Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:42]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([O:40][CH3:41])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)#[N:43]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of methyl 14-cyclohexyl-7(R,S)-({[(4-methylphenyl)sulfonyl]oxy}methyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.35 M) in DMF was treated with NaCN (1.2 eq) and the resulting mixture was stirred overnight at RT. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc. The combined organic layers were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 9:1) affording the product as a yellow foam (90%). (ES+) m/z 429 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:27]([O:29][C:30](=[O:35])[CH:31](Br)[CH2:32][CH3:33])[CH3:28].C([O-])([O-])=O.[Na+].[Na+].O>CN1CCCC1=O>[CH2:32]([CH:31]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:30]([O:29][CH2:27][CH3:28])=[O:35])[CH3:33]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 75 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
A mixture of 2,4-dihydro4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol), 2-bromo-butanoic acid ethyl ester (0.055 mol) and Na2CO3 (0.15 mol) in 1-methyl-2-pyrrolidinone (250 m1) was stirred at 75° C. over 2-Bromobutanoic acid ethyl ester (0.015 mol) was added again. The mixture was stirred at 75° C. for 6 hours, at room temperature for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The solution was filtered. The filtrate was dried, filtered and the solvent was evaporated. The residue was triturated in diisopropylether and ethylacetate, filtered off and dried, yielding 10 g (43%) of (±)-ethyl α-ethyl-4,5-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]phenyl]-5-oxo- 1H-1,2,4-triazol-1-acetate (interm. 1).
Reaction SMILES: CO[C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1.[N:19]#[C:20][NH2:21]>CO>[C:20]([NH:21][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1)#[N:19]
Reactant: COC(=N)CCCCc1cc(CN(C)C)ccn1
Reactant: N#CN
Solvent: CO
Product: CN(C)Cc1ccnc(CCCCC(=N)NC#N)c1
Reaction time: 8 h

Procedure:
Methyl-5-(4-dimethylaminomethyl-2-pyridyl)pentanoimidate is added to a methanol solution of cyanamide. After standing overnight N-cyano-5-(4-dimethylaminomethyl-2-pyridyl)pentanoamidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1

Procedure:
The above bis(4-fluorophenyl)(pyridin-4-yl)methanol (0.73 g, 2.45 mmol) was hydrogenated (60 pounds per square inch) in the presence of platinum oxide (0.1 g) catalyst in acetic acid (15 mL) for 6 hours at room temperature. The reaction mixture was filtered and concentrated. The concentrated filtrate was diluted with ice/water (20 mL) and neutralized with 10% aqueous sodium carbonate. The title product was collected by filtration. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46-7.54 (m, 4H), 7.051-7.13 (m, 4H), 5.35-5.45 (bs, 1H), 2.87-2.97 (d, J=6.2 Hz, 2H), 2.45-2.56 (m, 3H), 1.24-1.38 (m, 2H), 1.16-1.22 (m, 2H); MS (DCI/NH3) m/z 304 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2nc(CCCCCBr)oc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(CCCCCC#N)oc2-c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
A solution of 5 g of 4,5-Bis(4-methoxyphenyl)-2-(5-bromopentyl)oxazole in 23 cm3 of ethanol and 1.1 g of potassium cyanide dissolved in 9 cm3 of water are brought to reflux for 15 hours. After evaporation of the solvent, the organic/inorganic residue is dissolved in 40 cm3 of diethyl ether and 10 cm3 of water, and the ether phase is separated and washed with 10 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness. The viscous residue (4.4 g) is chromatographed on a column of useful diameter 2 cm containing 80 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diazopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.2 and 1.2 liters are concentrated to dryness. 3.5 g (80%) of 6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexanenitrile are obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]([O-:4])([OH:3])=O.[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.O=[C:18]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)C2.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:3]=[C:1]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:20][CH:19]([CH2:27][CH:23]([CH2:22]3)[O:4]1)[CH2:18]2
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
Solid NaHCO3 (0.3 mol) and mCPBA (0.3 mmol, 77% purity) were added to a solution of ketone 1C (0.19 mmol) in DCM (5 mL) t 0° C. The reaction mixture was allowed to warm to rt and was maintained for 1 h. The reaction mixture was diluted with a saturated, aqueous solution of sodium bisulfate (10 mL) and was extracted with DCM (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (10/90 to 30/70 EtOAC/hexane) to provide lactone 13A in 85% yield. Data: LC/MS (ESR) m/z 282 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=O.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[CH:20]=1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(C=O)c1
Reactant: Nc1cccnc1
Product: C[Si](C)(C)CCOC(=O)c1cccc(CNc2cccnc2)c1
Yield: 77 %

Procedure:
By using 500 mg of 2-(trimethylsilyl)ethyl 3-formylbenzoate and 188 mg of 3-aminopyridine, the reaction similar to Preparation Example 14 was performed, thereby obtaining 505 mg of 2-(trimethylsilyl)ethyl 3-[(pyridin-3-ylamino)methyl]benzoate.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:26]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:23])[S:19][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-c2cn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylic acid (62.5 mg) in DMA (2 mL) were added EDCI hydrochloride (43.8 mg) and HOBt ammonium salt (34.7 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (55.9 mg).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)(c2ccccc2C)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCC(CN)(c2ccccc2C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Cyano-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine (504 mg) was dissolved in ethanol (10 ml), added with 10% palladium/carbon (500 mg) and 5 N aqueous hydrochloric acid (0.74 ml) and stirred at room temperature for 15 hours under hydrogen gas pressure (30 psi) by using Paar apparatus. Insoluble solids were removed by filtration, and then ethanol was evaporated under reduced pressure. The residue was added with dichloromethane (50 ml) and adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate. The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([C:33]4[C:34]([F:36])=[C:35]5[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:38])[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCNCC3)C(=O)O1
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCN(c2c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c2F)CC3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI) AP+, 567. NMR (DMSO6)1. 1-1.22 (m, 4H), 1.78 (s, 3H), 3.0 (m, 4H), 3.35 (m, 6H), 3.65 (m, 1H), 4.05 (m, 2H), 4.65 (m, 1H), 7.13 (d, 1H), 7.26 (dd, 1H), 7.35 (d, 1H), 7.78 (d, 1H), 8.17 (t, 1H), 8.62 (s, 1H).
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22](O)=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3].CN(C)C=O.S(Cl)([Cl:35])=O>ClCCl>[F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22]([Cl:35])=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc2c(O)c(C(=O)O)ccc12)c1cccc(S(=O)(=O)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(O)c(C(=O)Cl)ccc12)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C

Procedure:
5-(3-Fluorosulphonylbenzamido)-1-hydroxy-2-naphthoic acid (11) (10 g, 26 m.mole) was suspended in dry dichloromethane (200 ml), containing dimethylformamide (0.5 ml) and thionyl chloride (10.8 g, 91 m.mole). The mixture was heated under reflux with stirring for 2.5 hours, during which time the required acid chloride had crystallized as a pale yellow solid. After cooling to 5° C., the acid chloride was removed by filtration and washed with a little cold, dry dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[Cl:13][CH2:14][C:15]1[N:12]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:11][CH:17]=1
Reactant: NC(=O)/C=C/c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Product: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
The (E)-3-(4-fluorophenyl)-2-propenamide (17.55 g) thus obtained and 1,3-dichloroacetone (12.85 g) were molten at 130° C. and stirred for 1.5 hours. After the reaction mixture was cooled to room temperature and extracted with ethyl acetate, it was washed with ice water, saturated aqueous sodium bicarbonate, and saturated saline. After drying with anhydrous sodium sulfate, the solvent was distilled off; the residue was purified by column chromatography (eluent: diethyl ether-hexane=1:9→3:17) to yield the titled compound (10.5 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N1CCOCC1)C>ClCCl>[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:10])[CH3:11])=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(N)cc2)ccc1-c1cnco1
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(NC(C)=O)cc2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of 30 mg (0.074 mmol) of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, 8 mg (0.078 mmol) of acetic anhydride and 17 mg (0.15 mmol) of N-ethylmorpholine in 1 ml of dichloromethane was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue triturated with diethyl ether and collected by filtration to give 14 mg of N-[2-(4-acetamidophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 451 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].CO[C:9]1[CH:18]=CC=C2[C:10]=1CC(NCCCCC1C3(CCCCC3)C(=O)NC1=O)CO2.[CH3:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH:41]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]1[C:57](=[O:58])[C:56]3([CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)[CH2:55][C:54]1=[O:64])[CH2:42][O:43]2>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:10]([N:48]([CH2:49][CH2:50][CH2:51][CH2:52][N:53]1[C:57](=[O:58])[C:56]2([CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)[CH2:55][C:54]1=[O:64])[CH:41]1[CH2:40][C:39]2[C:44](=[CH:45][CH:46]=[CH:47][C:38]=2[O:37][CH3:36])[O:43][CH2:42]1)[CH2:9][CH3:18]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCC1C(=O)NC(=O)C13CCCCC3)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 29, but replacing the compound of Example 28 by the compound of Example 30, the product of the title is obtained.
Reaction SMILES: O[C@@H](C1C=CC=CC=1)[C@@H](N(C)[C:6](=[O:18])[C@H:7]([NH2:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[OH2:26]>>[NH2:17][C@H:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:18])=[O:26]
Reactant: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Reactant: O
Product: N[C@H](CCCc1ccccc1)C(=O)O

Procedure:
A solution of the compound of Example 199, Step A (400 mg, 1.18 mmol) in water (10 mL) was heated to reflux for 20 h. The reaction was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were back extracted with water (2×20 mL) and the combined aqueous extracts were concentrated down to a white solid. The solid was triturated with EtOH to remove residual pseudoephedrine and deliver Example 199, Step B (135 mg, 60%): +APcI MS (M+1)+ 194.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CO.CCOCC>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[C:19]=1[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1cccc(C)c1NC(=O)CCCn1ccnc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(C)c1NCCCCn1ccnc1

Procedure:
A solution of 27.27 g of N-(2,6-dimethylphenyl)-1H-imidazole-butanamide hydrobromide salt in 250 ml of dry tetrahydrofuran was added dropwise with stirring to 530 ml of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for 2 hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautious addition of 285 ml of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined organic layers were dried with potassium carbonate and concentrated to give 25.1 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-butanamine as an oil which was dissolved in 200 ml of methanol, treated with 23.9 g of fumaric acid and diluted with 600 ml of ether. The resulting solid amounted to 37.0 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-butanamide (E)-2-butenedioate(1:2) salt, mp 146°-147° C. Recrystallization from methanol-ether gave the analytical sample, mp 148°-149° C.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)([O-:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[NH:10][CH:9]=2)=[CH:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 65 °C
Yield: 72 %

Procedure:
To a stirred solution of sodium (2.51 g, 105 mmol, 7 eq) in absolute methanol (50 mL) was added 5-nitroindole (2.43 g, 15.0 mmol) and N-t-butoxycarbonyl4-piperidone (8.96 g, 45.0 mmol, 3.0 eq). The resulting reaction solution was heated at reflux (65° C.) under nitrogen for 24 hours. The resulting reaction solution was evaporated under reduced pressure, and the residue was partitioned between a saturated solution of sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was removed, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the extraction residue using silica gel (approximately 100 g) and elution with ethyl acetate in hexanes [1:2 to 1:1 gradient] afforded the title compound (72%) as yellow solid: mp, decomposes 230° C.; 1H NMR (CDCl3) δ 9.24 (br s, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.09 (dd, J=1.4 and 9.4 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 6.17-6.15 (m, 1H), 4.16-4.13 (m, 2H), 3.68 (t, J=5.8 Hz, 2H), 2.58-2.48 (m, 2H), 1.50 (s, 9H); Anal. calcd for C15H21N3O4.0.1 H2O: C, 62.63; H, 6.19; N, 12.17. Found: C, 62.71; H, 6.09; N, 11.81.
Reaction SMILES: [Cl:1]Cl.[Si:3]([O:10][CH:11]([CH:13]1[CH:16](SC)[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Si:3]([O:10][CH:11]([CH:13]1[CH:16]([Cl:1])[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C1SCC(=O)S1
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C2SCC(=O)S2)C1Cl
Reaction time: 0.5 h

Procedure:
A solution of an equimolar amount of chlorine in carbon tetrachloride was added to a solution of p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-(4-oxo-1,3-dithiolan-2-ylidene)acetate (134 mg) in methylene chloride (3 ml), with ice cooling. The solution was stirred at that temperature for 30 minutes and then solvent was distilled off to afford the desired product quantitatively.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[C:10]([CH2:23]O)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21].CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:10]([CH2:23][C:1]#[N:3])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Triethylamine (0.12 ml, 0.87 mmol, 2.0 equiv) was added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol (109 mg, 0.44 mmol) in CH2Cl2 (1.5 ml). At −25° C., a solution of methanesulfonyl chloride (0.05 ml, 0.66 mmol, 1.5 equiv) in CH2Cl2 (1.5 ml) was then added dropwise. After 15 minutes at 0° C., cold water (4° C., 10 ml) was added, and the mixture was extracted with CH2Cl2 (2×40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mesylate was dissolved in N,N-dimethylformamide (2 ml) and treated at 0° C. with potassium cyanide (39 mg, 0.60 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 hours, until TLC analysis indicated complete conversion. After dilution with water (50 ml), the mixture was extracted with CH2Cl2 (2×200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 100:0 to 80:20) afforded the title compound (54 mg, 48%, mixture of 2 regioisomers). The regioisomers could be separated by preparative HPLC. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile: 1H NMR (400 MHz, CDCl3): δ=8.20 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H), 7.55 (dd, J=8.4/6.6 Hz, 1H), 4.59 (s, 2H), 3.96 (s, 2H), 2.78 (s, 6H). MS (ES+): 259 (M+H)+.