Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])[C:4]=2[CH:3]=[CH:2]1.[N+:25]([O-])([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][CH2:11][O:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]([N+:25]([O-:27])=[O:26])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])c2sccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
286 g (0.853 mol) of 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole were suspended in 6.3 l of glacial acetic acid. Temperature was raised to 60° C. The resulting clear solution was cooled to 25° C. 132 ml (3.18 mol) of 100% nitric acid were added within 3 minutes. The reaction mixture was cooled below 30° C. After crystallization the suspension was stirred at 18 to 20° C. for 1 hour. The precipitate was filtered with suction and washed with 2×600 ml of tert-butyl methyl ether. The residue was suspended in 4 l of acetic ester for 15 minutes. 200 g (1.9 mol) of sodium carbonate in 3 l water were added. The resulting suspension was stirred for 1 hour. Acetic ester was distilled off followed by addition of 2 l of water. The suspension was stirred for 30 minutes. The precipitate was filtered with suction, washed with water and dried (50° C., 24 hours).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)[Cl:30]>Cl>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:30]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
11.83 g of Boc-Phe-Met-OMe (see Biochemistry, 8, 4183 (1969), incorporated herein) is dissolved in 100 ml methylene chloride after which HCl is passed into the solution for about 40 minutes. After evaporation of the solution to dryness, 75 ml ethyl acetate is added, resulting in a precipitate. The solid substance is separated by filtration, washed with petroleum ether, and dried. Melting point 123°-124° C. Rf in To:EtOH (8:2)=0.43 on SiO2.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:26]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.200 g, 0.56 mmol), 4-phenoxy-benzylamine (0.7 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.108 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.75 (s, 2H), 6.94-7.40 (m, 1H), 7.92 (d, 1H). GC-MS: m/z 441 (M)+.
Reaction SMILES: C(OC([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C@H:9]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:13][C:12](=[O:21])[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:31][C:32](C)([O-])C.[K+].C(I)C>C1COCC1>[CH2:31]([N:13]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:9]([NH:8][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:10][CH2:11][C:12]1=[O:21])[CH3:32]
Reactant: COc1ccccc1CN(C(=O)OC(C)(C)C)[C@@H]1CCC(=O)N[C@@H]1c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1C(=O)CC[C@@H](NCc2ccccc2OC)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 50 ml (0.12 mmol) of cis-5-(N-tert-butoxycarbonyl-2-methoxybenzylamino)-2-oxo-6-phenylpiperidine and 0.2 mL of THF. To the system were added 13.5 mg (0.12 mmol) of potassium tert-butoxide and 20 μL (0.24 mmol) of ethyl iodide. The reaction mixture was stirred at room temperature for 3 hours (during this period, additional potassium tert-butoxide (13.5 mg) and ethyl iodide (20 μL) were added to the system). The mixture was partitioned between methylene chloride and aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of methylene chloride. The combined organic fractions were dried (sodium sulfate) and concentrated with a rotary evaporator. The crude material was purified by flash column chromatography using 3:97 methanol/chloroform as the eluant to obtain 42 mg of cis-N-ethyl-5-(2-methoxybenzylamino)-2-oxo-6-phenylpiperidine.
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([NH:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@H:25]1Cl)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[NH:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N[C@H]1[C@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 33.8 %

Procedure:
Following a procedure similar to that of Example 1 but using 1.311 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 3.658 g of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride there was obtained 1.0 g of 1-(4-nitrobenzyl)-4-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:47]=[CH:46][C:41]2[O:42][CH2:43][CH2:44][O:45][C:40]=2[CH:39]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]3[S:11][C:7]4[C:6]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:14])=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: NCC(=O)c1ccc2c(c1)OCCO2
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccc4c(c3)OCCO4)nc12
Yield: 50.2 %

Procedure:
0.35 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.22 g 1,1′-carbonyl-diimidazole in 6 ml DMF were stirred at room temperature for 4 hours. 0.30 g 2-amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone hydrochloride and 0.18 g triethylamine were added and stirring was continued over night at room temperature. 100 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 1:1 yielded 0.28 g (50%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-amide as a yellow solid; M.p.: 206–208° C.; MS (ISP): m/e=470 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:13]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[Cl:21]S([N:25]=[C:26]=[O:27])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:21].[C:26](=[O:27])([O:1][CH2:2][CH2:3][CH:4]([NH2:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[NH2:25]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccccc1C(CCO)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1C(N)CCOC(N)=O
Product: Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 172A, 242 mg (0.86 mmol) were introduced in 12 ml of acetonitrile under argon, and admixed dropwise at −15° C. with 105 μl (1.20 mmol) of chlorosulphonyl isocyanate. The reaction mixture was stirred at −10° C. for 30 minutes. Then 12 ml of water were added and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled, rendered basic using saturated aqueous sodium hydrogen carbonate solution and extracted with three times 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was admixed with 6 ml of a 4M solution of hydrogen chloride in dioxane, the components were stirred together for 10 minutes, and the mixture was concentrated on a rotary evaporator. The residue was dried in an HV. This gave 186 mg (83% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Reactant: CN(C)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C=C2C(=C(C3=CCN(CC(=O)N(C)C)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 70 °C

Procedure:
To a suspension of Example 48 (100 mg, 0.284 mmol) in N,N-dimethylformamide (4 mL) was added triethylamine (0.237 mL, 1.703 mmol) and 2-chloro-N,N-dimethylacetamide (41.4 mg, 0.341 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 10-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.57-2.62 (m, 2H), 2.79 (t, J=5.04 Hz, 2H), 2.84 (s, 3H), 2.89 (s, 3H), 3.03 (s, 3H), 3.30-3.37 (m, 4H), 4.07 (s, 2H), 5.85 (s, 1H), 7.26-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.62-7.66 (m, 1H), 8.24 (d, J=5.19 Hz, 1H), 11.62 (s, 1H). MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=O)=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(CCC(=O)O)c1C

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (55 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:22]([O:26][C:27](=[O:37])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.C1C[O:48][CH2:47]C1>>[CH2:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][C@@H:2]([NH:1][C:47]([NH:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:37])=[CH:34][CH:33]=1)=[O:48])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: -10 °C

Procedure:
(R)-ethyl 2-amino-5-(benzyloxycarbonylamino)pentanoate (1 equivalent, 146 mg, 0.50 mmol) was dissolved in anhydrous THF (4 mL) and trisphosgene (0.33 equivalent, 49 mg, 0.17 mmol) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, and then refluxed for 2 h. Tert-butyl-N-[4-(aminomethyl)phenyl]carbamate (1 equivalent, 110 mg, 0.50 mmol) and triethylamine (2 equivalent, 138 μl, 1 mmol) were added successively and the resulting solution was stirring at room temperature overnight. The reaction mixture was concentrated, washed by 30 ml of NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (EDP/EtOAc) to afford the urea protected (146 mg, 54%) as a colourless oil Rf=0.59 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (s, 5H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.84-6.66 (m, 1H), 5.62-5.42 (m, 2H), 5.28-5.10 (m, 1H), 5.00 (s, 2H), 4.46-4.29 (m, 1H), 4.18 (d, J=5.5 Hz, 2H), 4.05 (q, J=7.1 Hz, 3H), 3.16-3.00 (m, 2H), 1.82-1.28 (m, 4H), 1.43 (s, 9H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N:26]=[C:27]=[O:28])[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:25])([F:24])[CH:21]([Cl:23])[F:22]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CO>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:6][C:27]([NH:26][C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]([F:24])([F:25])[CH:21]([Cl:23])[F:22])=[C:13]([Cl:12])[CH:14]=1)=[O:28])=[O:5]
Reactant: NC(=O)c1ccc(F)cc1Cl
Reactant: O=C=Nc1ccc(OC(F)(F)C(F)Cl)c(Cl)c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CO
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(OC(F)(F)C(F)Cl)c(Cl)c1
Yield: 78.3 %

Procedure:
3.47 g (0.02 mol) of 2-chloro-4-fluorobenzamide and 7.2 g (0.022 mol) of 3-chloro-4-(2-chloro-1,1,2-trifluoroethoxy)-phenyl isocyanate are melted for two hours at 180° C., in the presence of one drop of dibutyl-tin dilaurate. After the mixture has been cooled, the solid product is comminuted in hot methanol, and the product is filtered off under suction and dried. 7.2 g (76.5% of theory) of 1-(2-chloro-4-fluoro-benzoyl)-3-(3-chloro-4-(2-chloro-1,1,2-trifluoro-ethoxy)-phenyl)-urea of melting point 186° C. are obtained.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3F)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (1.28 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.08 g of desired compound (melting point: 70.0°-73.0° C.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O:14][C:15]([C:17]1([CH2:24][CH2:25]OC)[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=O)C.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:23][CH:20]1[CH2:21][CH2:22][C:17]2([C:15](=[O:14])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH2:25][CH2:24]2)[CH2:18][CH2:19]1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Isopropoxy-phenylamine (11.3 g) was added to a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (11.5 g) in toluene (361 ml). The mixture was stirred for 10 minutes at RT. Then, dimethylaluminiumchloride (0.9 M in hexane, 99 ml) was added dropwise and the reaction mixture was heated to reflux for 4 h. The mixture was then cooled to 0° C., water (50 ml) was added dropwise then AcOEt (300 ml). The mixture was stirred further 30 minutes, more AcOEt was added, the layers were then separated, the organic layer was dried over MgSO4, filtered and the solvent was evaporated off. The crude product was triturated with diethyl ether/heptane to give the title compound as a mixture of cis/trans isomers as brown solid (14.3 g) which was used directly in the next step. MS (m/e): 304.190 [MH+].
Reaction SMILES: [Cl:1]CCl.[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10]2.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH3:14])[C:11]([C:15]([Cl:1])=[O:17])=[CH:10]2
Reactant: ClCCl
Reactant: Cn1c(C(=O)O)cc2cccc(Br)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Cl)cc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (2 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid (200 mg), oxalyl dichloride (0.10 mL) and N,N-dimethylformamide (5 mL) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, azeotroped twice with toluene to obtain a crude product of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride. Separately, a solution was prepared by dissolving 2M trimethylsilyldiazomethane (0.60 mL) and trimethylamine (0.16 mL) in tetrahydrofuran (2 mL)-acetonitrile (2 mL) and a tetrahydrofuran (1 mL)acetonitrile (1 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride was added thereto, and then the mixture was stirred at room temperature for 4 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 85:15) to obtain the titled compound having the following physical properties (72 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][S:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:37])=[O:36]>>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH3:33])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:41]=[CH:40][C:39]([NH:38][S:35]([CH3:34])(=[O:36])=[O:37])=[CH:44][CH:43]=4)=[CH:3][CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:32])[C:24]=2[CH:25]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared according to example 33, using the intermediate from step c) and {4-[(methylsulfonyl)amino]-phenyl}boronic acid, MS (ES) m/e 647 [M+H]+
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](O)(=O)[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)O.[OH:21][NH-]>O>[C:3]1([CH:2]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:11][CH2:10][NH:9][C:1]2=[O:21])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [NH-]O
Reactant: NCCc1ccccc1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: O
Product: O=C1NCCc2ccccc2C1c1ccccc1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A suspension of 31.4 mL of phenethylamine (0.25 mol) and 42.6 g of DL-mandelic acid (0.28 mol, 1.12 eq.) in 600 mL of xylenes was heated to reflux with a Dean-Stark water separator for 8 hr. The reaction was cooled, and the xylenes removed in vacuo. The resulting residue was partitioned between saturated NaHCO3 and CH2Cl2. The CH2Cl12 layer was dried (Na2SO4) and the solvents removed to yield a solid which was recrystallized from THF to yield, after drying, 56 g of hydroxyamide (88%) as a white, crystalline solid, mp 95°-96° (Lit 97°-98° ) To 350 g of PPA at 25° was added 30.7g of this solid (120 mmol) with mechanical stirring. The reaction was heated to 65° for 2 hr, then poured onto ice in a 4L beaker. The resulting suspension was stirred vigorously, the solids pulverized under H2O and filtered, washing well with H2O. Drying of the solid in vacuo and recrystallization from absolute EtOH provided 27 g of 1-phenyl-1,3,4,5-tetrahydro-3(2H)-benzazepin-2-one (95%) as a white solid, mp 189°-191° .
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate (30 mg, 0.046 mmol) in 5 ml of methylene chloride was added 2 ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness. The residue was dissolved in MeOH (3 ml), which was added dropwise into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid as white solid. Yield: 20 mg, 74%.