Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: CC(C)CCNc1nc2ccccc2cc1[N+](=O)[O-]

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99°-100° C. Analysis: Calculated: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 64.8; % H, 6.6; % N, 16.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([NH2:11])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10](/[N:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nn1ccc2ncc(Br)cc21
Reactant: O=Cc1ccccc1
Product: Brc1cnc2ccn(/N=C/c3ccccc3)c2c1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-amine (200 mg, 0.95 mmol) and benzaldehyde (120 mg, 1.2 eq) was heated to 60° C. for 10 min. Heptanes (2.0 ml) was added and the mixture was heated to reflux for 10 min. The product was purified by column chromatography (heptane:EtOAc=1:1) to yield a grey solid (130 mg, yield 46%).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].C([Li])CCC.F[C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:22]([CH2:23][N:24]([CH3:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][N:20]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:19]=2)=[CH:14][CH:13]=1>C1COCC1>[CH:3]([N:2]([CH3:1])[C:12]1[N:17]=[CH:16][C:15]([C:18]2[C:22]([CH2:23][N:24]([CH3:36])[CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][N:20]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:5])[CH3:4]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc(F)nc1
Reactant: CNC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C)c1ccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cn1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of methyl(propan-2-yl)amine (150 mg, 2.05 mmol, 4.00 equiv) in anhydrous THF (3 mL) maintained under nitrogen at −30° C. was added dropwise a 2.5M solution of n-butyllithium (1 mL, 5.00 equiv) in hexanes. After stirring for 30 min at −30° C., a solution of tert-butyl N-[2-([[3-(6-fluoropyridin-3-yl)-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]-N-methylcarbamate (200 mg, 0.45 mmol, 1.00 equiv) in THF (3 mL) was added. The resulting solution was stirred at room temperature for 4 h and then quenched by the addition of water (1 mL). The mixture was extracted with 3×10 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuum. The residue was purified on a silica gel column eluted with 0-3% of methanol in dichloromethane to give 0.18 g (80%) of (R/S) tert-butyl 2-(((3-(6-(isopropyl(methyl)amino)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl(methyl)carbamate as a yellow oil. LCMS (method A, ESI): RT=1.11 min, m/z=501.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]([CH:12]([CH3:14])[CH3:13])[C:21](=[O:22])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1C(=O)NC(=O)N(Cc2ccccc2)C1=O

Procedure:
To a suspension of 22.53 g (150 mmol) of benzylurea and 30.34 g (150 mmol) of diethyl isopropylmalonate in 77 ml of methanol, 36.6 ml (150 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 34.96 g (89.5%, white crystal) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28](OC)[O:29]C)[CH:20]=1)=[O:14].Cl>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28]=[O:29])[CH:20]=1)=[O:14]
Reactant: COC(OC)c1cc(OCCCS(=O)c2nccn2-c2ccccc2C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1-n1ccnc1S(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 8 h

Procedure:
3.3 Grams of 1-(2-methylphenyl)-2-[3-(3-dimethoxymethyl-4-nitrophenoxy)propylsulfinyl]imidazole was added to 100 ml of tetrahydrofuran and 10 ml of 4 N hydrochloric acid. The mixture was stirred overnight and extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, dried with magnesium sulfate, and concentrated to obtain 2.8 g of 1-(2-methylphenyl)-2-[3-(3-formyl-4-nitrophenoxy)propylsulfinyl]imidazole as a light yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])O.[Na+].CC(C)=O.O>[CH2:2]([O:9][C:10](=[O:11])[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:15]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCC1CCCN(CCc2ccc(F)cc2)C1)OCc1ccccc1
Yield: 54.8 %

Procedure:
A solution of 3-(benzyloxycarbonylaminomethyl)-piperidine hydrochloride (199 mg, 690 μmol) was dissolved in aqueous sodium hydrogen carbonate and the solution was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was combined with toluene-4-sulfonic acid 2-(4-fluorophenyl)ethyl ester (97 mg, 690 μmol) and potassium carbonate (190 mg, 1.38 mmol) in acetone (15 mL) and the mixture was heated at reflux for 17 hours. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate, to provide a white solid (140 mg, 66%). 1H NMR (300 MHz, CD3OD) δ7.30 (m, 5H), 7.22 (m, 2H), 6.99 (t, J=9 Hz, 2H), 5.07 (s, 2H), 3.1-2.7 (m, 5H), 2.55 (m, 2H), 2.00 (m, 1H), 1.8-1.5 (m, 4H), 0.98 (m, 1H). Mass spec (ES+) m/z 371.4 (M+H+, 100%).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]([CH2:22][CH2:23][CH3:24])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9])[CH2:5][CH3:6]>C1COCC1.CO.O.O.Cl>[CH2:22]([N:7]([CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
Lithium hydroxide monohydrate (0.0680 g, 1.6 mmol) is added to a mixture of methyl 3-[(dipropylamino)carbonyl]-5-ethylbenzoate (PREPARATION 20, 0.450 g, 1.6 mmol) in a mixture of THF/methanol/water (2/1/1, 8 mL). The mixture is stirred at 20-25 degrees C. for 3 hours. The mixture is then diluted with water (20 mL) and hydrochloric acid (1 N) is added to bring the pH to less than 3. The aqueous mixture is extracted with ethyl acetate. The organic phase is separated and washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound, MS (ESI+) for C16H23NO3 m/z (M+H)+=278.2.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[CH:20][N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[I:26]I>C1COCC1>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([I:26])[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OCc1ccccc1)c1nn2cncc2c(=O)[nH]1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of compound 11 (1.2 g, 4.4 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 3.5 ml) dropwise at −78° C. over 30 minutes and the resulting reaction mixture was stirred below −70° C. for another one hour. Then a solution of iodine (2.2 g, 8.8 mmol) in THF (20 mL) was added dropwise and the dark brown mixture was allowed to warm up to room temperature slowly over one hour. The reaction was quenched with saturated aqueous solution of Na2SO3 (60 mL), and then the mixture was extracted with EtOAc (200 mL×2). The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 2:1) to afford compound 12 (450 mg, 25% yield) as a yellow solid. LC-MS: m/z 397 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.94 (s, 1H), 7.36˜7.32 (m, 5H), 4.65˜4.55 (m, 3H), 1.60 (d, J=6.4 Hz, 3H).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccc(Cl)cc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 16.6 g. of 2,4-dichlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2,4-dichlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[S:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10][CH2:9]1>CN(C)C=O.C(=O)([O-])O.[Na+]>[S:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:4]4[N:5]=[CH:6][CH:7]=[N:3]4)[O:23][C:22]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:12][CH2:13]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cc(F)c(C3=CCSCC3)c(F)c2)C(=O)O1
Reactant: c1c[nH]nn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2nccn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
Sodium hydride (60% in oil, 148 mg, 3.7 mmol) was suspended in dry N,N-dimethylformamide (5 ml) and 1,2,3-triazole (0.26 g, 3.7 mmol) was added under nitrogen. It was stirred for 5 minutes at room temperature and methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (see Example 86; 1.0 g, 2.47 mmol) was added. It was heated to 75° C. for 3.5 hours, then cooled to room temperature, diluted with aqueous sodium hydrogencarbonate solution (5%, 100 ml) and extracted with ethylacetate (2×100 ml). The organic phase was washed with water (2×50 ml), brine (100 ml), dried over magnesium sulfate and the solvent was evaporated in vacuo. Chromatography on silica gel with a gradient of 10–50% ethylacetate in hexanes gave the title compound (0.65 g). MS (ESP): 379. (MH+) for C17H16F2N4O2S
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:15].Cl.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:39])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:30][CH2:29]1.[NH4+].[Cl-].Cl>C1COCC1.C(OCC)C>[ClH:17].[ClH:15].[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([C:25]([C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])([OH:39])[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][N:36]([CH3:37])[CH3:38])[CH2:30][CH2:29]2)=[CH:4][CH:5]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CN(C)CCC1CCN(CCC(=O)c2ccc(Cl)cc2Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCC1CCN(CCC(O)(c2ccc(-c3ccccc3)cc2)c2ccc(Cl)cc2Cl)CC1
Yield: 15.6 %

Procedure:
The Grignard reaction was started with magnesium (0.08 mol) and a few ml of a mixture of 4-bromobiphenyl (0.08 mol) in THF (150 ml). Then the rest of the mixture of 4-bromobiphenyl in THF was added dropwise. The resulting reaction mixture was stirred and refluxed for 1 hour and then cooled. 1-(2,4-dichlorophenyl)-3-[4-[2-(dimethylamino)ethyl]-1-piperidinyl]-1-propanone dihydrochloride (0.023 mol) dissolved in diethyl ether (50 ml) was added dropwise. The mixture was stirred and refluxed for 1 hour, then cooled, decomposed with NH4Cl 10% and stirred. A diluted aqueous HCl solution was added. The mixture was stirred for a while. The organic layer was separated, washed with H2O, dried and filtered. The filtrate was saturated with HCl/2-propanol. The precipitate was filtered off and crystallized from CH3OH and diethyl ether. The precipitate was filtered off and dried, yielding 1.05 g (7.8%) of (±)-α-[(1,1 ′-biphenyl)-4-yl]-a-(2,4-dichlorophenyl)-4-[2-(dimethylamino)ethyl]-1-piperidine-propanol dihydrochloride (comp. 34).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].CC(C)([O-])C.[K+].[Br:11][C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:4][CH:2]([CH3:3])[CH3:1])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1
Reactant: CC(C)O
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-propanol (1.997 mL) in dry tetrahydrofuran (THF) (50 mL) under nitrogen was added potassium tert-butoxide (3.49 g). The reaction mixture was heated to 50° C. for 10 min, then 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (D40) (6.3 g) was added. The resulting mixture was stirred at 50° C. overnight. After cooling the reaction, the solvent was removed in vacuo, the residue was diluted with ethyl acetate (100 mL), washed with water, the organic phase was dried over sodium sulphate, concentrated and the residue was purified by column chromatography to give 4-bromo-1-[(1-methylethyl)oxy]-2-(trifluoromethyl)benzene (D41) (5.21 g) as a clear oil. δH (CDCl3, 600 MHz): 1.36 (6H, d), 4.60 (1H, m), 6.88 (1H, d), 7.55 (1H, dd), 7.66 (1H, d).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=O)=O.CCCCCC.C(O)C>CC(C)=O>[N:1]1([CH:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]([O:18][CH3:17])=[O:28])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CS(=O)(=O)OCOC(=O)Cc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COC(=O)C(c1ccc(Cl)cc1)n1cncn1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A suspension of 3.2 g of 1,2,4-triazole and 8.3 g of K2CO3 in 300 ml of anhydrous acetone is refluxed over 1 hour. After cooling to 10° C., 14 g of methyl α-(methanesulphonyloxymethyl-4-chlorophenyl-acetate is added. The temperature is then allowed to spontaneously rise to room temperature, and the reaction mixture is stirred for one hour, is filtered over fritted glass and the filtrate is concentrated under vacuum, 13 g thus being obtained of raw solid product, which is suspended with 10 ml of 1:1 n-hexane+ethanol mixture.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:22]1[S:23][C:24]2[C:25]([N:30]=1)=[N:26][CH:27]=[CH:28][CH:29]=2>CN(C=O)C>[S:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:30]=[C:22]1[O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][O:6][C:7]=2[CH:12]=1
Reactant: Clc1nc2ncccc2s1
Reactant: OCCc1coc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-benzofuran-6-ol (0.42 g, 2.4 mmol) in DMF (24 mL) was added Cs2CO3 (0.77 g, 2.4 mmol) and 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (0.49 g, 2.4 mmol) and the reaction mixture was stirred (rt, 15 h) and then heated (50° C., 2 h). The reaction mixture was cooled (rt) and partitioned with EtOAc and brine (50 mL each). The aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-100%) to provide the title compound as an amber oil (0.42 g, 57%). MS (ESI): mass calcd. for C16H12N2O3S, 312.3; m/z not found. 1H NMR (500 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=8.0, 1.6, 1H), 7.61-7.57 (m, 3H), 7.30 (dd, J=8.4, 2.2, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.95 (q, J=6.1, 2H), 2.97-2.94 (m, 2H), 1.75 (t, J=5.5, 1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N+:10]([O-:13])=[CH:11][CH:12]=1)([O-])=O>CN(C)C=O>[CH3:1][S:2][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N+:10]([O-:13])=[CH:11][CH:12]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc[n+]([O-])c(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
Sodium thiomethoxide (1.06 g, 15.2 mmol) was added at 25° C. to 4-Nitro-[2,2′]bipyridinyl 1-oxide (3.0 g, 13.8 mmol) in dimethyl formamide (15 mL) and stirred for 2 hours at 50° C. The reaction mixture was added into ice (200 g) under vigorous stirring, the solid formed was filtered and washed with water (100 mL) and ether (100 mL), the filtrate was concentrated, diluted with water, extracted with dichloromethane (3×100 mL), dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (0-100% Ethyl acetate in Hexane) to afford 4-methylsulfanyl-[2,2′]bipyridinyl 1-oxide as a white solid (650.0 mg, 22%).
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N1CC[O:33]CC1)C.ClC(OCC(C)C)=O.N1CCCC(C(OCC)=O)C1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:33])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CCN1CCOCC1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCOC(=O)C1CCCNC1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 161.1 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (266 mg, 0.71 mmol, 1.0 eq), N-ethylmorpholine (135 uL, 1.06 mmol, 1.5 eq) in acetonitrile (5.0 mL) was treated with isobutyl chloroformate (101 uL, 0.78 mmol, 1.1 eq) followed by ethyl nipecotate (220 uL, 1.40 mmol, 2.0 eq). Purification by flash chromatography provided 150 mg (41%) of L-isoleucine, N-[1-[2-[N-(piperidine-3-carboxylic acid ethyl ester)]-2-oxoethyl]-L-prolyl] benzylamide as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[N+:22]([O-])([OH:24])=[O:23]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Reaction time: 0.01 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (5.64 g) in THF (10 ml) was added NH4NO3 (3 g) and concentrated HNO3 (3 ml). After 30 sec., the reaction mixture turned to dark red with reflux occurring. The reaction mixture was quenched with solid NaHCO3 and H2O, and extracted with AcOEt. The extract was dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent; Hexane→1:1, Hexane/AcOEt) to give N-(tert-butoxycarbonyl)-3-nitro-L-tyrosine methyl ester (3.42 g). The obtained compound was treated in a similar manner as described in R. Example 4 to give 3-Nitro-L-tyrosine methyl ester, hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([O:20]C)=[O:19])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)[CH3:3].[OH-].[Li+].[NH4+].[Cl-]>O1CCOCC1.O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)[CH3:3]
Reactant: COC(=O)c1cc(CN(C)C)cc(-c2ccc(C)cc2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-((dimethylamino)methyl)-4′-methylbiphenyl-3-carboxylate (90 mg, 0.32 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added lithium hydroxide (20 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 2 h, and then treated with aq. NH4Cl and extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography to afford the title compound. 1H NMR (CD3OD, 400 MHz): 8.29 (s, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 4.27 (s, 2H), 2.81 (s, 6H), 2.38 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]#[N:16])[C:11]([I:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:34])[NH:18][C:9]4[CH:10]=[C:11]([I:17])[C:12]([CH2:14][C:15]#[N:16])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC(C)(C)OC(=O)Nc1cc(CC#N)c(I)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1cc2c(cc1I)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-cyanomethyl-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamic acid tert.-butyl ester (Example M21) (520 mg, 0.89 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light pink solid (297 mg).