Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1.O.O.O.FC(F)(F)C(C(F)(F)F)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of 20.4 g (0.08 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 19.8 g (0.09 mole) of hexafluoroacetone trihydrate in 300 ml toluene was heated at reflux for 6 hours. Analysis by tlc indicated a small amount of starting material remained so another 1.0 g of hexafluoroacetone trihydrate was added and the mixture was refluxed another 0.5 hour. After stirring at room temperature overnight, the mixture was concentrated by rotary evaporation. The residue was purified by chromatography on 2 pounds of silica gel, eluting with toluene. The chromatographed product was decolorized with charcoal, then recrystallized from hexane to give 21.5 g (63%) of product, m.p. 112°-113°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1.[C:18](=[O:21])([O-])[OH:19].[Na+]>O1CCOCC1.O>[CH2:2]([O:19][C:18]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: NCc1ccccc1-c1ccccc1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1-c1ccccc1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 163.3 %

Procedure:
500 mg (2 mmol) of benzyl N-succinimidocarbonate dissolved in 2.5 ml of dioxane were added dropwise at 0° C. to a solution of 455 mg (2 mmol) of 2′-aminomethylbiphenyl-2-carboxylic acid (precursor 3) and 336 mg (4 mmol) of sodium hydrogencarbonate in 5 ml of dioxane and 5 ml of water. After stirring at RT for 4 h, the mixture was concentrated in vacuo, diluted with water, acidified and extracted with ethyl acetate. 590 mg of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:15][CH2:14]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:13]2[CH2:14][CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1OC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1OC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methyl 5-chloro-2-cyclopropoxybenzoate was dissolved in THF/H2O (1:1, 400 mL), then sodium hydroxide (16 g, 0.4 mol) was added. The mixture was heated to 60° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature, then the pH was adjusted to 4 using 4N aqueous HCl, resulting in precipitation of the product. The precipitate was collected by filtration and azeotroped with toluene to afford 19 g (96%) of 5-chloro-2-cyclopropoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ: 12.96 (br, 1H), 7.58 (m, 2H), 7.43 (q, 1H), 3.91 (m, 1H), 0.81 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]([O:13][C:14](ON=C(C1C=CC=CC=1)C#N)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([O:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: NCCCCCCO
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCCCO
Yield: 106.7 %

Procedure:
Four grams of 6-amino-1-hexanol (34.1 mmols) was dissolved in 30 ml of chloroform and ice-cooled. Seven grams of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) dissolved in 20 ml of chloroform was added, and the mixture was ice-cooled and reacted for 16 hours. Chloroform was evaporated, and the residue was separated and purified by silica gel column chromatography to obtain 6.59 g of the captioned compound. Yield: 89 %.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:17](OCC)=[O:18]>C(OCC)(=O)C>[CH:17]([NH:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:18]
Reactant: COC(=O)C(CN)c1cccc(OC)c1
Reactant: CCOC=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(CNC=O)c1cccc(OC)c1

Procedure:
The compound obtained in Step B (20.25 g; 0.08 mol), in the form of a base, is dissolved in 130 ml of ethyl formate (1.81 mol). The reaction mixture is heated at reflux for 6 hours and then evaporated under reduced pressure. The oil obtained is taken up in ethyl acetate. The organic phase is washed with basic water (NaHCO3), dried over magnesium sulphate, filtered and evaporated to yield the title product in the form of a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(#N)C>[OH:34][C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:23]2[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:21]([NH:1][C@@H:2]3[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[CH:22]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)O)CC3)c2)CC1
Temperature: 75 °C
Reaction time: 48 h
Yield: 143.2 %

Procedure:
To a suspension of cis-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265 mmol). The reaction was stirred at 75° C. After 48 hours, the reaction mixture was concentrated, diluted with water (10 mL), and extracted with DCM and EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide cis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid as an orange powder (0.76 g, 143% yield).
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:16][CH3:17])[C:5]1[CH:12]=[C:11]([S:13][CH3:14])[C:8]([C:9]#[N:10])=[C:7]([OH:15])[N:6]=1.I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:17][O:16][CH:4]([O:3][CH3:2])[C:5]1[CH:12]=[C:11]([S:13][CH3:14])[C:8]([C:9]#[N:10])=[C:7]([O:15][CH:19]([CH3:21])[CH3:20])[N:6]=1
Reactant: COC(OC)c1cc(SC)c(C#N)c(O)n1
Reactant: CC(C)I
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(SC)c(C#N)c(OC(C)C)n1
Temperature: 120 °C
Yield: 80 %

Procedure:
6-Dimethoxymethyl-2-hydroxy-4-methylsulfanyl-nicotinonitrile sodium salt synthesized as described by Mahata, P. K. et al. Tetrahedron 59, 2003, 2631-2639 (3.5 g, 13.3 mmol) in 40 mL of anhydrous DMF was heated at 120° C. while 2-iodopropane (1.6 mL, 16.0 mmol) was added dropwise. The resulting mixture was heated at 120° C. for another 30 min before it was cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, evaporated in vacuo. Purification on an Analogix MPLC system (SiO2 column) eluting with 10% EtOAc in hexanes yielded the titled compound as a light yellow solid upon standing (3.0 g, 80% yield).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20]C(O)=O>C1(C)C=CC=CC=1>[Cl:6][CH2:1][C:2](=[O:3])[CH2:20][C:14]1[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CCl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 ml of oxalyl chloride and 0.5 ml of dimethylformamide were added to a stirred suspension of 5.12 g of (2,6-dichlorophenyl)acetic acid in 120 ml of toluene. The mixture was stirred at room temperature for 2.5 hours and then evaporated to dryness. The residue was suspended in 40 ml of diethyl ether and the suspension was added gradually to 250 ml of a 0.25M solution of diazomethane in diethyl ether. The mixture was stirred at room temperature for 2 hours and then cooled to 0° C. Hydrogen chloride was then bubbled through the mixture for 10 minutes. 300 ml of water were added to the mixture and the phases were separated. The organic phase was washed with 200 ml of saturated sodium hydrogen carbonate solution and 300 ml of water, dried over anhydrous sodium sulphate and evaporated to give 6.04 g of 1-chloro-3-(2,6-dichlorophenyl)-2-propanone in form of a white solid. This solid was taken up in 21 ml of chloroform, 7.19 g of triphenylphosphine were added and the solution was stirred and heated under reflux for 6 hours. The mixture was cooled and poured into 200 ml of diethyl ether. The resulting precipitate was collected, washed with diethyl ether and dried to give 8.605 g of [3-(2,6-dichlorophenyl)-2-oxopropyl]triphenylphosphonium chloride in the form of a white solid. This solid was taken up in 1.5 l of warm water and the mixture was filtered. The filtrate was stirred while 12.5 ml of 5% sodium hydroxide solution were added. The mixture was extracted twice with 600 ml of diethyl ether each time and the combined extracts were washed with 1 l of water, dried over anhydrous sodium sulphate and evaporated. The residue was recrystallized from 150 ml of diethyl ether and yielded 4.286 g of [3-(2,6-dichlorophenyl)-2-oxopropylidene]triphenylphorphorane of melting point 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[C:13]1([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([CH:4]([NH:23][CH2:22][CH2:21][NH:20][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: COC(=O)C(Cl)c1ccccc1
Reactant: NCCNC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
A solution of 9.2 g of α-chlorophenylacetic acid methyl ester, dissolved in 10 ml of acetonitrile, is added dropwise in the course of 10 minutes, while stirring, to a mixture of 11.3 g of N-diphenylmethyl-ethylenediamine, 5.05 g of triethylamine and 70 ml of acetonitrile. The mixture is then heated under reflux for 18 hours. It is then concentrated to dryness by evaporation under reduced pressure, triturated with 100 ml of 10% sodium hydroxide solution and extracted twice by shaking with 100 ml of diethyl ether each time. The ether phases are combined, washed three times with 30 ml of saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated by evaporation. The residue obtained after concentration by evaporation is shaken with 10% (by weight) sodium hydroxide solution and diethyl ether in order to remove any excess triethylamine. The ether phases are further treated as indicated above. Finally, drying is effected at approximately 0.15 mbar. N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine is obtained which is converted into the diacetate for characterisation. For that purpose, 14.8 g of base are dissolved in 15 ml of diethyl ether and 15 ml of hexane, and glacial acetic acid is added dropwise while stirring and cooling. The precipitate is filtered with suction, recrystallised from approximately 360 ml of diethyl ether and 90 ml of hexane and dried under reduced pressure (under 0.2 mbar). The N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine acetate melts at 78°-81° C. Pure N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine can be freed from this by treatment with 10% sodium hydroxide solution, extraction by shaking with diethyl ether, drying over magnesium sulphate and evaporating off the solvent.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClC(c1cccnc1)c1cccnc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Reaction time: 8 h

Procedure:
To the solution of 2-bromo-3-hydroxypyridine (0.90 g, 5.18 mmol) and 3-[chloro(pyridin-3-yl)methyl]pyridine (2-1) (0.82 g, 3.99 mmol) in DMF (10 mL) at 0° C. was added Cs2CO3 (1.95 g, 5.98 mmol). The mixture was stirred overnight, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (2-2). LRMS m/z (M+H) Calcd: 343.2, found: 343.0.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CCO.O>[CH2:15]([S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH3:16]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of ethyl2-(4-(ethylsulfonyl)phenyl)acetate (10.0 g, 39 mmol) in EtOH (100 mL) was added a solution of NaOH (5.7 g, 142.5 mmol) in water (100 mL). The reaction mixture was stirred at rt for 16 h. EtOH was removed under reduced pressure. The aqueous layer was adjusted to pH=1 with 6 N aq. HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product 2-(4-(ethylsulfonyl)phenyl)acetic acid (7.3 g, 82%) as a white solid. LC-MS tR=0.573 min in 5-95AB—1.5 min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 228.8 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.88 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 3.77 (s, 2H), 3.12 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Br)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCC(=O)OCc1ccccc1

Procedure:
60.97 g (355.7 mmol) of α-bromopropionyl chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature is kept between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is recrystallized from diisopropyl ether.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[N:10](C(OC(C)(C)C)=O)[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.C(O[CH:23](N(C)C)[N:24](C)C)(C)(C)C.NO.Cl.Cl>O1CCOCC1>[CH:8]12[NH:10][CH:4]([CH2:5][O:6][CH2:7]1)[CH2:3][C:2]1[O:1][N:24]=[CH:23][C:9]2=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Product: c1noc2c1C1COCC(C2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol) and tert-butoxy-N,N,N′,N′-tetra-methyl-methanediamine (522 mg) in dioxane (10 mL) was stirred at 60° C. for 16 h. The solvent was removed in vacuo, and the residue was dissolved in EtOH (10 mL). To it NH2OH.HCl (462 mg, 3 mmol) was added. After stirring at room temperature for 2 h, 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a as an oil (yield 100%), which was used without further purification. MS: calc'd (MH+) 167, measured (MH+) 167.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:30]2[N:29]=[CH:28][CH:27]=[N:26][C:25]=2[C:24]([C:31](O)=[O:32])=[CH:23][CH:22]=1.FC1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:31]([C:24]2[C:25]3[N:26]=[CH:27][CH:28]=[N:29][C:30]=3[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[F:14])=[CH:22][CH:23]=2)=[O:32])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccccc2F)c2nccnc12
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: OB(O)c1ccccc1F
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3ccccc3F)c3nccnc23)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture overnight and using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid. The latter compound was prepared as described in Steps 1.2-1.7 but using 2-fluorophenylboronic acid in Step 1.4. Title compound: ESI-MS: 431.0 [M+H]+; tR=3.93 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 96:3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.CC1C=CC=C(C)[N+]=1[O-:25].C(OO)(=O)C>C(OCCCC)(=O)C.C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:25])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: CC(=O)OO
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 98.3 %

Procedure:
To a stirred solution of 3.32 g (15.5 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (98.8% pure by GC) in n-butyl acetate (15.5 mL) cooled in a wet-ice bath (ca. 2° C.) was added 1.91 g (15.5 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 1.77 g (23.2 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 30 min). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The reaction solution was transferred into a separatory funnel, was diluted with n-butyl acetate (70 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 15 mL). The butyl acetate layer was further washed with water (50 mL), and the combined water washes were back-extracted with n-butyl acetate (30 mL). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 65 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (50 mL) and the white solid thus obtained was dried in a vacuum oven 60 hours at 55° C. (25 mm Hg), giving 3.51 g (98.4%) of naproxen.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55](Cl)(=[O:57])=[O:56])=[C:50]([CH:59]([CH3:61])[CH3:60])[CH:49]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:57])=[C:50]([CH:59]([CH3:60])[CH3:61])[CH:49]=2)(=[O:40])=[O:41])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C(C)C)c2)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE 1.0 g, 2.71 mmol) and 2 mL of Et3N in 20 mL of CH2Cl2 was added 4-chlorosulfonyl-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester the (Intermediate 65, 1.6 g, 3.25 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.76 g, 79%) as a white foam.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]#[CH:24])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].C(N(CC)CC)C>O1CCCC1.[Cu]I>[CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@@H]1[C@H](O)[C@@H](C#Cc2ccccc2C(F)(F)F)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol (40 mg, 0.12 mmol) in tetrahydrofuran (4 mL) under nitrogen was added catalytic amounts (3 mg) of (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol (II) and copper (I) iodide, followed by 1-iodo-2-trifluoromethylbenzene (0.042 mL). Triethylamine (0.4 mL) was then added, and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with methanol:methylene chloride (6.5:1), to yield (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethynyl}-oxolane-3,4-diol, a compound of Formula I.