Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:10]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26].[H-].[Na+].CI>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:19]2[CH2:20][CH2:21][N:22]([CH3:2])[CH2:23][CH2:24]2)[N:10]1[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)N2c3cccc(N4CCNCC4)c3CCC2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N2c3cccc(N4CCN(C)CC4)c3CCC2C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.26 g (0.52 mmol) of 1,2,3,4-tetrahydro-2-methyl-5-(piperazin -1-yl)-1-(4-methylbenzenesulfonyl)quinoline prepared in example 14 and 67 mg (1.56 mmol, 45%) NaH was dissolved in 2 mL DMF at 0° C. After stirring 1 h at 0° C., the mixture was cooled to −78° C. and MeI was added (32 μL, 0.52 mmol). The reaction mixture was stirred over 1 night at room temperature After evaporating the solvent, the residue was dissolved in 15 mL water and extracted with EtOAc. The crude product was purified by column chromatography (eluent: CH2Cl2-MeOH 0.5%). Yield: 82 mg (38%) Rf=0.65 (CH2Cl2-MeOH 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[C:7](=O)[C:6]=2[CH:17]=1.[BH4-].[Na+].O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1CCSc2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-4-carboxylate (24.94 g) in THF (200 ml) was cooled to −20° C., and to the mixture was added dropwise a solution of sodium boro hydride (2.99 g) in methanol (30 ml). While the temperature of the mixture was kept at −15 to 20° C., the mixture was stirred for 1 hour. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue (24.38 g) was dissolved in THF (200 ml). To the mixture was added triethylamine (26 ml) and then to the mixture was added dropwise at 0° C. methanesulfonyl chloride (9.2 ml). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 15 hours. To the mixture was added dropwise 1,8-diaza-bicyclo[5,4,0]-7-undecene (17.9 g), and the mixture was stirred for 3 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:10). Under reduced pressure, the mixture was concentrated, and the resulting crystals were recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (11.00 g).
Reaction SMILES: [OH-].[K+].CO[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([O:9]CC)=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].S(=O)(=O)(O)O>CO>[OH:9][C:7]1[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C=C(OC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
A solution of 1 M potassium hydroxide in methanol (30 ml) is added to a cooled mixture of 5A (4.6 g), methyl thioglycolate (2.46 g) and methanol (10 ml). The resulting reaction mixture was stirred for 24 hours at room temperature. Then the mixture was poured on ice and acidified with 6N sulfuric acid (pH=2). The mixture is extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue is distilled under reduced pressure to yield the product as a clear liquid (3.4 g, 65 %) with a boiling point of 42-45 ° C. at 0.10 mm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2/[CH:13]=[C:17](/[C:16](=[O:15])[CH3:25])\[C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)/C(=C/c1cccc2c(=O)cc(C)oc12)C(=O)OCCC#N
Yield: 92 %

Procedure:
1.50 g (7.97 mmol) of the compound from Example 5A, 1.86 g (9.57 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)], 91 μl (1.59 mmol) of acetic acid and 158 μl (1.59 mmol) of piperidine are dissolved in 30 ml of anhydrous dichloromethane and stirred under reflux with a water trap overnight. The mixture is then washed with water, the organic phase is dried with magnesium sulfate, and the volatile components are removed in a rotary evaporator. 2.91 g (approx. 7.33 mmol) of the 2-cyanoethyl (2Z)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylidene]-3-oxobutanoate crude product obtained in this way are mixed with 0.990 g (9.00 mmol) of 4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)], taken up in 40 ml of 2-propanol and stirred at the reflux temperature overnight. After cooling, the resulting precipitate is filtered off and washed with a little diethyl ether. Drying under high vacuum results in 1.20 g (38% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH3:16])[CH:7]=1.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH2+:19]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[CH3:16][O:15][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH3:17])[CH:11]=[CH:10][C:9]=1[C:12](=[O:14])[CH3:13]
Reactant: C[C@@H]1CCC[NH2+]1
Reactant: COc1cc(OCCCCl)ccc1C(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: COc1cc(OCCCN2CCC[C@H]2C)ccc1C(C)=O
Yield: 57.2 %

Procedure:
In a 250 mL round bottom flask, 1-[4-(3-chloro-propoxy)-2-methoxy-phenyl]-ethanone (6.18 g, 25.5 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (12.4 g, 50.9 mmol), potassium carbonate (14.1 g, 102 mmol), and potassium iodide (20 mg, 0.12 mmol) in acetonitrile (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, then washed with water three times. The organics were extracted three times with 3% citric acid solution. The combined aqueous layers were basified with sat. NaHCO3 sol. and extracted with methylene chloride, then dried over MgSO4. The solvents were removed under vacuum to produce 4.25 g (57%) of oil. MS m/z 292 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:25]1[N:26]=[C:27]([NH:30]C(=O)C(F)(F)F)[S:28][CH:29]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].[Cl-].[Na+].Cl>O>[CH3:1][O:2][N:3]=[C:4]([C:25]1[N:26]=[C:27]([NH2:30])[S:28][CH:29]=1)[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.6 %

Procedure:
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.5 g.) was suspended in a solution of sodium acetate trihydrate (12.2 g.) in water (30 ml.). The mixture was stirred for 15 hours at ambient temperature. The reaction mixture was saturated with sodium chloride and adjusted to pH 5.0 with conc. hydrochloric acid with stirring and ice-cooling. Precipitating insoluble material was filtered off. The filtrate was adjusted to pH 3.0 with conc. hydrochloric acid and further adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.1 g.), mp 210° to 220° C. (dec.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[Br:11].S(=O)(=O)(O)O.N([O-])=O.[Na+].[C:21]([Cu])#[N:22].[C-]#N.[K+]>C(O)(=O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[C:3]([Br:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Br)c1
Reactant: N#C[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [C-]#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C#N)c(Br)c1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a solution of the product obtained in step 1 (9.50 g, 44.38 mmol) in acetic acid (160 mL) was added sulfuric acid (95%, 7.4 mL) at 0° C. After stirring for 10 min a solution of NaNO2 (3.06 g, 44.38 mmol) in water (30 mL) was added slowly. Stirring was continued for 30 min. The reaction mixture was added drop wise to a solution of CuCN (3.975 g, 44.38 mmol) and KCN (8.667 g, 133.1 mmol) in water (60 mL). Stirring was continued for 30 min at 0° C. and 2 h at RT. Then the reaction mixture was poured into water (400 mL). Filtration of the resulting suspension gave the desired product as red solid (5.7 g, 57%), which was used in the following step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CS(C)=O.O.C(OC(C)C)(C)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 74.4 %

Procedure:
A suspension of 1.2 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 1.4 g of 1-methylpiperazine and 20 cm3 of dimethyl sulphoxide is heated at a temperature close to 95° C. for 45 minutes. After cooling to a temperature close to 20° C., the reaction mixture is diluted with 100 cm3 of water and extracted with 3 times 30 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at a temperature close to 50° C. The solid obtained is taken up in 20 cm3 of diisopropyl ether, drained, washed with 10 cm3 of the same solvent and recrystallized from 150 cm3 of ethyl acetate. 1.1 g of 1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 223° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.FC(F)C(OC(=O)C(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[N:34]([C:2](=[O:1])[CH:4]([F:7])[F:5])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: O=C(OC(=O)C(F)F)C(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1C(=O)C(F)F

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol), 2,2-difluoroacetic anhydride (4.7 mg, 0.027 mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (90 μL) was stirred at room temperature for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.21 (d, J=7.1 Hz, 1.2H), 1.29 (d, J=6.6 Hz, 1.8H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.58-2.69 (m, 1H), 2.98-3.07 (m, 2.4H), 3.11-3.17 (m, 0.6H), 3.35-3.44 (m, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H), 4.11 (d, J=17.2 Hz, 1H), 4.42-4.51 (m, 1H), 4.60-4.67 (m, 0.6H), 4.73-4.77 (m, 0.4H), 5.05 (d, J=17.7 Hz, 0.6H), 5.11-5.18 (m, 0.4H), 5.89-6.22 (m, 1H), 6.39-6.73 (m, 1H), 6.85-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 517.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[OH-].[Na+].Cl>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of methyl [(3S)-6-({3′-chloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.676 g, 1.18 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from diethyl ether-ethyl acetate to give the title compound (0.418 g, yield 63%) as colorless crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N+:25]([C:28]1[CH:29]=[C:30]([CH2:34][C:35]([OH:37])=O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26].[C:38]([O:42][C:43]([N:45]1[CH2:49][C@@H:48]([CH2:50][N:51]([CH:68]([CH3:70])[CH3:69])[C:52](=[O:67])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=2)[C@H:47]([CH2:71][NH:72][CH:73]2[CH2:75][CH2:74]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[C:38]([O:42][C:43]([N:45]1[CH2:49][C@@H:48]([CH2:50][N:51]([CH:68]([CH3:69])[CH3:70])[C:52](=[O:67])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=2)[C@H:47]([CH2:71][N:72]([CH:73]2[CH2:74][CH2:75]2)[C:35](=[O:37])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=2)[CH2:46]1)=[O:44])([CH3:40])([CH3:41])[CH3:39]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc([N+](=O)[O-])c2)C2CC2)C(C)C)ccc1OC
Reaction time: 0.17 h

Procedure:
At 0° C. HBTU (426 mg, 1.12 mmol) is added to a solution of 3-nitrophenylacetic acid (187 mg, 1.03 mmol) in CH3CN (10 mL) and the resulting solution is stirred for 10 min. Then a solution of (3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.375 mmol). (500 mg, 0.94 mmol) and triethylamine (1.04 mL, 7.5 mmol) in CH3CN (10 mL) is added at 0° C. and the reaction mixture is stirred at RT for another 2 h. For workup a sat. solution of NaHCO3 is added and the mixture is extracted with ethyl acetate. Washing of the combined extracts with brine, drying (Na2SO4), filtration and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 9:1) to give the title compound. MS (LC-MS): 597.0 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mumin): 6.47 min.
Reaction SMILES: CS(C)=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][C:19]=2[N:20]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=[O:28])=[CH:21][C:19]=2[N:20]=1
Reactant: OCCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Oxalyl chloride[(COCl)2 ] (0.88 g) was added dropwise to a solution of dimethyl sulfoxide (DMSO) (1.0 g) in dichloromethane (30 ml) at -30° C. To the mixture was added 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]-propanol (2.0 g). The mixture was stirred for 30 minutes at the same temperature. To the mixture was added triethyl amine (3.19 g). The mixture was stirred for 30 minutes, warmed to 0° C. and poured into 2N HCl. The organic layer was separated, washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:2, v/v), 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionaldehyde (1.54 g, 77%) was obtained. Recrystallization from ether-isopropyl ether gave colorless needles. Melting point: 81-82° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>C1(C)C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:16]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
A solution of 415 g. of crude p-nitrophenyl isocyanate in 4.5 l. of toluene was stirred at room temperature. The mixture was filtered and 35 g. of insoluble impurity removed. The material in solution was 380 g. (2.32 mol) of purified p-nitrophenyl isocyanate. The solution was stirred under dry nitrogen, and 3-(aminomethyl)pyridine (250 g., 2.32 mol) was added dropwise. An exotherm to 40° C. was noted. The resulting thick suspension was stirred overnight and then vacuum filtered. The product was washed with hexane and dried in a vacuum oven at 60° C. overnight to give 610.7 g. melting at 220°-221.5° C. The product was a 98% yield of 1-(3-pyridylmethyl)-3-(4-nitrophenyl)urea. This product after recrystallization from 2-methoxyethanol melted with decomposition at 223°-225° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:16][CH2:15]2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(N(CC)CC)C>[CH3:24][N:23]([CH2:22][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][C:38]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:42][CH:41]=3)=[O:39])[CH:13]=2)[CH2:18]1)[CH3:25]
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
DMF solution (0.25 ml) of 2M HOBt, DMF solution (0.30 ml) of 2M WSCD, triethylamine (0.14 ml) and DMAP (0.132 g) were added to DMF solution (3 ml) of 6-amino-2-(N,N-dimethylamino)methyltetralin (0.139 g) and 4-(4-methoxy phenyl) benzoic acid (0.118 g). After the reaction mixture was stirred at room temperature for 12 hours, 10% potassium carbonate solution was added, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystal was washed with diethyl ether, which was recrystallized using ethyl acetate-hexane, to give the titled compound (0.124 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:17]([NH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.C(OCC)(=O)C>[S:8]1[C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([NH:25][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:27]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reactant: Nc1ccc2ncsc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)Nc2ccc3ncsc3c2)c1)c1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 0.1 g of 6-aminobenzothiazole and 0.1 g of pyridine added to 5 ml of tetrahydrofuran and stirred at room temperature was introduced dropwise 0.2 g of 3-(benzoylamino)benzoyl chloride dissolved in 1 ml of tetrahydrofuran. The resulting solution was stirred at room temperature for 1 hour, and then ethyl acetate and 1N hydrochloric acid were added thereto for separating the organic phase. The organic phase was washed with saturated sodium hydrogen carbonate solution one time, and then dried over anhydrous magnesium sulfate. The solution was filtered off, the filtrate was collected, and the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain 0.15 g of the desired product (Yield: 52%) as a white solid.