Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:7]1[N:8]([CH2:17][C:18]2[CH:26]=[CH:25][C:24]3[C:20](=[C:21]([Br:38])[N:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([O:35]CC)=[O:34])[N:23]=3)[CH:19]=2)[C:9]([C:13]([O:15]C)=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[Br:38][C:21]1[N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([OH:35])=[O:34])[N:23]=[C:24]2[C:20]=1[CH:19]=[C:18]([CH2:17][N:8]1[C:9]([C:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=[C:7]1[CH2:3][CH2:4][CH2:5][CH3:6])[CH:26]=[CH:25]2.[Na+:2].[Na+:2].[Br:38][C:21]1[N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([OH:35])=[O:34])[N:23]=[C:24]2[C:20]=1[CH:19]=[C:18]([CH2:17][N:8]1[C:9]([C:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=[C:7]1[CH2:3][CH2:4][CH2:5][CH3:6])[CH:26]=[CH:25]2
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(C(=O)[O-])n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethanol (5.5 ml) and 1N aqueous sodium hydroxide (1.38 ml) were added to methyl 2-butyl-4-chloro-1-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carboxylate (0.132 g, 0.230 mmol) as obtained in Example 8, and the mixture was stirred at room temperature for one day. The mixture was concentrated in an evaporator, and ion-exchanged water (5 ml) was added thereto, followed by stirring. Conc. hydrochloric acid was dropwise added thereto to adjust its pH to 5-6. The resultant solid was filtered off and washed three times with ion-exchanged water (2.5 ml). Two equivalent amounts of N/10 aqueous sodium hydroxide was added to dissolve the solid obtained by drying in vacuo at 37° C. for two days. Lyophilization of the solution afforded 0.104 g of disodium 1-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-2-butyl-4-chloro-1H-imidazole-5-carboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:27]2[CH2:29][CH2:28]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[N:9][C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O.CCOC(C)=O>[CH:27]1([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(-c2ccco2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccco2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 25 °C
Yield: 9.8 %

Procedure:
A solution of 0.076 g (1.87 mmol) of 3-cyclopropyl-5-furan-2-yl-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid ethyl ester and 0.013 g (5.42 mmol) of LiOH in 4 ml of THF, 2 ml of MeOH and 2 ml of H2O was stirred at 80° C. for 4.5 hours. The reaction mixture was then cooled to RT, diluted with EtOAc and washed with 10% KHSO4 solution and brine. The aqueous phases were extracted twice with EtOAc. The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 69 mg (96%) of the title compound as white powder. MS: 377.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)([OH:9])[CH2:5][CH2:4]1.[NH2:29][C:30]1[C:35](I)=[CH:34][CH:33]=[CH:32][N:31]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=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].C(Cl)Cl.O>[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:4][CH2:5][C:6]([C:10]2[NH:29][C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[C:11]=2[CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)([OH:9])[CH2:7][CH2:8]1
Reactant: Nc1ncccc1I
Reactant: CN(C)C1(c2ccccc2)CCC(O)(C#CCCCOC2CCCCO2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(O)(c2[nH]c3ncccc3c2CCCOC2CCCCO2)CC1
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
4-(Dimethylamino)-4-phenyl-1-(5-(tetrahydro-2H-pyran-2-yloxy)pent-1-ynyl)cyclohexanol (700 mg, 1.82 mmol), 2-amino-3-iodopyridine (363 mg, 1.65 mmol), lithium chloride (74 mg, 1.73 mmol) and sodium carbonate (525 mg, 4.95 mmol) was dissolved in dimethylformamide (20 ml) under an argon atmosphere. Argon was subsequently allowed to flow through the solution for 10 min and the catalyst ([Pd(dppf)Cl2×CH2Cl2], 135 mg, 0.17 mmol) was then added. The reaction mixture was heated at 105° C. (oil bath temperature) for 3 h. A TLC showed that the starting substances had been used up completely. The black reaction mixture was cooled to room temperature and water (50 ml; stirring for 10 min), methylene chloride (50 ml) and saturated sodium chloride solution (for phase separation, 80 ml) were added in succession. The phases were separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were washed with water (20 ml) and with saturated sodium chloride solution (3×20 ml), dried over sodium sulfate and filtered and the volatile constituents were then removed completely in vacuo. The residue was separated by chromatography [silica gel 60 (200 g); chloroform/ethanol 19:1 (500 ml), 9:1 (500 ml), 4:1 (500 ml), methanol (1,000 ml)]. It was possible to obtain a diastereoisomer of the alcohol (4-(dimethylamino)-4-phenyl-1-(3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)cyclohexanol) (m.p.: 238° C.) in a yield of 28% (221 mg, 0.46 mmol) as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2cccs2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cccs2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(thiophen-2-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(thiophen-2-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([CH2:12][C:13]([F:15])([F:14])[F:16])[N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of ethyl 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate (1.74 g, 7.36 mmol) in tetrahydrofuran (5.0 mL) was added 8N sodium hydroxide (4.6 mL), and the mixture was stirred at room temperature for 2 hr. 6N hydrochloric acid (6.0 mL) was added to the mixture (pH=3), and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, and washed with ethyl acetate/hexane to give the title compound (1.28 g, 84%) as a white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([N:8]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])C>C(O)(=O)C.[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[CH2:5][CH:6]([CH3:7])[N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CC(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reaction time: 0.17 h
Yield: 5.3 %

Procedure:
To a solution of 1.07 g (0.030 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester in 20 mL of acetic acid was added 1.0 g (0.018 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hrs and then filtered while hot. 50 mL of water and 50 mL of ethyl acetate were added and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-96:4) gave 0.45 g of (rac)-2-chloro-9-cyclopentyl-8-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-3) as a white solid.
Reaction SMILES: [H-].[K+:2].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H][H]>O1CCCC1>[C:3]1([O-:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[K+:2]
Reactant: [H][H]
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: [O-]c1cccc2ccccc12

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH2:16])[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CC(O)=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC3CCCCC3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Step A Reductive Amination: To a solution of 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (250 mg, 0.68 mmol) in DCE (6.5 mL) was added cyclohexanone (0.071 mL, 0.68 mmol), and NaBH3(OAc)3 (250 mg, 1.2 mmol). HOAc (0.05 mL, 0.82 mmol) was then added drop-wise and the solution was allowed to stir at ambient temperature for two hours after which the reaction was judged complete by TLC. The solution was filtered through silica gel, concentrated in vacuo and purified via normal phase SiO2 chromatography using a 0% to 15% ethyl acetate/hexane gradient, affording 180 mg of 7-Cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a viscous yellow oil.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=1)=O.[CH:30]([C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:34]=1[NH2:35])([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:33]([CH:30]([CH3:32])[CH3:31])[C:34]=1/[N:35]=[CH:1]/[C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=[CH:5][CH:4]=1)([CH3:42])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1-c1cccc(C=O)n1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2ccccc2CN(C(=O)OC(C)(C)C)c2ccccc2)n1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran (50 mL) and 4 angstrom molecular sieves (ca. 15 mL) were added to tert-butyl 2-(6-formylpyridin-2-yl)benzyl(phenyl)carbamate (11) (03.63 g, 9.34 mmol). Then 2,6-diisopropylaniline (1.66 g, 9.34 mmol) was added followed by a catalytic amount of p-toluenesulfonic acid monohydrate (0.003 g, 0.015 mmol). The mixture was stirred overnight then filtered and evaporated to a thick yellow oil. After several days the oil began to crystallize. Methanol (40 mL) was added and the mixture was stirred to give a yellow crystalline solid. The mixture was cooled to 5° C. for a couple of hours then the solid was collected on a glass fit and dried under reduced pressure. Yield: 3.93 g, 76.8%. 1H NMR (CD2Cl2, 500 MHz): 8.26 (s, 1H), 8.19 (d, 1H), 7.87 (t, 1H), 7.54 (d, 1H), 7.32-7.42 (m, 4H), 7.02-7.20 (m, 8H), 5.11 (s, 2H), 2.99 (sept, 2H), 1.34 (s, 9H), 1.18 (d, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C1COCC1>[CH2:21]([O:28][CH2:29][C:30]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)COCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added benzyloxyacetyl chloride (1.26 ml, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo and the residue was slurried in diethyl ether (30 ml), filtered, recrystallized from a minimal amount of acetic acid, slurried in ethyl acetate (15 ml), and filtered to give 1.35 g (80%) of product: mp 204–206° C.; 1H NMR (DMSO-d6) d 11.20 (s, 1H), 10.40 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.50–7.28 (m, 5H), 5.17 (dd, J=5.0 and 12.5 Hz, 1H), 4.72 (s, 2H), 4.21 (s, 2H), 2.99–2.85 (m, 1H), 2.67–2.51 (m, 2H), 2.12–2.08 (m, 1H); 13C NMR (DMSO-d6) d 172.78, 169.78, 169.01, 168.27, 166.67, 137.04, 136.52, 135.93, 131.29, 128.36, 127.82, 124.40, 118.38, 116.08, 72.78, 69.23, 48.97, 30.92, 21.98; Anal. Calcd. For C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.77; H, 4.54; N, 9.82.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].N#N.C[O:10][C:11](=O)[C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:15]=[C:14]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:13]=1.O>CCOCC>[CH2:31]([O:30][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:15]=1)[CH2:11][OH:10])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCOc1cc(OCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCC)c1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a 250 mL flame dried RBF, LAH (1.43 g, 38.7 mmol) and a magnetic stir bar were added. The flask was sealed with a rubber septum into which N2 inlet/outlet needles were added. Dry ether (10 mL) was added via a syringe to the RBF to wet the LAH. Some gas was evolved. Methyl-3,5-diundecoxybenzoate (15.0 g, 31.5 mmol) was dissolved in dry ether (120 mL) and then cautiously added to the flask via a syringe over a period of 20 minutes. The dark grey solution was left to stir overnight. After approximately 18 hours, water (12 mL) was added very cautiously (drop wise) until the solution color changed to bright white. The contents of the RBF were then transferred to a 2 L separatory funnel. The RBF was alternately rinsed 3 times with distilled H2O (20 mL) and ether (20 mL). One final rinse was made with 1M HCl (20 mL). All rinses were emptied into the separatory funnel. Distilled H2O (200 mL) and ether (200 mL) were added to the separatory funnel. The contents of the separatory funnel were separated into an aqueous layer and an ether layer. The aqueous layer was washed 3 times with ether (200 mL). Ether washes were added to the ether layer. The ether layer was then washed 3 times with distilled H2O (200 mL), once with saturated NaCl (125 mL) and then dried with MgSO4. MgSO4 was removed using gravity filtration. The ether layer was then concentrated using rotary evaporation. The result was a colorless viscous liquid. The liquid solidified under high vacuum after approximately 2 hours. This produced a 13.0 g yield or a 92.1% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.20-1.45 (m, 32H, CH2(CH2)8), 1.69-1.78 (m, 5H, OCH2CH2 & OH), 3.92 (t, J=6.6, 4H, OCH2), 4.61 (d, J=5.5, 2H, ArCH2OH), 6.37 (t, J=2.2, 1H, ArH), 6.48 (d, J=1.9, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.79, 26.13, 29.34, 29.44, 29.48, 29.68, 29.71, 32.00, 65.57, 68.13, 100.58, 105.10, 143.25, 160.60.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[N:10]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[N:10]1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
To a solution of 4-(1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)benzoyl chloride (28 mg, 0.062 mmol) in 0.62 mL of DCM at Rt was added morpholine (0.016 mL, 0.19 mmol) and the mixture stirred for 10 mins. The solvents were evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 30-70% CH3CN in 0.1% TFA/H2O over 10 mins to give 25 mg (69%) of the title compound as white solid containing 0.6 eq of TFA.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[C:14]([Cl:16])[CH:15]=1)[CH:12]=[O:13].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:8]([Cl:7])[CH:9]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH:12]=[O:13]
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (9.4 g, 67.8 mmole) was added to a stirred solution of 4,6-dichlorosalicylaldehyde (10.8 g, 56.5 mmole) in dimethylformamide (80 ml). The resulting mixture was stirred at 60° for 30 minutes and treated with benzyl bromide (10.6 g, 62.1 mmole). This mixture was stirred one hour at 60° C. and then poured into ice water (1000 ml) to give the title compound (15.9 g, 100%) which melted at 98°-100° C. after recrystallization from hexane. pmr (CDCl3) δ 5.10 (2H, s), 7.33 (5H, s), 10.40 (H, s).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:12][CH2:13][CH2:14][OH:15]>>[Cl:12][CH2:13][CH2:14][O:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Cl:1]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: OCCCl
Product: O=C(OCCCl)c1ccccc1CCl
Reaction time: 10 h
Yield: 94 %

Procedure:
180 g of o-(chloromethyl)benzoic acid chloride was placed in a double-neck 500 ml flask equipped with a cooler, thermometer and dropping funnel. 50 ml of 2-chloroethanol was added dropwisely, while maintaining the internal temperature of reactor at 40˜50° C. After all amounts of 2-chloroethanol were infused, the reacting solution was stirred for 10 hours, while maintaining the internal temperature of reactor at 40˜50° C. The residue was subjected to fractional distillation under reduced pressure at the reactor equipped with a fractional distiller to afford 165 g of desired compound (yield 94%) as oil.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12](=[N:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:16]#[N:17])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43]([F:47])[CH:42]=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[F:47][C:43]1[CH:42]=[C:41]([CH2:40][N:6]2[C:5]([C:12](=[N:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=3)[C:16]#[N:17])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH:46]=[CH:45][N:44]=1
Reactant: Fc1cc(CBr)ccn1
Reactant: COc1ccc(CON=C(c2cc(C)cc(C#N)c2)c2[nH]c(=O)[nH]c(=O)c2C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CON=C(c2cc(C)cc(C#N)c2)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccnc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-(4-methoxybenzyloxyimino)-methyl]-5-methyl-benzonitrile (71 mg, 0.164 mmol, 1.2 eq.) was dissolved in 2.0 mL DMF. Potassium carbonate (19 mg, 0.137 mmol, 1 eq.) and 4-bromomethyl-2-fluoro-pyridine (26 mg, 1 eq.) were added to the reaction, followed by lithium iodide (18 mg, 1 eq.) The reaction was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 20-80% EtOAc/hexane) to white powder (32 mg, 36%). LC-MS shows 542.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.80 (br, 1H), 7.93 (d, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.32 (d, 2H), 7.21 (s, 1H), 6.92 (d, 2H), 6.72 (d, 1H), 6.40 (s, 1H), 5.08 (dd, 2H), 4.90 (d, 1H), 4.22 (d, 1H), 3.80 (s, 3H), 2.32 (s, 3H), 2.20 (m, 1H), 1.16 (d, 3H), 1.12 (d, 3H).