Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCOCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1ccc(CNCCCOCc2ccccc2)cc1

Procedure:
A solution of 6.0 g (22 mmol) of 4-bromomethyl-2'-cyanobiphenyl, 5.8 g (35 mmol) of 3-benzyloxypropylamine and 3.6 g of triethylamine in 50 ml of 1,4-dioxane is heated to boiling under reflux for 18 hours. After working up analogously to Example 23a), an oil is obtained which, after flash-chromatographic purification (ethanol:ethyl acetate: 1:4), gives the title compound (TLC system B7; Rf value 0.39).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1>C1COCC1>[CH2:1]=[C:12]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: C[Mg]Br
Reactant: O=C1c2ccccc2CCc2ccccc21
Solvent: C1CCOC1
Product: C=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Add methylmagnesium bromide (3M solution in Et2O, 48.0 mL, 144 mmol) dropwise to a cooled (0° C.) solution of dibenzosuberone (20.0 g, 96.03 mmol) in THF (140 mL) under N2 (exothermic). Let solution warm up to room temperature and continue stirring for 2 h. Cool solution to 0° C. and quench with saturated aqueous NH4Cl (exothermic, emits gas). Extract into ethyl acetate, dry organics (MgSO4) and concentrate in-vacuo. Dissolve residue in 4N HCl/dioxane (40 mL) and stir at room temperature overnight. Concentrate and dilute with H2O. Extract into ethyl acetate, dry organics (MgSO4) and concentrate to a yellow oil. Purify crude product by loading onto a 30 g plug of silica gel and eluting with hexanes until eluent shows no UV activity. Combine and concentrate hexane washes to afford 16.72 g (84%) of the title compound as a white solid, mp 65.1° C. HPLC shows 98% purity.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1)#[N:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C(O)(C)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:5]=1)#[N:2]
Reactant: N#CCc1cn(N)c2ccccc12
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: N#CCc1cn(Nc2ccncc2)c2ccccc12

Procedure:
The title compound was prepared from 3-cyanomethyl-1H-indol-1-amine and 4-chloropyridine hydrochloride in isopropanol at 90° C. for 6 hours in substantially the same manner as in Example 1, m.p. 80°-83° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:24])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=1[OH:21]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][O:21][C:20]2[C:19]([O:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=2[O:14][CH3:13])=[CH:7][CH:8]=1
Reactant: COc1cc(C)cc(OC)c1O
Reactant: CC(CCBr)c1ccc(F)cc1
Product: COc1cc(C)cc(OC)c1OCCC(C)c1ccc(F)cc1
Yield: 81.7 %

Procedure:
Example 4a (2.54 g, 11 mmol) and 3,5-dimethoxy-4-hydroxy-toluene (1.68 g, 10 mmol) were reacted as described under General Procedure A and the crude product was purified by flash chromatography (silica-gel, hexane/EtOAc 19:1) to provide the product as a clear oil (2.6 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 6.97-6.91 (m, 2H), 6.35 (s, 2H), 3.85-3.37 (m, 8H), 3.10-3.02 (m, 1H), 3.28 (s, 3H), 2.04-1.89 (m, 2H), 1.26 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](Cl)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([NH:27][CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([N:27]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[O:12])[CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)C1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-methanesulfonylpiperidine-4-carbonyl chloride in dichloromethane (10 ml) was added to a suspension of (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-ethylamine hydrochloride (1.21 grams, 5 mmole) in dichloromethane (10 ml). The mixture was cooled to 0° C., and triethylamine (1.7 ml, 12.2 mmol) was added dropwise. When the addition was complete, the mixture was warmed to room temperature and stirred for about 1 hour. Saturated ammonium chloride was added (20 ml) and the separated organic layer was extracted once with dichloromethane (20 ml). The combined organic layers were washed with 1N hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), dried over magnesium sulfate, and concentrated to give (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylcarbonyl)amine as an off white foam (2.21 g).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Br:16]NC(=O)CCC(N)=O>C1COCC1>[Br:16][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of 1-triisoproylsilyl-pyrrole (13.2 g, 0.059 mol) in 250 mL of THF at -78° C. was added 10.45 g (0.0587 mol) of N-bromosuccinamide (NBS), and the mixture was stirred at -78° C. for 3 h. The reaction mixture was warmed to room temperature and concentrated in vacuo, and the resulting residue in hexane was stirred overnight. The hexane solution was filtered through alumina eluting with hexane, the eluate was concentrated in vacuo, and the residue was distilled (b.p. 107°-108° C./0.2 mm) to afford 10.4 g (58.4%) of 3-bromo-1-triisopropylsilyl-pyrrole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide(0.050 g, 0.152 mmol), morpholine (0.027 mL, 0.305 mmol) and sodium triacetoxyborohydride (0.014 g, 0.228 mmol) in 1,2-dichloroethane (6 mL) was added acetic acid (0.013 mL, 0.228 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo to give a residue that was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(3-(morpholinomethyl)phenyl)oxazole-4-carboxamide (0.022 g, 0.056 mmol, 37%) as a white solid. 1H NMR (DMSO) δ 2.39 (4H, br m), 3.54 (2H, br m), 3.59 (4H, t), 7.38-7.45 (3H, m), 7.50 (1H, t), 7.71-7.78 (3H, m), 8.13-8.17 (2H, m). LCMS (2) Rt: 2.62 min; m/z (ES+) 400.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC(S(O[CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1.CCCCCC[C@@H](O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: CCCCCC[C@H](C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
p-Benzyloxyphenol (50 g), ethanol (150 ml) and 50% NaOH aqueous solution (25 g) were mixed with stirring, followed by pouring in the mixture, optically active 1-methylheptyl p-toluenesulfonate derived from S-(+)-2-octanol, heating the mixture under reflux for 4 hours, distilling off most of ethanol, extracting with toluene, washing with acid, alkali and water, drying, concentrating and purifying the concentrate according to column chromatography with activated alumina (150 g) to obtain oily p-benzyloxy-(1-methylheptyloxy)benzene (68.6 g), which was then subjected to hydrogenolysis with 5% Pd-C catalyst in ethanol, followed by removing the catalyst, concentrating the solution and subjecting the concentrate to vacuum distillation to obtain oily p-(1-methylheptyloxy)phenol (IIIa-2) (30.7 g) having a b.p. of 129°-130.5° C./0.5 Torr.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:12]1[CH2:13][CH:14]2[CH2:15][OH:16].C(N(CC)CC)C>C(Cl)Cl>[S:2]([OH:4])(=[O:10])(=[O:3])[CH3:1].[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:12]1[CH2:13][CH:14]2[CH2:15][OH:16]
Reactant: CS(=O)(=O)Cl
Agent: OCC1CC2C=CC=CC21OCCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulfonylchloride (1.13 g) is added dropwise to a stirred solution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene (1.83 g) and triethylamine (1.58 ml) in methylene chloride (32 ml) at 5° C. under nitrogen. The reaction mixture is stirred at RT for about 2 hours, washed with water, saturated NaCl, dried over Na2SO4, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Diethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)malonate (10 g) was dissolved in 100 mL ethanol and cooled to 0° C., NaOH solution (4 eq) was added slowly to the reaction mixture for about 15 min. The reaction mixture was heated gently up to 60° C. for 5 h. Progress of the reaction was monitored by TLC analysis. After complete conversion of starting material solvent was evaporated under reduced pressure, the residue dissolved in H2O, acidified with 6N HCl to pH-2. The solid material was collected via filtration, washed with water, dried under reduced pressure to yield 6.5 g (90%) of 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>O1CCOCC1.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:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:3][C:2]=2[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:11][CH2:12]1
Reactant: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(-c2nccs2)c1

Procedure:
A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole (0.090 g), and tetrakis(triphenylphosphine)palladium(0) (0.069 g) in dioxane (2 mL) was heated at 90° C. for 4 hours. After cooling, the mixture was loaded onto a silica gel column and eluting with 1:3 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:13]1[CH2:12][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:15][C:14]1=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CNC(=O)O2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(C2CN(C(C)=O)C(=O)O2)cc1OC
Yield: 73 %

Procedure:
8.9 mmol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone is combined with 10 ml. of acetic anhydride and 5 ml. of pyridine and heated for 5 hours to 100°. After concentrating the reaction mixture, it is recrystallized from ethyl acetate, thus obtaining 3-acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone in a 73% yield, m.p. 175°-182°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].C1(N=C=NC2CCCCC2)CCCCC1.[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.O>O1CCOCC1>[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[N:33]([C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=1)[CH2:32][CH2:31]2
Reactant: O=C(O)CNC(=O)c1cccc(Br)c1
Reactant: C1CN2CCC(CC2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(=O)N1CCN2CCC1CC2)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.77 g (3 mmol) of N-(3-bromobenzoyl)glycine dissolved in 30 ml of dioxane is placed in a 100 ml round-bottomed flask, 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 30 minutes, 0.38 g (3 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further two hours. 30 ml of water are added and the precipitate formed is filtered off, the filtrate is extracted with chloroform and the organic phase is then extracted with aqueous 0.1N hydrochloric acid solution. The aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:10][C:11]1[C:16]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OCc1ccccc1Cl
Reactant: Brc1ccccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1Br
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Add 85% manganese(IV) oxide (500 g, 5.75 mol) to a slurry of (2-bromopyridine)-(2-chlorophenyl)-methanol (392 g, 1.131 mol) in toluene (2.5 L), heat to a reflux and stir. After one hour cool to ambient temperature and filter through Celite®. Concentrate the solution under reduced pressure. Purify by recrystalization from MTBE: heptane (2:1) to give title compound 312.4 g (80%). 1H NMR (300 MHz, CDCl3), δ 8.50 (dd, 1H, J=1.83, 4.73), 7.78 (dd, 1H, J=1.83, 7.63), 7.60 (dd, 1H, J=1.53, 7.63), 7.53-7.34 (m, 4H); MS (IS) m/z 296.0 (M+1), 298.0 (M+1); m.p.=76.3° C.; Analysis for C12H7BrClNO: calcd: C, 48.60; H, 2.38; N, 4.72; found: C, 48.71; H, 2.48; N, 4.61; Rf=0.40 (hexane:ethyl acetate 2:1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH:15]([CH3:17])[CH3:14])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol) in methanol (15 mL) was added acetone (1.07 eq), sodium cyano borohydride (2.0 eq) and few drops of acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). 1H-NMR (CDCl3) δ: 1.05 (6H, d), 1.45 (9H, s), 1.60 (1H, m), 2.80–3.00 (2H, m), 3.20–3.70 (4H, m). ESI-MS m/z: 229 (M+1), UV retention time: 0.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH2:40]C)[C:6]([NH:8][C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7].[H-].[Na+].[CH3:50]N(C)C=O.CI>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:38][C:39]=1[CH3:40])[C:6]([N:8]([CH3:50])[C:9]1[C:13](/[CH:14]=[CH:15]/[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:12][N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)=[O:7]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2CC)c(OC)c1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Yield: 41 %

Procedure:
To a mixture of diethyl (E)-2-[3-({3-methoxy-4-[(5-ethyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (20.8 mg, yield 41%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[OH-].[K+].O.O.Br[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16]>CS(C)=O>[Br:16][C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16])[CH:3]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
Into a 250 mL round-bottom flask were placed 18.72 g (0.17 mol) of 1,3-dihydroxybenzene (resorcinol) and 75 mL of DMSO. The solution was purged with nitrogen gas for one hour followed by adding 223.62 mL of 1.52M (0.34 mol) KOH-water water solution dropwise to the solution, with the reaction flask resting in an ice-bath. The reaction mixture was then heated at 100° C. for one day followed by distilling off most of the water from the reaction solution. The rest of reaction solvents were evaporated slowly under vacuum. The salt was dried at 120° C. under the vacuum line for at least two days. Then 75 mL of dry DMSO and 109.2 g (0.42 mol) of 1,2-dibromo tetrafluoroethane was transferred to the flask via a closed system. The mixture was stirred at 35° C. for 3 days. The reaction mixture was filtered to remove the KBr, then the reaction mixture was washed with acetone in a 500 mL separatory funnel and the organic layer was diluted with 150 mL of methylene chloride. The combined organic layer was washed first with 10% of sodium bicarbonate water solution, and then with 0.01N HCl and finally with distilled water until neutral. The solution was dried over sodium sulfate overnight. After the removal of the sodium sulfate by filtration and the evaporation of the solvents, the crude product was purified by distillation under reduced pressure with an oil bath at a temperature of 100-110° C. A total of 64 g (0.136 mol) of 1,3-di(2-bromotetrafluoro ethoxy)benzene was obtained in 80.4% yield, which had a boiling point of 76-80° C. (at 10−2 torr). The amount of hydrogen by-product in the product was about 5.4%.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([OH:17])[C:16]2[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.S(OC)(OC)(=O)=O>C(O)C>[CH3:1][O:17][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]=[CH:13][CH2:12]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1CC=CC2
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: COc1cccc2c1CC=CC2
Temperature: 40 °C
Yield: 92.5 %

Procedure:
Add powdered potassium carbonate (193.1 g, 1.397 mol) to a solution of commercially available 5,8-dihydronaphthalen-1-ol [68.08 g, 90% potency based on 1H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0° C. with ice water and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperature between 5° C. and 10° C. Heat the reaction mixture to 40° C. until TLC shows the absence of starting material (about 2 hr). Filter off the solids by vacuum filtration and concentrate. Dilute the residual brown oil with diethyl ether (500 mL), wash with 10% aqueous ammonium hydroxide (500 mL), water (500 mL), brine (500 mL), dry (sodium sulfate) and concentrate to give the crude product as a brown oil (73 g). Purify the crude product by short path distillation under vacuum (bp 120-130° C./5 Torr) to give the title compound as a clear oil (69.0 g, 92.5% potency corrected) (contains some 1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity).