Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30]([OH:32])=O)[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:32])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]=2)=[CH:38][C:37]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)=[CH:36][N:35]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 40 °C
Yield: 91.4 %

Procedure:
300 mg of 3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]propionic acid (compound C4) and 156 mg of 2,3-diamino-5-(4-chlorophenyl)-pyridine (compound F4) are dissolved in 13 ml of pyridine and sequentially treated with 280 mg of O-[(ethoxycarbonyl)canomethylene-amino]-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate and 153 μl of diisopropylethyl amine. The reaction mixture is warmed to 40° C. for 120 h. Purification of the crude product by chromatography on silica gel (eluent: dichloromethane/methanol 8:1) afforded 405 mg of the title compound as an oil. ESI-MS: 624.1/626.1 (MH+, 100%/38%). TLC: Rf=0.32 (dichloromethane/methanol 8:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH2:8]([C:5]1[N:4]=[C:3]([CH2:2][N:1]=[CH:12][N:13]([CH3:15])[CH3:14])[O:7][N:6]=1)[CH3:9]
Reactant: CCc1noc(CN)n1
Reactant: COC(OC)N(C)C
Product: CCc1noc(CN=CN(C)C)n1
Yield: 74.8 %

Procedure:
A mixture of 26 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 30 ml of dimethylformamide dimethylacetal is heated for 6 1/2 hours to 80° C. (bath temperature). Subsequently, 16 ml of methanol is removed by distillation and the resultant product is purified by bulb tube distillation, thus obtaining 27.9 g (74.8%) of an oil having a boiling point of 130-150° C. (0.05 torr); nD20 :1.4924.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([C@H:25]5[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]5C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([C@H:25]5[CH2:29][C@@H:28]([OH:30])[CH2:27][NH:26]5)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)[C@H]4C[C@@H](O)CN4C(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)[C@H]4C[C@@H](O)CN4)CC3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 240A (100 mg, 0.186 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL, 2.60 mmol) and the mixture was stirred at room temperature for 4 hours and concentrated. The residue was dissolved in dichloromethane (2 mL) and treated with 2M hydrogen chloride in ether (2.5 mL) and filtered. The solid was washed with diethyl ether and concentrated to obtain the title compound as the hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) δ 1.70-1.80 (m, 1H), 2.53-2.79 (m, 2H), 3.09-3.32 (m, 2H), 4.60-4.06 (m, 7H) 4.37-4.43 (m, 2H), 4.44 (dd, J=38.4, 9.5 Hz, 1H), 4.57-4.77 (m, 1H), 6.44 (bs, 1H), 6.62-6.69 (m, 1H), 7.01-7.38 (m, 3H), 8.29 (d, J=5.3 Hz, 1H), 8.46-8.80 (m, 1H), 10.24 (bs, 1H), 12.57-12.65 (m, 1H). MS (ESI(+)) m/e 437 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[C:17]([NH:22]C(=O)C(C)(C)C)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[NH2:22][C:17]1[C:16]([CH2:15][NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: Nc1ncccc1CNC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 6.0 g (0.0158 mol) of N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide and 100 ml of conc. hydrochloric acid was refluxed for 3 hours. The mixture was evaporated down in vacuo, the residue remaining was dissolved in a little water and made alkaline by the addition of solid potassium carbonate. It was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was thoroughly triturated with diisopropylether and yielded 4.2 g (89.7% of theory) of colourless crystals of melting point 114° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C1(C)C=CC=CC=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:18]=[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(CCl)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.69 mmol), tetrabutylammonium hydrogensulfate (0.844 g, 2.48 mmol) and 2-chloro-1-(piperidin-1-yl)ethanone (8.08 g, 49.69 mmol) were added to toluene (75 mL) to this was added sodium hydroxide (49.7 g, 496.86 mmol) in water (20 ml) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the crude product as an orange liquid (15.60 g, 96% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.49 (9H, s), 1.51-1.60 (2H, m), 1.61-1.68 (2H, m), 1.81-1.90 (3H, m), 3.05-3.13 (2H, m), 3.35-3.47 (2H, m), 3.50-3.62 (4H, m), 3.71-3.79 (2H, m), 3.80-3.89 (2H, m), 4.13-4.19 (2H, m).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][C@@H:20]([C:25]([OH:27])=O)[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]([C@@H:20]2[CH2:19][C:18]3[CH:28]=[C:29]([O:30][CH3:31])[C:15]([O:14][CH3:13])=[CH:16][C:17]=3[C:23](=[O:24])[CH2:22][S:21]2)=[O:27])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: COc1cc2c(cc1OC)C(=O)CS[C@H](C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@@H]2Cc3cc(OC)c(OC)cc3C(=O)CS2)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.228 g) in dichloromethane (5 ml) was added to a solution of (S)-(+)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.28 g) and diethyl 4-aminobenzylphosphonate (0.241 g) in N,N-dimethylformamide (DMF) (5 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.167 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residue was treated with ethanolisopropyl ether and the solid was removed by filtration. The filtrate was concentrated and the residual oil was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform-methanol (15:15:1, v/v), (2S)-(+)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxamide (0.202 g, 40%) was obtained. Colorless amorphous solid. Melting point 97-99° C. Optical rotation [α]D (23° C.) +155.3° (c=0.50, CHCl3).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[CH:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]1C(OC(C)(C)C)=O)(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:32]>>[ClH:32].[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[CH:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][NH:17]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)C
Agent: Cl
Product: COC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 20E (100 mg, 0.20 mmol) was added hydrogen chloride (1 mL, 4M solution in dioxane). After stirring for 2 h at rt, the reaction was triturated with ether and filtered to give 24A (90 mg) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([C:22]3[C:23](=[O:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[C:27]=3[CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:33]>C(O)(=O)C>[ClH:33].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([C:22]3[C:23](=[O:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[C:27]=3[CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccc(-n3ccnc3)cc2)=C(C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In acetic acid (17 ml) was dissolved 1.70 g (3.92 mmole) of methyl 7-[4-(1-imidazolyl)phenyl]-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)heptanoate, and concentrated hydrochloric acid (7.8 ml) was added to the solution, followed by stirring at 100° C. for 1 hour. The solvent was distilled off, and acetone was added to the residue, followed by concentration under reduced pressure. The crystals, which separated out, were collected by filtration and recrystallized from ethanol/ethyl ether to give 1.30 g (73%) of 7-[4-(1-imidazolyl)phenyl]-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)heptanoic acid.hydrochloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].S(=O)(=O)(O)O.[CH:11](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCCl
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: ClCCCOC(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 3.85 g (40.7 mmol) of 3-chloro-1-propanol in benzene (4 ml) was added conc. sulfuric acid, followed by a solution of 5 g (27.2 mmol) of benzhydrol in benzene (6 ml), and the mixture was refluxed, under argon atmosphere, for 0.8 hours. The reaction mixture was diluted with benzene, washed with water and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and there was obtained 6.80 g (26.1 mmol) of benzhydryl 3-chloropropyl ether.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:25])/[CH:20]=[C:21](\[CH3:24])/[CH2:22]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:25])/[CH:20]=[C:21](\[CH3:24])/[CH2:22][S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1
Reactant: COC(=O)/C=C(\C)CBr
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\C)CSc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-butenoic acid methyl ester (0.75 g, 5.76 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dibromotriphenylphosphorane (2.68 g, 6.34 mmol). The reaction is stirred at -15° C.-0° C. for two hours, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-butenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-bromo-3-methyl-2-butenoic acid methyl ester (0.22 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in uacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.43, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 134-136° C.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][C@@H:16]([C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C@@H:16]([C:23]([F:24])([F:25])[F:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F
Yield: 99 %

Procedure:
2.2 g of [R]-1-trifluoromethylheptyl 4-benzyloxybenzoate, (13) 100 mg of PdOH/C in 50 ml of ethyl acetate was stirred at RT over night under H2 atmosphere. Then the catalyst was filtered out and filtrate was evaporated to dryness to give the pure compound in yield of 99%.
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([OH:9])=O.[CH3:22][CH2:23][O:24]CC>C(OC(=O)C)(=O)C>[C:23]([CH:10]1[C:11]2[C:12](=[CH:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=2)[C:13](=[O:14])[O:15][C:7]1=[O:9])(=[O:24])[CH3:22]
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reaction time: 16 h

Procedure:
Pyridine (5.0 ml, 62 mmol) is added slowly to suspension of 2-carboxymethyl-4-methoxy-benzoic acid (10 g, 48 mmol) in acetic anhydride (80 ml) at 0° C. After stirring for 16 h, ether (100 ml) is added. The resulting solid is collected and dried to give 10 g of 4-acetyl-6-methoxy-isochroman-1,3-dione.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[OH:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=1>>[CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11]([O:37][C:38]3[CH:39]=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(OCC2CCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: Oc1cncc(Cl)c1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cncc(Cl)c3)nc(OCC3CCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Cyclobutylmethoxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (the Mrf product from Example 83), (40 mg, 0.08 mmol) was reacted with 2 equivalents each of n-butyl lithium and 3-hydroxy-5-chloro-pyridine according to the procedure described in Reference Examples 6 and 7 to afford 2-cyclobutylmethoxy-4-(5-chloro-3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=546 (M++1); Rt=5.20 min. 1H-NMR 400 MHz (CDCl3): δ 1.80-1.98 (m, 4H), 2.10-2.11(m, 2H), 2.74 (m, 1H), 4.20 (d, J=7 Hz, 2H), 7.10-7.18 (m, 3H), 7.20-7.28 (m, 3H), 7.35 (d, J=2 Hz, 1H), 7.63 (m, 1H), 8.05 (d, J=2 Hz, 1H), 8.10 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(O)C(N)(CO)CO.Cl>P([O-])([O-])([O-])=O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=P([O-])([O-])[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
Each of the proteolytic enzyme-treated azuki bean prepared in Example 2 and an enzyme-treated defatted soybean prepared using the same method as Example 2 was dissolved in 0.25 M phosphate buffer (pH 6.8) used as assay buffer to a concentration of 16.7 mg/mL to give a sample. Measurement of α-glucosidase activity was carried out in the manner described below. Specifically, 60 μL of the sample was added to wells of a 96-well plate while 60 μL of assay buffer was added to wells for control. Subsequently, 20 μL of yeast-derived α-glucosidase (Oriental Yeast Co., Ltd.) adjusted to a concentration of 1.25 U/mL (10 μg protein/mL) was added followed by incubating for 10 minutes at 37° C. Next, 20 μL of a 250 mM solution of sucrose in assay buffer was added followed by incubating for 20 minutes at 37° C. (the concentration of each enzyme-treated product during the reaction was 10 mg/mL). Following completion of incubation, 100 μL of 2 M Tris-HCl buffer (pH 7.0) was added to stop the reaction. After stopping the reaction, 50 μL of the reaction liquid in each well was transferred to a separate 96-well plate followed by the addition of 200 μL of a Glucose CII Test Wako reagent (Wako Pure Chemical Industries, Ltd.) and incubating for 5 minutes at 37° C. Following completion of incubation, the absorbance at 505 nm was measured, and the amount of glucose formed was determined from a calibration curve prepared using glucose standards. Furthermore, the α-glucosidase activity was calculated as indicated below based on a value of 100% for the value of α-glucosidase activity of the control. α-Glucosidase activity(%)=(A/B)×100
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:20]2[CH2:35][N:24]3[CH2:25][CH2:26][N:27]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:28][CH:23]3[CH2:22][CH2:21]2)[OH:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:20]2[CH2:35][N:24]3[CH2:25][CH2:26][N:27]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:28][CH:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:13]=1
Reactant: OC(c1ccc(F)cc1)C1CCC2CN(c3ncccn3)CCN2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: O=C(c1ccc(F)cc1)C1CCC2CN(c3ncccn3)CCN2C1

Procedure:
The title compound was prepared according to the oxalyl chloride/DMSO oxidation step of Example 46 starting with (4-fluoro)phenyl-[(7RS,9aSR)-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl]-methanol (Example 46). 13C NMR (CDCl3): δ 27.3, 28.3, 48.6, 54.1, 56.7, 59.9, 110.1, 115.77, 116.05, 131.20, 131.32, 132.4, 158.0, 161.1, 163.4, 166.7. HRMS calcd for C19H21FN4O: 340.1699, found: 340.1539.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[CH:15]1.CN(C)[CH:25]=[O:26].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[S:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: CN(C)C=O
Reactant: c1ccc2sccc2c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 68.9 %

Procedure:
Butyllithium (54 mL, 134 mmol) is added dropwise to a solution of N,N,N',N'-tetramethylethylenediamine (15.57 g, 134 mmol) in tetrahydrofuran under nitrogen at 0° C. The reaction mixture is treated dropwise with a solution of benzothiophene (15.00 g, 112 mmol) in tetrahydrofuran, warmed to room temperature, treated with additional N,N,N',N'-tetramethylethylenediamine (15.57 g, 134 mmol) and butyllithium (54 mL, 134 mmol), stirred at room temperature for 13 hours, cooled to 0° C., treated with N,N-dimethylformamide (24.40 g, 336 mmol), warmed to room temperature, stirred for five hours, poured into one molar hydrochloric acid and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to obtain an orange oil. Flash chromatography of the oil using silica gel and a 15% ethyl acetate in hexane 25 solution gives the title product as an orange oil (12.51 g, 69%).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[O:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Oc1ccccc1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Oc1ccccc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 4-fluoro-3-methylbenzoate (740 mg, 3.5 mmol), phenol (700 mg, 7.4 mmol), potassium carbonate (993 mg, 7.2 mmol) and methylsulfinylmethane (10 mL) was stirred at 120° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=80:1) to give tert-butyl 3-methyl-4-phenoxybenzoate as a colorless oil (654 mg, 66%). 1H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 7.32-7.28 (m, 2H), 6.84-6.77 (m, 3H), 2.26 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:18])[C:12]=2[CH:11]=[N:10]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:61][N:62](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:4]1[C:3]([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([OH:18])=[C:12]3[CH:11]=[N:10]2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:61]#[N:62]
Reactant: CN(C)C=O
Reactant: O=c1[nH]cnc2c1cnn2-c1c(Cl)cccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cccc(Cl)c1-n1ncc2c(O)ncnc21
Temperature: 160 °C
Yield: 91 %

Procedure:
1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (Intermediate AH4) (1012 mg, 3.11 mmol) and zinc cyanide (329 mg, 2.80 mmol) were dissolved in DMF (15 mL). Sealed into a microwave tube. The tube was purged with nitrogen. 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (180 mg, 0.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (142 mg, 0.16 mmol) added. The reaction was heated to 160° C. for 15 minutes in the microwave reactor, then allowed to cool to ambient temperature. The DMF was removed by evaporation. The crude product was absorbed onto silica and then purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM to afford the product (769 mg, 91%). 1H NMR (400 MHz, DMSO) δ 7.89-7.83 (1H, t), 8.14 (1H, s), 8.15 (2H, d), 8.49 (1H, s), 12.56 (1H, s); m/z (ES+) (M+H)+=272; HPLC tR=1.29 min.