Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:30])[CH2:21][S@@:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:30])[CH2:21][S@@:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)C[S@](=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(C[S@](=O)c1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 40.5 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-{1-hydroxy-2-[(S)-phenylsulfinyl]ethyl}pyrrolidine (600 mg) was subjected to DMSO-DCC oxidation as in Example 1-D), followed by purification of the reaction product by medium pressure silica gel column chromatography (eluate; chloroform:methanol=99.5: 0.5) to give 242 mg of the title compound (See Table 3 ).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)=[CH:33][CH:32]=4)[CH:27]=3)[CH:23]=[N:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[C:24]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([CH2:37][NH:38][CH3:39])=[CH:35][CH:36]=4)[CH:27]=3)[CH:23]=[N:22][CH:21]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cncc(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3cncc(-c4ccc(S(=O)(=O)C(C)C)cc4)n3)on2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl N-[[4-[5-[6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-methyl-carbamate (85 mg, 0.1549 mmol) in DCM (5 mL) and the reaction was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The reaction mixture was passed through a 2 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (45.6 mg, 66% Yield). 1H NMR (400.0 MHz, DMSO) d H NMR (400.0 MHz, DMSO) δ 9.67 (s, 1H), 9.46 (s, 1H), 8.72 (d, 2H), 8.21 (d, 2H), 8.19 (s, 1H), 8.11 (d, 2H), 7.67 (d, 2H), 3.87 (s, 2H), 3.69 (sept, 1H), 2.43 (s, 3H) and 1.35 (d, 6H) ppm; MS (ES+) 449.2; LCMS Retention time: 1.09 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Cl:29][C:30]1[C:31]([CH3:58])=[C:32]([NH:38][C@H:39]([C:54]([OH:57])([CH3:56])[CH3:55])[C:40]([NH:42][NH:43][C:44](=[O:53])[C:45]2[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=2)=O)[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]>C(Cl)Cl.C1COCC1>[Cl:29][C:30]1[C:31]([CH3:58])=[C:32]([NH:38][C@@H:39]([C:40]2[O:53][C:44]([C:45]3[CH:46]=[CH:47][C:48]([C:51]#[N:52])=[CH:49][CH:50]=3)=[N:43][N:42]=2)[C:54]([OH:57])([CH3:55])[CH3:56])[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of triphenylphosphine (1.70 g, 6.48 mmol) in DCM (50 mL) was added I2 (1.63 g, 6.42 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (1.8 mL, 12.9 mmol) was added, followed by a solution of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-cyanobenzohydrazide (1.37 g, 3.22 mmol) in DCM (10 mL) and THF (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (10 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (1.18 g, 90%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.19 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.71 (d, J=9.0 Hz, 1H), 5.14 (d, J=9.0 Hz, 1H), 4.67 (s, 1H), 2.39 (s, 3H), 1.53 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N+:1]([C:9]1[CH:10]=[CH:11][C:6]([CH3:12])=[CH:7][CH:8]=1)([O-:4])=[O:2]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
reacting toluene with nitric acid having an acid concentration of between about 60 and about 75% by weight based upon the total amount of acid plus water, at a reaction temperature of between about 60° C. and about 75° C., and employing between about 3 and about 5 moles of nitric acid per mole of toluene to produce mononitrotoluene;
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14].[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:21][N:20]=1.O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:19]([NH:18][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[O:15])[NH:20][N:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)[nH]n1
Yield: 59.1 %

Procedure:
A solution of 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (0.400 g, 1.19 mmol) and 3-amino-5-t-butylpyrazole (0.165 g, 1.19 mmol) in DMF (1 mL) was stirred at 80° C. overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (230 mg, 59% yield) as a pink foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=6.8 Hz, 1H), 7.20-7.14 (m, 2H), 5.85 (brs, 1H), 1.34 (s, 9H), amine and urea protons not visible; MS (EI) m/z: 327.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH3:22])[CH:7]=[C:8]([C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])[CH:9]=1)=[O:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CCO>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:10]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[N:6]([CH3:22])[CH:7]=1)=[O:11]
Reactant: CCNCC
Reactant: Cn1cc(C(=O)c2ccc3ccccc3c2)cc1C(=O)CCl
Solvent: CCO
Product: CCN(CC)CC(=O)c1cc(C(=O)c2ccc3ccccc3c2)cn1C
Yield: 27.3 %

Procedure:
A solution of 2.5 g (0.008 mole) of 2-chloro-1-[4(2-naphthalenoyl)-1-methyl-1H-pyrrol-2-yl]ethanone and 2.5 mL (0.024 mole) of diethylamine was refluxed for 3 hr in 50 mL of EtOH. After cooling, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (90:10:1 CH2Cl2:MeOH:NH4OH). The resulting oil was treated with ethereal HCl in EtOH. The resulting gum was converted to the free base by partitioning between Et2O/NaHCO3. This was again chromatographed on silica gel (90:10:1 CH2Cl2:MeOH:NH4OH). The resulting oil was converted to the fumarate salt in 2-PrOH/EtOH. The solid was filtered to give 0.76 g (27%) of Compound 1. mp 130-132° C. CIMS m/z=349 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.4 (Ar, 1H); 8.15-8.0 (Ar, 4H); 7.85 (Ar, 1H); 7.7-7.6 (Ar, 2H); 7.2 (Ar, 1H); 6.6 (s, 2H); 4.0 (s, 3H); 3.7 (s, 2H); 2.6 (q, 4H); 1.0 (t, 6H). Anal calc'd for: C22H24N2O2.C4H4O40.33H2O: C, 66.40; H, 6.14; N, 5.96. Found: C, 66.38; H, 6.43; N, 5.73, KF water 1.22.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>C(OC)(C)(C)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1cccc(O)c1C(C)=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(OC)c2C(C)=O)cc1
Temperature: 35 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
1-(2-Hydroxy-6-methoxyphenyl)ethanone (1300 g, 7.82 mol) and dimethylformamide (10.4 L) are added to a 22 L flask and stirred to obtain a solution. Potassium carbonate (2700 g, 19.54 mol) is added in portions, then stirred for at least 30 min. Using an addition funnel, 4-methoxybenzyl chloride (14700 g, 9.39 mol) is added dropwise over 2.5 h to the mixture while maintaining the temperature <30° C. The reaction mixture is warmed to 35° C. and that temperature is held for 12 h. The reaction conversion is monitored by HPLC and deemed complete after 13 h at 35° C. The slurry is filtered and the resulting solids washed with dimethylformamide (1 L). Extractive work-up of the filtrate with ethyl acetate and water, followed by concentration, provided a waxy yellow solid. To the waxy yellow solid is added methyl t-butyl ether (2.6 L). The resulting slurry is agitated. The now free flowing slurry is filtered and washed with methyl t-butyl ether (1 L). The white solid is vacuum dried yielding 1539 grams (69%) of the title compound. mp 105-107° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:32][OH:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a suspended solution of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.2 g) in ethanol (20 ml) was added sodium borohydride (60.6 mg) under ice-cooling and stirred, and further stirred for an hour at 0° C. and another an hour at 3° C. The reaction mixture was added with water and the resultant mixture was adjusted to pH 6 to 7 with 2N hydrochloric acid, and the solvent was distilled off. The residue was extracted with ethyl acetate and washed with water and dried. After removal of the solvent, the resultant oil (1.3 g) was purified by column chromatography on silica gel with an eluent (a mixture of ten parts of benzene and one part of ethyl acetate by volume) to give an oil which was immediately crystallized. The resultant crystals were recrystallized from a mixture of diethyl ether and n-hexane and dissolved in benzene. The benzene solution was subjected to azeotropic process five times to give pure crystals of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 51° to 57° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-4-trifluoromethylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][C:12]([O:14]C)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]>CO.[OH-].[K+]>[N+:1]([CH2:4][C:5]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]
Reactant: COC(=O)CC1(C[N+](=O)[O-])CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1(C[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 795.2 %

Procedure:
A solution of 4.3 g (0.02 mol) of methyl 1-(nitromethyl)cyclohexyl-acetate in a mixture of 50 ml of methanol and 20 ml of 10% aqueous potassium hydroxide is stirred at room temperature for 24 h, then the methanol is distilled off in vacuo. The pH of the resulted aqueous solution is adjusted to 7 with 10% aqueous potassium dihydrogenphosphate solution. The solution is extracted three times with 30 ml of ethyl acetate, the combined organic layers are dried over sodium sulphate and concentrated to yield 32 g (80%) of the title compound as oil.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: Cl
Reactant: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/2 mL at 0° C. A solution of NaNO2 (0.185 g, 2.68 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.528 g) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To a 25 mL vial which contained a suspension of -(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (293 mg, 1 mmol) and dry Cs2CO3 (400 mg, 1.2 mmol) in anhydrous acetone (15 mL) was added 2-chloro-benzooxazole (154 mg, 1 mmol) at rt. The reaction mixture which resulted was allowed to stir at rt for 72 h. The mixture was poured onto 100 mL ice-water solution and this solution was allowed to stir at 0° C. for 1 h. The solid formed was filtered out, dried through air to provide the title product (300 mg, 75%); LCMS; 88% APCI+, Calcd: 410.50. Found m/z: 411.28 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.78-2.01 (m, 4H), 3.28-3.46 (m, 2H), 3.73-3.97 (m, 1H), 4.08-4.21 (m 2H), 6.93-7.02 (m, 2H), 7.18-7.33 (m, 4H), 7.41 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:12].Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:12]
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CC3CCCC3C2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in ACN was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 477.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50]O)=[O:45])([CH3:42])([CH3:41])[CH3:40].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][O:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COCOc1c(C(=O)OC)c(O)cc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1c(C(=O)OC)c(OCCCCNC(=O)OC(C)(C)C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a mixture of methyl 3-hydroxy-1-(methoxymethoxy)-2-naphthoate (41 mg, 0.16 mmol), triphenylphosphine (41 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-4-hydroxy-1-butylamine (33 mg, 0.17 mmol) in THF (0.5 mL) was added diethylazodicarboxylate (30 μL, 0.19 mmol). The mixture was stirred at ambient temperature for 30 minutes, concentrated under reduced pressure and purified on silica gel eluting with 30% ethyl acetate/hexanes to provide the titled compound (28 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](C)([C:14]([O-])=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.Cl>O>[CH3:14][CH:8]([C:9]([OH:11])=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
In a 200 ml round-bottom flask is placed 15.03 g (~43.7 mmol) of ethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate, 62 ml of glacial acetic acid, and 22 ml of 6 N aqueous hydrochloric acid. The mixture is refluxed under nitrogen for 24 hours. On cooling to room temperature, the solution is diluted with 250 ml of water and the mixture is extracted with 4×50 ml of methylene chloride. The combined extracts are washed with 2×100 ml of water and then with 8×40 ml (0.2 N) of aqueous potassium hydroxide solution. Extracts 1-4 are combined, acidified to pH <1 with concentrated hydrochloric acid, and the resulting solution is extracted with 3×50 ml of methylene chloride. The organic extracts are dried over sodium sulfate and concentrated in vacuo to give 7.13 g (38.8% overall) crude flurbiprofen. Extract 5 is backwashed with 3×15 ml methylene chloride, acidified with concentrated hydrochloric acid, and the resulting mixture is extracted with 3×20 ml methylene chloride to give 1.84 g (10.0%) crude flurbiprofen. Fractions 6-8 are combined and the pH is adjusted to ~9.0. After washing with 3×30 ml methylene chloride, the aqueous is acidified with concentrated hydrochloric acid and is then extracted with 3×50 ml of methylene chloride. Drying and concentration of the extracts gives 0.53 g (4.0%) crude flurbiprofen Ib.
Reaction SMILES: C([Mg]Br)(C)C.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([O-:10])=O.[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22](C)([CH3:26])[C:23](O)=O)[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1>O1CCCC1.CCOCC>[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22]([CH3:26])([CH3:23])[C:8](=[O:10])[CH2:7][C:6]([O:12][CH2:13][CH3:14])=[O:11])[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: CC(C)[Mg]Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Isopropyl magnesium bromide (0.7M solution in tetrahydrofuran) was added to a solution of mono-ethyl malonate(1.44 g) in tetrahydrofuran at 0° C. The mixture was stirred at 20° C. for 0.5 hour and at 40° C. for 0.5 hour. 2-(2,3-Dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionic acid (2 g) and carbonyldiimidazole(1.42 g) was stirred in tetrahydrofuran for 8 hours and the resulting imidazolide solution then added to the above mixture at 0° C., stirred at 20° C. for 3 hours and refluxed for 2 hours. The mixture was diluted (ether), washed (5% hydrochloric acid), dried (MgSO4),evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:2) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (1.4 g), NMR 1.25(3H, t), 1.47(6H, s), 1.94(3H, s), 3.60(2H, s), 4.15(2H, q), 5.26(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13](=[O:15])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2c(=O)o1
Temperature: 50 °C
Reaction time: 12 h
Yield: 175.5 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (8.0 g, 51.6 mmol) in THF (110 mL) was added triphosgene (7.6 g, 25.8 mmol). The resulting suspension was stirred at 50° C. for 12 h. The reaction mixture was cooled to RT and filtered to give 8.2 g of the title compound as a pink solid (87%). 1H NMR (DMSO-d6, 500 MHz) δ=6.95 (d, J=8.5 Hz, 1H), 7.02-7.05 (m, 1H), 7.69-7.72 (m, 1H), 11.85 (brs, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[NH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2>C(O)C.C(Cl)Cl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: NC1c2ccccc2-c2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCNC1c2ccccc2-c2ccccc21
Reaction time: 36 h

Procedure:
1.0 ml of ethyl acrylate was added to a solution of 9-aminofluorene (1.24 g) in ethanol (20 ml). The resultant mixture was stirred at 80° C. for 5 hours and, then, at room temperature for 36 hours. The residue obtained by condensing the reaction mixture was dissolved in methylene chloride and, then, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: methylene chloride-ether) to give 1.25 g of N-(9-fluorenyl)-β-alanine ethyl ester.