Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16](=[N:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30]>C(Cl)Cl>[CH2:21]([N:20]([S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])[C:16](=[N:15][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:17][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN=C(SCC)N(CCCCCCC)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.8 g (0.018 mole) of triethylamine was added to 4.5 g (0.015 mole) N,N'-diheptyl-S-ethyl-isothiourea in 50 ml methylene chloride in a stirred round bottom flask. A solution of propanesulfonyl chloride (0.018 mole, 2.6 g) in 8 ml methylene chloride was added dropwise to the above solution at 0° C. The mixture was stirred 1.5 hours at room temperature then at 30°-35° C. for 1.5 hours. The cooled solution was washed twice with 20 ml water, once with 25 ml saturated sodium bicarbonate solution and twice more with 20 ml of water. The organic phase was dried over magnesium sulfate and evaporated invacuo to yield the product as a yellow oil. nD30 1.4805. Yield was 5.2 g (85.4% of theory). The structure was confirmed by IR spectrum. Compound No. 203 in Table I.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 150 °C

Procedure:
In a glass flask, were placed under a nitrogen stream 1,380 g of p-hydroxybenzoic acid and 1,120 g of acetic anhydride. The mixture was refluxed at 150° C. for 2 hours and then the temperature was raised while removing acetic acid by distillation. When the temperature reached 230° C., the p-acetoxybenzoic acid formed by acetylation was transferred into a double-arm kneader which had been heated to 230° C. At this stage, the p-acetoxybenzoic acid was liquid. While agitating at low speed, the temperature of this liquid was raised to 330° C. taking a period of one hour. When the temperature had reached 310° C., an increase in torque was observed. Polymerization was continued with increased speed of agitation until the mixture in the kneader was transformed into powder. 100 Grams of the powder were tested for particle diameter. It was found that 73% of the sample had a particle diameter of 0.1 mm or less. The polymerization was continued at 330° C. The degree of conversion when the polymerization system was transformed into a powder was 95%. After a further 2 hours of reaction, there were obtained 1,130 g of fine powder, corresponding to a yield of 94%. Ninety-one percent of the fine powder was found to have a particle diameter of 0.1 mm or less. On differential thermal analysis, the powder showed a heat absorption at 342° C. The loss on heating in the air at 370° C. for one hour was 0.65% by weight. The number average molecular weight was 11,000.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].O>O1CCCC1>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 100 mL of tetrahydrofuran was dissolved 17 g of p-aminobenzenesulfonamide. This solution was cooled to 0° C. on an ice bath. To this solution was dropwise added 5 g of acryloyl chloride. After completion of the addition, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 1 hour. Subsequently, the reaction mixture was heated at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into 1 L of distilled water. Thus, N-(p-aminosulfonylphenyl)acrylamide was obtained as precipitated white particles.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][NH2:13].[C:14](Cl)(=O)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:15]([C:14]1[N:6]2[CH:5]=[CH:4][C:3]3[C:8]([C:7]2=[N:12][N:13]=1)=[CH:9][CH:10]=[CH:11][C:2]=3[Br:1])[CH2:16][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: NNc1nccc2c(Br)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nnc2c3cccc(Br)c3ccn12

Procedure:
A mixture of 5-bromo-1-hydrazinoisoquinoline (4.76 g., 0.02 mol.) and butyryl chloride (2.1 ml., 0.02 mol.) in dichloromethane (100 ml.) was allowed to reflux overnight. The solvent was removed in vacuo and the residue was heated at reflux for three hours in xylene (100 ml.) and triethylamine (2.8 ml., 0.02 mol.). The mixture was filtered and the xylene removed in vacuo to provide the crude product. Recrystallization from ethanol (≈100 ml.) gave the pure product, 4.4 g. (76%); m.p. 197°-199°C., m.p. (hydrochloride salt) 200°-201°C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:20]1[CH:21]=[C:22](I)[CH:23]=[CH:24][CH:25]=1)([OH:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:20]1[CH:21]=[CH:22][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:25]=1)([OH:19])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.96 g (20 mmole) of meta-carboxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled till room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, and dissolved in aqueous alkali. Aqueous phase was separated and treated with aqueous HCl. White precipitated was isolated washed with cooled ethanol and dried under vacuum to obtain 2 g (43%) of 2-(4-carboxy-phenyl)-indene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15](=O)[NH:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]2[C:10]3[C:15]([Cl:32])=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH:7]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1nc[nH]c(=O)c12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Cl)c12
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of (4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl)-acetic acid ethyl ester (1.78 g, 6.17 mmol, 1 equiv, from step 3) in toluene (15 mL) were added diisopropylethylamine (1.18 mL, 6.79 mmol, 1.1 equiv) and phosphorous oxychloride (0.63 mL, 6.79 mmol, 1.1 equiv) at 0° C. under argon. The flask was equipped with a reflux condenser and heated at 80° C. for 5 h. The reaction mixture was cooled to rt and quenched with ice/saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (20% EtOAc/hexane) to yield 1.12 g (3.6 mmol, 56%) of a light yellow solid. 1H-NMR (DMSO-d6) δ 9.01 (s, 1H), 8.64 (d, J=8.6 Hz, 1H), 8.15 (s, 1H), 7.61 (d, J=8.6 Hz, 1H), 4.10 (q, 2H), 3.92 (s, 2H), 1.20 (t, 3H), LCMS RT=3.19 min, [M+H]+=307
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[OH-].[Na+].C(Cl)Cl.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27](=[O:31])[C:28](Cl)=[O:29])=[CH:19]1>O>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][C:28](=[O:29])[C:27](=[O:31])[C:20]1[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=1)[CH2:5]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)N[C@@H]2CN3CCC2CC3)c2ccccc21
Yield: 30.8 %

Procedure:
(S)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride salt (7.5 g; 37.5 mmol) and sodium hydroxide (2.0 g; 50.0 mmols) were dissolved in 50 ml of water. The solution was cooled in an ice bath and 100 ml of methylene chloride was added. The mixture was stirred while approximately one third of a solution containing 1-methy-α-oxo-3-indoleacetyl chloride (10.8 g; 48.7 mmol) was added in a dropwise fashion, after which additional sodium hydroxide (3.0 g; 75.0 mmol) in 20.0 ml of water was mixed in. The remaining 1-methy-α-oxo-3-indoleacetyl chloride was then added and the reaction mixture was stirred for 10 minutes. The aqueous layer was then separated from the organic phase and rinsed with methylene chloride. The combined organic phase was dried over potassium carbonate. Filtration and evaporation of the solvent resulted in 5.1 g of crude product. The crude product was purified by chromatography (silica gel 60; 7% MeOH in CH2Cl2 containing approximately 0.5 % NH4OH) to yield 3.6 g (11.5 mmmol) of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-α-oxo-3-indoleacetamide, m.p. 186°-187° C., [α]D25 -41° (CHCl3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=O.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.N.O>CN(C=O)C>[NH2:30][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
356 mg (1 mmol) of (Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 10 ml of DMF and combined with 194 mg (1 mmol) of CDI. The mixture is stirred for 2 hours at ambient temperature, 2 ml of methanolic ammonia solution are added, then stirring is continued for 16 hours at ambient temperature. Then water is added, the precipitate is removed by suction filtering, washed with water and a little ether and dried at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([Cl:31])[CH:21]=1>>[Cl:31][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][C:27]([F:28])([F:29])[F:30])[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 444.11 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 68.4 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)thio-3-cephem-4-carboxylate (80 mg) (as obtained in Example 1) was dissolved in dimethylformamide (1.6 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (77 mg) thereto, was stirred at a temperature of -20° to -10° C. for 30 minutes (for the esterification reaciton), after which cold water (5 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate, and the organic layer separated was washed with an aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purified by a column chromatography on a silica gel column (15 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (65 mg; 68%) as white powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH:6]1[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7]1=[O:15].CCN(CC)CC.S([Cl:31])(C)(=O)=O.[Li+].[Cl-]>CN(C=O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[CH:6]1[CH2:5][C:4]1[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=1[CH2:2][Cl:31]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CC(=O)N(C)C(Cc2ccccc2CO)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(C)C(Cc2ccccc2CCl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[2-(hydroxymethyl)benzyl]-1,4-dimethylpiperazine-2,5-dione (1.48 g, 5.64 mmol) and Et3N (1.57 ml, 11.28 mmol) in DMF was cooled to 0° C. Mesyl chloride was added via syringe at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting overnight. More Et3N (2 equivalents) and mesyl chloride (1.1 equivalents) was added at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting for 6 hours. LiCl (478 mg, 11.28 mmol) was added and the reaction stirred at ambient temperature for 1.5 hours. The mixture was partitioned between NH4Cl and EtOAc and extracted with EtOAc (3×). The combined organic solutions were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase chromatography (0-3% MeOH(NH3)/CH2Cl2) to give a yellow oil (1.47 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[C:31]([CH3:32])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cc1C
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (0.1 g, 84%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Product: O=C(NC1CCCCC1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 66 μl (0.515 mmol) of cyclohexyl isocyanate in analogy to Example 16a. The title compound ##STR79## is obtained as white crystals (165 mg, 66%) of melting point 229° C. (decomposition). TLC:methylene chloride/methanol/conc. ammonia (700:50: 1) Rf =0.44, FD-MS:M+ =628, 630.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:17]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[O:18])[CH2:16][CH:15]=[CH:14][CH2:13]1>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:14]12[O:9][CH:15]1[CH2:16][N:12]([C:17]([O:19][CH2:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=1)=[O:18])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC=CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccc2ccccc2c1)N1CC2OC2C1
Reaction time: 96 h
Yield: 43.6 %

Procedure:
mCPBA (4.203 g, 17.04 mmol) was added to a solution of naphthalen-2-ylmethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (2.15 g, 8.52 mmol) in chloroform (35 mL), and the reaction was stirred for 4 days. The reaction mixture was diluted with saturated NaHCO3 and chloroform, and the organic layer was washed with CHCl3, dried over sodium sulfate and condensed. The residue was purified by silica gel chromatography, eluting with a gradient from 1% EtOAc/DCM to 15% EtOAc/DCM, to provide the desired product as a solid (1.0 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7]=1[F:26])=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:26][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CCl)c(F)c2)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CN3CCOCC3)c(F)c2)CC1
Reaction time: 5 h
Yield: 83.4 %

Procedure:
A mixture of tert-Butyl 4-[4-(2-Chloro acetylamino)-3-fluoro phenoxy]piperidine-1-carboxylate (3.31 g, 0.0085 moles, obtained in preparation 3), morpholine (0.89 g, 0.01 moles) and potassium carbonate (1.75 g, 0.012 moles) in acetonitrile (30 mL) was stirred for 5 hours at reflux temperature. The mixture was concentrated under reduced pressure and the residue, thus obtained, was partitioned between ethyl acetate (50 mL) and water (50 mL). The resulted aq. Phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated. The crude compound was purified by flash chromatography (ethyl acetate:hexane, 3:7) to obtain the title compound 3.1 g (Yield: 83.5%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])=[C:5]2[C:22](O)=[O:23])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH2:33])[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:25][C:26]1([CH3:34])[O:30][CH:29]([CH2:31][O:32][NH:33][C:22]([C:5]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[O:23])[CH2:28][O:27]1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OCC(CONC(=O)c2c(Nc3ccc(I)cc3F)c3cnccc3n2C2CC2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a heterogeneous mixture of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (160.0 mg, 0.37 mmol) and O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (113.1 mg, 0.77 mmol, 2.1 eq) in anhydrous N,N-dimethylformamide (5.7 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (278.3 mg, 0.74 mmol, 2.0 eq) and N,N-diisopropylethylamine (0.25 mL, 1.46 mmol, 4.0 eq), and the resulting homogeneous reaction mixture was stirred under N2 at RT for 16 h. The reaction mixture was quenched with MeOH (2 mL), and the crude material was absorbed onto silica. The crude mixture was purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the product as an orange waxy solid (75.4 mg; 36.4%). LC-MS (method C): [M+H]+=567.2, RT=0.73 min.
Reaction SMILES: [OH-:1].[K+].O.[OH:4][C:5]1([C:18](N)=[O:19])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[O:8][CH2:7][CH2:6]1>CC(O)C>[Cl:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[C:14]2[C:9]=1[O:8][CH2:7][CH2:6][C:5]2([C:18]([OH:19])=[O:1])[OH:4]
Reactant: [OH-]
Reactant: COc1cc(Cl)c2c(c1)C(O)(C(N)=O)CCO2
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(Cl)c2c(c1)C(O)(C(=O)O)CCO2

Procedure:
KOH (1.2 g; 21 mmol) and water (25 mL) were added to a solution of 4-hydroxy-8-chloro-6-methoxychroman-4-yl-carboxylic amide (0.39 g; 1.5 mmol; from step (iv) above) in i-PrOH (25 mL). The reaction mixture was refluxed overnight, i-PrOH was evaporated and the water solution was washed with ether. The reaction mixture was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. Yield: 0.38 mg (97%).
Reaction SMILES: [C:1]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:20][OH:21].Cl>C(N(CC)CC)C>[OH:21][NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CCCCCCC(=O)O)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CCCCCCC(=O)NO)cc1
Yield: 48 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50b for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 48% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 7.94 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 3.88 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.11 (t, J=7.5 Hz, 2H), 1.59-1.79(m, 4H), 1.37 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 24.15, 25.04, 28.59(2), 32.51, 37.88, 55.21, 113.54, 129.58, 130.20, 163.39, 171.10, 200.06.