Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(=[C:3]1[C:9]([CH3:11])([CH3:10])[CH:8]2[C:5]([CH3:13])([CH2:6][CH:7]2[OH:12])[CH2:4]1)O.C(COC)[O:15]C>O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:13][C:5]12[CH2:6][CH:7]([OH:12])[CH:8]1[C:9]([CH3:11])([CH3:10])[C:3](=[O:15])[CH2:4]2
Reactant: COCCOC
Reactant: CC12CC(=NO)C(C)(C)C1C(O)C2
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Product: CC12CC(=O)C(C)(C)C1C(O)C2
Reaction time: 0.5 h

Procedure:
To a solution of 600 mg of the oxime (V) in a mixture of 10 ml of dimethoxyethane and 5 ml of water, was added 6 ml of 16% titanium trichloride and the mixture was kept at 50° to 60° C. for 30 minutes under an argon atmosphere. After cooling, the mixture was admixed with 20 ml of water and extracted with methylene chloride. The extract was washed with an aqueous sodium bicarbonate solution, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 425 mg of an oil. This oil was chromatographed over silica gel to give 305 mg of an oil (IV): nD20 1.4787; MS: m/e 168 (M+).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24](NS(C4C=CC=CC=4)(=O)=O)=[O:25])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrCC1C=CC(C(OC(C)(C)C)=[O:57])=CC=1OC.Cl>CN(C)C1C=CN=CC=1.N1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24]([OH:25])=[O:57])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCN1
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 41 %

Procedure:
The starting indole was obtained as follows: A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl)]-3-methoxybenzoic acid (0.68g)(prepared as described in Example 1, parts (a) through (i)) and 4-(dimethylamino)pyridine (0.17 g) in morpholine (4 ml) was heated at 80° for 48 hours under a nitrogen atmosphere. The reaction was diluted with water and acidified with 10% (v/v) hydrochloric acid. The resultant precipitate was collected by filtration and washed with water. The product was purified by recrystallization from ethyl acetate to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(morpholinocarbonyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid as a white powder (0.31 g, 41%); partial NMR (80 MHz, CDCl3) 1.2-1.8(m, 9H, cyclopentyl), 2.70(dd, 2H, CH2NH), 3.15(t, 2H, COCH2), 3.2-3.7(m, 8H, morpholino), 3.92(s, 3H, OCH3), 5.35(s, 2H, ArCH2), 6.58(t, 1H, NH), 7.17(d, 1H), 7.9(s, 1H, H7 -indole).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:16]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:16])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800 mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol;) and iodine (244.2 g, 1.04 mol;). The reaction mixture was stirred rt 4 h. The aqueous layer containing product was separated and washed with hexane (400 mL×2). The aqueous layer was neutralized to pH=7 with HCl and then extracted EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated to the crude product, which was washed with EtOAc to afford 163 g of 6-chloro-2-iodopyridin-3-ol, yield: 75%. 1H NMR (DMSO, 400 MHz): δ11.13 (s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Into a 500 mL round bottomed flask were added 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.80 g, 20.96 mmol), 2-methoxyphenyl boronic acid (3.76 g, 24.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.756 g, 1.08 mmol), acetonitrile (100 mL) and 100 mL of 2M Na2CO3 (aq). The flask was fitted with a reflux condenser and heated at 60° C. with rapid stirring under N2 for 8 h. The reaction mixture was filtered to obtain a grey-tan precipitate, which was dissolved in EtOAc and washed with water followed by brine. Concentration of this solution afforded 7.70 g (80%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.54 (dd, J=1.5, 7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39 (m, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.34 (s, 3H); MS: m/z 456.9/458.9 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=S)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N=C=NC(C)C)(C)C.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:33]2[N:34]([CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:23][C:24]=2[CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: COc1cc(N=C=S)cc(OC)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(OC)cc(OC)c1)n2CCCN(C)CCc1ccccn1
Temperature: 25 °C
Yield: 76 %

Procedure:
3,5 dimethoxyphenylisothiocyanate (571 mg, 1 eq) and diisopropylcarbodiimide (1.35 ml, 4 eq) are added successively to a solution of methyl 3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate (1.0 g, 1 eq) in tetrahydrofuran (10 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in ethyl acetate (100 ml) and water (40 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 99:1 to 98:2) produces the expected compound in the form of a beige foam (1.12 g; 76% yield).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:28][C:29]1[O:33][C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[N:31][C:30]=1[CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O.[K+].[Br-]>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:40][CH2:39][C:30]2[N:31]=[C:32]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[O:33][C:29]=2[CH3:28])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 42. 1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (m, 1H), 7.41 (dd, 1H, J=5.2, 1.2 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.11-7.07 (m, 3H), 6.90 (d, 2H, J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.20 (t, 2H, J=6.6 Hz), 3.25 and 3.14 (d of Abq, 2H, J=14.0 Hz), 2.99 (t, 2H, J=6.4 Hz), 2.37 (s, 3H), 1.43 (s, 3H). IR (KBr) 3600, 3000, 1727, 1611, 1504, 1265 cm−1. HRMS (ES+) m/z exact mass calcd for C27H25NO6F3S 548.1354, found 548.1362.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])=[C:5](I)[CH:4]=1)#[N:2]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:16]=[CH:15][C:6]2[O:7][CH2:8][CH:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C=CCOc1ccc(C#N)cc1I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC1COc2ccc(C#N)cc21
Reaction time: 0.25 h
Yield: 137.4 %

Procedure:
To a cooled (−100° C.) solution of methyl 4-[4-cyano-2-iodo-phenoxy]-but-2-enoate (4.3 g, 12.5 mmol) (reference example 1 a) in THF: Et2O (4:1, 125 mL) was added dropwise n-buLi (5.5 mL, 2.5 M in hexanes). On complete addition, the reaction mixture was stirred for 15 min then quenched with 1 M aqueous HCl (20 mL). This mixture was diluted with ethyl acetate and washed, sequentially, with water and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (eluting with 25% ethyl acetate in hexanes) to give 3.73 g of the title compound. 1H NMR (CDCl3) d 2.63 (dd, 16, 8 Hz, 1H), 2.80 (dd, J=16, 5 Hz, 1H), 3.74 (s, 3H), 3.91 (m, 1H), 4.35 (dd, J=8, 6 Hz, 1H), 4.86 (t, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.47 (m, 2H). MS (EI) m/z 203 (M)+. MS (EI) m/z 217 (M)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22]O)=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:34]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22][Br:34])=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1Oc1ccc2[nH]cc(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation is carried out in analogy to the procedure of Example VII from 2.0 g (4.18 mmol) of benzyl alcohol derivative from Example XXI and 2.82 g (6.69 mmol) of dibromotriphenylphosphorane in 40 ml of acetonitrile. After stirring for 3 hours at room temperature, 0.3 equivalent of dibromotriphenylphosphorane is again added. The mixture is additionally stirred for 5 hours at 70° C. and afterwards overnight at room temperature. The purification of the product is carried out on silica gel using toluene as eluent.
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClC[CH2:6][C:7]1[CH:8]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[C:10]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:12]=1Cl>CO>[CH3:1][N:2]1[C:12]2=[N:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[CH2:6][CH2:3]1
Reactant: CNC
Reactant: COC(=O)c1cc(CCCl)c(Cl)nc1C(=O)OC
Solvent: CO
Product: COC(=O)c1cc2c(nc1C(=O)OC)N(C)CC2
Temperature: 25 °C
Reaction time: 64 h
Yield: 14 %

Procedure:
Dimethylamine (7.5 g, 166.6 mol) is bubbled into a solution of dimethyl 5-(2-chloroethyl)-6-chloro-2,3-pyridinedicarboxylate (20.0 g, 66 mmol) in methanol (400 mL) over three hours. The resulting solution is stirred for 64 hours at room temperature and then four and one-half hours at reflux. After cooling the mixture is concentrated under vacuum and the crude product chromatographed on 250 g silica using 2:1 hexanes:ethyl acetate and then 1:1 hexanes:ethyl acetate as eluant, affording 2.32 g (14%) of dimethyl 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5,6-dicarboxylate, which is recrystallized from methylene chloride/hexanes, having a melting point 132°-133° C.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[C:20]([N+:42]([O-])=O)=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:46][C:47]1[N:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH:49]=O.O.[OH-].[Na+]>C1COCC1.CO.C(OCC)C.[Pd]>[NH2:46][C:47]1[C:48]([C:49]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[C:21]3=[N:22][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([N:8]5[CH2:9][CH2:10][CH:5]([C:3](=[O:4])[N:2]([CH3:45])[CH3:1])[CH2:6][CH2:7]5)[CH:12]=4)=[CH:18][CH:19]=[C:20]3[N:42]=2)=[CH:51][CH:52]=[CH:53][N:54]=1
Reactant: CN(C)C(=O)C1CCN(c2cccc(-c3ccc([N+](=O)[O-])c(Nc4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)n3)c2)CC1
Reactant: Nc1ncccc1C=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of tert-butyl (1-{4-[(6-{3-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (5.4 g, 8.9 mmol) in THF/MeOH (150 mL, 1:1), was added Pd on carbone (5% wet, 1 g). The mixture was stirred under hydrogen gas (1 atm) for 2 h. The mixture was filtered through celite and evaporated. The residue was dissolved in acetic acid (30 mL) and 2-aminonicotinaldehyde (1.1 g, 9.3 mmol) was added then the mixture was stirred at rt for 1 h. The mixture was heated at 80° C. for 1 h and the mixture was poured into water and neutralized with sodium hydroxide (20 g). The solid was collected by filtration and purified with silica gel column chromatography (hexane/ethyl acetate/methanol, 10:0:0 to 0:10:1) to give a pale orange solid. The solid was slurried in diethyl ether (200 mL) and collected to give the titled compound as a pale yellow solid (3.4 g, 62%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[N-:17]=[N+]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[CH2:1]([O:4][C:5]([C:7]1[C:15]2[C:14](=[O:16])[NH:17][CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOC(=O)c1c[nH]c2c1C(=O)CCC2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCOC(=O)c1c[nH]c2c1C(=O)NCCC2
Yield: 23.4 %

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid propyl ester (2.0 g) and NaN3 (2.0 g) in 50 mL of trifluoroacetic acid is stirred at 60-80° C. for a period of 3 days during which additional 2.5 g NaN3 of is added on first, second and third day. After diluted with water, the mixture is extracted with Ethyl acetate. The extract is washed with NaHCO3, brine and concentrated under reduced pressure. The residue is subject to a silica gel chromatography eluting with 10% MeOH in CH2Cl2 to give 500 mg of 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acid propyl ester as a foam.
Reaction SMILES: [C:1]([N:4]([C:13]1[CH:49]=[CH:48][C:16]([CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]([N:25]([C:27]2[C:28]([Cl:47])=[C:29]([C:43]([Cl:46])=[CH:44][CH:45]=2)[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[CH:37]3)[CH3:26])=[O:24])=[O:20])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]([C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]([N:25]([C:27]2[C:28]([Cl:47])=[C:29]([C:43]([Cl:46])=[CH:44][CH:45]=2)[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[CH:37]3)[CH3:26])=[O:24])=[O:20])=[CH:48][CH:49]=1)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CC(=O)OC(C)(C)C)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(CC(=O)O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 8-[3-[N-[4-(N-acetyl-N-tert-butoxycarbonylmethylamino)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (143 mg) in dichloromethane (1.4 ml) was added trifluoroacetic acid (0.05 ml) at ambient temperature and the mixture was stirred at the same temperature. After 1 hour, to the solution was added trifluoroacetic acid (1 ml). After 5 hours the solvent was removed in vacuo to give 8-[3-[N-[4-(N-acetyl-N-carboxymethylamino)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (124 mg) as amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:14]1([S:20]([N:9]2[C:6]3=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[CH:11]=[CH:10]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of tetrabutylammonium bromide (1.05 g, 3.24 mmol) and 5-methoxy-1H-pyrrolo[2,3-b]pyridine (16 g, 108.1 mmol) in dichloromethane (300 mL) at 0° C. was added powdered sodium hydroxide (13 g, 324.3 mmol). The mixture was then stirred at 0° C. for 5 min. Then benzene sulfonyl chloride (18 mL, 140.54 mmol) was added to the above mixture slowly and the resulting mixture was stirred at 0° C. for 15 min before it was warmed to room temperature and stirred for 12 h. The mixture was filtered and the filtrate concentrated in vacuo and then washed with hexane to afford 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (28.8 g, 93%) as a white solid: LC/MS m/e calcd for C14H12N2O3S [M+H]+ 289.33, observed 289.0.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[NH4+].[CH:13]1C=CC=CC=1.C(OCC)C>>[CH3:13][CH:4]([OH:5])[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1cccc(Cl)c1Cl
Yield: 90 %

Procedure:
Iodomethane (324.89 g, 2.288 mol) was added dropwise, with stirring, to magnesium turnings (54.88 g, 2.288 mol) in dry ether (1 liter), to form methyl-magnesium iodide. 2,3-Dichlorobenzaldehyde (200 g, 1.144 mol) dissolved in benzene/diethyl ether (1 liter, 50:50) solution was added dropwise, with stirring, to the Grignard. The reaction mixture was allowed to stir at room temperature overnight. The solution was refluxed for 2 hours, and then allowed to cool. The reaction mixture was poured into saturated ammonium chloride solution (5 liters) and the organic layer separated. The aqueous layer was extracted with ether (3×2 liters). The organic phases were combined, washed with brine (1×2 liters), dried over anhydrous magnesium sulphate, filtered and evaporated down. α-Methyl-2,3-dichlorobenzyl alcohol (196.4 g, 90% yield) was obtained as a yellow oil which crystallised on standing to give a pale-yellow solid. T.l.c. (SiO2 ;CHCl3) showed no impurities so no further purification was carried out. However, if necessary the alcohol may be recrystallised from 40-60° C. petroleum ether to afford white prisms of melting point 53° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[CH3:24][CH:25]([CH3:34])[C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:8]1[C:7]([N:31]2[CH2:32][CH2:33][C@H:29]([NH:28][C:26](=[O:27])[CH:25]([CH3:24])[CH3:34])[CH2:30]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: CC(C)C(=O)N[C@H]1CCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(=O)C(C)C)C1
Temperature: 65 °C
Yield: 47.9 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.17 g, 0.24 mmol, from Example 47, Step 2), 2-methyl-N-[(3S)-pyrrolidin-3-yl]propanamide hydrochloride (0.035 g, 0.18 mmol), palladium acetate (0.82 mg, 0.0036 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.4 mg, 0.0054 mmol), and cesium carbonate (0.22 g, 0.69 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (31 mg, 47%). LCMS calculated for C19H23ClN3O2 (M+H)+: m/z=360.1; Found: 360.1.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>O1CCCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([O:13][N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 18 h

Procedure:
1.04 Grams of Z-Tyr-OH was dissolved in 30 ml of tetrahydrofuran, to this solution 0.38 g of N-hydroxysuccinimide was added, then the reaction mixture was ice-cooled, 0.68 g of dicyclohexylcarbodiimide was added under ice-cooled condition, and the whole mixture was stirred at 4° C. for 18 hours. The precipitate formed was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, to the residue obtained was added ethyl ether and petroleum ether and was decanted, then dried to obtain the desired product.