Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17](OC)=[O:18])[N:14]=[C:13]([C:21](OC)=[O:22])[CH:12]=2)[CH:8]=[C:7]([C:25](OC)=[O:26])[N:6]=1)=O.[BH4-].[Na+].Cl>O1CCOCC1.O>[OH:18][CH2:17][C:15]1[CH:16]=[C:11]([C:9]2[CH:10]=[C:5]([CH2:3][OH:2])[N:6]=[C:7]([CH2:25][OH:26])[CH:8]=2)[CH:12]=[C:13]([CH2:21][OH:22])[N:14]=1
Reactant: COC(=O)c1cc(-c2cc(C(=O)OC)nc(C(=O)OC)c2)cc(C(=O)OC)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cc(-c2cc(CO)nc(CO)c2)cc(CO)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g (128.77 mmol) of 2,2',6,6'-tetra(methoxycarbonyl)-4,4'-bipyridine is dissolved in a mixture of 400 ml of dioxane/400 ml of water and, in portions, 48.71 g (1.28 mol) of sodium borohydride is added thereto. The mixture is stirred overnight at room temperature. The solution is acidified with 5N hydrochloric acid and evaporated to dryness. The residue is suspended in 1 liter of 1N sodium hydroxide solution and extracted three times with 250 ml of chloroform. The organic phases are dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from ethanol/ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:33][CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:32])[CH:7]=1)([O-:22])=[O:21]
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])ncn1)c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Into a 100 mL round bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (100 mg, 0.31 mmol, 1.00 equiv) in toluene (10 mL), 1-(3-(trifluoromethyl)phenyl)ethanamine (71 mg, 0.38 mmol, 1.20 equiv), BINAP (9 mg, 0.01 mmol, 0.05 equiv), Cs2CO3 (144 mg, 0.44 mmol, 1.40 equiv), and Pd(dba)3 CHCl3 (6.5 mg, 0.01 mmol, 0.02 equiv). The resulting solution was stirred for 3 h at 120° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The product was obtained as 80 mg (54%) of a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:24]C)[CH:19]=1.[CH3:26]I>CO>[OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH3:26])[C:20](=[O:24])[CH:19]=1
Reactant: CI
Reactant: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Solvent: CO
Product: Cn1ccc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)cc1=O

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.281 g, 0.797 mmol) was refluxed in methanol (17 mL) with MeI (0.0798 ml, 1.28 mmol) for 48 hrs. Concentration and purification by silica gel chromotography (20:1 DCM/MeOH) afforded the titled compound along with recovered starting material.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:45])[C:11](=[O:44])[CH2:12][N:13]([C:33]1[C:42]([CH3:43])=[CH:41][C:36]2[C:37]([CH3:40])=[N:38][O:39][C:35]=2[CH:34]=1)[CH2:14][C:15]([NH:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])(=[O:23])=[O:22])=[O:16].[F:46][CH2:47][CH2:48]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:45])[C:11](=[O:44])[CH2:12][N:13]([C:33]1[C:42]([CH3:43])=[CH:41][C:36]2[C:37]([CH3:40])=[N:38][O:39][C:35]=2[CH:34]=1)[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:48][CH2:47][F:46])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])(=[O:22])=[O:23])=[O:16]
Reactant: Cc1cc2c(C)noc2cc1N(CC(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])CC(=O)N(C)N1Cc2ccccc2C1
Reactant: OCCF
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc2c(C)noc2cc1N(CC(=O)NCCN(CCF)S(=O)(=O)c1ccccc1[N+](=O)[O-])CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
The compound (557 mg, 0.876 mmol) of step A, 2-fluoroethanol (84 mg, 1.31 mmol) and triphenylphosphine (345 mg, 1.31 mmol) were dissolved in tetrahydrofuran (4.4 ml), and the mixture was stirred at room temperature. Thereto was slowly added a 40% diisopropyl azodicarboxylate-toluene solution (0.70 ml), and the mixture was stirred at the same temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (561 mg, yield 94%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:4]([C:24]([O:26]C)=[O:25])[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:4]([C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: COC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 99.1 %

Procedure:
To a stirred solution of 0.22 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]-naphthalene-2-carboxylic acid, methyl ester in 4.5 ml of THF and 0.86 ml of methanol was added 1.7 ml of 1M sodium hydroxide. The mixture was stirred at ambient temperature for 11 h. The mixture was diluted with water, acidified to pH 1-2 with 1M HCl, extracted twice with ethyl acetate, dried (sodium sulphate), filtered and concentrated to provide 0.21 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]naphthalene-2-carboxylic acid as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C([N:10](CC)CC)C.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=C[C:16]=1Cl>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=[CH:16][C:2]=1[C:3]([NH2:10])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1cnc2ccccc2n1
Product: NC(=O)c1cnc2ccccc2n1
Reaction time: 1 h

Procedure:
To the lactone from method A (100 mg, 0.27 mmol) was added neat trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h and the trifluoroacetic acid removed in vacuo. The remaining residue was solvated in methylene chloride (10 mL) and triethylamine (0.15 mL, 1.07 mmol). Quinoxalyl chloride (58 mg, 0.3 mmol) was added as a solid and the mixture stirred for 18 h. The mixture was transferred to a separatory funnel and washed with citric acid (2×10 mL), NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4) and the solvents filtered. The filtrate was concentrated in vacuo and the resulting residue was chromatographed on silica gel (10 g) eluting with 2:1 hexanes:ethyl acetate to provide 99 mg of the quinoxaline amide. This material was solvated in MeOH and ammonia gas was bubbled in for 5 min. The resulting solution was stirred for 16 h and the solvent removed in vacuo. The remaining residue was recrystallized (methylene chloride/methanol/Hexanes) to provide the title compound (90 mg, 72%). 1H NMR (400 MHz, CD3OD): d 9.38 (1H, s), 8.21 (1H, dd, J=4.4, 2.5 Hz), 8.14 (1H, dd, J=4.4, 2.5 Hz), 7.93 (2H, m), 7.26 (2H, d, J=6.9 Hz), 7.17 (2H, t, J=7.1 Hz), 7.09 (1H, t, J=7.3 Hz), 4.30 (1H, m), 3.75 (1H, m), 3.03-2.98 (2H, m), 2.47 (1H, m), 1.77 (1H, m), 1.56 (2H, m), 1.4 (2H, m), 1.07 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8](I)=[CH:7][CH:6]=2.[CH3:18][S:19]([O-:21])=[O:20].[Na+].C(N)CN>CS(C)=O.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1nc2ccc(I)cc2nc1O
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: NCCN
Product: CCOC(=O)c1nc2ccc(S(C)(=O)=O)cc2nc1O
Temperature: 110 °C

Procedure:
A degassed mixture of ethyl 3-hydroxy-6-iodoquinoxaline-2-carboxylate (351 mg, 1.0 mmol), sodium methanesulfinate (132 mg, 1.3 mmol), copper(I) triflate benzene complex (25 mg, 5 mol %) and ethylenediamine (0.01 mL, 10 mol %) in anhydrous DMSO (1.0 mL) was heated at 110° C. in a sealed reaction vessel for 20 h. The cooled mixture was diluted with ethyl acetate (10 mL) and filtered through a plug of silica gel under reduced pressure, eluting with additional ethyl acetate (50 mL). The filtrate was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to provide ethyl 3-hydroxy-6-(methylsulfonyl)quinoxaline-2-carboxylate as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 11.61 (br S, 1H), 8.16 (d, J=8.9 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=9.9 Hz, 1H), 4.58 (q, J=6.7 Hz, 2H), 3.16 (s, 3H), 1.49 (t, J=6.7 Hz) ppm; ESI MS m/z 297 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=O)=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][C:18](=[O:23])[NH:19][CH2:20][CH2:21][NH2:22])([CH3:16])([CH3:15])[CH3:14].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH2:11][NH:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1cc(CC=O)ccc1F
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-5-(2-oxoethyl)benzonitrile (1.5 g, 9.2 mmol), tert-butyl(2-aminoethyl)carbamate (1.5 g, 9.2 mmol), NaCNBH3 (1.2 g, 18.4 mmol) and acetic acid (1.6 g, 27.6 mmol) in methanol (20 mL) was stirred at ambient temperature overnight. The solvents were evaporated, and the residue was basified with saturated NaHCO3 to pH=7-8, and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified with silica gel column chromatography to give tert-Butyl (2-{[2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1>>[CH2:1]([O:3][C:4]1[N:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1

Procedure:
The acid (149) was reacted with cyclopropylsulfonamide according to the procedure described in example 147, which gave the title compound, m/z=670 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=1[CH3:24]>ClCC(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl>[OH:16][C:17]1[C:18]([CH3:24])=[C:19]([OH:23])[CH:20]=[CH:21][C:22]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cccc1O
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(O)ccc(C(=O)c2ccccc2C(=O)O)c1O
Reaction time: 1 h

Procedure:
Aluminum chloride (21.4 g, 161 mmol) was added to a stirring suspension of phthalic anhydride (6 g, 40 mmol) in tetrachloroethane (200 mL) under nitrogen. 1,3-Dihydroxy-2-methylbenzene (5 g, 40 mmol) was added and the mixture quickly thickened. After the precipitates were broken up with a spatula the reaction continued for 1 hour. The solution was diluted with ethyl acetate (˜600 mL) and washed with 1M hydrochloric acid (2×200 mL). The product was extracted from the organic layer into a saturated solution of sodium bicarbonate in water (600 mL). The basic aqueous phase was acidified with 3M hydrochloric acid to a pH of 5. The product was extracted from the aqueous phase into ethyl acetate (400 mL), washed with brine (2×100 mL), dried over magnesium sulfate and concentrated to give a brownish solid. The solid was slurried in dichloromethane (20 mL) and filtered to give 2-(2,4-dihydroxy-3-methylbenzoyl)benzoic acid as an off white powder (4.6 g, 16.9 mmol, 42% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=O)[CH2:11][CH3:12]>C(Cl)Cl>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:14][S:13][CH2:10][CH2:11][CH3:12]
Reactant: CCCSCC(=O)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCSC=C(c1ncc[nH]1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by an addition of 2.10 g of 2-n-propylthio-2'-hydroxyacetophenone. The thus-obtained mixture was stirred at room temperature for 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The methylene chloride extract was then subjected to a post treatment in the same manner as in Example 5. The reaction product was separated by column chromatography, thereby obtaining 0.2 g of Isomer A (Compound 18) and 1.0 g of Isomer B (Compound 19) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-n-propylthioethylene as colorless crystals respectively.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23](I)[S:24][C:17]=12)[NH2:11].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>O.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.CCO>[F:7][C:8]1[CH:9]=[C:10]([NH2:11])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:24][C:17]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)sc23)c(F)c1
Temperature: 80 °C

Procedure:
A vigorously stirred mixture of cesium carbonate (190 mg, 0.583 mmol), 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 150 mg, 0.388 mmol), phenylboronic acid (59.2 mg, 0.486 mmol), toluene (4 mL) and EtOH (1 mL) was degassed under nitrogen for 10 minutes, and then Pd(PPh3)4 (22.4 mg, 0.0194 mmol) was added. The reaction mixture was heated at 80° C. for 18 hours, then cooled to room temperature and diluted with water (20 mL). The reaction mixture was extracted with EtOAc, and the organic layer was dried organic over sodium sulfate, filtered and concentrated. The residue was purified on a Biotage 40S (2:1 EtOAc/Hexane). The product was a light orange solid (75 mg, 53%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (d, J=5.5 Hz, 1H), 7.75 (m, 3H), 7.46 (t, J=7.2 Hz, 2H), 7.40 (m, 1H), 7.06 (t, J=8.8 Hz, 1H), 6.54 (m, 1H), 6.50 (m, 2H), 3.84 (br s, 2H). LRMS (ESI pos) m/e 337 (M+1).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15](=[O:16])[CH2:14][O:13][CH2:12][C@@H:11]1[C@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[CH2:20]([O:19][C@H:17]([CH3:18])[C@H:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:12][O:13][CH2:14][C:15]([OH:1])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COCC(=O)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A 2 N sodium hydroxide solution (250 mL) was added to a methanol (250 mL) solution of (R)-3-((R)-1-benzyloxyethyl)-5-oxomorpholine-4-carboxylic acid t-butyl ester (40 g), and stirring was continued for 3 hours at room temperature. The methanol was removed under a vacuum, and ether was added, and the aqueous layer was partitioned. The aqueous layer was washed with ether, and the pH was adjusted to approximately pH 4 with a 5% citric acid solution. The resultant was extracted twice with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (42.1 g) was obtained. The physical property values are as follows.
Reaction SMILES: [C:1]([O:6][CH3:7])(=O)[C@@H:2]([CH3:4])O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1[C:28](C)=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30].C1([SH:37])C=CC=CC=1>CC#N>[CH3:7][O:6][C:1](=[S:37])[C@H:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:30]=1)[CH3:4]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1cccc(C)n1
Reactant: Sc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=S)[C@@H](C)c1ccccc1
Yield: 40.8 %

Procedure:
(R)-Methyl lactate (0.553 g, 5.31 mol) was carried through the reaction sequence of Example 5 with triflic anhydride (1.03 ml, 6.11 mmol) and 2,6-lutidine (0.74 ml, 6.38 mmol) in 10 ml of CH3CN. Thiophenol (0.73 ml, 6.91 mmol) and TEA (1.93 ml, 13.8 mmol) were added and the workup described in Example 5 followed by purification by silica gel chromatography using 25 to 1 hexane to ethyl acetate as eluent gave (S)-methyl-2-phenylthiopropionate as a clear yellow oil (0.511 g, 2.60 mmol, 49%). [α]D =-165.4° (c=1.2, MeOH). 1H NMR δ7.43 (m, 2H), 7.29 (m, 3H), 3.78 (q, 1H, J =7.12 Hz), 3.65 (s, 3H)), 1.47 (d, 3H, J=7.12 Hz); 13C NMR δ172.87, 133.15, 133.01, 128.92, 128.00, 52.11, 45.07, 17.43.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C:15](=[O:28])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:9]2[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:12](=[O:13])[N:11]([CH2:14][C:15](=[O:28])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[N:10]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
119 mg (0.23 mmol) of tert.-butyl[3-(4-chlorophenyl)-5-oxo-1-(2-oxo-2-{[3-(trifluoromethyl)-benzyl]amino}ethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-acetate from Example 420 are dissolved in 9 ml of dichloromethane and treated with 3 ml of trifluoroacetic acid. This is stirred for 24 hrs at RT. The reaction mixture is then treated with 10 ml of toluene and concentrated under reduced pressure. A further 10 ml of toluene are added, and the mixture again evaporated. This procedure is repeated once again. The crude product is then freed of solvent residues under high vacuum. 110 mg (quantitative) of the target compound are thus obtained.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[CH3:23][C:24](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:25].C(OC(=O)C)(=O)C>C1COCC1>[C:24]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Oc1ccc(C=Cc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=Cc2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a 4-neck 1 L flask fitted with nechanical agitation, condenser, addition funnel, nitrogen bubbler, and temperature controller was added, in order, THF (450 g), triethylamine (I2.2 g, 0.12 mol), and 4-hydroxy stilbene (19.6 g, 0.10 mol). To this solution at room temperature was slowed added with stirring, via addition funnel, acetic anhdyride (12.3 g, 0.12 mol). When the addition of acetic anhydride was complete, the reaction solution was heated to 60° C. and held at this temperature with stirring for 2 hours. The reaction was cooled to room temperature then THF was removed in vacuo. The resulting residue was diluted with methylene chloride (500 mL) then extracted with 0.1 N HCl (1 ×500 mL), 30% saturated NaHCO3 (1 ×500 mL) and saturated NaCl (1 ×500 mL). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give the 4-acetoxy stilbene as a light tan needle-like crystalline powder (22.7 g, 95%).
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=1.Cl.[CH3:30][O:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][CH3:16])=[CH:25][N:24]=1)=[O:28]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1ccc(C(=O)N(C)OC)nc1
Reaction time: 19 h
Yield: 129.7 %

Procedure:
Add N-methylmorpholine (1.22 mL, 11.1 mmol) and isobutylchloroformate (1.44 mL, 11.1 mmol) to a solution of fusaric acid (2.0 g, 11.1 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (1.1 g, 11.1 mmol) and N-methylmorpholine (1.22 mL, 11.1 mmol). Stir the reaction for at 0° C. 15 minutes and then room temperature for 19 hours. Dilute the reaction with methylene chloride and wash with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the organic solution with sodium sulfate, filter, and concentrate in vacuo to provide the title compound 3.2 g (100%) as a clear yellow oil.