Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[C:16]([Cl:26])=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2CCC(C)C)c1OC(C)=O
Yield: 55.8 %

Procedure:
A solution of 4-acetoxy-7-cyano-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.44 g, 1.28 mmol) and N-chlorosuccinimide (0.188 g, 1.41 mmol) in 8 mL of N,N′-dimethylformamide was heated at 100° C. for 1 h. Ethyl acetate (100 mL) was added. The organic solution was washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude produce was purified by flash chromatography from silica gel with a gradient of 0-40% ethyl acetate in hexanes to afford 0.27 g of the title compound as a white solid. MS: (+) m/z 378.3 (M+1).
Reaction SMILES: [OH:1][P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH:4]([NH:12]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].ClCCl>>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[NH2:12][CH:4]([P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])([OH:3])=[O:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 98 %

Procedure:
Phenylmethyl N- [2 -[[hydroxy [2 -phenyl-1-[[(tert-butoxy) carbonyl]amino]ethyl]phosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-phenylalaninate is treated with a trifluoroacetic acid/dichloromethane mixture for one hour at room temperature. The mixture is evaporated to dryness. The product obtained is precipitated from ether. The product is recovered in a yield of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([NH:33][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:4]=3)=[O:10])=[CH:19][CH:18]=2)=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: Nc1ccc(N)nc1
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,5-diaminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield N1-(6-aminopyridin-3-yl)-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[C:19]#[N:20]>C1COCC1>[NH2:20][C:19]([C:18]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=1[F:16])=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C=C(N)c1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Following the procedure of Huckin and Wilson (Can. J. Chem. 1974, p 1346), 850 mg of methyl acetoacetate (7.32 mmol, 1 eq.) were added slowly to a cooled (0° C.) and stirring suspension of NaH (60% dispersion in mineral oil, 1 eq.) in dry THF. When evolution of H2 had ceased (10 min.), 1.05 equivalents of n-butyllithium (2.5M in hexanes) were slowly added, producing an orange solution. After an additional 10 minutes at 0° C., 1 equivalent of 2-fluoro-5-methoxybenzonitrile (1.11 grams, 7.32 mmol) was added dropwise and the resulting red solution was allowed to come to room temperature. After stirring overnight (20 h) the reaction mixture was brought to 0° C. and quenched with 1.5 mL of 12M HCl followed by H2O (20 mL). The mixture was extracted with ether (4×) and the combined ether layers were washed (4×) with saturated aqueous NaCl solution, dried (Na2SO4) and concentrated to give a red oil. Purification via column chromatography (Silica gel, EtOAc/Hexanes eluent) afforded methyl 5-amino-3-oxo-5-(2-fluoro-5-methoxyphenyl)-pent-4-enoate as a pale yellow oil.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:20]1(/[CH:30]=[CH:31]\[C:32](O)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1(/[CH:30]=[CH:31]\[C:32]([N:15]2[CH2:16][CH2:17][C:18](=[O:19])[N:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)/C=C\c1cccc2ccccc12
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Product: O=C(/C=C\c1cccc2ccccc12)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (Z)-3-naphthalen-1-yl-acrylic acid gave the title compound as light yellow foam. MS: 420.1 (MH+).
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl.O.C(Cl)Cl.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]2[CH2:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:6])[CH2:7]2)(=[O:19])[CH3:18]
Reactant: O=C1CC2CCC(C1)N2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1C2CCC1CC(=O)C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([NH:28]C=O)[CH:19]=2)[C@H:13]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:12]1)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:42]>CO>[ClH:42].[NH2:28][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][C@H:13]1[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:31]
Reactant: O=CNc1cc(C(=O)N2CCN(C(=O)/C=C/c3ccccc3)C[C@H]2Cc2c[nH]c3ccccc23)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Nc1cc(C(=O)N2CCN(C(=O)/C=C/c3ccccc3)C[C@H]2Cc2c[nH]c3ccccc23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (2R)-4-(trans-cinnamoyl)-1-[3-formylamino-5-(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (280 mg) and aqueous 10% hydrochloric acid (1 ml) in methanol (10 ml) was stirred at room temperature for 6 hours. The mixture was evaporated under reduced pressure. The resulting powder was collected by filtration and dried to give (2R)-1-[3-amino-5-(trifluoromethyl)-benzoyl]-4-(trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazine hydrochloride (280 mg).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:15]([OH:18])[CH2:16]Cl)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.ClCCl>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:18][CH2:16]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A solution of potassium hydroxide (6.52 g. 0.1–16 mol, 1.2 equiv.) in 970 mL of absolute ethanol was treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32.3 g, 0.097 mol). This solution was stirred at room temperature for 15 minutes and then concentrated in vacuo to give a white solid. The solid was dissovled in dichloromethane and washed with water, dried over anhyd MgSO4, filetered and concentrated in vacuo to give a white solid. The solid was crystallized from hexanes and ethyl acetate to give 22.3 g, 77% of 3(S)-[N-(benzyloxycarbonyl)amino]-1,2(S)-epoxy-4-phenylbutane, mp 102–103° C., FAB MS: MH+=298.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[N:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15](=[O:22])[C:14]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=1.Cl>O1CCCC1>[CH3:10][C:11]1[N:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:15](=[O:22])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C)cc(Oc2ccccc2)c([N+](=O)[O-])c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.38 g (14.7 mmol) of phenol in solution in 20 ml of tetrahydrofuran are added dropwise to a suspension of 0.58 g (14.5 mmol) of sodium hydride in tetrahydrofuran. The mixture is left for 0.5 hour at room temperature, it is cooled to −70° C. and 5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(tri fluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate in solution in 20 ml of tetrahydrofuran are added dropwise. The temperature of the reaction medium is allowed to return to 0° C. and the medium is stirred at this temperature for 1 hour. The mixture is poured over 20 ml of a 1 N aqueous hydrochloric acid solution and extracted with twice 200 ml of dichloromethane. The medium is washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The product is recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][C:7](=O)[CH2:6]1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:12].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][C:7](=[S:12])[CH2:6]1)=[O:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C1CNC(=O)C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CNC(=S)C1

Procedure:
10 g of 4-methoxycarbonyl-pyrrolidine-2-one II (prepared as described in P. L. Paytash, E. Sparrow and I. C. Gathe, J. Am. Chem. Soc. 72, 1415 (1950)) were dissolved in 170 ml of absolute toluene under the influence of heat. 16.7 g of P4S10 ×4 pyridine (Riedel de Haen, Hanover, West Germany) and 42 g of kieselguhr (as a filtration aid) were then added in succession. The mixture was subsequently warmed at 90°-100° C. for 3 hours, while stirring and under nitrogen as an inert gas. The solid was then filtered off with suction and the residue on the filter was rinsed with hot toluene. The filtrate was concentrated in vacuo.
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[CH3:20][S:21]([C:24]1[CH:50]=[CH:49][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][NH:45]3)=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>O>[CH3:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[C:43]([CH:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:15]([NH2:14])=[O:16])=[CH:42][C:32]3[NH:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[N:35][C:31]=3[CH:30]=2)=[CH:49][CH:50]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of dimethylaminopyridine and 0.029 ml of trimethylsilyl isocyanate were added to a methylene chloride (1 ml) solution of 17.1 mg of 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7), and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:30][CH2:31][CH2:32][CH2:33]O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:33][CH2:32][CH2:31][I:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCCI
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) in tetrahydrofuran (100 mL) at 0° C. was added triphenylphosphine (22.6 g, 86.33 mmol), 3-iodopropanol (16.73 g, 89.93 mmol), and diethylazodicarboxylate (14.3 mL, 86.33 mmol). The resulting mixture was stirred at 25° C. overnight. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried and concentrated. The residue was triturated with 8:1 ether/ethyl acetate to induce the precipitation of 22 g of triphenylphosphine oxide which was separated by filtration. The filtrate was preabsorbed onto silica gel and flash-chromatographed (5:1 hexane/ethyl acetate) to afford 17.5 g (79%) of white solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](OC)=[O:32])=[CH:25][CH:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl.[NH2:43][C:44]1[NH:45][CH2:46][CH2:47][CH2:48][N:49]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31](=[O:32])[NH:43][C:44]2[NH:49][CH2:48][CH2:47][CH2:46][N:45]=2)=[CH:27][CH:28]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
438 mg of tert-butyl (2S)-2-(benzyloxycarbonylamino)-3-(4-(methoxycarbonylmethyloxy)benzoylamino)propionate, 606 mg of potassium tert-butoxide and 732 mg of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride were dissolved in 10 ml of absolute dimethylformamide, and the solution was stirred at room temperature for 14 h and then concentrated to dryness in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[CH:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(F)c(Cl)c1
Product: CC1Cn2c(cc(OCc3ccc(F)c(Cl)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3-chloro-4-fluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydro imidazo[1,2-c]pyrimidin5(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[NH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:16])[C:11]=2[C:12]=1[C:13]([OH:15])=O)([O-:3])=[O:2].[CH3:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[CH2:18]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:13]([C:12]2[C:11]3[C:10](=[O:16])[CH2:9][CH2:8][CH2:7][C:6]=3[NH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:15])=[CH:24][CH:25]=1)[CH3:17]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C1CCCc2[nH]c([N+](=O)[O-])c(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(NC(=O)c2c([N+](=O)[O-])[nH]c3c2C(=O)CCC3)cc1
Reaction time: 67 h
Yield: 18.6 %

Procedure:
A mixture of 2-nitro-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (0.18 g, 0.8 mmol), p-phenetidine (0.52 mL, 4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (767 mg, 4 mmol) in 50% aqueous dioxane (10 mL) was stirred for 67 hours, then concentrated in vacuo. Aqueous 3.6N hydrochloric acid was added, the mixture cooled in an ice water bath, and the precipitate collected, rinsed with water then diethyl ether, and dried. Purification on Silica gel (10% methyl alcohol/dichloromethane) gave N-(4-ethoxyphenyl)-2-nitro-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 56) (51 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)=CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (78 mg, 76%), MS (ISP) m/z=413.5 [(M+H)+], mp 164.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.C(OCC)(=O)C.[CH2:25]([OH:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([O:29][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCO
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110° C. for 4 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (3×50 ml), dried with sodium sulfate, filtered and concentrated in vacuo. The residue (2.2 g) was added dropwise at −10° C. to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at −10° C. under argon and then stirred for 20 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (10N; 100 ml) and extracted with dichloromethane, and the organic phase was dried over sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 239.23 (C11H13NO5); MS (ESI): 240 (M+H+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](Cl)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:18]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:18])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: N
Product: COc1ccc(C(N)=O)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
Vigorously stirred aqueous ammonia solution (70 mL; 32% w/w) is treated dropwise with warm molten 3-cyclopentyloxy-4-methoxybenzoyl chloride (25.7 g) during a period of 20 minutes, keeping the temperature below 20° C. Stirring is continued at 20° C. for 2 hours, and then the suspension is filtered. The resulting solid is washed with water until free of ammonia, and is then dried under vacuum at 40°-45° C., to give 3-cyclopentyloxy-4-methoxybenzamide (21.78 g), in the form of a buff solid.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:32])[CH2:29][C:24]2([S:28][CH2:27][CH2:26][S:25]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([OH:33])=[O:32])[CH2:29][C:24]2([S:25][CH2:26][CH2:27][S:28]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reaction time: 1 h

Procedure:
(S)-7-[[[(2,2-Dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (2.4 g) in dry dichloromethane is treated with 3.0 ml of trifluoroacetic acid under argon at room temperature. After 1 hour, the trifluoroacetic acid and dichloromethane are removed in vacuo and the resulting oil partioned between ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried (MgSO4) and evaporated. The residue (4.0 g) is chromatographed on 130 g of silica eluting with dichloromethane/acetic acid/methanol (18:1:1) to give (after azeotropic removal of acetic acid with toluene) 1.5 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])c(F)c1

Procedure:
To an acetonitrile (25 mL) solution of 3-fluoro-4-nitrophenol (1.57 g; 10.0 mmol) and potassium carbonate (2.09 g; 15.1 mmol), 4-bromo-1-butene (2.21 g; 16.0 mmol) was added, and the mixture was refluxed and then reacted overnight. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by column chromatography (solvent, hexane:methylene chloride=6:4) using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-2-fluoronitrobenzene (1g) (1.71 g, 81% of yield, a light yellow oil) represented by the following formula.