Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:16]C(OC(C)(C)C)=O)[C:10]([C:13]([O-:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.F[C:27](F)(F)[C:28](O)=O>C(Cl)Cl>[NH2:16][C:9]1[C:10]([C:13]([O:15][CH2:27][CH3:28])=[O:14])=[N:11][CH:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)[CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(Cc2ccc(F)cc2)cnc1C(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N

Procedure:
A solution of 5-(4-fluorobenzyl)-3-[(tert-butoxy)carbonyl]amino-2-pyridinecarboxylate (29 g, 77 mmol) in CH2Cl2 (200 mL) and trifluoroacetic acid (60 mL) was stirred at rt overnight. The solvent was removed in vacuo and the crude material was dissolved in EtOAc and washed with NaHCO3 solution and brine. The organic layer was dried, concentrated and chromatographed on silica gel eluting with 20-60% EtOAc/hexanes to yield the product as a light yellow solid: 1H NMR (d6-DMSO) δ 7.76 (1H, d, J=1.7 Hz), 7.25 (2H, m), 7.15 (2H, t, J=9 Hz), 6.92 (1H, d,J=1.7 Hz), 6.62 (2H, br s), 4.23 (2H, q, J=7 Hz), 3.87 (2H, s), 1.26 (3H, t, J=7 Hz), AP+ MS: 275 (M+H+, 100); HRMS calcd for C15H15FN2O2+H+: 275.1196. Found: 275.1206.
Reaction SMILES: ClCCCl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[C:17]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1

Procedure:
To 300 ml. of 1,2-dichloroethane maintained at 0° C. were added 6.0 g. (0.022 mole) of 2-(4-methoxyphenyl)-6-methoxybenzothiophene and 3.10 g. (0.022 mole) of benzoyl chloride. The mixture was stirred vigorously, and 3.2 g. (0.024 mole) of aluminum chloride were added in small portions. The resulting red solution was stirred for one hour, and water then was added. The yellow organic layer was separated, washed with 200 ml. of 1N sodium hydroxide and then with 200 ml. of saturated sodium chloride solution. The mixture then was dried over potassium carbonate, and the solvent was evaporated to give a pale yellow solid which was purified by chromatography over silica gel using benzene and 5% ethyl acetate in benzene as eluant. The appropriate fractions gave product as yellow crystals. The product was recrystallized from methanol to obtain 3.5 g. (42 percent) of 2-(4-methoxyphenyl)-3-benozyl-6-methoxybenzothiophene, melting point 110.5°-111° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:30]1CCCC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 15° C. solution of 325 g. (1.25 mole) of 2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters of tetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a 1.3 M solution in hexane (reaction temperature is maintained at 15°-18° C.). The reaction mixture is allowed to warm to room temperaure and is stirred 2 hours longer. It is then quenched by addition to a solution of 170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature ≤30° C.). The resultant mixture is allowed to warm to room temperature and is then stirred an additional 2 hours. The organic layer is separated and the aqueous phase extracted once with one liter of ether. The combined organic phase is washed with 500 ml. of water and 500 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 315 g. (99%) of the title product.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:28]=3)[C:23](=[O:38])[C:22]=2[CH:21]=1)([O:17][CH2:18][CH3:19])=[O:16]>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:23]1([OH:38])[C:24]2[CH:25]=[C:26]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=2[C:30]2[C:22]1=[CH:21][C:20]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:32][CH:31]=2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCC)ccc1-2
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)c1ccc2c(c1)C(O)(c1ccccc1-c1ccccc1)c1cc(C(=O)OCC)ccc1-2
Reaction time: 3 h

Procedure:
A Grignard reagent prepared from 0.97 g (40 mmol) of magnesium turnings and 9.32 g (6.8 ml, 40 mmol) of 2-bromobiphenyl in 50 ml of dry diethyl ether was added dropwise to a boiling solution of 13 g (40 mmol) of 2,7-dicarbethoxy-9-fluorenone in 100 ml of dry diethyl ether in the course of 2 hours. When the addition had ended, the mixture was boiled for a further 3 hours. After cooling overnight, the precipitate which had separated out was filtered off with suction and washed with cold ether. The magnesium complex which had been filtered off with suction was hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice-water. After 1 hour, the 9-(2-biphenylyl)-2,7-dicarbethoxy-9-fluorenol formed was filtered off with suction, washed with water and sucked dry. For the cyclization reaction, the dried fluorenol was boiled in 100 ml of glacial acetic acid, after addition of 3 drops of concentrated hydrochloric acid, for 6 hours. The mixture was left to crystallize overnight and the product formed was filtered off with suction and washed with glacial acetic acid and water.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)C.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: NCCCCCO
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCCCCO)c(OC)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 5-aminopentan-1-ol (194 mmol), 2,4-dimethoxybenzaldehyde (213 mmol) and acetic acid (213 mmol) in methanol (500 ml) was stirred at 10° C. for 0.5 h. NaBH4 (22 g) was added portionwise at −10° C. and the mixture was stirred for 10 minutes. Then the reaction mixture was allowed to warm to 10° C. and stirred for 1.5 h. Saturated NaHCO3 was added and the mixture was stirred for 0.5 h. The mixture was extracted by CH2Cl2 (3×100 ml). The combined organic phase was washed by saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. Yield: 46 g (69% purity, 65% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:8]([N+]([O-])=O)[CH:7]=1)[CH:2]=[CH2:3].Cl[Sn]Cl.O.C[N:41](C=O)C>>[CH2:1]([O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[NH2:41])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: Cl[Sn]Cl
Solvent: O
Product: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of 4-[tert-butoxycarbonyl-(4-trifluoromethoxy-benzyl)-amino]-3-nitro-benzoic acid allyl ester (4.0 mmol) were dissolved in 20 ml DMF. 2.8 g SnCl2×2 H2O (12 mmol) are added and the reaction stirred at room temperature for 16 h. The crude was filtered over Kieselgel and the solvent evaporated. MS(ISP): 467.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:19](=[O:36])[C@@H:20]([NH:28]C(=O)OC(C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([N:8]1[C:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:12]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=2[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(C(N)=O)cc(-c3ccncc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a 20 ml vial was added crude (S)-tert-butyl 1-(4-carbamoyl-6-(pyridin-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate 60.B (75 mg, 0.1 mmole), 20 ml of DCM and 10 ml of TFA. The reaction was stirred at room temperature for 12 hours at which time the crude was partitioned between 600 ml DCM and 100 ml saturated sodium carbonate. The organic layer was extracted once more with 100 ml of water, the organic layer dried with sodium sulfate and the solvent removed to give (S)-1-(2-amino-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxamide 60.0 as an off white solid. (49 mg, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Br:11])[CH:3]=1.[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH2:21][N:15]3[CH:14]=[CH:13][CH:12]=[C:16]3[CH2:17]2)=[O:7])=[C:4]([Br:11])[CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccn2Cc2ccccc21
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Step b) (4-Fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzo-diazepin-10-yl)-methanone: A solution of 4-fluoro-2-bromobenzoyl chloride (5.32 g) from step a), in dichloromethane (35 ml), was added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (3.44 g) and triethylamine (2.27 g) in dichloromethane (80 ml) and cooled in an ice bath. The cooling bath was removed and after stirring for 16 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale purple foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in the intermediate (4-fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone as a tan foam (6.91 g), MS m/z: 384 (M)+. This material was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].Cl.[CH3:15][N:16](C)CCCN=C=NCC.CN>C(Cl)Cl.CO>[CH3:15][NH:16][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzoic acid (4.0 g, 21.6 mmol) and EDC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (4.36 g, 28.1 mmol) in methylene chloride (100 mL) was added methylamine (11.3 mL of a 2 M solution in MeOH, 22.7 mmol) and the solution was stirred at room temperature overnight. The solution was washed with 1 N HCl, dried over MgSO4 and concentrated to a solid. The solid was triturated with butyl chloride and collected by filtration to give the N-methyl-3-fluoro-4-nitrobenzamide (3.81 g, 96%).
Reaction SMILES: C[Si](C)(C)[N:3]=[C:4]([C:22]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32])[C:5]([C:11]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=1[F:21])=[N:6][Si](C)(C)C.[C:35](Cl)(Cl)=[O:36]>>[F:28][C:27]1[C:22]([C:4]2[C:5]([C:11]3[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=3[F:21])=[N:6][C:35](=[O:36])[N:3]=2)=[C:23]([F:32])[C:24]([F:31])=[C:25]([F:30])[C:26]=1[F:29]
Reactant: O=C(Cl)Cl
Reactant: C[Si](C)(C)N=C(C(=N[Si](C)(C)C)c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Product: O=C1N=C(c2c(F)c(F)c(F)c(F)c2F)C(c2c(F)c(F)c(F)c(F)c2F)=N1
Yield: 82 %

Procedure:
Analogous to Example 13, 5.33 g (10 mmol) of N,N'-bis(trimethylsilyl)-1,2-di(pentafluorophenyl)-ethanediimine, which was made in Example 2, was reacted with 10 mmol (1.0 g) of phosgene to yield 3.4 g (8.2 mmol, 82%) of 4,5-di(pentafluorophenyl)-2H-imidazol-2-one as a dark red solid. This product is also referred to as decafluorobenzilimidazolone. 3C[1H]NMR (δ; CDCl3) 177.6 ppm (>C=O--; s), 156.2 ppm (>C=N--; t, J3 =13.4 Hz), 112.6 ppm (i, t, J2 =23.6 Hz), 138.1 ppm (dt, J1 =254 Hz), 142.7 (dm, J1 =254 Hz), 144.5 ppm (dd, J1 =249 Hz). Elemental analysis was carried out: calcd (found) for C15F10N2O: C, 43.50% (43.57%), F, 45.87% (45.82%), N, 6.76% (6.71%), O, 3.86% (3.78%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the N-t-butyloxycarbonyl-3-nitro-α-methylbenzylamine (1.79 g, 6.74 mmol) in dimethylformamide (50 1 mL) was added tin(II) chloride dihydrate (9.12 g, 40.4 mmol) and the reaction was stirred at room temperature for 48 hours. The dimethylformamide was removed under vacuum, residue resuspended in dichloromethane (100 ml), washed with brine (100 mL), filtered through a celite pad, and solvent removed to provide the crude aniline.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[C:27]=1[C:28]([OH:30])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:28]([C:27]1[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:32][CH:33]=[CH:34][C:26]=1[F:25])=[O:30]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:25][C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccsc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 77.2 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g, 0.98 mmol) was reacted with 3-thiophene carboxaldehyde (0.166 g, 1.48 mmol) in 5.0 mL of 4% KOH in EtOH at room temperature to afford 0.265 g (77%) of the title compound as a cream-colored solid, mp 61-62° C.: CI-MS m/e 350 (M+), 351 (M++1);
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([N:20]([CH2:31][C:32]#[N:33])C(=O)OCC3C=CC=CC=3)[N:19]=[C:6]2[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]>CO.[Pd]>[C:32]([CH2:31][NH:20][C:18]1[N:19]=[C:6]2[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=3)[C:4]([CH3:44])=[C:3]([C:1]#[N:2])[C@@H:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[N:7]2[N:17]=1)#[N:33]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC#N)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC#N)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(cyanomethyl)-carbamate (10.0 mg, 17 μmol) was dissolved in degassed methanol (3 ml). After addition of palladium on activated carbon (10%; 2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (7.4 mg, 96% of theory).
Reaction SMILES: C([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([NH:8][CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(F)CNC1CCCC1
Yield: 84.8 %

Procedure:
A solution of ethyl 3-(benzyl(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.5 g, 11.4 mmol) in ethanol (30 mL) was hydrogenated with Pd(OH)2 (20%, 400 mg, 0.57 mmol) in presence of TFA (11.4 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (2.1 g, 85%) as light yellow liquid. [M+H] calc'd for C11H20FNO2, 218; found 218.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CNc1nc(NS(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 63.1 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 2.5 ml (0.15 mol) of pyrrolidine were stirred in 20 ml of ethanol in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6 with 1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.22 g (63%) of 4 -amino-N-(2-methylamino-6-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >300° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Br)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C)P(N(C)C)(N(C)C)=O.[OH:48][CH2:49][CH2:50][CH2:51][C:52]([O-:54])=[O:53].[Na+]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH2:17][O:54][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][OH:48])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: O=C([O-])CCCO
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(COC(=O)CCCO)=CS[C@H]12
Reaction time: 1.5 h

Procedure:
To a solution of 2.24 g. (3.8 mmol) of benzhydryl 7-(2-thienylacetamido)-3-bromomethyl-3-cephem-4-carboxylate in 20 ml. of hexamethylphosphoramide (HMPA) at 0° C. under nitrogen was added a suspension of 0.530 g. (4.2 mmol) of sodium 4-hydroxybutanoate in 25 ml. of HMPA. After stirring 1.5 hours, ethyl acetate was added, and the resulting solution was washed with water (5X) and brine and dried over anhydrous MgSO4. Evaporation in vacuo to dryness provided 2.12 g. of product which was combined with that of an identical reaction ran on a 1 mmol scale. The combined products were chromatographed on a silica gel column using a cyclohexane:ethyl acetate (1:2) eluant to provide 293 mg. of a mixture of the title product and the corresponding 3-cephem compound. For the title product: nmr (CDCl3) δ1.7-2.6 ##STR26## 3.55 (m, 2, CH2OH), 3.83 (s, 2, side chain CH2), 4.63 (bs, 1, --CH2OH), 5.0 (s, 1, C4 --H), 5.23 (d, 1, J = 4 Hz, C6 --H), 5.58 (dd, 1, J = 4 and 8 Hz, C7 --H), 6.42 (bs, 1, C2 --H), 6.95 (s, 1, ester CH), and 7.36 (m, 13, thienyl + ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[F:12]>[Ni].C(O)C.N.CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[F:12]
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1F
Temperature: 25 °C

Procedure:
Add a slurry of Raney nickel in ethanol (1.2 g, 1.2 ml) to 4-cyano-2-fluoro-benzoic acid methyl ester (5.8 g, 30.0 mmol) in 2N ammonia in methanol (580 mL). Purge with nitrogen gas (3×), purge with hydrogen gas (3×), and pressurize with hydrogen gas to 419 KPa. Heat the reaction at 40° C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to the crude title compound (6.9 g, 99%). MS (m/z): 184 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)(Cl)Cl>[F:32][C:28]1([F:31])[CH2:29][CH2:30][N:26]([C:22]2[N:21]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:25]=[N:24][CH:23]=2)[CH2:27]1
Reactant: FC1(F)CCN(c2cncc(Cl)n2)C1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: FC1(F)CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)C1
Temperature: 100 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 1 eq) and 2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrazine (54) (1 eq) in 1,4-dioxane (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (2 eq) followed by addition of Pd(dpp)Cl2 (0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 135 in 6 mg quantity.