Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:15]
Reactant: OO
Reactant: Clc1ccccc1Cc1ccccn1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccccc1Cl
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 2-(o-chlorobenzyl)pyridine (32 g, 0.16 moles) and hydrogen peroxide (30% w/v, 10.7 g, 36.0 ml, 0.31 moles) in glacial acetic acid (100 ml) was heated at 75° C. for 17 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (30 g) the chloroform was removed to give 2-(o-chlorobenzyl)pyridine-N-oxide (34.4 g, 100%) as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2(O)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].CCN(S(F)(F)[F:30])CC.[NH4+].[Cl-]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2([F:30])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)c(O)c(F)c2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(F)c(O)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
In a plastic container, a solution of tert-butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-hydroxypiperidine-1-carboxylate D1f (0.4 g, 1.2 mmol) in dichloromethane (10 mL) is treated with DAST (0.31 mL, 2.4 mmol) at room temperature. The mixture is stirred for 30 min and treated with sat. aqueous NH4Cl (3 mL). The mixture is extracted with dichloromethane, washed with sat. aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to yield tert-butyl 4-(3,5-difluoro-4-hydroxyphenyl)-4-fluoropiperidine-1-carboxylate D1g as an oil. 1H-NMR (400 MHz, CDCl3) δ=7.01 (d, J=7.2 Hz, 2H), 4.03 (br. s, 2H), 3.19 (br. s, 2H), 1.88 td, J=13.3, 4.8 Hz, 2H), 1.66 (dq, J=14.1, 2.2 Hz, 2H), 1.47 (s, 9H); 19F-NMR (376 MHz, CDCl3) δ=−134.1 (2F), −161.9 (1F). LCMS calcd. for C16H21F3NO3+ ([M+H]+): 332.1, found: 331.8. The product is used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[O:27][CH3:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CO/C=C/c1cccc(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)c1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D102) (152 mg, 0.365 mmol) and sodium iodide (109 mg, 0.729 mmol) in Acetonitrile (10 mL) was added TMSCl (0.093 mL, 0.729 mmol) dropwise. The reaction mixture was stirred at room temperature overnight (16 h). The reaction was quenched with water (10 mL). Then EA (10 mL) was added to the reaction mixture. The organic phase was separated. The aqueous phase was extracted with EA (10 mL×2). The combined organic layers was dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography (EA/Hexane: 0 to 50%) to afford [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]acetaldehyde (D103) (87.6 mg). MS (ES): C20H19ClN2O3S requires 402.1. found 403.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O>[S:5]([CH2:4][CH2:3][CH2:2][O:1][S:12]([CH2:15][CH2:9][CH2:10][OH:11])(=[O:14])=[O:13])([OH:8])(=[O:7])=[O:6]
Reactant: O=S1(=O)CCCO1
Reactant: O=S(=O)(O)CCCO
Solvent: O
Product: O=S(=O)(O)CCCOS(=O)(=O)CCCO

Procedure:
1 mol of 3-hydroxy propane sulfonic acid is heated to 137° C. with 3 mol of water for 2 hours. Further treatment as described under (a) results in a crystallizing oil which has a water content of 8% and is also free from 1,3-propane sultone.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]#[CH:25])[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N+:27]=[N-:28].CN(C=O)C>>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]5[N:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[N:27]=[N:28][CH:25]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Solvent: CN(C)C=O
Product: COc1cc(OCc2cnnn2-c2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 110 °C
Yield: 13.9 %

Procedure:
In a 5 mL microwave vial, was added 2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Example 9A, 27 mgs, 0.076 mmol), azidobenzene (Example 9B, 30 mgs, 0.252 mmol), anhydrous DMF (2.5 mL, 32.3 mmol) and (Cp*RuCl)4 (12 mgs) under a nitrogen atmosphere. The vial was capped and heated at 110° C. for 20 min. in the microwave apparatus. The solvent was evaporated and the residue was purified by silica gel chromatography ISCO, concentrated and twice triturated with methanol (2×1 mL). To the solid was added acetonitrile (2 mL) and water (4 mL) and the mixture was freeze dried over the weekend to give the title material (5 mgs, 10.54 μmol, 14% yield). LC (Method F): 2.480 min. HRMS (ESI) calcd for C23H19N6O4S [M+H]+ m/z 475.1183. found 475.1234. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.35 (s, 1H), 8.12 (s, 1H), 7.66-7.73 (m, 2H), 7.53-7.63 (m, 3H), 6.84 (dd, J=2.0, 0.8 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 5.40 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9]Cl)[CH:4]=1.[CH3:11][O-:12].[Na+]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:12][CH3:11])[CH:4]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)ccn1
Temperature: 70 °C
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 4-chloro-2-chloromethylpyridine hydrochloride (0.43 g), sodium methoxide (1.11 g) and methanol (15 ml) was stirred at room temperature for 10 hours and at 70° C. for 7 hours. The reaction mixture was concentrated, and the residue was combined with water and methylene chloride, and the organic phase was separated. After washing with saturated aqueous sodium bicarbonate followed by drying and concentrating, a title compound (0.28 g) was obtained as a tan oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(O)(=O)C>C(O)(C)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[C:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
Following a procedure similar to that of Example 1C but using 64.9 g. of 2-(2-oxocyclohexyl)acetophenone and 37 g. of 4-methoxyaniline in 180 ml. glacial acetic acid there was obtained 80.9 g. of 1-(4-methoxyphenol)-2-phenol-4,5,6,7-tetrahydroindole; m.p. 132°-133°C. (isopropyl alcohol).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[C:29]([C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:2])=[CH:26][CH:27]=1)(=[O:30])[NH2:31]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: NC(=O)c1ccc(N)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(N)=O)cc3)(CC1)CC2
Yield: 19.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobenzamide (46.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-carbamoylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.2 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.[C:9]1([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:16]([OH:17])[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:21]([OH:22])[N:3]2[N:4]=1)[CH3:8]
Reactant: CCc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CCc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-ethyl-1,2,4-triazole and 15.00 g diethyl phenylmalonate in 18 mL N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The solution was diluted with 5N NaOH solution, the resulting mixture was stirred for 30 min. The aqueous layer was washed with diethylether, acidified at 0° C. with concentrated HCl until precipitation of the product was complete. The precipitate was collected by filtration to yield the product, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6]1[N:7]=[C:8]([NH:11]C(OCC(Cl)(Cl)Cl)=O)[S:9][CH:10]=1)[CH3:2]>C(O)=O.[Zn]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [Zn]
Solvent: O=CO
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Yield: 71.2 %

Procedure:
To a solution of 2.80 g of α-t-butyloxycarbonylamino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester in 60 ml of 90% formic acid is added 2.80 g of zinc dust under cooling and stirring. The mixture is stirred for 1 hour and zinc dust is filtered off. The filtrate is poured into water and the resultant solution is extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water, and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.26 g (yield, 71.2%) of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester as crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH2:25]Br.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH:14]([CH2:25][C:24]3[CH:27]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[N+:28]([O-:30])=[O:29])[C:15]([O:17][CH3:18])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCc1cc(-c2nc(C(Cc3cc(F)ccc3[N+](=O)[O-])C(=O)OC)cs2)ccn1
Temperature: -78 °C

Procedure:
Methyl 2-[2-(2-ethyl-4-pyridyl)-1,3-thiazole-4-yl]acetate (520 mg, 2.0 mmol) (Example 12(a)) was dissolved in toluene and the solution was concentrated by rotary evaporation. This procedure was repeated, and the dry residue was dissolved in 18 mL anhydrous THF (18 mL). The solution was cooled to −78° C., and LHMDS (2.1 mL, 1.0 M in THF, Aldrich) was added slowly via a syringe. To the resulting red solution, 5-fluoro-2-nitrobenzyl bromide (400 mg, 1.7 mmol) was added as a solid in one portion. The reaction was warmed slowly to RT over 4 h. Saturated aqueous NH4Cl (50 mL) was added, and the mixture was extracted with 100 mL of EtOAc. The organic layer was separated, washed with H2O (100 mL), dried (Na2SO4), and concentrated. Flash chromatography (gradient elution: 10-40% EtOAc in hexanes) of the crude material afforded the title compound as a clear oil. MS m/z: 416 (M+1). Calc'd for C20H18FN3O4S: 415.10.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:18])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(NC2CCCC2)c1Br
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 4.69 mmol) in acetonitrile (20 mL), cesium carbonate (3.0 g, 9.2 mmol) and methyl iodide (3.38 g, 23.4 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered and the residue washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford desired methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1.1 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:32][CH2:31][CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=CCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CCCN)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1ccc(CCCNCCCc2cccc(Cl)c2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester (from Preparation 5, Step C, 0.118 g, 0.5 mmol) and N,N-diisopropylethylamine (0.071 g, 0.55 mmol) in 10 mL MeOH was stirred at room temperature for 30 minutes and 3-(3-chloro-phenyl)-propionaldehyde (from Preparations 3, 0.093 g, 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0° C., NaBH4 (30.3 mg, 0.801 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with 1:1 NaHCO3:H2O and was washed with CH2Cl2. The CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (171 mg). MS 352 (M+1).
Reaction SMILES: [CH:1]12[CH2:8][C:7](=[O:9])[CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2]2.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[O:9]1[CH2:10][CH2:11][O:12][C:7]21[CH2:8][CH:1]1[CH:6]2[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OCCO
Reactant: O=C1CC2C=CCCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C1=CC2CC3(OCCO3)C2CC1

Procedure:
A mixture of 6.4 g bicyclo[4.2.0]oct-2-en-7-one (III), (Tetrahedron, 27, 615 (1971)), 18.62 g ethylene glycol, 100 ml benzene, and 25 mg p-toluenesulfonic acid is heated at reflux for 4 hr using a Dean-Stark trap to effect continuous removal of water. The cooled reaction mixture is poured onto 100 ml saturated sodium bicarbonate solution and the resulting mixture is extracted with three 75 ml portions of diethyl ether. The combined organic extract is washed with 100 ml saturated sodium chloride solution and is then dried over sodium sulfate. The solvent is removed under vacuum and the residue is distilled under vacuum to give 7.12 g of spiro[bicyclo[4.2.0]oct-2-ene-7,2'-[1.3]dioxolan] (IV).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]1=2.[C:24]([Mg]Br)#[CH:25]>>[CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[C:24]#[CH:25])[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]1=2
Reactant: C#C[Mg]Br
Reactant: Cc1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Product: C#CC(O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Yield: 98 %

Procedure:
In a similar manner to that of Example 1 f, by reacting 950 mg (3.1 mmol) of 5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 4.5 mL (4.5 mmol) of 1 N ethynylmagnesium bromide solution. A colorless oil is obtained (m=1 g; yield=98%).
Reaction SMILES: [CH:1]([S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=[O:5])=[O:4])=[CH2:2].[CH2:40]([NH2:42])[CH3:41]>CO>[CH2:40]([NH:42][CH2:2][CH2:1][S:3]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=[O:4])=[O:5])[CH3:41]
Reactant: CCN
Reactant: C=CS(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Solvent: CO
Product: CCNCCS(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
4-Ethenesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0734 g, 0.133 mmol) was dissolved in methanol (1.5 mL), and the solution was added with 70% aqueous ethylamine solution (1.5 mL), followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the residue was purified by thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-[2-(ethylamino)ethanesulfonyloxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0338 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]4=[O:31])=[CH:21][CH:20]=3)=[N:11][N:12]([CH3:18])[C:13]=2[C:14]([O:16]C)=[O:15])=[CH:5][CH:4]=1.O.[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]4=[O:31])=[CH:21][CH:20]=3)=[N:11][N:12]([CH3:18])[C:13]=2[C:14]([OH:16])=[O:15])=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(OCc2ccc(OC)cc2)c(-c2ccc(N3CCCCC3=O)cc2)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2c(-c3ccc(N4CCCCC4=O)cc3)nn(C)c2C(=O)O)cc1
Temperature: 120 °C

Procedure:
To a solution of methyl 4-(4-methoxybenzyloxy)-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazole-5-carboxylate T-21 (440 mg, 1.0 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (124 mg, 3.0 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 20 minutes. Solvent was removed under reduced pressure. Ethyl acetate and 0.1 N hydrochloric acid were added. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 4-(4-methoxybenzyloxy)-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazole-5-carboxylic acid T-22 (100 mg, 0.23 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-])=O)[C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>[C].[Pt].CO>[NH2:25][C:24]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(NC2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A mixture of methyl 3-[(1-benzylpiperidin-4-yl)amino]-4-nitrobenzoate (17.1 g, 46.3 mmol), 5% platinum carbon (5.13 g), tetrahydrofuran (115 mL) and methanol (115 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The m reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from diisopropyl ether/ethyl acetate to give the title compound (8.40 g, yield 53%) as pale-red crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Product: O=C(O)c1cc(-c2nc(-c3ccccn3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 79 %

Procedure:
2′-Nitro-4-(4-pyridin-2-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (200 mg, 79%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(bromoacetyl)pyridine hydrobromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J=4.9 Hz, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.26-8.30 (m, 2H), 8.15 (d, J=7.5 Hz, 2H), 8.00-8.05 (m, 1H), 7.76-7.81 (m, 1H), 7.62-7.68 (m, 1H), 7.41-7.49 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](O)(=[O:41])[C:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:29]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([OH:28])[C:26]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:41])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.17 g, 0.45 mmol) in DMF (1 mL) was added benzilic acid (0.23 g, 0.51 mmol), N-methylmorpholine to pH=8 (as measured on wetted E. Merck pH indicator strips), and BOP reagent (0.31 g, 0.70 mmol). After 1 hour of mixing at room temperature, HPLC analysis indicated complete consumption of the starting amine. The mixture was filtered and purified on a preparative HPLC. Pure fractions were pooled and lyophilized to yield 1-(2,2-diphenyl-2-hydroxyethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a solid (0.23 g, HPLC RT=3.75 min, method A; LC-MS m/z=578).