Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH2:14][OH:15])[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]3)=[CH:4][CH:3]=1.BrC1C=CC(C23C(COC)C2CN(C(OC(C)(C)C)=O)C3)=CC=1.[Cl:46][C:47]1[CH:48]=[C:49](O)[CH:50]=[CH:51][C:52]=1[Cl:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:46][C:47]1[CH:48]=[C:49]([CH:50]=[CH:51][C:52]=1[Cl:53])[O:15][CH2:14][CH:13]1[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH:12]1[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC2C(CO)C2(c2ccc(Br)cc2)C1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2C(COc3ccc(Cl)c(Cl)c3)C2(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl 1-(4-bromophenyl)-6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.31 mmol) obtained in Step 4 of Intermediate IX, in dry THF (10 mL), were sequentially added 3,4-dichlorophenol (428.0 mg, 2.62 mmol), triphenylphosphine (688.4 mg, 2.62 mmol) and diethyl azodicarboxylate (0.414 mL, 2.62 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at r.t. overnight. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with 1N NaOH (3 mL). The compound was extracted with ethylacetate. The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford the title compound (500 mg, 74%) as a viscous oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu][C:27]#[N:28]>CN1CCCC1=O>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([C:27]#[N:28])=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cnoc1-c1ccc(I)cc1)N1CCC(c2ccccc2)C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
A mixture of 4-[(3-phenylpyrrolidin-1-yl)carbonyl]-5-(4-iodophenyl)isoxazole (125 mg, 0.28 mmol) and copper(I) cyanide (101 mg, 1.13 mmol) in N-methylpyrrolidinone (5 mL) was stirred 150° C. for 2 h. Some material lost on work-up. The residue was purified on reversed phase HPLC to yield the title compound (5 mg). HRMS (ESI, pos. ion) m/z calcd for C21H17N3O2: 343.1321, found 343.1313.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-:18])(=O)=O)=CC=1.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>O1CCCC1>[CH3:23][C:22]1[C:21]([C:20]([O:25][CH3:26])=[O:24])=[CH:16][NH:17][CH:18]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]cc1C
Yield: 42 %

Procedure:
To a solution (100 mL) of potassium t-butoxide (23.0 g) in tetrahydrofuran was added dropwise a solution (50 mL) of p-toluenesulfonylmethyl isocyanide (25.0 g) and methyl crotonate (12.3 mL) in tetrahydrofuran with stirring under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (7.6 g, 42%) as an oil.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Yield: 29629.7 %

Procedure:
The title compound was prepared following the procedure described for Step-4 of Intermediate-1 using methyl 2-fluoro-4-(methylamino)-5-nitrobenzoate (12.00 g, 0.0562 mmol) and sodium methoxide (22.73 g, 0.4210 mmol), methanol to afford 4.00 g of the desired product. 1HNMR (DMSO-d6): δ 3.02 (d, J=4.5 Hz, 3H), 3.75 (s, 3H), 3.94 (s, 3H), 6.28 (s, 1H), 8.57 (s, 1H), 8.62 (bs, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(#N)C>[C:26]12([NH:36][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:7]=3)[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCCNC23CC4CC(CC(C4)C2)C3)cc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 43.7 %

Procedure:
Mix 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole (0.250 g, 0.739 mmol), potassium carbonate (0.205 g, 1.48 mmol), 1-adamantanamine (0.560 g, 3.70 mmol) and acetonitrile (4.0 mL) and heat at 75° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak (1 g) silica gel cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a step gradient from 40% ethyl acetate in dichloromethane to 100% ethyl acetate to 20% methanol in ethyl acetate to give the title compound (132 mg, 44% yield). Purity by LC/MS (APCI)=98%, [M+H]+=409.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@@H:26]([OH:39])[CH2:27][O:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH:43]([O:45][CH2:46][CH3:47])=[CH2:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])[CH2:27][O:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2R)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (43.0 g, 0.0774 mol) in methylene chloride (500.0 mL, 7.800 mol) was added ethyl vinyl ether (15.0 mL, 0.157 mol) followed by pyridinium p-toluenesulfonate (4.0 g, 0.016 mol). The mixture was stirred at rt for 3 g. After concentrated to dry, the residue was purified by silical gel column (eluting with 0 to 20% EtOAc in hexane) to provide the ether compound (38.1 g, 78.4%). MS (ESI): (M+H)+=628.1.
Reaction SMILES: [CH:1]1([C:4]([CH:12]2[CH2:14][CH2:13]2)([OH:11])[C:5]#[C:6][Si](C)(C)C)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH:1]1([C:4]([CH:12]2[CH2:14][CH2:13]2)([OH:11])[C:5]#[CH:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#CC(O)(C1CC1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC(O)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dicyclopropyl-3-(trimethylsilyl)prop-2-yn-1-ol (2.25 g, 10.6 mmol) in THF (100 mL), a 1M solution of tetrabutyl ammonium fluoride in THF (37.2 mL, 37.2 mmol) was added. The reaction was then stirred 1 hour at room temperature. The reaction mixture was then poured into an aqueous 5% NH4OAc solution and diluted with ethyl acetate. The isolated organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (ethyl acetate/hexanes, 20:80) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 4.17 (s, 1H), 2.75 (s, 1H), 1.25-1.15 (m, 2H), 0.65-0.55 (m, 2H), 0.55-0.30 (m, 6H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.ClCl>O>[C:1]([N:5]=[N:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC1(C#N)CCCCC1
Agent: ClCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N=NC1(C#N)CCCCC1
Reaction time: 0.25 h

Procedure:
To a rapidly stirred mixture of 39.0 g. (0.2 m. ) 1-tert.-butylhydrazo-1-cyanocyclohexane, 200 ml. methylene chloride and 100 ml. water was added 14.3 g. (0.2 m.) chlorine at such a rate that the reaction temperature did not exceed 5 ° C. The reaction was stirred an additional 15 mins. after the addition was complete. The methylene chloride layer was separated, washed twice with 50 ml. portions of saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated on a rotating evaporator to obtain 35.0 g. of liquid product that assayed 86.5% by an ultra violet spectrophotometric analysis. Distillation gavea product, b.p. 71° C./1.2 mm. of Hg that assayed 97.6% as 1-tert.-butylazo-1-cyanocyclohexane. The infrared spectrum was in accord with this structure.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CN1CCOCC1.Cl>[Cu].C(OCC)(=O)C.CN(C)C=O>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1I
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1ccc(Cl)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To N,N-dimethylformamide 0.9 mL solution of 2-iodo-4-phenoxybenzoic acid 45 mg were added 4-chloroaniline 27 mg, copper powder 5 mg and N-methylmorpholine 0.036 mL, and it was stirred under application of pressure at 180° C. for 15 minutes. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 65-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-chloroanilino)-4-phenoxybenzoic acid 9 mg of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.[C:16](=O)([O-])[O-].[K+].[K+].BrCC(OC)=O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2cc(Cl)ccc2n1CC(=O)O
Agent: COC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 48 h
Yield: 101.6 %

Procedure:
A mixture of (5-chloro-2-methylindol-1-yl)acetic acid (25 g), potassium carbonate (100 g) and N,N-dimethylformamide (220 mL) was treated dropwise with methyl bromoacetate (37 g), and the resulting mixture was stirred at 60° C. for 2 days. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and pentane (1:10 to 1:0 by volume) to afford the title compound as a white solid (27 g).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[NH2:9][C:6]1[C:5]([CH2:10][NH:18][C@@H:17]([CH3:19])[C:16]([O:15][CH2:13][CH3:14])=[O:20])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2.5 g, 7.3 mmol) in DMF (10 mL) is added L-alanine ethyl ester hydrochloride (1.67 g, 10.9 mmol) and triethylamine (5 mL, 36 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and the product extracted with ethyl acetate (4×20 mL), the combined organic layers are dried over sodium sulfate and concentrated. The crude reaction mixture is purified using preparative HPLC to give the final product as a white solid (530 mg, 25%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.47 (s, 1H), 6.20 (b, 1H), 4.15-4.07 (m, 2H), 3.49 (b, 2H), 3.27 (m, 1H), 3.34 (s, 2H), 1.17-1.24 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[S:5](=[O:18])(=[O:17])[N:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:18]=[S:5]1(=[O:17])[N:6]([C:8]2[C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12][C:13]=2[Cl:14])[CH2:7][C:2](=[O:1])[CH2:3][N:4]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CN1CC(O)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CN1CC(=O)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(4-hydroxy-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetate (400 mg, 0.96 mmol) in dichloromethane (20 mL), was added Dess-Martin periodinane (1.30 g, 3.07 mmol) and agitated for 5 hr at room temperature. The resultant was washed with ethyl acetate (50 mL) and the white solid formed thus was filtered through celite upon washing with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=7:3), giving the compound of interest (344 mg, 86%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.83 (s, 2H), 4.45 (s, 2H), 4.40 (s, 2H), 4.25 (s, 2H), 4.18-4.10 (q, 2H, J=7.1, 7.1, 7.1 Hz), 1.22-1.17 (t, 3H, J==7.1, 7.1 Hz).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH3:20])[C:17](=[O:21])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:21])[C@H:18]([CH3:20])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: C[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
2.93 g of sodium azide (45.1 mmol) was added to a solution of 9.90 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl ester obtained in Example (76d) (30.1 mmol) in N,N′-dimethylpropyleneurea (100 ml) at room temperature, and the mixture was stirred at 60° C. for three days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=5/1) to obtain 7.56 g of the title compound (yield: 91%).
Reaction SMILES: OC1C=CC=CC=1C1C=CC=CC=1C(O)(C)C.O1C=CC=CC1.C1C(O)=CC=C(C)C=1.[CH3:32][C:33]1[CH:48]=[CH:47][C:36]2[O:37]C(C)(C)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:35]=2[CH:34]=1>CC(C)=O>[OH:37][C:36]1[CH:47]=[CH:48][C:33]([CH3:32])=[CH:34][C:35]=1[C:40]1[CH:39]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1ccc2c(c1)-c1ccccc1C(C)(C)O2
Agent: C1=CCOC=C1
Agent: CC(C)(O)c1ccccc1-c1ccccc1O
Agent: Cc1ccc(O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(O)c(-c2ccccc2)c1

Procedure:
He reports in J. Chem. Soc., 1933, 1400, that to synthesize this compound, he first had to prepare the δ-lactone of 2'-hydroxy-2-biphenylenecarboxylic acid. His initial attempts to prepare this lactone by reaction of magnesium with o-bromophenyl-o-bromobenzoate or by diazotization of phenyl anthranilate failed. He was able to make it in 22 percent yield by reaction of phenol with anthranilic acid diazonium sulfate. The lactone was reacted with an excess of methyl magnesium iodide to give an almost quantitative yield of 2'-hydroxy-2-biphenylisopropanol, also known as o-(o-hydroxyphenyl)-α,α-dimethylbenzyl alcohol. This latter compound was dehydrated in about 90 percent yield to the desired pyran. He also made the 2-methyl homologue of the pyran by using p-cresol in place of phenol. M. Anchel and A. H. Blatt reported in J. Am. Chem. Soc., 63, 1948 (1941), that Cahn was mistaken when he reported that the 2,6,6-trimethyl-6H-dibenzo[b,d]-pyran, when heated with a mixture of hydrochloric and acetic acids, underwent opening of the pyran ring and loss of acetone to form 2-hydroxy-5-methylbiphenyl. The showed that instead the product was 1,9,9-trimethyl-4-fluorenol, the fluorenol isomer of the above trimethyldibenzopyran. They also showed that the fluorenol could be obtained directly from the 2'-hydroxy-5'-methyl-2-biphenylisopropanol by heating it with the mixture of hydrochloric and acetic acids in a sealed tube at 200°. The yield increased and then decreased with time being 35, 71, 68 and 51 percent after 8, 24, 31 and 48 hours, respectively. If the heating was stopped at the end of 30 minutes, an 80 percent yield of the pyran was obtained.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C(CCCCCCCCC[Si](OCC)(OCC)C)C([O-])=O)[CH:8]=[C:9](/[CH:12]=[N:13]/[C@@H:14]2CCCC[C@H:15]2/[N:20]=[CH:21]/[C:22]2[CH:27]=[C:26](C(C)(C)C)[CH:25]=[C:24](C(C)(C)C)[C:23]=2[OH:36])[C:10]=1[OH:11])(C)(C)C>C(Cl)Cl.CN(C=O)C>[CH:26]1[CH:25]=[CH:24][C:23](=[O:36])/[C:22](=[CH:21]\[NH:20][CH2:15][CH2:14][NH:13]/[CH:12]=[C:9]2\[C:10]([CH:5]=[CH:6][CH:7]=[CH:8]\2)=[O:11])/[CH:27]=1
Reactant: CCO[Si](C)(CCCCCCCCCC(C(=O)[O-])c1cc(/C=N/[C@@H]2CCCC[C@H]2/N=C/c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1)OCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL flask was placed amorphous silica gel (0.320 g; 200 m2/g, fully hydroxylated; previously activated in a 100° C. vacuum oven for 20 hrs). Monomeric salen ligand 5 (2.31 mL; as a 0.0411 M solution in 2:1 CH2Cl2/DMF, 0.095 mmol) was syringed on top of the silica. The sides of the flask were rinsed with 1 mL CH2Cl2 and the slurry was stirred under nitrogen at room temperature for 30 min. Vacuum was applied on the mixture to evaporate CH2Cl2 and most of the DMF, after which the flask was placed in a 100° C. oil bath under vacuum for overnight stirring under full vacuum. After 20 hrs, the contents of the flask were rinsed with CH2Cl2 and filtered through a glass frit, with sequential washes of CH2Cl2, MeOH and CH2Cl2. The solid was collected into a vial and dried in a vacuum oven at 50° C. for 48 hrs to give a bright yellow powder (0.345 g). The yellow filtrate was concentrated in vacuo to yield 0.034 g of a yellow oil, E; ligand concentration based on weight difference is calculated as 157 μmol/gsolid. Thermogravimetric analysis of a sample revealed a ligand concentration of 149 μmol/gsolid. Elem. anal. found (%): C, 7.1; N, 0.38. C/N wt % ratio calcd. for C44H68N2O6Si: 18.86. Found: 18.68.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:2]1.[ClH:15]>O1CCOCC1.C(OCC)C>[ClH:15].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C

Procedure:
Tert-butyl 2-morpholinoacetate (11 g, 54.7 mmol) was stirred with HCl, 4M in dioxane (54 mL), giving a white precipitate (a mild exotherm was observed) which slowly dissolved with stirring at room temperature. Ten minutes after complete dissolution, the mixture solidified. Then the mixture was warmed to 60° C. and the thick suspension was stirred vigorously overnight. The mixture was then cooled to room temperature, diluted with diethyl ether (60 mL) and filtered to collect the title compound (8 g, 80%) as a white solid. 1H NMR (CD3OD, 400 MHz): δ (ppm) 4.13 (s, 2H), 3.94 (brm, 4H), 3.41 (brm, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:45][CH3:46])[C:10]([C@@H:12]1[C@@H:17]2[CH2:18][CH2:19][N:14]([C@@H:15]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:16]2[NH:20][CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[O:30][CH3:31])[CH2:13]1)=O)[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:45]([N:9]([CH2:10][C@@H:12]1[CH2:13][N:14]2[CH2:19][CH2:18][C@H:17]1[C@@H:16]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[O:30][CH3:31])[C@H:15]2[CH:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:7][CH3:8])[CH3:46]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1[C@H](NCc1cc(OC)ccc1OC)[C@@H]2C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H]1CN2CC[C@H]1[C@@H](NCc1cc(OC)ccc1OC)[C@H]2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a suspension of lithium aluminum hydride (80 mg, 2.1 mmol) in THF (10 ml) was added 24 (220 mg, 0.41 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Na2SO4 /10H2O (320 mg, 1 mmol) was added then the mixture was stirred for 10 minutes. After removal of the precipitate, the solution was concentrated. The residue was dissolved in hexane (20 ml) then filtered and concentrated to give 25 (210 mg, 0.39 mmol, 95%) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=2)=[C:8]([C:10](OCC)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:10]([C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=1)=[O:11]
Reactant: CCOC(=O)c1nc(NC(C)=O)sc1Cc1cccc(S(C)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C=O)c(Cc2cccc(S(C)(=O)=O)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.4 %

Procedure:
Ethyl 2-(acetylamino)-5-[3-(methylsulfonyl)benzyl]-1,3-thiazole-4-carboxylate (54.7 mg) was suspended in THF (1 ml) under N2 atmosphere, and then lithium aluminium hydride (7.79 mg) was added portionwise to the suspension at 0° C. The reaction mixture was refluxed for 2.5 hours, and quenched with MeOH and 1N—HCl at 0° C. Anhydrous MgSO4 was added to the mixture, and stirred at r.t. for 1 hour. The suspension was filtered in vacuo. The filtrate was concentrated in vacuo. The residual oil (114.8 mg), CHCl3 (1 ml), CH3CN (1 ml) and Dess-Martin periodinane (88 mg) were combined at 0° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 1 hour, and diluted in CHCl3. The organic solution was washed with saturated NaHCO3, water and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give N-{4-formyl-5-[3-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (61.2 mg) as a yellow amorphous.