Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][C:19]([O:21][CH3:22])=[O:20].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: COC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCSCC(NC(=O)OC(C)(C)C)C1=O
Reaction time: 1 h
Yield: 69.6 %

Procedure:
6-t-Butoxycarbonylamino-perhydro-1,4-thiazepin-5-one (0.1 g) and methyl iodoacetate (0.1 g) are dissolved in 1 ml of THF. Sodium hydride (50% suspension in oil) is added in batches. After one hour at room temperature, the reaction is quenched with 2 ml of 10% ammonium chloride solution. The crude product is extracted into methylene chloride, and subsequently chromatographed on silica gel (40:1 chloroform-methanol) to yield the pure product (0.09 g). The NMR spectrum is consistent with the assigned structure. A sample is obtained by recrystallization from ether-methanol and analyzes for C13H22N2O5S.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:23])=[C:8]([C:24]([O:26][CH3:27])=[O:25])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:23][C:9]1[C:10]2[C:15](=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1nc(COC(C)=O)c2c(Oc3ccccc3)cccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2c(Oc3ccccc3)cccc2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 4c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (4c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[CH2:8]([N:10]([CH2:13][CH2:14][CH2:15]Cl)[CH2:11][CH3:12])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:15][CH2:14][CH2:13][N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCCSc1nnnn1C
Yield: 23.7 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.4 g) and N,N-diethyl-3-chloropropylamine (3.0 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (2.8 g) and potassium iodide (0.1 g), and the mixture is refluxed for 4 hours. After acetone is distilled off, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over sodium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (neutral alumina, made by Merck) and eluted with n-hexane to give 1-methyl-5-[3-(N,N-diethylamino)propylthio]-1,2,3,4-tetrazole (1.09 g) as colorless liquid, nD25 =1.5040.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[C:10]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)(=[O:12])[CH3:11]>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]([C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7])([OH:12])[CH3:11]
Reactant: CC(=O)c1ccco1
Reactant: Cc1nn(C)c(C)c1Br
Product: Cc1nn(C)c(C)c1C(C)(O)c1ccco1

Procedure:
4-Bromo-1,3,5-trimethylpyrazole was converted into the corresponding 4-lithio compound which was then reacted in situ with 2-acetylfuran.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Na+].[O:15]1[CH2:18][CH:17](O)[CH2:16]1>CN(C=O)C>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH:17]1[CH2:18][O:15][CH2:16]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OC1COC1
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2COC2)c(C)c1
Temperature: 80 °C

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (498 mg, 3 mmol) was added DMF (3 mL) and sodium hydride (240 mg, 6.0 mmol) followed by oxetan-3-ol (445 mg, 6 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled and quenched with brine solution and extracted with EtOAc (3×10 mL). The organic layer was separated and dried over sodium sulfate and evaporated to give methyl 3-methyl-4-(oxetan-3-yloxy)benzoate. To methyl 3-methyl-4-(oxetan-3-yloxy)benzoate was added sodium hydroxide (3 mL of 1 M NaOH, 3 mmol) solution and the reaction mixture was stirred for 1 hour. The reaction was acidified with 1 M HCl solution to pH 3 and extracted with EtOAc. The organics were separated and dried and concentrated in vacuo to give 3-methyl-4-(oxetan-3-yloxy)benzoic acid. ESI-MS m/z calc. 208.1. found 209.3 (M+1)+; Retention time: 1.04 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23].Cl>CCCCCC.C(OCC)(=O)C.C(Cl)Cl>[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cc1ccc(N)cc1NC(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C)c(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(5-Amino-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (3.27 gm 14.99 mmol) was taken up on anhydrous DCM (75 mL) and cooled to 0EC. Pyridine (3.56 g, 44.97 mmol, 3.64 mL) was added followed by a slow addition of acetyl chloride (1.18 g, 14.99 mol, 1.07 mL). The reaction was allowed to warm to room temp and stir for 30 min. The reaction mixture poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane/ethyl acetate) Yield 2.93 g. 1H NMR (CDCl3, 300 MHz) δ 2.13 (s, 3H), 2.23 (s, 3H), 7.25 (d, J=9 Hz, 1H), 7.23 (d, J=9 Hz, 1H), 7.61 (s, 1H).
Reaction SMILES: C(O)(C)C.[S:5](=[O:9])(=[O:8])([OH:7])[OH:6].COS([O-])(=O)=O.[CH2:16]([N+:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])([CH3:36])[CH3:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[S:5](=[O:7])(=[O:6])([OH:9])[O-:8].[CH2:37]([N+:34]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:36])[CH3:35])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: O=S(=O)(O)O
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: COS(=O)(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])O
Temperature: 840 °C
Reaction time: 4 h

Procedure:
Seventy-five (75) kilograms of isopropyl alcohol and 25 kilograms of deionized water were charged in a 50 gallon glass lined reactor. The reactor agitator (three armed retrieve curve impeller) was started at 100 RPM and full cooling (water at 8° to 10° C.) was applied to the reactor jacket. Eighteen (18) kilograms of 93 percent sulfuric acid (technical grade) were added slowly to the reactor, after which 30 kilograms of technical grade distearyl dimethyl ammonium methylsulfate (obtained from Zeeland Chemical Co., d Cambrex Company formerly Hexcel Company of Zeeland, Mich.) were charged in the reactor. The reactor loading port was closed and cooling water was applied to the reactor reflux condenser and the agitator speed adjusted to 150 RPM. The reactor was heated to approximately 840° C. using hot water supplied to the reactor jacket. The reaction was effected for 4 hours under a slight reflux after which cooling was applied to initiate the crystallization. The mixture was agitated for two hours under full cooling at 16° to 18° C. before transferring to a 70 gallon agitated Nutsche vacuum filter. The filtrate was drained and collected in a storage vessel for solvent recovery or disposal. The wet cake was reslurried with 100 kilograms of the second wash filtrate from the previous batch (containing an approximate 75:25 ratio of isopropanol and water) for 30 minutes, after which the filtrate (about 100 kilograms) was drained by vacuum filtration and collected in order to be used as the solvent system for the next synthesis batch. After additional reslurry washes were performed using wash filtrates from a previous batch, the wet cake was discharged from the filter and recrystallized from 100 kilograms of isopropanol In a 50 gallon glass lined reactor. This was performed by dissolving the materials under agitation at 600° C., cooling and recovering the wet dimethyl distearyl ammonium bisulfate cake by filtration. After vacuum drying, 22.27 kilograms (75.8 percent yield) of recrystallized distearyl dimethyl ammonium bisulfate were recovered. Analyticals: melting point (DSC) 91.4° C., H2O content 0.65 percent, bisulfate content (by titration) 14.65 percent.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[C:15](=C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)=[O:35]>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:35])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
Following the ozonization procedures described in Example 9, a solution of 350 mg. of p-nitrobenzyl 7-phenylacetamido-3-methylenecepham-4-carboxylate in 250 ml. of methylene chloride was cooled to -78° C. and was ozonized. The intermediate ozonide was decomposed in situ with sulfur dioxide and the reaction product was recovered and obtained crystalline by extraction with ethyl acetate.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:14]>CCOCC.CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14]
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
2 M HCl in Et2O (1.8 L) was added to a solution of compound 7a (92.8 g, 0.24 moles) in MeOH (500 mL). The mixture was stirred for 3 hours at room temperature then the resulting solid was filtered and dried to give 5-methoxy-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide hydrochloride 7b (61.1 g, 89% yield).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:36][CH3:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:28][C:27]([C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[O:29])[CH3:37]
Reactant: CCI
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of Example 598, (0.05 g, 0.11 mmol) in DMF (1 ml) under N2 was added iodoethane (0.062 ml, 0.33 mmol) and Cs2CO3 (0.036 g, 0.11 mmol). The mixture was stirred overnight, diluted with EtOAc, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, acetone/dichloromethane gradient) gave the title compound (0.043 g, 80%). MS(FIA) (m/z) 488.4 [M+1].
Reaction SMILES: [CH2:1]([OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:30]([O:24][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: OCCCCCCCCCCCCCCCCCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Yield: 83.2 %

Procedure:
1,22-Docosanediol 1 (2.00 g, 5.84 mmol) and imidazole (0.817 g, 12.0 mmol) were placed in each of two nitrogen-purged 150 mL three-necked flasks fitted with a thermometer and magnetic stir bar. The flasks were resealed and purged with nitrogen. Dimethylformamide (40 mL) was added to each flask and the cloudy mixtures were heated until they became homogenous at 63° C. tert-Butyldimethylsilyl chloride (0.904 g, 6.00 mmol, in 10 mL DMF) was slowly added to the reaction mixture (the transfer was aided with an additional 5 mL of DMF) and the mixture was allowed to react for 24 hours at 60°-65° C. The solutions were cooled down to room temperature and filtered to recover starting material using water (25 mL) to aid in transfer. The filtrate was diluted with water (300 mL) and extracted with methylene chloride (500 mL). The organic layer was dried (Na2SO4) and concentrated. A very low mass balance led to the discovery that much of the desired material was contained in the recovered solid that had been previously filtered off. None of the desired compound was found in the aqueous wash by TLC. The recovered solid was suspended in methylene chloride (100 mL), stirred, and refiltered. The filtrate was combined with the previously isolated material and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% ethyl acetate/hexane). Concentration of the desired fractions using acetone to reduce violent bumping yielded the desired material 2 as a white solid (2.22 g, 46.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:18]([C:17]2[CH:16]=[N:15][N:11]3[C:12]([CH3:14])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:27]=[CH:26][CH:25]=1)(=[O:29])(=[O:30])[NH2:31]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 442.4 [(M+H)+]; mp 308-310° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:13]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)C2C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-1,3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53) in THF (20 mL) is added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise addition of 2.5M n-BuLi (4.16 mL, 10.4 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (405 μL, 6.5 mmol) and let stir for 20 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 45% ethyl acetate/hexanes) to give 679 mg of title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[NH:20][CH2:19][CH2:18][NH:17][C:16]2=[O:21])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH:22](OCC)=[O:23]>>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:20]([CH:22]=[O:23])[CH2:19][CH2:18][NH:17][C:16]2=[O:21])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(C2NCCNC2=O)cc1
Reactant: CCOC=O
Product: CCN(CC)CCOc1ccc(C2C(=O)NCCN2C=O)cc1

Procedure:
29.2 g (0.1 mol) of 3-(4-diethylaminoethoxyphenyl)-piperazin-2-one are acylated by boiling with ethyl formate and the mixture is worked up, as described in Example 5. After being worked up, the product is precipitated as the salt of naphthalene-1,4-disulphonic acid by adding this acid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[C:14]([O:21][CH3:22])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[F-].[K+].[OH-].[Na+]>CN(C=O)C>[CH2:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=2[O:21][CH3:22])[N:9]=1)[CH3:11]
Reactant: COc1c(O)cccc1C=O
Reactant: CCc1ccc(C#N)c(Cl)n1
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C#N)c(Oc2cccc(C=O)c2OC)n1
Reaction time: 16 h
Yield: 62 %

Procedure:
2-Chloro-6-ethylnicotinonitrile (0.27 g, 1.6 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.25 g, 1.6 mmol) and potassium fluoride (0.29 g, 4.9 mmol) were heated with stirring in dry DMF (4 mL) at 120° C. for 6 h, then at 80° C. for 16 h. The reaction mixture was cooled, poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 6-ethyl-2-(3-formyl-2-methoxy-phenoxy)-nicotinonitrile (0.28 g, 61%) as a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(N2CCOCC2)cc1
Product: CN(C(=O)Oc1ccc(N2CCOCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from and 4-morpholin-4-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was extracted with dichloromethane from citric acid (5%). The combined organic phases were evaporated and the product crystallized from ethanol (22%, crystals). HPLC-MS: m/z=313.2 (M+1); Rt: 3.75 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[O:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=2)[CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cc(NC=NN)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NN=CNc1cc(C(=O)NCC(=O)NC(CC(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To 600 mg (0.00082 mole) of the product of Example 38 in 12 ml of H2O and 12 ml of CH3CN was added 140 mg (0.0033 mole) of LiOH. The reaction was stirred at room temperature for 1.5 hours. The pH was lowered to 2.5 with TFA and the product isolated by reverse phase prep HPLC to yield (after lyophilization) 520 mg of (±) β-[[2-[[[3-[(aminoiminomethyl)amino]-5-(trifluoromethyl)phenyl]carbonyl]amino]acetyl]amino]-3,5-bis(trifluoromethyl)benzenepropanoic acid, trifluoroacetate salt as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[C:10]([CH:25]=O)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].Cl>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[C:10]([CH:25]=[N:34][OH:35])=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)Cc2c(C=O)c(-c3ccccc3)n(Cc3ccccc3)c21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1CN(Cc2ccccc2)Cc2c(C=NO)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of the compound from Example 13 (1.0 g) hydroxylamine hydrochloride (0.5 g) and anhydrous pyridine (50 ml) was stirred at room temperature for 18 hours and poured into 2N hydrochloric acid (500 ml). A gummy precipitate was formed, which was separated and crystallised by heating with methanol to give the oxime (0.9 g) M.pt 171°-2°C. (Found: C, 80.3; H, 6.9; N, 9.6. C29H29N3O requires: C, 80.0, H, 6.7; N, 9.6%).