Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:40]3([F:39])[CH2:42][CH2:41]3)=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1(F)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(F)CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, 1-fluorocyclopropanecarbonyl chloride (20 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions, and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.5 mg, 89% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=O)[CH3:20].O.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH3:20][C:19]1[N:1]([C:2]2[C:10]3[O:9][C:8]4[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cccc2c3c(oc12)CCCC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1-c1cccc2c3c(oc12)CCCC3
Yield: 72.1 %

Procedure:
A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg), 2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol (3 ml) was refluxed for 1 hour and poured into water. The mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethanol and water to give 6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg).
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].O>>[C:1](=[O:7])([OH:3])[OH:2].[NH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: O=C=O
Solvent: O
Solvent: OCCNCCO
Product: O=C(O)O

Procedure:
Carbon dioxide was introduced into a mixture of diethanolamine (900 g=8.57 mol) and 80 g of water (4.44 mol) until saturation. In the course of 75 minutes, 73 l of CO2 (3.26 mol) were introduced into one sample and 72 l (3.21 mol) into another sample. The reaction temperature rose to 63° C. without cooling.
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S@@:39]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:41]2[CH:42]=[CH:43][C:44]([NH2:45])=[CH:46][CH:47]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: CCCn1cncc1C[S@](=O)c1ccc(N)cc1
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline di-p-toluoyl-D-tartrate monohydrate (494 mg) was dissolved in ethyl acetate (5 ml) and 1 N hydrochloric acid (2.52 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.52 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, and then the solvent was again distilled off under reduced pressure to give (S)-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. Then, to a solution of 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylic acid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, and then oxalyl chloride (0.065 ml) was added at 0° C. The mixture was returned to room temperature and stirred for 30 minutes under a nitrogen atmosphere, and then the resulting solution was added dropwise to a solution of (S)-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine (1.2 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was returned to room temperature and stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated brine once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resultant was separated and purified by basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:20) to give (S)-3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline]-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxamide (199 mg) (Compound 3) as a yellow amorphous material.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([Cl:47])=[C:42]([N+:44]([O-])=O)[CH:43]=1)(=[O:38])=[O:37])(C)(C)C>>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([Cl:47])=[C:42]([NH:44][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:43]=1)(=[O:37])=[O:38]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: NCCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and [2-(4-amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.17) according to general procedure II and subsequent removal of the protecting group with trifluoroacetic acid in dichloromethane at 0° C. for 3 h. Orange solid. MS (ISP) 595.0 [(M+H)+]; mp 150° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:26]([NH:28][C:29]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:30])[CH3:27]
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
A solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) in THF (1.5 mL) was added with triethylamine (11 μL, 0.08 mmol) and ethyl isocyanate (40.3 μL, 0.51 mmol), followed by stirring at room temperature for 5 hours. Further, the reaction mixture was added with potassium carbonate, stirred for 30 minutes and added with water. The precipitated solid was collected by filtration and the solid was triturated in ethanol to obtain Compound 21 (53 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[C:28]([Cl:44])[CH:27]=2)([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[N:45]1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)(C)CCCO)=CC=1>>[Cl:44][C:28]1[CH:27]=[C:26]([C:20]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[C:2]([Cl:1])[CH:3]=2)([CH3:25])[CH2:21][CH2:22][CH2:23][O:24][NH2:45])[CH:31]=[CH:30][C:29]=1[O:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CC(CCCON)(c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
The desired compound was prepared according to the method of Example 5, steps 1 and 2, except substituting 4,4-bis(3-chloro-4-(2-quinolylmethoxy)phenyl)pentan-1-ol, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:19][OH:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: ON=Cc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a suspension of 4-(4-fluoro-benzyloxy)-benzaldehyde (21.9 g, 95.2 mmol) and hydroxylamine hydrochloride (7.3 g, 105 mmol) in 400 mL water/ethanol 9:1 was added a solution of NaOH (9.5 g in 100 mL of water) dropwise over 15 min. The now yellow solution was stirred for 2 h at rt after which the reaction was adjusted to pH 5-6 with acetic acid. The resulting white precipitate was collected by filtration and washed with water. The wet filter cake was dissolved in ethyl acetate and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(4-fluoro-benzyloxy)-benzaldehyde oxime (23.5 g, 95.8 mmol) as a yellowish crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccccc1-c1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccccc1-c1ccccc1C
Yield: 45.7 %

Procedure:
The above compound, 2-amino-2′-methyl-biphenyl (11.0 g, 60 mmol) was added to dry toluene (250 mL) containing triethyl amine (24 g, 24 mmol) and stirred under a nitrogen pad. Ethyl chloroformate (26 g, 240 mmol) was slowly added to the stirred solution via a syringe. The reaction mixture was washed with brine and the organics separated, dried over magnesium sulfate and concentrated to give N-ethoxycarbonyl-2-amino-2′methyl biphenyl as a colorless oil (7.0 g, 46% yield) whose structure was confirmed by GCMS and NMR.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[CH:19]([O:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([Cl:30])[C:27](Cl)=[N:26][CH:25]=1)([CH3:21])[CH3:20].O>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:27]1[C:28]([Cl:30])=[CH:29][C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:32])=[CH:25][N:26]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)OC(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
NaH (60% dispersion in mineral oil, 0.23 g, 12.0 mmol) was washed (2×) with hexanes then suspended in THF (10 mL) to which 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.89 g, 4.0 mmol) in THF solution was added. The solution was stirred at room temperature for 10 minutes at which time isopropyl-5,6-dichloronicotinate (1.00 g, 4.3 mmol) in THF solution was added. After 15 minutes of stirring at room temperature, the solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL) . The organics were dried over MgSO4 and concentrated to 1.5 g tan, viscous oil. Crude product was chromatographed using silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 petroleum ether/ethyl acetate as the mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(isopropoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.72 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([NH2:29])=[O:28].C(N(CC)CC)C>COCCO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][NH:21][CH:22]([C:27]([NH2:29])=[O:28])[CH2:23]2)=[CH:8][CH:9]=1
Reactant: NC(=O)C1CNCCN1
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCO
Product: NC(=O)C1CN(CCCCN(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 70 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 17.7 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 23.3 parts of 2-piperazinecarboxamide, 17.6 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 48 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water and a small amount of methanol. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume). The product was filtered off and dried, yielding 12.82 parts (55.0%) of 4-[4-[bis(4-fluorophenyl)amino]butyl]-2-piperazinecarboxamide; mp. 67.4° C. (int. 28).
Reaction SMILES: Cl.[NH2:2]O.[CH:4]([O-:6])=O.[Na+].ClC1[C:18]([CH:19]=O)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>C(O)=O>[C:19]([C:18]1[C:4](=[O:6])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[N:2]
Reactant: NO
Reactant: O=C[O-]
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc2ccccc2[nH]c1=O
Temperature: 110 °C

Procedure:
A mixture was prepared from 6 liters of 97% formic acid, 300 g of hydroxylamine hydrochloride, 500 g of sodium formate, and 700 g of 2-chloro-3-quinolinecarboxaldehyde and this mixture was heated to reflux (110° C.). The resulting solution was then maintained at 110° C. for 18 hours. The solution was then cooled and the solid which crystallized was separated by filtration and then successively washed twice with water, once with ethanol and once with methylene chloride to give 3-cyano-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[S:9])=[CH:4][CH:3]=1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C[O:52]CC1.N(C(OCC)=O)=NC(OCC)=O>CO>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH3:30])[CH:11]=2)=[S:9])=[CH:4][CH:3]=1.[C:43]1([P:36](=[O:52])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Oc1c(C(=S)NCc2ccc(Cl)cc2)cnc2ccc(CN3CCOCC3)cc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Product: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flame-dried flask is charged with N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarbothioamide (0.060 g) from Preparation No. 47, triphenylphosphine (0.045 g), and freshly distilled THF (1.5 mL). To this solution is added methanol (8.00 μL) and diethyl azodicarboxylate (28.00 μL). The reaction is stirred at room temperature for 18 h. Monitoring of the reaction still shows a significant amount of starting material left. Additional PPh3 (0.025 g), methanol (5.00 μL), and diethyl azodicarboxylate (14.00 μL) are added and the reaction is stirred for 18 h. Since monitoring of the reaction still shows some starting material, 10 equivalents each of PPh3, methanol, and diethyl azodicarboxylate are added. A reasonable exotherm is seen after adding diethyl azodicarboxylate. The reaction is immediately monitored by TLC and starting material is consumed. The solvents are removed and the residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by column chromatography (eluent CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (2 L), 4% MeOH:CH2Cl2 (1 L), 7% MeOH:CH2Cl2 (1 L)) affords the title compound contaminated with triphenylphosphine oxide. These fractions are combined and concentrated and the residue is again adsorbed onto silica. Purification by a second chromatography (eluent 1:1 hexanes:ethyl acetate (1 L), 45:55 hexanes:ethyl acetate (1 L), 4:6 hexanes:ethyl acetate (1 L), 35:65 hexanes:ethyl acetate (1 L), 1:3 hexanes:ethyl acetate (1 L), 2:8 hexanes:ethyl acetate (1 L), 1:9 hexanes:ethyl acetate (1 L), 100% ethyl acetate (1 L), 2% MeOH:CH2Cl2 (1 L), 4% MeOH:CH2Cl2 (1 L)) affords the title compound as a light yellow residue. The residue is dissolved in CH2Cl2 and hexanes are added until cloudy. The solution is placed in the freezer overnight and the title compound as a solid is subsequently filtered and dried (0.020 g).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:18][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:20]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
0.73 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (b) above] was dissolved in 1.53 ml of anisole, and 7.25 ml of trifluoroacetic acid and 0.25 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 90 minutes, after which 1,2-dichloroethane was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The resulting residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 420 mg of the title compound, in the form of an amorphous powder.
Reaction SMILES: C([CH:4]([CH2:10][CH2:11][C:12](=[O:23])[CH:13]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:14](=O)[CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.C(N(CC)CC)C.O>CO>[CH2:8]([O:7][C:5]([CH:4]1[CH2:10][CH2:11][C:12](=[O:23])[C:13]([C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[C:14]1[CH3:15])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(CCC(=O)C(C(C)=O)c1cc(C)no1)C(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCC(=O)C(c2cc(C)no2)=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
0.85 g of the obtained ethyl 2-acetyl-5,7-dioxo-6-(3-methylisooxazol-5-yl)octanoate was dissolved in 5 ml of methanol and 0.32 g of triethylamine was added. The resulting solution was stirred at room temperature for 2 hours and then heated at reflux for 3 hours. After cooling, water was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The obtained residue was purified on silica gel column chromatography to give 0.27 g of the title compound as a colorless liquid.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].C.Cl>O.C(O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.3 %

Procedure:
A solution containing 9.4 g of KCN in 20 ml of water is prepared and then it is poured dropwise over a mixture containing 20 g of 2-bromo-1-(4-bromophenyl)ethanone dissolved in 800 ml of 90% ethanol. After stirring for 5 hours at RT, the solid formed is filtered and then it is rinsed with ice-cold water. The solid obtained is dissolved in 400 ml of water and then activated charcoal is added, the mixture is kept stirring for 20 minutes, and then filtered on Celite®. The filtrate obtained is treated with HCl at 10% and the white precipitate formed is filtered, washed with water and then dried under vacuum. 7.63 g of the expected compound are obtained. m.p.=164° C.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH:2]([N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])[CH3:13])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: CC(Br)C(=O)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To 5.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)-1-propanone in 20 ml of N,N-dimethylformamide, 3.27 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), and the resulting organic layers were combined, washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.02 g of the desired crude product as brown crystals. The crystals were used in the next step without further purification.