Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][O:10][CH:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(N)([NH2:24])(=O)=O>C1S(=O)(=O)CCC1>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][O:10]2)=[CH:13][CH:14]=1)#[N:24]
Reactant: NS(N)(=O)=O
Reactant: CCCCCC1CCC(c2ccc(C(=O)Cl)cc2)OC1
Solvent: O=S1(=O)CCCC1
Product: CCCCCC1CCC(c2ccc(C#N)cc2)OC1

Procedure:
A solution of 29.5 g of p-(5-pentyl-2-tetrahydropyranyl)benzoyl chloride and 8 g of sulfamide in 500 ml of tetramethylene sulfone is heated at 120° for 4 hours, evaporated and worked up as usual. 2-p-cyanophenyl-5-pentyltetrahydropyran is obtained.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11])[C:2]([CH3:4])=[O:3].[BH4-].[Na+].CO>C(O)C.O>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[CH:10]([OH:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc(N)c(C(=O)c2ccccc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(N)c(C(O)c2ccccc2Cl)c1

Procedure:
A solution of 108.92 g of 5-acetamino-2-amino-2'-chlorobenzophenone in 1.4 l of ethanol is treated dropwise at room temperature with a solution of 15.9 g of sodium borohydride in 100 ml of water. The solution obtained is then heated to boiling under reflux until decolourization occurs and subsequently, after the addition of 300 ml of methanol, heated for a further 15 minutes. The organic solvents are distilled off in vacuo and the residue is suspended in 0.5 l of water. The crystals obtained are recrystallized from ethanol/water. There is obtained 5-acetamino-2-amino-2'-chlorobenzhydrol of melting point 137°-138°.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].O>CCCCCC>[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:21]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCCCCC(=O)OCc1ccc2c(c1)OCO2
Temperature: 50 °C
Yield: 84.4 %

Procedure:
Piperonyl alcohol (442 mg, 2.90 mmol), 8-methylnonanoic acid (500 mg, 2.90 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (25 ml) was added, and Novozyme 435 and the precipitated piperonyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography, Merch Art. 13895) (n-hexane:ethyl acetate=4:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give piperonyl 8-methylnonanoate (0.75 g, yield 84.3%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:24])[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[C:31](=[O:34])([O-])O.[Na+].Cl[CH2:37]Cl>>[C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:23]([C:12]2[S:13][C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=3)[N:11]=2)=[O:24])[CH2:30][CH2:29]1)(=[O:34])[CH3:37]
Reactant: ClCCl
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nc(C(=O)N3CCNCC3)sc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(-c2nc(C(=O)N3CCN(C(C)=O)CC3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4,5-bis(4methyoxyphenyl)-2-piperazin-1-ylcarbonylthiazole hydrochloride (0.40 g) in dichloromethane (30 ml) was added to a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The separated organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of dichloromethane (10 ml) and triethylamine (0.14 ml). To the mixture was added dropwise a solution of acetyl chloride (0.07 ml) in dichloromethane (5 ml), at 0° to 5° C., and the reaction mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was poured into water, and adjusted to pH 11 with aqueous solution of potassium carbonate, and extracted with dichloromethane. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water, dilute hydrochloric acid, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was recrystallized from a mixture of isopropyl ether and ethanol to give a crystal of 2-(4acetylpiperazin-1-yl)carbonyl-4,5-bis(4methoxyphenyl)thiazole (0.18 g).
Reaction SMILES: [C:1]([N:4]([CH2:13][C@@H:14]1[O:18][CH2:17][C@@H:16]([S:19]C(=O)C)[CH2:15]1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[SH:19][C@@H:16]1[CH2:17][O:18][C@@H:14]([CH2:13][N:4]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1](=[O:3])[CH3:2])[CH2:15]1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(C)=O)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(C[C@H]1C[C@H](S)CO1)OCc1ccccc1
Yield: 60.4 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.390 g of product from Example 72, 0.580 ml of 25% sodium methoxide/methyl alcohol, 0.850 ml of tetrahydrofuran and 1.26 ml of 2N hydrochloric acid/isopropyl alcohol to give 0.205 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[Cl:32][CH2:33]/[CH:34]=[CH:35]/[CH2:36]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:36]/[CH:35]=[CH:34]/[CH2:33][Cl:32])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClC/C=C/CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C[C@@H]2CN(C/C=C/CCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (1.0 g), (E)-1,4-dichloro-2-butene (0.31 ml) and powdered potassium carbonate (0.4 g) in dry acetonitrile (10 ml) was heated at 50° C. After 4 hours, the reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of toluene and ethyl acetate (4:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-chloro-2-butenyl]piperazine (0.53 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[Se:27][C:26]=1[C:34]([NH2:36])=[O:35].CN(C=O)C.[OH-].[Na+]>>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][C:25]4[CH:29]=[C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])[Se:27][C:26]=4[C:34]([NH2:36])=[O:35])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-(3-morpholinopropoxy)-6-methoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 216-220° C. IR (KBr) vmax 3342, 3120, 2957, 2853, 1633, 1572, 1497, 1457, 1393, 1315, 1234, 1141, 1113, 1021, 903, 854, 798 cm1; 1H NMR (400 MHz, CDCl3): δ 12.06 (1H, s, exchangeable with D2O), 8.86 (1H, s), 8.71 (1H, s), 7.34 (1H, s), 7.25 (1H, s), 5.57 (2H, s, exchangeable with D2O), 4.25 (2H, t, J=6.6 Hz), 4.06 (3H, s), 3.74 (4H, t, J=4.4 Hz), 2.59 (2H, t, J=7.2 Hz), 2.51 (4H, br s), 2.10-2.16 (2H, m), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.9, 168.6, 154.4, 154.3, 153.3, 150.1, 148.1, 147.4, 121.7, 109.6, 109.2, 108.3, 100.3, 67.3, 66.8, 56.2, 55.3, 53.7, 37.2, 32.6, 25.9; LC-MS (positive ion mode): m/z 546, 548 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[H-].[Na+]>C1COCC1.CCOCC>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][CH:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4]1
Reactant: COCCCCI
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCCCOC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Yield: 17.5 %

Procedure:
To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]O)[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.), piperidin-4-yl-methanol (1.15 g, 10 mmol, 1.0 eq.), and p-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml). The mixture was refluxed with a Dean-Stark condenser for 3-4 hours. After cooling to room temperature, the solution was washed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). The solution was then dried over anhydrous Na2SO4. The solvent was then removed under vacuum. The crude product 4-(1,1-diphenyl-methoxymethyl)-piperidine was obtained (2.33 g, 82.8% yield). ESMS 268.1 (M+1), 290.1 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:11][OH:12])=[N:6][CH:7]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) and hydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) and water (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g, 100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping the temperature between −5° C. and 5° C. The reaction mixture was then stirred at room temperature for 30 min. Then HCl (4 N) was added to acidify the mixture and the resulting precipitate was filtered off and washed with water to afford the title compound (4.41 g, 79%) as a light brown solid. MS: m/e=141.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]([CH:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]>>[CH3:7][O:8][C:9]([CH:11]([N:13]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=1[CH3:24])[CH3:12])=[O:10]
Reactant: COC(=O)C(C)Nc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COCC(=O)Cl
Product: COCC(=O)N(c1c(C)ccc([N+](=O)[O-])c1C)C(C)C(=O)OC

Procedure:
15.2 g of methoxyacetyl chloride are added dropwise at room temperature to 32 g of N-(1'methoxycarbonylethyl)-2,6-dimethyl-3-nitroaniline.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([O:11]CCC#N)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].[NH2:28]/[C:29](/[CH3:35])=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>C(O)(C)C>[CH3:34][O:33][C:31]([C:30]1[CH:24]([C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:28][C:29]=1[CH3:35])=[O:32]
Reactant: COC(=O)/C=C(/C)N
Reactant: N#CCCOC(=O)CC(=O)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)O)C1c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 55.1 %

Procedure:
A solution of 5.01 g of 2-cyanoethyl 3-phenyl-3-oxopropionate (23.1 mmol), 6.98 g of 4-nitrobenzaldehyde (46.2 mol), and 5.32 g of methyl 3-aminocrotonate (46.2 mol) in 100 mL of isopropanol were heated at reflux temperature for 2 days, cooled, and the solvent was removed in vacuo. The residue was dissolved in 50 mL of warm dioxane and 1.21 g of NaOH in 25 mL of water was added to the reaction mixture. The resulting maroon solution was stirred for 3 hrs. The solvent was removed in vacuo. The residue was partitioned between water (100 mL) and ethyl acetate (50 mL), separated, and washed with ethyl acetate (3×50 mL). The aqueous extract was acidified with concentrated HCl (pH 2-3), the precipitated solids were filtered, and washed with water (2×20 mL). The crude product was recrystallized from acetone-water mixture to give 5.02 g (55%) of yellow amorphous solid: mp 190°-191° C.; Anal. Calcd for C21H18N2 O4 : C, 63.96; H, 4.60; N, 7.10. Found: C, 63.86; H, 4.59; N, 7.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCNC(=O)Cc2ccc(OCc3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of N-[2-(3-methoxyphenyl)ethyl]-2-[4-(phenylmethoxy)phenyl]acetamide (5.739 g, 15.3 mmol) and phosphorous oxychloride (15 mL) in acetonitrile (40 mL) under nitrogen was heated at 80° C. for 5 hours. Solvents were evaporated. Ethyl acetate was added and evaporated three times. The residue was dissolved in methanol (50 mL) and sodium borohydride (2.00 g, 52.9 mmol) was carefully added to the solution in small portions. After 2 hours, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 0-10% methanol/CH2Cl2) to provide the title compound (1.54 g, 28% yield): 1H NMR (CDCl3) 7.36 (m, 6H), 7.12 (d, 2H), 6.91 (d, 2H), 6.73 (dd, 1H), 6.62 (m, 1H), 5.04 (s, 2H), 4.97 (t, 1H), 4.17 (br, 1H), 3.78 (s, 3H), 3.73 (m, 1H), 3.16 (m, 2H), 2.83 (m, 3H); ES−MS (m/z) 360 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)CCCN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
6-(3-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and the residue was purified by prep. HPLC chromatography to provide the desired compound (25% yield). LCMS: 544.30 (M+1)+; HPLC: 99.90% (@ 254 nm) (Rt; 4.765); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.2-9.6 (m, 1H), 8.92 (bs, 1H), 8.38 (s, 2H), 8.14 (s, 1H), 7.70-7.66 (m, 2H), 5.91 (s, 1H), 5.36-5.35 (m, 1H), 4.41 (d, 2H), 3.39 (4H merged in DMSO peak), 3.08-2.98 (m, 2H+3H), 2.79 (s, 6H), 2.24 (s, 3H), 2.13 (s, 3H). 2.13 (m, 2H), 1.55 (d, 6H, J=4.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1cc(O)cs1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(OCc2ccccn2)cs1

Procedure:
3.00 g (19.0 mmol) of methyl 4-hydroxy-2-thiophenecarboxylate, 3.11 g (19.0 mmol) of 2-chloromethylpyridine hydrochloride and 5.24 g (37.9 mmol) of potassium carbonate are heated under reflux in 60 ml of absolute 2-butanone for 10 hours under nitrogen. The mixture is then evaporated in vacuo and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase is extracted twice more with 100 ml of methylene chloride each time and the combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated. The residue is digested with diisopropyl ether.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:36][CH:37]=1.[C:46]([O-])(O)=O.[Na+]>C1COCC1.CC(=O)OCC>[C:41]([O:40][C:39]([NH:38][C:35]1[N:36]=[CH:37][C:32]([CH2:31][CH:15]([C:13]2[N:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][C:4]([CH3:46])=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:14]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:33][CH:34]=1)=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)Cc1cn(S(=O)(=O)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Reaction time: 0.08 h

Procedure:
A solution of 1.00 g (3.39 mmol) of methyl (1-benzenesulfonyl-1H-imidazol-4-yl)acetate (example 1d) in 100 ml of THF was cooled to −78° C. and 3.74 ml (3.74 mmol, 1M in THF) of lithium bis(trimethylsilyl)amide were added in three portions over the course of 3 min. The mixture was stirred at this temperature for 5 min and then 0.65 g (2.26 mmol) of tert-butyl (5-bromomethylpyridin-2-yl)carbamate (example 1b) was added in one portion. The mixture was stirred at −78° C. for 1 h and then allowed to reach RT. The mixture was poured into a mixture of EA and saturated NaHCO3 solution. After shaking, the organic phase was separated off, dried over Na2SO4, filtered and concentrated to dryness. The residue was recrystallized from EA/heptane. The resulting crystals were filtered off with suction, washed with a little EA and heptane and dried. 0.66 g of the title compound was obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=3[CH3:21])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:22][CH2:23][CH3:24])([CH2:5][C:4]([OH:25])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.959 g, 2.82 mmol) in THF/MeOH (7 mL/15 mL) was added 1 N NaOH (5.64 mL, 5.64 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (60 mL), dried over Na2SO4 and concentrated to provide 0.868 g (99%) of title compound as a white solid. 1H NMR (acetone-d6): 300 MHz δ 10.37 (bs, 1H), 7.35 (d, J=7.50 Hz, 1H), 7.03 (d, J=7.50 Hz, 1H), 4.05 (m, 2H), 3.08–2.91 (m, 4H), 2.54 (s, 3H), 2.09 (m, 2H), 1.45 (m, 1H), 1.03 (m, 1H), 0.84 (t, J=7.26 Hz, 3H).