Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of 5-bromo-2,3-dimethyl-benzoic acid (500 mg, 2.18 mmol, 1.0 eq), (3,4-difluorophenyl)boronic acid (378.6 mg, 2.40 mmol, 1.1 eq) and Na2CO3 (693 mg, 6.54 mmol, 3.0 eq) in a mixture of EtOH (2.5 mL), DMF (10 mL) and H2O (2.5 mL) was added Pd(PPh3)4 (126 mg, 0.11 mmol, 0.05 eq) under nitrogen. The mixture was stirred at 100° C. overnight. After cooling to room temperature, water was added and the diluted reaction mixture filtered through celite. The aqueous layer was extracted with EtOAc and the organic extract was discarded. The remaining aqueous layer was acidified to pH 2 by addition of 3M HCl. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (400 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[NH:30])OCC)=[CH:21][CH:20]=1>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCOC(=N)Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccc(F)cc1
Yield: 5.2 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours, then the solvent evaporated. The residue was purified by flash chromatography (chloroform/methanol) to obtain the product as a foam (0.49 g), m.p. 59°-64° C.
Reaction SMILES: C[O-].[Na+].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br>CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: Clc1ccc(-c2ccc(OCCCBr)cc2)cc1

Procedure:
A methanolic solution of sodium methoxide prepared by dissolving sodium (35.7 g) in anhydrous methanol (300 ml) was treated with 4-(4-chlorophenyl)phenol (311 g) and the resulting solution was added to a stirred solution of 1,3-dibromopropane (850 ml) in anhydrous methanol (500 ml) at reflux during a period of 6 hours. The mixture was stirred at reflux for a further period of 18 hours and was then evaporated to dryness in vacuo. The crystalline residue was triturated with petroleum ether (b.p. 40°-60° C.), filtered off and dried, and was then triturated with aqueous potassium hydroxide solution (1500 ml; 5% w/v), filtered off, washed well with water and dried. The solid was subjected to fractional crystallisation from a mixture of isopropanol and acetone. The first crop was discarded. The second crop (161 g) was dissolved in acetone, filtered, and evaporated. The third crop (53 g) was recrystallised from ethanol. The fourth crop was recrystallised from isopropanol and then twice from ethanol. The purified second, third and fourth crops were combined and dissolved in acetone, and the solution was filtered through diatomaceous earth. It was concentrated in vacuo to a volume of 300 ml and was then diluted with a mixture of methanol (200 ml) and water (500 ml). The resulting solid was filtered off and washed with water to give 3-[4-(4-chlorophenyl)phenoxy]propyl bromide (194 g), m.p. 103°-105° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:19][OH:20]>C(O)C>[OH:20]/[N:19]=[C:9](\[NH2:10])/[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc(CC#N)ccc1I
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C/C(N)=N/O)ccc1I
Yield: 50.3 %

Procedure:
2-(4-Iodo-3-methylphenyl)acetonitrile (2 g, 7.78 mmol) in ethanol (30 mL) was added dropwise to potassium carbonate (6.67 g, 48.24 mmol) and hydroxylamine hydrochloride (0.541 g, 7.78 mmol) in ethanol (30 mL) at reflux over a period of 5 minutes. The resulting suspension was stirred at reflux for 8 hours. The reaction mixture was allowed to cool overnight and the salts were filtered and washed with DCM (2×50 mL). The filtrate was evaporated to give crude product. The crude product was purified by flash silica chromatography on a combi flash companion 40 g cartridge, elution gradient 0 to 30% MeOH in DCM. Pure fractions were evaporated to dryness to afford (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (1.135 g, 50.3%) as a yellow gum.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 59 %

Procedure:
Using the procedure described in Example 159B, using ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureido}-1H-pyrazol-1-yl)acetate as solid (133 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.70 (s, 1H), 8.60 (m, 1H), 7.83 (s, 1H), 7.51 (d, 1H), 7.43 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.25 (d, 1H), 6.12 (s, 1H), 4.85 (s, 2H), 4.15 (q, 2H), 3.99 (s, 6H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 565 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:41])([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:40][C:32]([NH:41][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:31])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CC(C)(Cc1ccccc1)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1,1-dimethyl-2-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][O:10][C:11](=[O:13])[CH3:12])=[CH:7][C:6]=1[OH:16])=[O:4].C([O-])(=O)C.[Na+]>CO>[O:4]=[C:3]1[C:5]2[CH:15]=[CH:14][C:8]([CH2:9][O:10][C:11](=[O:13])[CH3:12])=[CH:7][C:6]=2[O:16][CH2:2]1
Reactant: CC(=O)OCc1ccc(C(=O)CCl)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCc1ccc2c(c1)OCC2=O
Temperature: 25 °C

Procedure:
A solution of acetic acid 4-(2-chloro-acetyl)-3-hydroxy-benzyl ester (2.20 g, 9.07 mmol) and sodium acetate (1.49 g, 18.13 mmol) in anhydrous methanol (40 mL) was heated to reflux for 2 h. The reaction mixture was allowed to cool to RT, and concentrated. The residue was dissolved in dichloromethane and washed with water. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, evaporated in vacuo, and the residue was purified by column chromatography (ethylacetate:hexane; 2:8) to give the acetic acid 3-oxo-2,3-dihydro-benzofuran-6-ylmethyl ester as an off white solid (1.29 g, 59%). 1H NMR (CDCl3, 400 MHz) 2.17 (s, 3H), 4.65 (s, 2H), 5.17 (s, 2H), 7.06 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 11.67 (s, 1H), 13C NMR (CDCl3, 100 MHz) 20.8, 65.3, 75.1, 112.3, 120.8, 121.2, 124.2, 146.9, 170.5, 174.2, 199.2.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)CCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 5-isopentyl-1H-indole-2-carbaldehyde (100 mg, 0.46 mmol) and methyl iodide (71 mg, 0.50 mmol) in 0.93 mL dimethylformamide was added potassium carbonate (71 mg, 0.51 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-isopentyl-1-methyl-1H-indole-2-carbaldehyde (16 mg, 15%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29]C(=O)OC(C)(C)C)=[CH:28][C:22]=2[S:21](=[O:38])(=[O:37])[N:20]=1.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:20][S:21](=[O:38])(=[O:37])[C:22]=2[CH:28]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 84 %

Procedure:
A solution of Example 34A (0.615 g, 1.14 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.456 g, 84%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.42 (m, 1 H) 0.74 (m, 7 H) 1.32 (m, 1 H) 1.58 (m, 3 H) 2.15 (m, 2 H) 7.07 (m, 2 H) 7.51 (m, 2 H) 7.77 (m, 2 H) 8.16 (m, 1 H) 13.57 (m, 1 H). MS (ESI−) m/z 438 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.CC1C2C(=CC=C([N+]([O-])=O)C=2)NN=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[N:3]=[C:2]2[CH3:1]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: CCO
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
tert-Butyl 3-methyl-5-nitro-1H-indazole-1-carboxylate. To a solution of 3-methyl-5-nitro-1H-indazole (0.95 g, 5.36 mmol) in ethanol (12 mL) was added di-tert-butyl dicarbonate (1.755 g, 8.04 mmol). The reaction was stirred at 50° C. for 5 h. The reaction mixture was cooled down to room temperature and the solvent was removed under reduced pressure. The crude was diluted with ethyl acetate (150 mL), washed with saturated sodium bicarbonate (100 mL), and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated down to give the title compound as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z 278.4 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Br)cccc1-c1ccccc1

Procedure:
A mixture of the product from Example 114A (2.2 g, 7.5 mmol), phenylboronic acid (919 mg, 7.5 mmol), sodium carbonate (7.55 mL, 2 M aqueous solution, 15.1 mmol) tetrakis(triphenyphosphine)palladium(0) (261 mg, 0.23 mmol) and 50 mL of toluene were refluxed for 16 hours under nitrogen. The reaction was cooled and partitioned between 50 mL of water and 50 mL of ethyl acetate. The aqueous portion was separated and extracted with 2×25 mL of ethyl acetate and the combined organic extracts were washed with 2×25 mL of water and 1×25 mL of brine and dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (95:5 hexane:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.63 (s, 3H) 7.35-7.60 (m, 6H) 7.71-7.79 (m, 2H); MS (DCI+) m/z 308.0 [M+NH4]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31]([OH:33])=O)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:31](=[O:33])[CH2:30][C@H:29]([O:28][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: O=C(CNCCCO)OCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)N(CCCO)CC(=O)OCc1ccccc1)OC(=O)CCCCCCCCC
Yield: 62.9 %

Procedure:
In the same manner as described in Example 2-(5), N-(3-hydroxypropyl)glycine benzyl ester (450 mg, 2.0 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (1.0 g, 2.5 mmol) in the presence of EDC·MeI (900 mg, 3.0 mmol) in CH2Cl2 to afford 0.76 g (63%) of N-(3-hydroxypropyl)-N-[(R)-3-decanoyloxytetradecanoyl]glycine benzyl ester as a colorless oil: 1H NMR (CDCl3) (1:1 mixture of rotomers) δ 0.88 (t, 6H, J=6.6 Hz), 1.1-1.7 (m, 35H), 1.78 (m, 1H), 2.26 (q, 2H, J=7.6 Hz), 2.37 and 2.54 (2 dd, 1H, J=14.9, 6.9 Hz), 2.60 and 2.89 (2 dd, 1H, J=14.8, 6.0 Hz), 3.51 (m, 4H), 3.70 (m, 1H), 3.95-4.25 (m, 2H), 5.1-5.25 (m, 3H), 7.35 (m, 5H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41].O>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:40]([CH3:42])[CH3:41])=[O:15])[C@H:3]1/[CH:17]=[CH:18]/[C@@H:19]([OH:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A solution of crude Travoprost acid (1.1 g from Example 9) in DMF (11 mL) was treated with K2CO3 (0.90 g, 6.5 mmol) and 2-iodopropane (0.74 g, 4.4 mmol). This mixture was then stirred at 80° C. for 2 hr under an atmosphere of nitrogen (TLC monitoring). Water (30 mL) and ethyl acetate (30 mL) were added and the mixture was stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 1.0 g of crude Travoprost. The crude Travoprost was purified by column chromatography and then concentrated under reduced pressure to provide 0.89 g of Travoprost (78.3% yield, 2 steps). UPLC (ACQUITY UPLC HSS C18) analysis of the product showed that no isomer and impurities were detectable.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1)=[O:27])[CH3:24]
Reactant: CCCOc1ccc(O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CCN=C=O
Product: CCCOc1ccc(OC(=O)NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 81 with ethyl isocyanate in the same manner as that of example 35. 1H NMR (CDCl3) δ: 8.20 (1H, d), 7.25 (1H, dd), 6.99 (1H, d), 5.06 (1H, br), 4.14 (2H, t), 3.32 (2H, m), 2.66 (2H, q), 2.58 (2H, q), 1.98 (2H, m), 1.28 (3H, t), 1.22 (3H, t), 1.14 (3H, t), 1.13 (3H, t).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)[CH:7]=2.B(Br)(Br)Br>>[OH:2][C:3]1[C:4]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH:7]=2
Reactant: COc1cccc(-c2ccc3cc(OC)c(C(=O)Nc4ccccc4)cc3c2)c1
Agent: BrB(Br)Br
Product: O=C(Nc1ccccc1)c1cc2cc(-c3cccc(O)c3)ccc2cc1O
Yield: 50 %

Procedure:
The compound is prepared by reaction of 3-methoxy-7-(3-methoxyphenyl)-N-phenyl-2-naphthamide (86 mg, 0.22 mol, 1 eq) with boron tribromide solution (4.45 ml, 4.45 mmol, 20 eq) according to method G. Purification by preparative thin-layer chromatography with hexane/ethyl acetate 6/4 as the eluent yielded the desired product in a yield of 50%, 39 mg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[C:22]([NH2:24])[CH:23]=2)[CH:17]=1.CCN(CC)CC>CN(C=O)C.O=S(Cl)Cl.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:24][C:22]1[CH:21]=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=[C:18]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)[CH:23]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h

Procedure:
Add 2 drops of DMF into 628 mg 3-iodo-4-methylbenzoic acid (2.2 mmol) in 20 mL SOCl2 and reflux for 2 h. After vacuum evaporation of SOCl2, add 6.0 mL anhydrous THF and get the pale yellow solution. Dissolve the product from step 1, 524 mg 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine (2.0 mmol) in 6.0 mL anhydrous THF and add 10 mmol Et3N, and the pale yellow solution prepared previously is added drop wise till it is all added. The reaction mixture rises to room temperature for 1 hr. The reaction was quenched with addition of brine and extracted with EtOAc. The combined extraction organic layers was dried and concentrated under vacuum, the residue was purified through column chromatography to afford 873 mg desired product. (90%)
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[C:28]([CH:33]=O)=[CH:29][CH:30]=[N:31][CH:32]=1)[CH2:20][CH2:19]2.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[CH2:20][CH2:19]2
Reactant: O=Cc1ccncc1N1CCc2cc(Cl)ccc2C1=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccncc2N2CCc3cc(Cl)ccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
NaBH(OAc)3 (84 mg, 0.4 mmol) was added into a solution of 5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-4-carbaldehyde (28.6 mg, 0.1 mmol) and 1-methyl-piperazine (10 mg 0.1 mmol) in DCM and MeOH (10 mL, 1:1). The reaction mixture was stirred at RT overnight before it was poured into ice-water (10 mL) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried over anhy. MgSO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.2 mg, 16%) as a white solid. MS: 371.1 (M+H+).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[I-].C1([C:18]([PH3+])([C:25]2[CH:30]=[CH:29]C=CC=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=CC=CC=1.[C:32]([N:39](C1CCCCC1)[C@H](C=O)C)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(C1CCCCC1)[C@H](CO)C)(OC(C)(C)C)=O>O1CCCC1.CS(C)=O>[C:35]([O:34][C:32]([NH:39][C@H:25]([CH:30]=[CH2:29])[CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1CCCCC1
Agent: C[C@@H](CO)N(C(=O)OC(C)(C)C)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A 0° C. solution of potassium hexamethyldisilazide (22.9 mmol in 115 mL of 5:1, tetrahydrofuran (THF): dimethyl sulfoxide (DMSO) was added dropwise to triphenylmethylphosphonium iodide (24.81 mmol). After stirring at 0° C. for 1 hour, the solution was cooled to -78° C. and a solution of Boc-cyclohexylalaninal [4.90 g, 19.08 mmol, prepared by Swern oxidation (Mancuso, A.J.; Huang,, S.-L.; and Swern, D., J. Org. Chem. 1978, 43, 2480) of Boc-cyclohexylalaninol] in dry THF (95 mL) was added. After stirring at -78° C. for 1 hour, the mixture was allowed to warm to room temperature. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ether (2×300 mL). The combined organic phase was washed with 10% HCl (200 mL), saturated NaHSO3 (2×200 mL), H2O (2×200 mL), saturated NaHCO3 (2×200 mL), and brine (200 mL), dried (MgSO4 ), filtered, and evaporated. The residue was purified by chromatography (40 m SiO2 ; ether:hexane, 15:85) to give the desired compound in 60% yield. Mass spectrum (M+H)+ =254.