Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[OH-].[K+].Br[CH2:20][CH3:21]>CS(C)=O>[CH2:20]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[CH:11]=[C:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:21]
Reactant: CCOC(=O)c1cc2cc(OC)cnc2[nH]1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(OC)cnc2n1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (150 mg, 0.68 mmol available, for example, from Shanghai Haoyuan Chemexpress Co., Ltd) in DMSO (4 ml) was added powdered potassium hydroxide (115 mg, 2.04 mmol) followed by bromoethane (0.071 ml, 0.95 mmol). The mixture was stirred at rt for 2 hr then further bromoethane (0.020 ml) was added and the mixture stirred for a further 18 hr. The reaction was quenched by the addition of water then partitioned between water and diethyl ether. The organic phase was washed with water then passed through a hydrophobic frit and finally concentrated under reduced pressure to give the product as an orange/brown oil. The crude material was purified with column chromatography (eluted with DCM and ethyl acetate from 0 to 10%) to give the title compound as clear oil (60 mg, 36%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:25][NH:24][C:23]=1[NH2:34]>ClCCCl>[CH3:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:25][NH:24][C:23]=1[NH:34][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: Cc1ccccc1-c1n[nH]c(N)c1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1n[nH]c(NC(=O)CCCN2CCCC2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-pyrrolidin-1-yl-butyric acid (118.0 mg, 0.8 mmol, 1.5 eq) in 1,2-dichloroethane (3 mL), N,N′-carbonyldiimidazole (113.0 mg, 0.7 mmol, 1.4 eq) was added and the mixture was stirred at room temperature for 1 hour, then N,N-diisopropyl ethyl amine (87 μL, 0.5 mmol, 1.0 eq) was added and the mixture was stirred at room temperature for further 1 hour until complete dissolution of the suspension. 4-Methyl-5-o-tolyl-2H-pyrazol-3-ylamine (93.5 mg, 0.5 mmol, 1.0 eq) was added and the reaction was stirred for 18 hours, then at 50° C. for 1 day, until the conversion of the less stable ring nitrogen-acylated isomer to the title compound was observed (as monitored by LC-MS). The solvent was removed under reduced pressure, the crude was purified by SiO2 column to give 44.0 mg of the title compound (yield: 27%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]1[N:7]2[N:12]=[CH:13][CH:14]=1.NC1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.[CH2:39](O)[CH3:40]>>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)=[C:10]([NH:11][C:2]2[CH:40]=[CH:39][N:9]=[C:8]3[C:3]=2[CH:4]=[N:5][C:6]2[N:7]3[N:12]=[CH:13][CH:14]=2)[CH:21]=1
Reactant: Clc1ncnc2c1cnc1ccnn12
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Reactant: CCO
Product: Oc1ccc(Sc2ccc(OCc3cccc(F)c3)cc2Nc2ccnc3c2cnc2ccnn23)cc1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
The product from Example 1b (82 mg, 0.40 mmol) was reacted with 4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (148 mg, 0.40 mmol) in 5 mL of ethanol at 70° C. for 24 hours. After cooling to room temperature the solvent was removed under vacuum and the product was purified by HPLC with ammonium acetate to give the title compound as a pale yellow solid (18 mg, 8.5%). 1H NMR (DMSO-d6) δ ppm: 5.15 (brs, 2H) 6.60 (d, J=8.86 Hz, 2H), 6.95 (d, J=2.75 Hz, 1H), 7.01 (dd, J=2.96 Hz, 2.75 Hz, 1H), 7.12 (d, J=8.46 Hz, 2 h), 7.16-7.20 (m, 3H), 7.30 (m, 2H), 8.31 (d, J=2.32 Hz, 1H), 8.63 (brs, 1H), 9.40 (s, 1H) 10.51 (br s, 1H); (ESI+) m/z 511 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16](N)[CH2:17][NH2:18].[S]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]1[NH:18][CH2:17][CH2:16][N:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CC(c1ccccc1)c1ccccn1
Reactant: NCCN
Agent: [S]
Product: c1ccc(C(C2=NCCN2)c2ccccn2)cc1
Temperature: 125 °C

Procedure:
Under a nitrogen atmosphere, carefully reflux (bath temperature of 125° C) a mixture containing 19.4 g. of 2-pyridylbenzyl cyanide, 6.6 g. of ethylene diamine and 0.2 g. of sulphur for 5 hrs. Cool the reaction mixture and under a nitrogen atmosphere dissolve the residue in 300 ml. of benzene, and water wash, dry (over anhydrous potassium carbonate) and filter the benzene solution. Concentrate the filtrate to a small volume whereupon the product crystallizes. Filter the crystals to yield 2-[α-(2-pyridyl) benzyl]-imidazoline, m.p. 134°-136° C. The maleate salt, m.p. 132°-135°C, is prepared from maleic acid and is crystallized from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](=[O:8])[O:6][CH:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:20](=[CH2:22])=[N-:21]>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)C>[N+:20](=[CH:22][C:11](=[O:13])[CH2:10][CH2:9][CH:5]1[O:6][C:7](=[O:8])[C:3]([O:2][CH3:1])=[C:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N-:21]
Reactant: COC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC1=C(c2ccccc2)C(CCC(=O)C=[N+]=[N-])OC1=O
Reaction time: 1 h

Procedure:
A solution of 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (500 mg) in thionyl chloride (2 ml) was heated at 70° C. with stirring for 1 hour. After cooling, the solvent was removed under the reduced pressure to give a residue which was taken up in methylene chloride. To this solution was added dropwise a solution of diazomethane in diethyl ether. The solvent was removed under the reduced pressure to give 5-(4-diazo-3-oxobutyl)-3-methoxy-4-phenyl-2(5H)furanone (465 mg) which was recrystallized from diisopropyl ether.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:9][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7]1)=[O:5].[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38](O)=[O:39])[N:33]=[N:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.O>[CH2:18]([O:17][C:8]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:38](=[O:39])[CH2:37][CH2:36][C:34]2[N:33]=[N:32][NH:31][CH:35]=2)[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:9]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]nn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
146 mg (0.34 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride in 2 ml of dimethylformamide are added to a solution of 47 mg (0.34 mmol) of 3-(1H[1,2,3]triazol-4-yl)propanoic acid, 119 mg (0.37 mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 ethyl acetate/heptane). 78.6 mg of N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 45%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Cl:20])C(=O)C1.CCOC(C)=O>CN(C=O)C.CCCCCC>[Cl:20][C:3]1[C:2]([OH:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cncc(O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c(O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl 5-hydroxynicotinate (20 g, 0.119 mol, in DMF (200.0 mL) was added NCS (19.18 g, 0.143 mol, Aldrich). The reaction mixture was stirred for 2 h at 80° C. After completion of the reaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 solution (50 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, and purified by column chromatography, silica gel (100-200 mesh), using 10-15% EtOAc in petroleum ether as the eluent to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ: 8.61 (d, J=2.1 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 5.94 (br. s., 1H), 4.53 (q, J=6.9 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). MS (ESI, positive ion) m/z: 202.1 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[OH:39]>>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:6]([N:8]3[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]3[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)=[O:18])=[O:7])=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)cc2)N(C(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and 4-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=543.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[N:2]1C(OCC1C=CC=CC=1)=O.[H][H].Cl.CCOCC>CO.[Pd]>[NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCNN1
Reaction time: 0.08 h

Procedure:
3-(1,1-Dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (5.30 g, 12.03 mmol) was dissolved in methanol (100 mL) and 10% Pd/C (degussa type) (1.06 g, 0.996 mmol) was added. The mixture was stirred under a balloon of hydrogen for 60 min. LCMS showed clean deprotection. HCl in ether (6.02 mL, 12.03 mmol) was added, and the mixture was stirred 5 min. The catalyst was filtered off and the filtrate was evaporated, yielding 1,1-dimethylethyl 3-pyrazolidinecarboxylate.HCl (2.45 g, 11.74 mmol, 98% yield) as an orange solid.
Reaction SMILES: CN(C)CCN.[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:10][CH:9]=1.C(O)(=O)C.[C:30]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])(=O)[CH3:31]>CCO>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])=[C:33]([C:30](=[N:15][O:14][CH2:13][C:11]2[S:12][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH3:31])[CH:38]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(Cl)s1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NOCc1ccc(Cl)s1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
N,N-Dimethylethylenediamine (178 μL, 1.54 mmol) was added to a solution of N-(5-chlorothiophen-2-ylmethoxy)phthalimide (220 mg, 0.75 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (1 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (211 mg, 0.70 mmol) in EtOH (2 mL), and the mixture stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-{4-chloro-2-[1-(5-chlorothiophen-2-ylmethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 194 (280 mg, 90%), as white crystals. 1H n.m.r. (400 MHz, CDCl3) δ 11.37, br s, 1H; 7.63, d, J=8.8 Hz, 1H; 7.48, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 6.94, d, J=3.8 Hz; 6.81, d, J=3.8 Hz; 5.24, s, 2H; 2.33, s, 3H. HRMS (M+) 445.9540.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1)(=[O:8])=[O:7].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](C=O)=[N:33]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:11][N:12]([CH2:14][C:34]2[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:32][N:33]=2)[CH2:13]1)(=[O:7])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC(CS(=O)(=O)c2nccs2)C1
Reactant: O=Cc1nsc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CC1CN(Cc2nsc3ccccc23)C1)c1nccs1
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
tert-Butyl 3-[(1,3-thiazol-2-ylsulfonyl)methyl]azetidine-1-carboxylate (51 mg, 0.16 mmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 30 min. then concentrated in vacuo. The residual oil was taken up in MeOH (2 mL), then NaCNBH3 (16.2 mg, 0.26 mmol) and 1,2-benzisothiazole-3-carbaldehyde (28.6 mg, 0.18 mmol) [prepared by the method of T. Hasegawa, Y. Akiyama, T. Imai, E. Sato, Y. Yamamoto, J. Tanaka, H. Nagaso, K. Fuji, K. Murase, M. Shiiyama, WO 98/08816] were added. The mixture was stirred overnight then partitioned between 0.5 N NaOH (20 mL) and EtOAc (20 mL). The aqueous phase was washed with EtOAc (20 mL) and the organic layers were combined, washed with saturated brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, on silica gel, eluting with 50–60% EtOAc in DCM to give the title compound as a colourless oil (19 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 2.96–3.06 (1H, m), 3.12 (2H, m), 3.57 (2H, t, J=7.6 Hz), 3.72 (2H, d, J=7.3 Hz), 4.04 (2H, s), 7.41–7.45 (1H, m), 7.50–7.54 (1H, m), 7.74 (1H, d, J=3.1 Hz), 7.91 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=3.0 Hz), 8.10 (1H, d, J=8.1 Hz). m/z (ES+) 366 (M+H)+.
Reaction SMILES: C(OC(=O)CC1(C(N[CH2:19][CH:20]([CH2:28][C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:21]([O:23]C(C)(C)C)=[O:22])=O)CCCC1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>C(O)(C(F)(F)F)=O.CCOC(C)=O.[Pd]>[Cl:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([Cl:36])[CH:32]=1)[CH2:28][CH:20]([CH3:19])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)OCc2ccccc2)CCCC1)Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(Cc1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 2 h
Yield: 113.1 %

Procedure:
To a solution of tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-2-(3,5-dichlorobenzyl)propanoate (130 mg, 0.237 mmol) in TFA (1.5 ml), pentamethylbenzene (351 mg, 2.370 mmol) was added at room temperature. After stirred for 2 hr, the reaction mixture was concentrated under reduced pressure. The obtained crude material was hydrogenated under hydrogen atmosphere (1 atm) with Pd/C in EtOAc for 0.5 hr at room temperature. The reaction mixture was filtered, and the filtered cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire, H2O (0.1% TFA)/CH3CN) to give 341-(carboxymethyl)cyclopentanecarboxamido)-2-(3,5-dichlorobenzyl)propanoic acid (62.5 mg); Retention time=0.71 minutes (condition B); MS (m+1)=402.0; 1H NMR (400 MHz, DMSO-6, mixture of rotamers) δ ppm 1.47-1.58 (m, 6H) 1.95-2.05 (m, 2H) 2.54-2.63 (m, 2H) 2.68-2.85 (m, 3H) 3.13-3.29 (m, 2H) 7.24 (d, J=1.8 Hz, 2H) 7.42-7.43 (m, 1H) 7.60-7.63 (m, 1H); HRMS (ES+) m/z for C18H22Cl2NO5 [M+H]+ calcd 402.0875. found 402.0854
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH:17]=[CH:16][N:15]=1)[C:21]([OH:23])=[O:22]
Reactant: Clc1cccnc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of diisopropylamine (7.0 mL, 50 mmol) in anhydrous THF (100 mL) at −25° C. was added a 1.6M solution of nBuLi in hexanes (31 mL, 50 mmol) dropwise under an inert atmosphere. The reaction mixture was then cooled to −78° C. and 2,3-dichloropyridine was added. The reaction mixture was stirred at −78° C. for 3 hours, then poured onto solid carbon dioxide and aged for 18 hours at room temperature. The mixture was diluted with water (100 mL) and washed with diethyl ether (3×40 mL) then cooled to 0° C., acidified with concentrated HCl (ca. 5 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (7.7 g, 80%). 1H NMR (d6-DMSO, 400MHz) 8.49 (d, J=5.0 Hz, 1H), 7.72 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N+:12]([O-:25])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide (0.3 g, 0.00096 mole), glacial acetic acid (2.5 ml), and m-chloroperbenzoic acid (0.66 g, 0.00384 mole) was heated at 60° C. for a total of 4 hrs. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfite. The aqueous solution was evaporated to dryness and the residue was dissolved in methylene chloride. The methylene chloride was extracted with a minimum of saturated sodium bicarbonate. The methylene chloride was dried and evaporated to a residue which crystallized upon standing. The solid was recrystallized from tetrahydofuran-hexanes with refrigeration overnight. The solid was collected by filtration and dried under high vacuum overnight to give 0.28 g (88%) of the title compound mp. 200°-201.5° C.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].OS(O)(=O)=O>O.C(O)C>[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]([OH:10])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1ccccc1OC(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CC(O)c1ccccc1OC(F)F
Reaction time: 0.33 h

Procedure:
7.2 g of potassium cyanide were dissolved in 30 ml of water and 6 ml of ethanol, while cooling. 16 g of 2-difluoromethoxybenzaldehyde were then added at 0°-5° C., while cooling. After subsequently stirring the mixture between 0° and 10° C. for 20 minutes, a mixture of 7 ml of concentrated H2SO4 and 18 ml of water was added dropwise. The mixture was subsequently stirred for a further 2 hours and was thereby allowed to come to room temperature. After extracting twice with methylene chloride, the organic phase was dried and the solvent was distilled off. 2-Difluoromethoxy-α-cyano-benzyl alcohol was obtained as a colorless oil, the structure of which was confirmed by a nuclear magnetic resonance spectrum. The yield was virtually quantitative.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CS(C)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCOCC1
Reaction time: 0.17 h

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (10.088 g, 45.9 mmol) in dimethyl sulfoxide (20.00 mL, 282 mmol) was added morpholine (6.00 mL, 68.8 mmol). A vigorous exotherm developed and the solution turned an intense orange-red. After 10 min LC-MS indicated no starting material remained and the desired product predominated. The reaction was poured into 200 mL satd aq. Sodium bicarbonate solution and the aq. Mixture was extracted with 200 mL Et2O. The ether extract was washed with 100 mL water followed by 100 mL brine then stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford an orange oil. Mass Spectrum (ESI) m/e=287.0 & 289.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([O:14][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1

Procedure:
To a solution of 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer (20 g) in ethyl acetate (200 ml) and tetrahydrofuran (100 ml) was added dropwise a solution of diphenyldiazomethane in ethyl acetate (0.9 m mole/ml, 80 ml) at ambient temperature, and the mixture was stirred for an hour. The reaction mixture was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (15.0 g), mp 164° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[Br:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.O>C(#N)C>[Br:25][C:26]1[CH:27]=[N:28][C:29]([N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[CH2:7]2)=[N:30][CH:31]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 76.8 %

Procedure:
Add to a solution of (2,4-dichlorobenzyl)-(S)-pyrrolidin-3-ylamine (300 g, 1.22 mol) in acetonitrile (2.25 L) at room temperature diisopropylethylamine (237 g, 1.83 mol) and 5-bromo-2-chloropyrimidine (237 g, 1.23 mol). Reflux for 1 hour. Cool the mixture to 20° C. Add water (45 mL, 2.5 mol) dropwise to give a solid. Stir for 17 h., filter the suspension, and wash the cake with acetonitrile (250 mL), and dry under vacuum at room temperature to give the title compound as a tan solid (377 g, 83%).