Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution of carbazole (3.34 g, 20 mmol) in DMF (80 mL) at 0° C. was added NaH (0.72 g, 30 mmol). After heating at 80° C. for 1.5 h, iodomethane (3.4 g, 24 mmol) was added dropwise. The resulting mixture was kept at 80° C. overnight. After cooling down to 0° C., the reaction mixture was carefully quenched with water and extracted with ethyl acetate three times. The combined organic phase was washed with water and brine. Then the organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluent (EA:PE=1:5) to afford methylated carbazole 1b (2.78 g) as yellow oil in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 2H), 7.46 (t, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 2H), 3.79 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.9, 125.6, 122.7, 120.2, 118.8, 108.4, 28.9.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: N#Cc1ccccc1
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Yield: 32.6 %

Procedure:
A solution of 8.76 g (0.050 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate in 180 g (35 equiv., 1.75 mol) of redistilled benzonitrile was held at reflux for 72 hours. The solution, which contained the product in 62% yield (gc assay), was concentrated under vacuum to 90° C (0.5 torr). The residue was heated with 200 ml of hexane at reflux; the supernatant was decanted, treated with charcoal, filtered, and concentrated under vacuum to 6.1 g of oil and solid. The mixture was chromatographed on 200 g of silica gel (Woelm, for dry column chromatography) with benzene. The first 500 ml of eluate contained 0.8 g of product and impurities. The next 1200 ml of eluate gave 3.82 g (33%) of pure liquid product (gc assay), which crystallized after several months, mp 32°-35° C; nD25 = 1.5937; mass spectrum m/e (rel. intensity, fragment) 234 (18, M+ ), 206 (3, M+ -C2H4), 189 (10, M+ -OEt), 135 (100, M+ -EtO2CCN), 103 (14, C6H5CN+).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1
Reactant: CCOC(=O)c1ccc(N(C)c2nc(=O)c3cccnc3s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(C(=O)O)cc1)c1nc(=O)c2cccnc2s1

Procedure:
The reaction procedure of Example 116 was followed except that 70 mg g of ethyl 4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoate, 0.9 ml of ethanol and 0.9 ml of a 0.25 N aqueous solution of sodium hydroxide were used. As a result, 61 mg of 4-(N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]benzoic acid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:7]=[C:6]([O:18]CC2C=CC=CC=2)[CH:5]=1>C1COCC1.CO.[Pd]>[OH:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 71.8 %

Procedure:
Methyl-3-(benzyloxy)-5-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]benzoate (6.1 g) (Intermediate 6) was dissolved in THF: Methanol mixture (1:1), and 10% Pd/C (0.6 g) was added to this mixture. The reaction mixture was stirred under hydrogen atmosphere for 16 h. After 16 h, TLC showed absence of starting material and formation of polar spot when checked in 10% methanol: chloroform, the reaction mixture was filtered through celite on Buckner funnel. The filtrate was concentrated under vacuum to get the solid product (3.27 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 1.89-1.92 (m, 1 H), 2.51-2.54 (m, 1 H), 2.77 (s, 3 H), 3.34-3.37 (m, 2 H), 3.80 (s, 3 H), 4.96 (t, J=7.2 Hz, 1 H), 6.66 (t, J=2 Hz, 1 H), 6.97 (t, J=1.6 Hz, 1 H), 7.01 (t, J=1.2 Hz, 1 H), 9.88 (s, 1H); ESI MS m/z (relative intensities): 266.2 (M+H)+ (100%); UPLC Purity: 99.00%, Ret. time: 2.67 min.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)=[O:28])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH:34][C:8](=[O:9])[CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic acid (prepared in Example 12A, 767 mg, 2.47 mmol) in methylene chloride (20 mL) at 25° C. was treated with 2-amino-thiazole-4-carboxylic acid ethyl ester (553 mg, 3.21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.64 g, 3.71 mmol), and triethylamine (1 mL, 7.41 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic extracts were washed with a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (564 mg, 49%) as a white foam: FAB-HRMS m/e calcd for C26H28N2O4S (M+H)+ 465.1848, found 465.1831.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:32][C:31]3[CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:30]=3[F:29])=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cc(C(F)(F)F)ccc3F)c3c(c21)CC(C)(C)O3
Yield: 34.5 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.065 g, 0.363 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.048 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.52 (s, 2H), 3.60 (s, 3H), 7.29 (s, 1H), 7.53-7.63 (m, 2H), 8.48 (s, 2H), 8.86 (d, J=5.4 Hz, 1H), 10.22 (m, 1H), 10.94 (s, 1H); MS [M]+: 568.08.
Reaction SMILES: [F:1][C:2]1([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[N+:24]([O-])=O)[C:15]2=[O:27])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:22](=[O:23])[N:14]([C:2]1([F:1])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13])[C:15]2=[O:27]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(F)(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-fluoro-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1.0 g, 2.6 mmol) and Pd/C (10%, 0.1 g) in methanol (100 mL) is shaken under hydrogen (50–60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]1([CH2:19][SH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:19]([S:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCc1ccccc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]nc(SCc2ccccc2)c2ccccc12
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (500 mg, 2.77 mmol), phenylmethanethiol (412 mg, 3.32 mmol) and sodium hydride (144 mg, 3.6 mmol) in DMF (30 mL) was stirred at 125 C for 2 hours. The reaction mixture was quenched with water, and extracted with EtOAc (2×). The combined organic layer was washed with water, and concentrated to give 456 mg (61%) of title compound. MS (APCI+) M/Z 269 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[S:27][C:28]=1[Cl:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:29][C:28]1[S:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=1[C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCn1nccc1-c1cc(C(=O)OC)sc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (2 g, 7.83 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.4 g, 0.78 mmol) in 1,2-dimethoxyethane (DME) (50 mL) and H2O (10 ml). After stirring for 3 h at 70° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAc/hexanes, 10-30%] to give the product [1.8 g, 85%] as an off white solid: LC-MS (ES) m/z 271 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.60 mL (4.3 mmol) of triethylamine was added and dissolved in a suspension of 0.69 g (3.9 mmol) of ascorbic acid in acetonitrile (8 mL). The above crude product of (5,9,13-trimethyltetradec-4-enyl)tosylate was added thereto at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [N:1]1[C:2]2[N:3]([N:7]=[C:8]3[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=23)[N:4]=[CH:5][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[C:2]2[N:3]([N:7]=[C:8]3[CH2:12][NH:11][CH2:10][C:9]=23)[N:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nn3nccnc3c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnn2nc3c(c2n1)CNC3
Reaction time: 1 h

Procedure:
To 77 mg (0.29 mmol) of the product from Step A in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture stirred for 1 h. The solvent was evaporated in vacuo and the residue purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 20% ethyl acetate/methanol containing 10% NH4OH gradient) to yield the title compound as a yellow solid. LC/MS 162.2 (M+1).
Reaction SMILES: C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C([O:13][C@@H:14]([C:46]4[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=4)C(=O)N3)=CC=2C1)=O)(C)(C)C.Cl.C[O:55][C:56](=[O:110])[C@@H:57]([NH:73][C:74]([CH:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([Cl:105])=[C:101]([C:106]([F:109])([F:108])[F:107])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78][NH:77]1)=[O:75])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[C:14]([N:77]1[CH:76]([C:74]([NH:73][C@@H:57]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)[C:56]([OH:55])=[O:110])=[O:75])[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([Cl:105])=[C:101]([C:106]([F:109])([F:107])[F:108])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78]1)(=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)C(=O)N3
Agent: Cl
Product: N#Cc1ccc(-c2ccc(C[C@H](NC(=O)C3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(C(F)(F)F)c4)cc3)C(=O)N5)C(=O)O)cc2)cc1

Procedure:
(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester was converted to (S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure L. and C. Title compound was prepared from (S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.05 mmol) following the general procedure F and B. LC-MS (m/z): 886.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:15]=1>>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:15]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1
Yield: 95 %

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 3-trifluoromethoxy-phenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 95% yield as a pale-brown solid. MS ISP (m/e): 472.0 (100) [(M+H)+].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.ClC(OC1C=CC(F)=CC=1)=O.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[O:29]>>[C:7]1([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[O:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:11][CH:12]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Agent: O=C(Cl)Oc1ccc(F)cc1
Product: Cc1ccc(OC(=O)NCCc2ccc(-c3ccccc3)cc2)cc1

Procedure:
The procedure is carried out in a manner similar to Example 4, replacing the 4-phenylbenzylamine with 2-(4-biphenyl)ethylamine and the 4-fluorophenyl chloroformate with 4-methylphenyl chloroformate.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]#[N:20])[C:10]2=[O:21])=[CH:4][C:3]=1[CH3:31].[OH:32][N:33]=[C:34](Cl)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)C.C1COCC1.O.C(OCC)(=O)C>[OH:29][C:25]1[C:26]([CH3:28])=[CH:27][C:22]([C:9]2([C:5]3[CH:4]=[C:3]([CH3:31])[C:2]([OH:1])=[C:7]([CH3:8])[CH:6]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[O:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[N:20]=3)[C:10]2=[O:21])=[CH:23][C:24]=1[CH3:30]
Reactant: COc1ccc(C(Cl)=NO)cc1
Reactant: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(CC#N)c3ccccc32)cc(C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2noc(CN3C(=O)C(c4cc(C)c(O)c(C)c4)(c4cc(C)c(O)c(C)c4)c4ccccc43)n2)cc1
Yield: 27.8 %

Procedure:
Combine [3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-yl]-acetonitrile (0.563 g, 0.878 mmol), N-hydroxy-4-methoxy-benzenecarboximidoyl chloride (1.63 g, 8.78 mmol), and diethyl ether (20 mL). Add a solution of triethylamine (1.35 mL, 9.66 mmol) in diethyl ether (10 mL) over 30 minutes. Stir the reaction at room temperature overnight. Dilute the reaction with ethyl acetate (200 mL) and water (200 mL). Separate the layers, and dry the organic layer with sodium sulfate. Concentrate in vacuo. Chromatograph on silica gel eluting with 20% ethyl acetate in hexanes and concentrate. Dissolve the resulting compound (0.217 g, 0.275 mmol) in THF (2 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.69 mL) and stir the reaction at room temperature for 30 minutes. Quench with 1N aqueous HCl (10 mL), ethyl acetate (50 mL), and water (40 mL). Separate the layers and wash the organic layer with brine (50 mL). Dry the ethyl acetate with sodium sulfate, and concentrate in vacuo. Chromatograph on silica gel eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.137 g of the title compound: mass spectrum (ion spray): m/z=562(M+1); 1H NMR(DMSO-d6): δ8.23 (s, 2H), 7.84-7.82 (m, 2H), 7.28-7.25 (m, 2H), 7.16-7.04 (m, 6H), 6.71 (s, 4H), 5.42 (s, 2H), 3.81 (s, 3H), 2.04 (s, 12H).