Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.CO>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cccc(F)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NNC(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
1,1-Dimethylethyl 2-[(6-fluoro-2-pyridinyl)carbonyl]hydrazinecarboxylate (510 mg, 2 mmol) was dissolved in 1,4-dioxane (5 mL) and treated with 4M HCl in 1,4 dioxane (5.00 mL, 20.00 mmol) at 0° C. The mixture was stirred to room temperature over 24 hr and was concentrated in vacuo, azeotroping with diethyl ether (3×50 ml) to afford a white solid. The solid was dissolved in methanol and loaded on to an SCX cartridge (Varian, 10 g), washing with methanol, and then eluting the product in free base form using 2M ammonia/methanol. The ammoniacal fractions were concentrated in vacuo to afford the product, 6-fluoro-2-pyridinecarbohydrazide (251 mg, 1.618 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:24].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][Br:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCBr
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 9a (1.0 g, 3.11 mmol) in 1 mL of pyridine at 0° C. was slowly added phosphorus tribromide (0.116 mL, 1.22 mmol) via syringe (Bradshaw et al., J. Het. Chem., 27:347-349 (1990)). The solution was allowed to stir overnight, at which time TLC analysis indicated that the reaction was complete. Water (25 mL) was poured into the reaction vessel and the organics were extracted into methylene chloride (3×25 mL). The combined organic layers were washed with sodium bicarbonate (25 mL), followed by brine (25 mL), dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified on silica gel using neat ethyl acetate as the eluant to give 400 mg (35% yield) of pure product 10a (FIG. 7). 1H NMR: 1.37 (s, 9H), 2.43 (t, 2H, J=6.4 Hz), 3.40 (t, 2H, J=6.4 Hz), 3.53-3.61 (m, 12H), 3.64 (t, 2H, J=6.4 Hz), 3.74 (t, 2H, J=6.4 Hz). 13C NMR: 27.90, 30.13, 36.06, 66.68, 70.17, 70.31, 70.32, 70.39, 70.46, 70.99, 80.22, 170.65.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][N:5]=[C:4]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:3]=12.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:7]([CH2:8][Cl:18])=[CH:6][N:5]=[C:4]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:3]=12
Reactant: CCn1nc(C)c2c(Cl)c(CO)cnc21
Reactant: O=S(Cl)Cl
Product: CCn1nc(C)c2c(Cl)c(CCl)cnc21

Procedure:
Into a three necked flask, fitted with a stirrer, reflux condenser and dropping funnel are added 94.6 g. of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-methanol (0.42 mol.) (U.S. Pat. No. 3,983,128; Example 2). While stirring 475 ml. of thionyl chloride are added dropwise within 45 minutes and the mixture is then refluxed for one and a half hours. The excess thionyl chloride is removed by a rotary evaporator and the residue is dissolved in benzene. The solvent is again removed and the remaining solid product is triturated with ligroin, filtered and dried at 70°, yield 91 g. of 4-chloro-5-chloromethyl-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine, which, after recrystallization from hexane, gives 83.5 g. of pure product, m.p. 96°-97°. Evaporation of the ligroin mother liquor and recrystallization of the residue gives a second crop of 5.7 g. (m.p. 95°-96°). Total yield: 89.2 g. (87%).
Reaction SMILES: [CH2:1]([CH:4]([C:8](=O)[CH3:9])[C:5](=O)[CH3:6])[CH2:2][CH3:3].[C:11]([NH:14][NH2:15])([NH2:13])=[NH:12].[ClH:16]>CO.O.Cl>[ClH:16].[CH3:9][C:8]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([CH3:6])[N:14]([C:11]([NH2:13])=[NH:12])[N:15]=1
Reactant: CCCC(C(C)=O)C(C)=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCc1c(C)nn(C(=N)N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 2.06 g of 3-propyl-2,4-pentanedione in 10 ml of methanol was added little by little to a solution of 1.56 g of aminoguanidine hydrochloride in 5 ml of water, 30 ml of methanol and 1 ml of concentrated hydrochloric acid, and stirred overnight at room temperature. The solvents were removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ethanol-ether to obtain 1.70 g of 3,5-dimethyl-4-propyl-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[O:10])[CH2:33][CH2:34]3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)[C@H]4CC[C@H](O)CC4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Trans-4-hydroxycyclohexanecarboxylic acid (1,991 g, 13.81 mmol) was added to a solution of trans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine (4.6 g, 11.51 mmol) in dichloromethane. HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate, 5.25 g, 13.8 mmol) and diisopropylethylamine (6.03 mL, 34.5 mmol) were added and the mixture stirred at room temperature for 14 h. The solvent was evaporated and the residue partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed twice with 5% aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification via silica gel chromatography (330 g Reveleris NP cartridge) with di-chloromethane/methanol (0-80%) as eluent yielded 6.05 g of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCCN
Reactant: N#Cc1ccccc1F
Product: COCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 2-methoxyethylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:14])[F:15])[CH:7]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1cccc(OC(F)(F)F)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(OC(F)(F)F)c2)c1
Yield: 37.2 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-trifluoromethoxyphenyl)acetamido]acetate (3.4 g) and 3-methylphenyl isocyanate (1.4 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(3-trifluoromethoxyphenyl)acetamido}acetate (1.75 g), m.p. 125° C., is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>>[CH:8](=[O:9])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: C=O
Reactant: Oc1ccccc1
Product: O=Cc1ccccc1O

Procedure:
A method in which a salicylaldehyde is prepared in good yield by one step reaction using as starting materials a phenol and a formaldehyde and a specific catalyst (a base represented by a tertiary amine and/or an organometallic salt):
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH:7]([CH3:13])[CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:13][CH:7]1[CH2:6][C:5]2[N:4]=[CH:3][C:2]([O:1][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:11][C:10]=2[C:9](=[O:12])[CH2:8]1
Reactant: CC1CC(=O)c2cc(O)cnc2C1
Reactant: ClCc1ccc2ccccc2n1
Product: CC1CC(=O)c2cc(OCc3ccc4ccccc4n3)cnc2C1
Yield: 67 %

Procedure:
By the method of Example 1, 7,8-dihydro-3-hydroxy-7-methyl-5 (6H)-quinolone and 2-chloromethylquinoline were converted to present title product in 67% yield, m.p. 141-144° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K]>CN(C=O)C>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: BrCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr
Reaction time: 24 h
Yield: 54.9 %

Procedure:
To a solution of 1,5-dibromopentane (9.00 ml, 65.22 mmol) dissolved in DMF (100 ml) was added potassium phthalimide (12.08 g, 65.22 mmol) at room temperature, and the reaction mixture was stirred for 24 hours. After the reaction was completed, distilled water was added, and the resulting reaction mixture was stirred for 10 minutes and extracted with ethyl acetate three times. Then, the organic phase was washed with a saline solution, dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane=1:3) to give the target compound (10.6 g, 55%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:19](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:19])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Reactant: CC(C)(C)O[K]
Solvent: ClCCl
Solvent: CI
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound of step 1 (2.73 g, 10.95 mmol) in abs. dichloromethane (50 mL) was mixed with tert-BuOK (1.47 g, 13.14 mmol) and methyl iodide (747 μl, 12 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was mixed with saturated NaCl solution (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccc(F)cc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)NC(=O)[C@@H](O)c2cc(F)cc(F)c2)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-O), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N+:6]([O-])[CH:7]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1cc(N)c(C)cn1
Yield: 86.5 %

Procedure:
A mixture of N-(5-methyl-4-nitro-1-oxidopyridin-2-yl)acetamide (3.1 g, 14.7 mmol) and Pd(OH)2 (20% on carbon, 1.6 g) in MeOH (80 mL) was allowed to stir under 40 psi of hydrogen at rt for 6 days. The reaction mixture was then filtered over celite and the filter cake was washed with DCM. The filtrate was concentrated to give N-(4-amino-5-methylpyridin-2-yl)acetamide (2.1 g, 86%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31][CH2:32][CH2:33]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][S:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: OCCSc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCSc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-naphthylthio)ethanol (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.55 g of 4-[[2-(2-naphthalenylthio) ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 63°-65° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@@H:33]([CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=1>ClCCl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:32][C@@H:33]([CH2:47][C:48]3[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=3)[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=3)=[O:15])=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1cc(C(C)=O)c2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCCn1cc(C(C)=O)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 2 h
Yield: 77.8 %

Procedure:
3-Acetyl-1-butyl-1H-indole-6-carboxylic acid (0.322 g) was dissolved in dichloromethane (15 mL). 1,1′-Carbonyldiimidazole was added (0.171 g). The mixture was stirred for 2 h and then a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.250 g) in dichloromethane (15 mL) was added. After stirring overnight, the mixture was partitioned between dichloromethane, water, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel using MeOH/dichloromethane (4/96) to give 3-acetyl-1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1H-indole-6-carboxamide (0.335 g). MS (ESI+) for C34H39F2N3O3+H1 m/z 576.30 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]=O)=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C:23]2([CH3:28])[CH2:22][NH:21][CH2:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:8]([N:21]1[CH2:20][CH2:19][C:18]2([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=3)[C:23]([CH3:28])([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22]1)[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: COc1cccc(C23CCCCC2(C)CNCC3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cccc(C23CCCCC2(C)CN(CCc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Phenacetaldehyde 87 mg (0.72 mmol) and 190 mg (0.72 mmol) of 10 were mixed in 1,2-dichloroethane (15 mL) and then treated with sodium triacetoxyborohydride 230 mg (1.08 mmol). The reaction mixture remained cloudy throughout the reaction. The mixture was stirred at room temperature under N2 atmosphere for 2 h. The reaction mixture was quenched by adding saturated NaHCO3, and the product was extracted with EtOAc. The EtOAc extract was dried (MgSO4), and the solvent was evaporated to give 0.25 g (95%) of a light yellow oil. Purification by chromatography on alumina using 10% ethyl acetate/hexane gave 0.23 g (89%) of desired product 11 as colorless clear viscous oil: 13C NMR (300 MHz, CDCl3) δ 158.9, 129.1, 128.6, 128.1, 126.2, 122.5, 117.1, 109.9, 63.2, 61.1, 55.5, 43.1, 37.4, 36.3, 34.0, 30.7, 22.4, 22.1.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30]CC)=[O:29])=[CH:20][N:21]3C(C)(C)C)=[CH:16][C:15]=2[F:34])[CH2:10]1)=O)(C)(C)C.[ClH:35].C(OCC)C>C(O)C>[ClH:35].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][NH:21]3)=[CH:16][C:15]=2[F:34])[CH2:10]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: N[C@@H]1CCN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)C1
Temperature: 120 °C

Procedure:
A suspension of EXAMPLE 15B (260 mg) in ethanol (60 mL) was treated with HCl gas to saturation, heated at 120° C. for 18 hours then cooled, treated with diethyl ether and filtered to provide the desired product. NMR (300 MHz, DMSO-d6) δ 13.32 (d, 1H), 8.42 (d, 1H), 8.36 (br s, 3H), 8.02 (d, 1H), 4.05-3.83 (m, 5H), 2.44-2.25 (m, 1H), 2.20-2.12 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])Cl>>[CH2:1]([N:5]1[CH2:7][CH2:8][CH2:9][Si:10]1([CH3:13])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(Cl)CCCCl
Reactant: CCCCN
Product: CCCCN1CCC[Si]1(C)C
Temperature: 10 °C

Procedure:
An initial charge of 508 g (6.94 mol) of 1-butylamine is admixed dropwise over the course of 2.5 h with 171 g (1.00 mol) of chloropropyldimethylchlorosilane and the mixture is heated at reflux for 12 h. Following distillative removal of the excess 1-butylamine, the residue is diluted with 350 ml of toluene and cooled to 10° C. The precipitate it forms is filtered off and the filtrate is distilled in vacuo. This gives 134.5 g of N-butyl-1,1-dimethyl-1-sila-2-azacyclopentane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[CH2:8][CH2:9][N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]3[C:12]([N:13]([CH3:28])[C:14](=[O:27])[N:15]([CH3:26])[C:16]3=[O:25])=[CH:11]2)[S:5][CH:6]=1.C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[C:11]3[N:10]([C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:17]4[C:16](=[O:25])[N:15]([CH3:26])[C:14](=[O:27])[N:13]([CH3:28])[C:12]4=3)[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3

Procedure:
Trifluromethanesulfonic anhydride (0.576 mL, 3.41 mmol) in DCM (3 mL) was added slowly to a solution of 6-(3-(4-chlorothiazol-2-yl)-3-hydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (490 mg, 1.137 mmol) and triethylamine (0.792 mL, 5.69 mmol) in DCM (40 mL) at 0° C. Further portions of triethylamine (0.792 mL, 5.69 mmol) and trifluoromethanesulfonic anhydride (0.576 mL, 3.41 mmol) were added to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by mass-directed HPLC under the following conditions afforded the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13](C(C(OCC)=O)=O)[C@@H:12]1[C@@H:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>CO>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[C@@H:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)OC
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionate (27 mg) in methanol (1 ml) was added triethylamine (27 μl) at room temperature. After stirring for 30 minutes, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine (twice) and water, dried over magnesium sulfate and evaporated to give methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-4-oxoazetidin-2-yl]propionate (14 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:14]=[C:13]2[O:26][CH2:27][CH2:28][CH3:29])=[C:4]([F:30])[CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:24])([F:25])[C:20]([F:23])([F:21])[F:22])[N:14]=[C:13]2[O:26][CH2:27][CH2:28][CH3:29])=[C:4]([F:30])[CH:3]=1
Reactant: CCCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CCCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-pentafluoroethyl-2-propoxy-6(1H)-pyrimidinone with concentrated sulphuric acid at 0° C. during 1.5 minutes there is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-2-propoxy-6(1H)-pyrimidinone, m.p. 109°-111° C.;
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].Cl.[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:13][C:12](=[O:14])[CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: O=C([O-])O
Reactant: C=CCc1ccccc1NCC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1ccccc1NCC(=O)OC

Procedure:
A solution of 0.06 mol of N-(2-allylphenyl)glycine, prepared as described by A. Padwa, R. Lim, J. G. MacDonald, H. L. Gingrich, and S. M. Kellar in J. Org. Chem., 1985, 50, 3816-3823, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(2-allylphenyl)glycine methyl ester.