Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=2[CH:21]=1.[CH2:22]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O>[CH2:22]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:2]2[CH:3]=[CH:4][C:5]3[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=3[CH:21]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CC(C)C)cc1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of methyl 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoate (10.0 g) in dimethylcarbonate (250 ml) was added a methanol solution of 28% sodium methoxide (6.8 g) and the mixture was heated at 50° C. for 3 hours under a nitrogen atmosphere. The mixture was cooled to 0° C., neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (8.6 g). A suspension of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.0 g), 4-(2-butoxyethoxy)phenylboric acid (4.8 g) and potassium carbonate (5.6 g) in toluene (60 ml), ethanol (6.0 ml) and water (6.0 ml) was stirred for 30 minutes under an argon atmosphere. After addition of tetrakis(triphenyl)phosphine palladium (0.9 g), the mixture was heated at 105° C. for 3 hours under an argon atmosphere. The mixture was cooled, followed by addition of water, and extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain yellow oil of methyl 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (5.43 g). The oil was redissolved in THF (50 ml) and methanol (50 ml). To the solution was added aqueous 2N sodium hydroxide solution (23 ml), and the resulting mixture was heated at 90° C. for 3.5 days. The mixture was cooled to 0° C., followed by addition of water, and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from diisopropylether-ethyl acetate to obtain yellow crystals of 8-[4-(2-butoxyethoxy)phenyl-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (1.04 g).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15]1>O1CCCC1.Cl.[Cu](I)I>[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:15]1
Reactant: O=C(Cl)C1CC(F)(F)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(F)(F)C2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 16 %

Procedure:
In a 3-neck flask at −30° C. containing ethyl 4-iodobenzoate (600 mg, 2.17 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise and then stirred at the same temperature for another 40 min. Copper iodide (124 mg, 0.650 mmol) was then added quickly in one portion. The mixture was brought to −15° C. for 20 min. to ensure the solid has dissolved. The reaction is then brought back to −40° C. Crude 3,3-difluorocyclobutanecarbonyl chloride (470 mg, 1.50 mmol pure) was then added and the reaction was then warmed to 0° C. over 1 h and then stirred at room temperature for 18 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide 680 mg of crude oil. Purification by silica gel flash chromatography (0-10% ethyl acetate in heptane) afforded impure ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate (130 mg, approximately 0.24 mmol pure) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.2 Hz, 2H), 4.39 (q, J=7.4 Hz, 2H), 3.34-3.15 (m, 1H), 3.12-2.78 (m, 4H), 1.40 (t, J=7.4 Hz, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][N:19]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1nccnc1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CN=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-phenoxyphenyl)pyrazin-2-amine (1.97 g) in THF (dry) (20 mL) was added to a suspension of NaH (60%, 1.50 g) and 2-chloroethanesulfonyl chloride (2.35 mL) in THF (dry) (20 mL) at 0° C. The mixture was stirred at room temperature overnight then at 80° C. for 4 hr. After cooling to room temperature, the mixture was added with water and EtOAc. The precipitate was collected by filtration, washed with water and EtOAc, and then recrystallized from EtOH-EtOAc to give the title compound (1.68 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])[N:3]=1.Cl.[NH2:27][OH:28].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:27][OH:28])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])[N:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc(N)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)c1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc(N)n2)cc1
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 1-{4-[2-amino-6-(2,5-dichloro-phenyl)-pyrimidin-4-yl-amino]-phenyl}-ethanone, hydroxylamine hydrochloride, 0.6 M aqueous sodium hydroxide solution (2 ml), and ethanol (20 ml) was stirred 16 hours. The mixture was extracted with tetrahydrofuran (3×15 ml). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on alumina eluting with 7% methanol-chloroform to provide the title compound (0.010 g, 10% yield). 1H NMR (DMSO-d6) δ 2.14 (s, 3H, CH3), 6.34 (s, 1H, Ar), 7.51-0.754 (m, 1H, Ar), 7.58-7.61 (m, 3H, Ar), 7.65 (d, 1H, J=2.5 Hz, Ar), 7.79 (d, 2H, J=8.8 Hz, Ar), 9.46 (s, 1H, NH), 11.02 (s, 1H, OH).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([I:1])=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCOc1ncccc1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ncc(I)cc1C(=O)O
Yield: 67.9 %

Procedure:
N-Iodosuccinimide (6.0 g, 26.7 mmol) was added to a solution of 2-n-butoxypyridine-3-carboxylic acid (Preparation 4; 3.46 g, 17.7 mmol) in trifluoroacetic acid (28 mL) and trifluoroacetic anhydride (7 mL) and the reaction heated under reflux in the absence of light, for 3 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed sequentially with water (2×), aqueous sodium thiosulfate solution, aqueous sodium citrate solution, 2 N hydrochloric acid, and brine, then dried (MgSO4) and evaporated under reduced pressure. The solid was triturated with pentane, filtered, washed with additional pentane and dried, to give the title compound as a white solid (3.86 g, 68%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([SH:10])=[CH:4][C:3]=2[O:2]1.[C:11]([O:15][C:16]([NH:18][C@H:19]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([O:15][C:16]([NH:18][C@H:19]([C:32]([O:34][CH3:35])=[O:33])[CH2:20][S:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: Sc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CSc1ccc2c(c1)OCO2)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
After 27.7 g of (3,4-methylenedioxy)thiophenol and 74 g of methyl N-(t-butoxycarbonyl)-O-tosyl-L-serinate were dissolved in 200 ml of chloroform, 20 g of triethylamine were added at room temperature, followed by stirring overnight. The reaction mixture was washed with water and then extracted with ethyl acetate. The extract so obtained was dried over anhydrous magnesium sulfate. After the solvent was distilled off, 49 g of crude oil were obtained. The crude oil was recrystallized from an ethyl acetatehexane system, whereby 42 g of methyl N-t-butoxycarbonyl-S-[(3,4-methylenedioxy)phenyl]cysteinate were obtained (yield: 66%).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2ccncc2c(=O)o1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2ccncc2c(=O)n1-c1ccccc1

Procedure:
Compound 17 (350 mg, 21.6 mmol) was mixed with aniline (200 mg, 21.6 mmol) in 3 mL of pyridine. The resulted solution was heated in a microwave for 25 min keeping temperature constant at 250° C. The crude material 18 was concentrated in vacuo, co-evaporated with toluene (3×10 mL), dried under vacuum for 1 h and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:18]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=2[F:16])[CH:3]=1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: O=[N+]([O-])c1ccc(F)c(-c2cncc(F)c2)c1

Procedure:
Trifluoromethanesulfonic acid 5-fluoropyridin-3-yl ester was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 1 to give 3-fluoro-5-(2-fluoro-5-nitrophenyl)pyridine as a white solid: δH (360 MHz, CDCl3) 7.39 (1H, t, J 9), 7.65 (1H, m), 8.31-8.36 (1H, m), 8.42 (1H, dd, J 7 and 3), 8.58 (1H, d, J 3), 8.67 (1H, d, J 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([Cl:23])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (1 drop) was added to a suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid from the preparation of Intermediate 85 as described above (200 mg, 0.72 mmol) and oxalyl chloride (95 ul, 1.08 mmol, 1.5 eq) in DCM (5 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness and azeotroped with toluene (2×50 ml). The organic layer was separated, dried and evaporated in vacuo to afford the title compound as a yellow solid, 213 mgs. No further purification carried out. LCMS sample dissolved in methanol, MS (ES+) m/z 291 [M+H]+ (C16H1535ClO3), corresponding to methyl ester generated from acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]([CH3:26])[CH3:25])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.B.[Cl-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:29]=[CH:28][CH:27]=[C:21]([CH2:22][N:24]([CH3:26])[CH3:25])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 50 °C

Procedure:
A solution of 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)-N,N-dimethylbenzamide (130 mg, 0.29 mmol) in THF (5 mL) was stirred at room temperature and 1 M borane in THF (1.45 mL, 1.45 mmol) was added. The solution was heated at 50° C. for 45 minutes. The mixture was then cooled and saturated ammonium chloride (5 mL) was added. The mixture was further diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (SiO2, 20% acetone/hexane) and the title compound obtained as a light yellow glass (73 mg). 1H NMR (300 MHz, CDCl3): δ 2.49 (6H, s), 3.87 (2H, s), 6.69 (1H, br s), 7.05-7.35 (6H, m), 7.49-7.50 (3H, m) and 7.81 (2H, d, J=9 Hz). MS, m/z: Calcd, 434.062. Found, 434.17 (M).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:23])[CH3:2].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>C(O)C>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
In a procedure similar to that described above in part B of this example, 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.57 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 6.0 ml of acetic anhydride were interacted with stirring at room temperature overnight. The reaction mixture was then diluted with 13.0 ml of ethanol and the precipitate which separated was filtered and washed with 6.0 ml of ethanol. The filter cake was then reslurried in 30 ml of methanol, filtered and washed successively with methanol and diethylether. The material was dried in vacuo to obtain 15.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3), a white crystalline solid which melted at 218°-222° C. The infrared spectrum was consistent with the structure. A benzene solution of the above product developed an intense grape-red color when streaked on a phenolic resin coated paper.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(SCCCc2ccccc2)cc1
Yield: 101.2 %

Procedure:
By the method of Preparation 7, 3-phenylpropyl mercaptan (41.1 g) and 4-bromobenzaldehyde (53.7 g) were converted to 70 g of present title product, isolated as an oil following chromatography on silica gel using 9:1 hexane:ethyl acetate as eluant; tlc Rf 0.4 (1:4 ethyl acetate:hexane).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=O)=[CH:27][CH:26]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:32]([CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1

Procedure:
Starting from 1 g (3.31 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 1.52 g (8.26 mmol) of 4-methoxyphenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 240 mg (17%) of the diastereomer which elutes more rapidly, M.p.: 41° C., and 134 mg (9%) of the diastereomer which elutes more slowly, M.p.: 48° C.
Reaction SMILES: [OH:1][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[N+:15]([O-])=O>CO.[Pd]>[OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[NH2:15]
Reactant: CC(C)(C)OC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(O)c(N)c1
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl 4-hydroxy-3-nitrobenzoate (4.4 g, 18.4 mmol) in methanol (50 mL), 10% Pd/C (200 mg) was added and the resulting suspension was hydrogenated at 50 psi for 4 hours. After filtering under a pad of celite, methanol was removed in vacuo to obtain the title compound as a greenish powder (3.5 g, 95%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[N:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[OH:21]>C(O)(=O)C>[Br:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:21])=[N:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=2
Reactant: COc1ccc2nccc(O)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COc1ccc2ncc(Br)c(O)c2n1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
N-Bromosuccinimide (263 mg, 1.48 mmol, 1.3 eq) is added at 15° C. to a stirred solution of 6-methoxy-[1,5]naphthyridin-4-ol (200 mg, 1.14 mmol, 1.0 eq) in acetic acid (3 mL). After 30 minutes stirring at 15° C., the reaction mixture is allowed to come at room temperature and the resulting cake is filtered, washed with acetic acid and dried to afford 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol as an off-white solid (280 mg, 97% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cnn(Cc3ccccc3)c2=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
To a sealed tube was added 2-benzyl-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (3.31 gm, 110.0 mmol), 4-cyanophenyl boronic acid (2.94 gm, 20 mmol), Pd(dppf)Cl2 dichloromethane complex (0.817 gm, 1.0 mmol), potassium phosphate (6.36 gm, 30 mmol) and THF (10 ml). The reaction solution was degassed with argon for 5 min and then sealed in a reaction tube. The reaction was then heated to 90° C. and keeped at this temperature for 4 hrs. The reaction was then cooled to rt and diluted with EtOAc (50 ml). The reaction mixture was then poured into a separatory funnel and the layers were separated. The organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-70% EtOAc/Hex to give 3.65 gm (92% yield) 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile. HPLC retention time (method B) 3.81 min; LCMS (M+H)=398.0.
Reaction SMILES: [C:1]([C:3]1[C:4](=[NH:19])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].OC1C=CC=CC=1C(C1C=CC=CC=1)=O.C(#N)CC#N.N1CCCCC1>C(O)C>[NH2:19][C:4]1[O:5][C:6]2[C:11]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]=1[C:1]#[N:2])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Agent: O=C(c1ccccc1)c1ccccc1O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: N#CCC#N
Product: N#CC1=C(N)Oc2ccccc2C1c1ccccc1
Reaction time: 2 h
Yield: 8 %

Procedure:
3-Cyano-2-imino-4-phenyl-2H-chromene. To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0–5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (8%) of the title compound. 1H NMR (CDCl3): 7.74–7.29 (m, 7H), 7.20–7.13 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]2[CH2:12][N:13]([CH2:16][C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([CH3:30])[CH:18]=3)[C:14](=[O:15])[C:10]=2[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([NH:3][C:4]([C:6]1[C:11]2[CH2:12][N:13]([CH2:16][C:17]3[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:30])[CH:18]=3)[C:14](=[O:15])[C:10]=2[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1nccc2c1CN(Cc1ccc(C(=O)OC(C)(C)C)c(C)c1)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)c1nccc2c1CN(Cc1ccc(C(=O)O)c(C)c1)C2=O
Yield: 89 %

Procedure:
A solution of tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (260 mg, 0.64 mmol, Step-3) in 4 M hydrogen chloride in dioxane (20 mL) is stirred overnight at rt. The mixture is concentrated to give 220 mg (89% yield) of the title compound as pale brown solid.