Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:37][CH:36]=3)[CH:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: O=C(Nc1ccc(B(O)O)cc1)c1ccccc1
Product: COc1cc(-c2cc3nccc(-c4ccc(NC(=O)c5ccccc5)cc4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 4-benzamidophenylboronic acid (37.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a pale yellow solid (55 mg, 81%). (HPLC (method F): 94%, RT: 4.14 min); MS (m/z) 481 [M+H]+, RT: 4.1 min.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](I)=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ncc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-iodo-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (9.7 mg, 0.0162 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (5.2 mg, 0.0243 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (1.0 mg, 0.00162 mmol) in 1N aqueous potassium carbonate (0.7 mL) and THF (0.7 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.40 (20% EtOAc/hexanes). LCMS calc. 639.2; found 639.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.55 (s, 1H); 7.87 (s, 1H); 7.74-7.68 (m, 3H); 7.02 (dd, J=4.5, 8.1 Hz, 1H); 6.72 (d, J=11.7 Hz, 1H); 5.64 (d, J=8.0 Hz, 0.5H); 5.48 (d, J=7.9 Hz, 0.5H); 4.84 (d, J=16.4 Hz, 0.5H); 4.77 (d, J=16.5 Hz, 0.5H); 4.21 (d, J=16.5 Hz, 0.5H); 3.96 (d, J=16.3 Hz, 0.5H); 3.92-3.85 (m, 0.5H); 3.8-3.73 (m, 3.5H); 3.25-3.17 (m, 1H); 1.30-1.18 (m, 6H); 0.56 (d, J=6.4 Hz, 1.5H); 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:34])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29](O)=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:32])[C:17]=3[CH:33]=2)[C:3]1=[O:35].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].N1(C2CCCCCCCCCC2)CCCCCCCCCN1.Cl>O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:34])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:32])[C:17]=3[CH:33]=2)[C:3]1=[O:35]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OCC(=O)O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)NS(C)(=O)=O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of {{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-6-fluoro-1,2-benzisoxazol-3-yl}-p-tolyl}oxy}acetic acid (1.54 g, 0.00312 mol) in tetrahydrofuran is added dropwise to a suspension of 1,1'-carbonyldiimidazole (1.06 g, 0.00655 mol) in tetrahydrofuran. The resultant mixture is stirred 1.5 hours and cooled to room temperature. A mixture of methanesulfonamide (0.594 g, 0.00624 mol), diazabicycloundecane (1.09 g, 0.00702 mol) and tetrahydrofuran is added dropwise. The resultant mixture is stirred overnight at room temperature and poured into 10% hydrochloric acid. The resultant white solid is filtered and dried to give the title compound (1.65 g, 91.6%, mp 123-125° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 80 °C
Yield: 84.9 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (185 mg), NaOH (120 mg), H2O (15 mL) and methanol (5 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 1 by concentrated aqueous HCl solution. The white precipitate was collected by filtration to give title compound as a white solid (150 mg).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29])[CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:29])[CH2:25][CH3:26]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: CCCC(CCC)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
50.3 g (230 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 200 ml of chloroform and 36.3 g (359 mmol) of triethylamine at ordinary temperature. A solution of 37.4 g (230 mmol) of dipropylacetyl chloride in 50 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CC(C)=O>[C:7]([CH:9]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 42.5 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1→1:1) to give the title compound as a pale-yellow oil (yield 10.41 g, 90%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]1[CH2:17][CH2:16][NH:15][C:14]1=O)=[O:12].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH2:22].P(Cl)(Cl)(Cl)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:22][C:21]1[C:20]([Cl:19])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:27])=[O:12]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C1NCCN1C(=O)c1ccc2ccccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl

Procedure:
Using the process described in Example 49, 1-(quinolin-2-oyl)-imidazolin-2-one and 2,6-dichloroaniline, in the presence of an excess of phosphorus oxychloride, give 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 196°-197.5° C.; the material is identical with the product obtained according to Example 46.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 64.3 %

Procedure:
A mixture of 1.0 g (3.2 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.63 g (3.8 mmole) of 4-amino-3-methoxy-benzoic acid in 76 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.92 g of crude 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](SC)[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30]Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([Cl:30])[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1SC)OCCC(=O)OCc1ccccc1
Reactant: ClCl
Solvent: ClCCl
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1Cl)OCCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
The product of Step E can also be prepared by dissolving 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(methylthio)-2-azetidinone (0.44 g.) in methylene chloride (10 ml.) and treating with chlorine (0.110 g.) in methylene chloride (2.0 ml.). The mixture is allowed to stand for 10 minutes at room temperature. The solvent is removed under reduced pressure to afford the 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-chloro-2-azetidinone as described in Step E. ##STR32##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1cc(Cl)ncn1
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: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 58.2 %

Procedure:
To a mixture of 4,6-dichloropyrimidine (1.49 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) in toluene (20 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by trituration with MeOH (15 mL) to obtain 1.31 g of the title compound as a white solid (purity was about 80% by HPLC analysis). HPLC/MS: retention time=3.65 min, [M+H]30 =225.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([C:17]#[N:18])=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30].ClC([O-])=O>N1C=CC=CC=1>[CH:32]1([O:31][C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:6]3[N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[C:13]4[C:8]([C:7]=3[C:17]#[N:18])=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=4)=[CH:24][CH:23]=2)[CH2:26][CH3:27])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2C2CCC2)cc1
Reactant: O=C(Cl)OC1CCCC1
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N(CC)C(=O)OC4CCCC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (35 mg, 0.10 mmol), prepared as in example 1CO, step C, is dissolved in pyridine (300 μL). Cyclopentyl chloroformate (25 μL, 0.17 mmol) is added. The reaction mixture is stirred at room temperature for 2.5 h. More chloroformate (10 μL, 0.07 mmol) is added to drive the reaction to completion. After an additional 90 min of stirring, the reaction mixture is partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography yields [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (41 mg, 87%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]CC=1.C(OCC)(=O)C>C1(=O)CCCCC1.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:21]=2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Reactant: C1=CCCCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 50.2 %

Procedure:
To a solution of 5 g of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 25 ml of cyclohexanone were added 5.96 g of cyclooctene and 0.5 g of 10% palladium carbon. The mixture was stirred at the internal temperature of 145° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding thereto diisopropyl ether and n-hexane and the resulting crystals were collected by filtration, whereby 3.2 g of the title compound was obtained.
Reaction SMILES: C(O[C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=O)C.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[C:37]([O:41][C:42](=[O:45])CBr)([CH3:40])([CH3:39])[CH3:38].[OH-].[Na+]>C1COCC1.CCOCC>[C:37]([O:41][C:42](=[O:45])[CH2:4][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid ethyl ester (3 g, 14.78 mmol) (N. Meanwell et al, J. Org. Chem, 1995, 60(6), 1565-82) in THF (100 ml) was treated with BTPP(5.4 ml, 17.74 mmol) followed by t-butylbromoacetate (2.4 ml, 16.3 mmol) and the mixture was stirred for 30 minutes. The solution was diluted with ether and washed with water, dired over MgSO4 and concentrated. The residue was dissolved in MeOH (30 ml) and treated with NaOH (10 N, 3 ml, 30 mmol) and stirred for 1 h at 23° C. The solvent was removed and the residue diluted with ether and washed with 1N HCl, saturated NaCl dried over MgSO4 and concentrated. The residue was purified by flash chromatography to give 1.84 g (50%) (2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00 g, 3.63 mmol) in DCM (20 mL), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.30 g, 4.03 mmol) was added and the reaction mass was stirred at RT for 2 h. After completion of reaction, excess of solvent was removed under reduced pressure to obtain 0.700 g of the crude product. To a solution of obtained crude product in DCM (5.0 mL), TFA (5.0 mL) was added and the reaction mass was stirred at RT for 2-3 h. Excess of the solvent was removed from the reaction mass under reduced pressure and the reaction mass was quenched in ice and filtered to obtain 0.700 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 4.45 (d, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.65-7.68 (m, 2H), 8.85 (d, J=6.6 Hz, 2H), 8.18 (d, J=6.3 Hz, 2H), 10.05 (s, 1H), 12.69 (s, 1H); MS (m/z): 463.17 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
3-Nitroaniline (0.222 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.149 g, 0.301 mmol, 56%).
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[CH:11][CH:10]=1.[Cl:19][CH:20](C(C)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1.O>[Cl:19][C:20](=[N:16][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]([F:17])([F:18])[F:6])=[CH:14][CH:13]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N#[N+]c1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
4-Trifluoromethoxybenzenediazonium tetrafluoroborate (63) (4.33 g, 15.7 mmol) was added to a solution of ethyl 2-chloroacetoacetate (64) (2.35 g, 14.3 mmol) in pyridine (6 mL) and water (6 mL) at −5° C. The mixture was stirred at −5° C. for 0.5 h and the precipitate was filtered and washed with ice cold water. Recrystallisation from EtOH/water gave ethyl 2-chloro{[4-(trifluoromethoxy)phenyl]hydrazono}ethanoate (65) (3.977 g, 82%) as pale orange needles: mp 128-130° C.; 1H NMR [(CD3)2SO] δ 10.68 (s, 1H), 7.43 (d, J=9.2 Hz, 2H), 7.34 (d, J=9.2 Hz, 2H), 4.30 (t, J=7.1 Hz, 2H), 1.30 (q, J=7.1 Hz, 3H). APCI MS m/z 309, 311 [M−H]−.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][C@@H:38]([CH2:41][CH3:42])[CH2:39][NH2:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:40][CH2:39][C@@H:38]([CH3:37])[CH2:41][CH3:42])=[O:33])=[CH:35][CH:36]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CC[C@H](C)CN
Product: CC[C@H](C)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 98.6 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.