Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:12])([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6])C.CO.[BH4-].[Li+]>C1COCC1>[CH3:6][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:12])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(C)N1CCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)N1CCCC1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
2-Methyl-2-pyrrolidin-1-yl-propionic acid ethyl ester (2.00 g, 10.8 mmol, 1 eq) was suspended in dry THF (20 mL) under Ar. Methanol (2.0 mL, 50 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (25 mL of 2M, 50 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature. After 18 hours, the reaction was quenched with methanol, then aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the crude residue was used in the next step.
Reaction SMILES: [C:1]([NH:10][OH:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[O:11]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:9])=[N:10]1
Reactant: O=C(NO)c1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1noc2ccccc12
Yield: 53.7 %

Procedure:
To a solution of salicylhydroxamic acid (1.53 g, 10 mmol) in THF (40 ml) was added a solution of carbonyldiimidazole (1.62 g, 20 mmol) in tetrahydrofuran (20 ml). The mixture was stirred at reflux for 4 hrs. before evaporation to dryness. Water (20 ml) and conc. HCl (aq.) (5 ml) were added and the solution was refrigerated (5° C.) for 30 min. The resulting precipitate was collected by filtration and washed with 2M HCl. The solid material was dissolved in methanol and concentrated in vacuo yielding 725 mg (54%) of the title compound 71. TLC (10% methanol in DCM): Rf=0.2. HPLC-MS (Method A): M+=136.1 (UV/MS(%)=94/100).1H-NMR (400 MHz, CDCl3, MeOD): δ=7.73 (1H, m); 7.56 (1H, m); 7.38 (1H, m); 7.28 (1H, m); 3.87 (1H, s).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][N:12]1[C:17](=[O:18])[C:16]2[N:19]=[CH:20][N:21](C(OC(C)(C)C)=O)[C:15]=2[CH:14]=[N:13]1.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl.O.N>O1CCCC1>[Cl:29][C:20]1[NH:21][C:15]2[CH:14]=[N:13][N:12]([CH3:11])[C:17](=[O:18])[C:16]=2[N:19]=1
Reactant: Cn1ncc2c(ncn2C(=O)OC(C)(C)C)c1=O
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2[nH]c(Cl)nc2c1=O
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
8.4 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added dropwise over one hour to a 300-ml tetrahydrofuran solution containing 1.68 g of t-butyl 5-methyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-carboxylate and 4.15 g of hexachloroethane under a nitrogen atmosphere at 0° C. The resulting mixture was stirred for 30 minutes. 2N ammonia water was added to the solution, and the mixture was stirred for three hours. Then, the reaction solution was concentrated to 50 ml, and washed with 20 ml of t-butyl methyl ether. The solution was acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, and washed successively with 10 ml of water and 10 ml of t-butyl methyl ether. Thus, 1.03 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([Br:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 549 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>CO.C(Cl)Cl>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: Nc1ccccc1F
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CNc3ccccc3F)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-fluoroaniline (55 mg, 0.50 mmol) as described in General Procedure X to afford Iai (12 mg, 18.2%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=392 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41](Br)[CH3:42])=[CH:37][CH:36]=1>C1COCC1>[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH3:42])[CH:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (4-tert-butyl-phenyl) acetic acid benzyl ester (Step C, 1.8 g, 6.38 mmol) in anhydrous THF (15 mL) was added LiHMDS (9.57 mL, 9.57 mmol, 1.0 M solution in toluene) at −78° C. The reaction mixture was stirred for 1.5 h at −78° C., and then 4-(1-bromo-ethyl)-benzoic acid methyl ester (1.7 g, 7.02 mmol, in THF 5.0 mL) was added dropwise, stirred for 2 h at −78° C. and then allowed to warm to rt for 1 h. After completion of the reaction quenched with saturated NH4Cl solution (20 mL) and stirred for 10 min. The reaction mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was recrystallization from minimum amount of EtOAc and hexane at room temperature to afford 4-[2-benzyloxycarbonyl-2-(4-tert-butyl-phenyl)-1-methyl-ethyl]-benzoic acid methyl ester as a mixture of diastereomers (2.3 g, 80%), d/r(2:1): 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.30-7.38 (m, 7H), 7.06 (d, J=6.9 Hz, 2H), 5.11 (dd, J=6.0, 12.9 Hz, 2H), 3.92 (s, 3H), 3.75 (d, J=7.5 Hz, 1H), 3.49-3.46 (m, 1H), 1.29 (s, 9H), 1.24 (d, J=6.9, Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:4); Rf=0.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2cc(F)cc(F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Methyl 2-(3,5-difluorobenzyl)piperidine-4-carboxylate (7.082 g, 26.30 mmol) was dissolved in DCM (170 mL) and DIPEA (5.50 mL, 31.56 mmol), then methyl carbonochloridate (2.88 mL, 36.58 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then additional methyl carbonochloridate (0.7 mL, 8.89 mmol) was added. The solution was stirred for 30 min then washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to give dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.55 g, 99%). MS m/z 328 (M+H)+
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][O:4][CH2:5][C@@H:6]([NH2:11])[CH2:7][CH:8]([CH3:10])[CH3:9].[H][H].Cl>C(O)C.[Pd]>[CH2:3]([O:4][CH2:5][C@@H:6]([NH2:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]([CH3:12])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)COC[C@@H](N)CC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)COC[C@@H](N)CC(C)C
Yield: 93.5 %

Procedure:
A suspension of (1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine (51.9 g, 0.3 mol) and 5% Pd/C (10.4 g) in ethanol (520 mL) was stirred for 18 hours at room temperature in a hydrogen atmosphere (1 atm.). To the resulting reaction mixture was added 6 mol/L aqueous hydrochloric acid (52 mL) under cooling in ice bath. The aqueous mixture was subjected to filtration using celite for removing insolubles and then placed under reduced pressure for distilling the solvent off. The residue was dissolved in water, and the resulting aqueous solution was made to approx. pH 10 by addition of potassium carbonate. The solution was subjected to extraction with diethyl ether. The organic portion was dried over sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained the titled compound (48.6 g, 92.6%) as an oily compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH3:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(=O)c1ccc(C)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(C)NCCCCNC(=O)OC(C)(C)C)nc1

Procedure:
Using General Procedure B: Reaction of 1-(5-methyl-pyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668) and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 with NaBH(OAc)3 gave {4-[1-(5-methyl-pyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
A mixture of 2-(p-tolyl) pyridine (118.88 g, 702.5 mmol), N-bromosuccinimide (131.29 g, 737.6 mmol, 1.05 equivalents) and CCl4 (1190 mL) was treated with benzoyl peroxide (1.70 g, 7.03 mmol, 0.01 equivalents) under nitrogen, stirred at 70° C. for 1.5 hours, and then allowed to cool to ambient temperature with stirring overnight. The reaction mixture was filtered, washed with CCl4 (2×250 mL), concentrated to oil, treated with isopropyl alcohol (420 mL) and cooled to −5° C. The resulting solid was filtered, washed with isopropyl alcohol (140 mL), and dried in a vacuum oven with a N2 bleed to afford the title compound (111.91 g, 64.2% yield). 1H NMR (CDCl3): δ 8.70(m, 1H), 7.99(m, 2H), 7.75(m, 2H), 7.52(m, 2H), 7.25(m, 1H), 4.58 (s, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:12][C:13]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:15]
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 207.5 %

Procedure:
To a solution of 2-adamantanol (912 mg, 5.99 mmol) in methylene chloride (15 mL), at 0° C. under nitrogen, was added a solution of triphosgene (653 mg, 2.2 mmol) and pyridine (484 μL, 5.99 mmol) in methylene chloride. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated to dryness under reduced pressure. Ethyl acetate was added to the residue and the resultant mixture was filtered. The filtrate was concentrated in vacuo to give 980 mg of the title compound as a white powder. 1H NMR (CDCl3) δ1.5-2.2 (m, 14H), 5.02 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17](Cl)=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH3:38][O:39][NH2:40]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17]([NH:40][O:39][CH3:38])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CON
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)Cl)=CS[C@H]12
Solvent: C1CCOC1
Product: CONC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-chlorocarbonyl-2-cephem-4-carboxylate reacts with 1.1 equivalents of methoxyamine in tetrahydrofuran at -76° C. to give benzhydryl 7-(2-thienylacetamido)-3-methoxyaminocarbonyl-2-cephem-4-carboxylate. 4'-Methoxybenzyl 7-butyramido-3-methylcarbonyldioxycarbonyl-3-cephem-4-carboxylate reacts with 1.1 equivalents phenylhydroxylamine in methylene chloride at -76° C. to provide 4'-methoxybenzyl 7-butyramido-3-phenylhydroxaminocarbonyl-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(N)=O)c1N
Reaction time: 60 h
Yield: 86.6 %

Procedure:
To 2-amino-3-methylbenzoic acid (1.5 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and diisopropylethylamine (7.5 ml, 42 mmol). The mixture was purged with N2 and stirred for 60 h. The mixture was poured into water and extracte with EtOAc (50 mL×3), and the combined extracts were washed with brine (20 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography eluting with 1:1 EtOAc/hexanes to afford 2-amino-3-methyl-benzamide as a white solid (1.3 g, 87%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22]4[N:23]3[N:26]=[N:27][N:28]=4)=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.[ClH:37].CO>CCOC(C)=O>[ClH:37].[ClH:37].[CH3:30][O:29][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:23]1[N:26]=[N:27][N:28]=[C:22]1[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)-n1nnnc1CC2
Reaction time: 24 h
Yield: 61 %

Procedure:
To a stirred solution of Compound 7 (110 mg, 0.23 mmol) in AcOEt (6 ml) was added an excess amount of HCl-MeOH, and stirred for 1 day. After the solvent was evaporated, the residual solid was recrystallized from MeOH-Et2O. The crystals precipitated were collected by filtration, washed with Et2O, and dried in vacuo at 30° C. to give Compound 8 (65 mg, 0.14 mmol, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=2)[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: NC(=S)c1cc(Cl)nc(Cl)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 25 °C

Procedure:
2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) was dissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9 mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixture was heated to reflux under N2 for 5 h. After cooling to RT, solvent was removed. The residue was extracted with CHCl3. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated to give a brownish solid. This crude was purified by chromatography on silica gel. Elution with hexane:acetone (90:10) gave a title compound as yellow solid. MS m/z: 303 (M+H). Calc'd. for C11H8Cl2N2O2S-303.16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:35][CH3:36])[N:9]=2)=[CH:4][CH:3]=1.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>>[CH3:38][CH2:37][NH:39][C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:14]=3[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:23]=3)[NH:19]4)=[CH:11][N:10]([CH2:35][CH3:36])[N:9]=2)=[CH:6][CH:7]=1)=[O:41]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)cc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)cc23)cc1

Procedure:
Following the procedure described in Example 48 using 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine and ethyl isocyanate provided the title compound. ESMS (M+H)+: 550.6
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23](O)=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:39])=O>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23]([Cl:39])=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1

Procedure:
A mixture of (E)-3-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid, from Example 31, (0.20 g, 0.41 mmol) in dichloromethane (5 ml) and thionyl chloride (Aldrich, 0.6 ml, 0.81 mmol) was refluxed for 1.5 hours. Volatiles were removed in vacuo to give (E)-3-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid chloride as a yellow solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][C:14](=[O:18])[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[Na+].O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(O)C2
Reaction time: 16 h
Yield: 772.3 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one (0.126 g) in EtOH (3 mL) was added NaBH4 (0.053 g). After 16 h, the mixture was treated with 1 M NaOH (5 mL) and water (10 mL). The mixture was stirred for 30 min then extracted with CH2Cl2. The organic layer was dried and concentrated. Chromatography on SiO2 (10 to 35% EtOAc/hexanes) afforded 0.98 g of the title compound. TLC (SiO2, 50% EtOAc/hexanes): Rf=0.18. MS (ESI): exact mass calcd. for C17H19FN2O, 286.15; m/z found, 287.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(NC(=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CCC(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetophenone (II), MS (m/e) 420, 375, 315, 301,287 and 283; IR (neat) 1684, 1597, 1581, 1449, 1392, 1369, 1251 and 1164 cm-1 ; NMR (CDCl3) 7.97, 7.56, 7.45, 4.18, 3.39, 2.60, 2.33 and 1.30 δ.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:24])[CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14].FC(F)(F)C(O)=O>ClCCl>[OH:7][NH:8][C:9](=[O:24])[CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (tetrahydro-pyran-2-yloxy)-amide (0.0.358 g, 1.062 mmol) in 5 mL of dichloromethane, was added trifluoroacetic acid (5 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-10% methanol/dichoromethane to give the title compound as an off-white solid (0.059 g, 22% yield). LC-MS: tR=7.1 min; m/z 254 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 0.89 (t, J=6.60 Hz, 3H), 1.27-1.36 (m, 4H), 1.39-1.49 (m, 1H), 1.60-1.67 (m, 1H), 2.23 (d, J=1.50 Hz, 3H), 2.24-2.32 (m, 1H), 2.62 (dd, J=13.50, 5.40 Hz, 1H), 2.79 (dd, J=13.50, 9.60 Hz, 1H), 6.88 (t, J=9.60 Hz, 1H), 6.95-6.96 (m, 1H), 7.01 (t, J=7.50 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:16]([NH:19][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])([CH3:18])[CH3:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(C)(C)N)o2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(C)(C)NC(=O)OCc3ccccc3)o2)CC1
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
To a solution of crude {1-[5-(1-amino-1-methyl-ethyl)-furan-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (451 mg, 1.61 mmol) in a mixture of THF (8.0 mL) and water (1.6 mL), was added Li2CO3 (297 mg, 4.02 mmol) followed by benzyl chloroformate (0.57 mL, 4.0 mmol). This was stirred for 2.5 h then diluted with water (50 mL) and extracted EtOAc (3×50 mL). The combined organic layers were dried with Na2SO4 and concentrated to give a red residue. The residue was purified by flash chromatography (silica, 20->40% EtOAc/hexanes) to give 324 mg of the title compound as a yellow oil, m/z 437.64 [M+Na]+.