.C(O)C>[Br:1][C:21]1[C:22]2[C:27]([C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([CH3:3])=[CH:5][CH:6]=3)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Reactant: BrBr
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 18.0 ml (352 mmol) of bromine in 100 ml of dichloromethane is added dropwise with vigorous stirring to a solution of 102.0 g (320 mmol) of 9-(4-methylnaphth-1-yl)anthracene in 2000 ml of dichloromethane at −5° C., and the mixture is stirred at room temperature for 12 h. The suspension is subsequently diluted with 1000 ml of ethanol. The precipitated solid is filtered off with suction, washed with 500 ml of a mixture of water and ethanol (1:1, v:v) and three times with 200 ml of ethanol. After washing twice with 1000 ml of boiling ethanol each time, the solid is dried under reduced pressure. Yield: 108.0 g (84.9% of theory), about 97% according to 1H-NMR.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Na+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCCl.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:14]([C:12]2[CH:11]=[CH:10][C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=2)=[O:15])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(CN2CCCCC2)c1
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cccc(NC(=O)c2ccc(-c3ccccc3)c(CN3CCCCC3)c2)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Into 20 ml of 1,2-dichloroethane were suspended 500 mg of a mixture of 2-(piperidin-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalents of sodium chloride, and then 174 mg of 3-methoxyaniline dissolved in 2 ml of 1,2-dichloroethane was added thereto. Under ice cooling, 694 mg of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 211 μl of N-methylmorpholine were added thereto, followed by 30 hours of stirring at room temperature. Water was added to the reaction solution and the organic layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain N-(3-methoxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide. The compound was dissolved in 3 ml of ethyl acetate and then 1 ml of a 4M ethyl acetate solution of hydrochloric acid was added thereto. The solvent was removed by evaporation and crystallization was effected from ethanol to obtain 103 mg of N-(3-methoxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:15]2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:15]2)=[CH:11][CH:10]=1)[CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=1
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(CNCc3ncc[nH]3)cc2C1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCC1=Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
The compound (27.3 mg) obtained in Example 11-14 was dissolved in methanol (1.37 ml) and added with sodium cyanoborohydride (9.0 mg) and 1-methyl-2-imidazole carboxaldehyde (11.8 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 3 hours. Then, the reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (31.5 mg) of the subject compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CSc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CSc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3-(methylmercapto)aniline (18 μl, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (21 mg, 58%). 1H NMR (CDCl3): 8.87–8.85 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 7.93–7.88 (m, 1H), 7.61 (s, 1H), 7.48–7.44 (m, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.17–7.14 (m, 1H), 7.10–7.06 (m, 1H), 7.01 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH:37]1[CH2:41][N:40]([CH2:42][CH3:43])[N:39]([CH2:44][CH3:45])[CH2:38]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:44]([N:39]1[CH2:38][CH:37]([NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[CH2:41][N:40]1[CH2:42][CH3:43])[CH3:45]
Reactant: CCN1CC(N)CN1CC
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 4- geranyloxybenzoic acid (1.10 g) in chloroform (20 ml), triethylamine (1.11 ml) and a solution of diphenylphosphinic chloride (0.95 g) in chloroform (5 ml) were successively added. After the reaction solution was stirred for 30 minutes, 4-amino-1,2-diethylpyrazolidine (0.57 g) was added and then the mixture was stirred at room temperature for one night. The reaction solution was washed with aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and then recrystallized from n-hexane, thereby yielding 1.39 g (87%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:30]=2[F:40])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]([F:38])([F:37])[F:39])[CH:32]=[CH:31][C:30]=2[F:40])=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(Cc4cc(OC(F)(F)F)ccc4F)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Cc1cc(OC(F)(F)F)ccc1F)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (71 mg, 0.118 mmol) in DCM (1 mL) was added TFA (0.3 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction was stirred at room temperature for 16 h. The mixture was concentrated and the residue was partitioned between DCM and aqueous sodium bicarbonate. The organic layer was dried and concentrated to give 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (39 mg, 68.4% yield) as a yellow syrup, which was directly without purification. LCMS retention time 1.686 min; LCMS MH+ 483.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]2[CH2:16][CH:15]2[C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([CH3:30])[CH:24]3[CH:27]([CH3:29])[CH3:28])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC>C1(C)C=CC=CC=1.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>[CH:27]([CH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([CH:15]3[CH2:16][CH:14]3[C:4]3[CH:5]=[C:6]4[C:11](=[C:2]([CH:31]=[CH2:32])[CH:3]=3)[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]4)[CH:26]=2)[CH2:21][CH2:22][N:23]1[CH3:30])([CH3:28])[CH3:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)C1c2cc(C3CC3c3cc(Br)c4cc(C#N)ccc4c3)ccc2CCN1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C2CC2c2ccc3c(c2)C(C(C)C)N(C)CC3)cc2ccc(C#N)cc12
Temperature: 100 °C

Procedure:
A solution of Example 41A (430 mg, 0.94 mmol) in toluene (10 mL) was treated with tributyl(vinyl)stannane (298 mg, 0.94 mmol), and Pd(PPh3)4 (109 mg, 0.09 mmol), flushed with argon, sealed in a tube, and heated to 100° C. for 20 hours. The mixture was cooled to room temperature, treated with ethyl acetate (10 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% methanol/dichloromethane to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[C:22]([C:24]([CH3:36])([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[CH3:25])#[N:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([O:26][C:24]([C:22]#[N:23])([CH3:25])[CH3:36])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(OC(C)(C)C#N)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x) and 3-(1-cyano-1-methylethoxy)benzoic acid (219 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100), and crystallized from ethyl acetate to give the title compound (141 mg, 54%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:20])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[C:12]([F:19])[CH:11]=3)=[O:4].COC(C1C=CC2C(=O)C3C(OC=2C=1)=CC=CC=3)=O>>[F:19][C:12]1[CH:11]=[C:10]2[C:15]([O:16][C:17]3[CH:18]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[C:9]2=[O:20])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc2c(=O)c3cc(F)ccc3oc2c1
Agent: COC(=O)c1ccc2c(=O)c3ccccc3oc2c1
Product: O=C(O)c1ccc2c(=O)c3cc(F)ccc3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 5, substituting 7-fluoro-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 2e for 9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 4a, the title compound 7-fluoro-9-oxo-9H-xanthene-3-carboxylic acid, 3e was obtained. MS m/z (MH+) 258.9.