Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21]1([C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]([CH2:31][C:32]([OH:34])=[O:33])[O:23]1)=O>COCCOC>[O:10]=[C:2]1[C:3](=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]([CH2:31][C:32]([OH:34])=[O:33])[O:23]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Product: O=C(O)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of oxindole (0.400 g, 3.0 mmol) in DME (8.0 mL) was added 9.0 mL LHMDS (1.0 M in THF). After stirring at room temperature for 10 min, phthalide-3-acetic acid (0.519 g, 2.7 mmol) was added as a solid in one portion. The mixture was rapidly stirred for 3.5 h and then quenched into 4% HCl aqueous solution (100 mL) to give a yellow solid. The solid was filtered, rinsed with H2O, MeOH and then 6:4/hexane:EtOAc to afford (0.105 g, 13%) of product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([O:36]C)=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([OH:36])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (60 mg, 0.10 mmol) in dioxane/H2O (11 mL/5 mL) was added LiOH.H2O (12.3 mg, 0.30 mol), and the mixture was stirred at 100° C. for 2 hours. After concentrated, the resulting residue was dissolved in H2O, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed by distillation to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (41 mg, yield: 70%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.36 (s, 1H), 8.26 (s, 1H), 8.13˜8.16 (m, 2H), 8.09 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42˜7.46 (m, 2H), 7.25˜7.27 (m, 1H), 7.09 (s, 1H), 6.92˜6.96 (m, 1H), 6.28 (s, 2H), 3.30 (s, 3H), 2.98 (d, 3H). MS (M+H)+: 602.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2c(Cl)c(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 435 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: C1CSCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSCC3)nc21
Yield: 38.5 %

Procedure:
A suspension of 0.271 g (1.0 mmol) of 7-chloro-1,4-dihydro-1-ethyl-6-fluoro-4-oxo,1,8-naphthyridine-3-carboxylic acid, 0.316 g (3.0 mmol) of thiomorpholine and 30 ml of acetonitrile was heated at reflux for 18 hours. The solvent was removed in vacuo and the residue was recrystallized from aqueous ethanol to give 130 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-1,8-naphthyridine-3-carboxylic acid; mp 241°-243° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([Si:13]([C:18]#[CH:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>C(NC(C)C)(C)C.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.[Cu]I>[CH2:14]([Si:13]([C:11]#[C:12][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: C#C[Si](CC)(CC)CC
Reactant: Ic1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a stirred solution of 5-iodoindole (0.50 g, 2.0 mmol) and (triethylsilyl)-acetylene (0.58 g, 4.0 mmol) in diisopropylamine (15 mL) was added Pd(PPh3)2Cl2 (0.07 g, 0.10 mmol) and CuI (0.04 g, 0.20 mmol) and the reaction mixture was stirred at r.t. for 16 h. The solvent was then removed in vacuo. EtOAc (15 mL) and water (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc/hexanes) gave the title compound (0.52 g, quantitative). δH (DMSO-d6) 11.30 (1H, br. s), 7.69 (1H, s), 7.45-7.41 (1H, m), 7.37 (1H, d, J 8.4 Hz), 7.15 (1H, dd, J 8.4 and 1.5 Hz), 6.48-6.40 (1H, m), 1.02 (9H, t, J 7.8 Hz), 0.65 (6H, q, J 7.9 Hz). MS (ES−) 254.0 (M−H)−.
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN1CCCC1=O>[I-:1].[N:25]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[C:19]([N:25]7[CH2:29][CH2:28][CH2:27][CH2:26]7)[CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: CN1CCCC1=O
Product: c1cc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)cc1N1CCCC1
Reaction time: 1 h

Procedure:
A mixture of 4.41 g. of 3,10-difluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 9.0 ml. of pyrrolidine and 130 ml. of N-methyl-2-pyrrolidinone is stirred and heated at 130°-160° C. for 4.5 hours, then cooled. The resulting precipitate is collected, washed with methanol and stirred with 100 ml. of 2% aqueous triethylamine hydroiodide for 1 hour. The resulting precipitate of 3,10-di-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. 345° C. (dec.), after crystallization from dimethylformamide/-2-propanol.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH2:5][C:6]([NH:14][C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[CH:20][CH:19]=2)([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].Cl>O1CCOCC1.O>[C:24]12([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]([NH:14][C:6]4([C:7]([OH:9])=[O:8])[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:35])=[O:2])[CH2:5]4)=[O:34])=[CH:19][CH:20]=3)[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2
Reactant: COC(=O)C1=CC=CC(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)(C(=O)OC)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC1(C(=O)O)C=CC=C(C(=O)O)C1
Yield: 105.3 %

Procedure:
A 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid dimethyl ester (158.9 mg, 0.34 mmol) in 1,4-dioxane/H2O (1:1, 3.5 ml) was treated with LiOHH2O (56.2 mg, 1.34 mmol) at room temperature. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=5:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-isophthalic acid as a white solid (161.7 mg, 100% yield).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH2:21]([N:18]1[C:19](=[O:20])[C:15]2[C:16](=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[C:17]1=[O:29])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
To an ice cooled solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2.5 g, 8.1 mmol) in anhydrous N,N-dimethylformamide (25 ml), sodium hydride (60% emulsion in paraffin oil, 500 mg, 12 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was again cooled to 0° C. and (2-bromoethyl)benzene (1.5 ml, 8.9 mmol) was added. The solution was then heated to 90° C. for 2 hours. The reaction was monitored by TLC and LCMS, and on completion of reaction, it was cooled to room temperature and ice cooled water (75 ml) was added. The reaction mixture was then extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2 g, 60%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.65 (s, 1H), 7.15-7.3 (m, 7H), 6.85 (d, 2H), 5.77 (s, 2H), 3.85 (t, 2H), 3.70 (s, 3H), 2.95 (t, 2H); LCMS: [M+H] 413. Trifluoroacetic acid (20 ml) was added to 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 2.1 mmol) at 0° C., and then stirred at 100° C. for 5 hours. The reaction was monitored by TLC, and on completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure and the residue was basified using aqueous ammonia to form a solid precipitate. The solid was filtered over a sintered funnel. The solid was washed with hexane and dried under reduced pressure to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (500 mg, 80%). The compound was used next without further purification. 1HNMR (400 MHz, DMSO-d6) δ: 14.50 (s, 1H), 9.00 (s, 1H), 8.50 (s, 1H), 7.05-7.15 (m, 5H), 3.95 (t, 2H), 2.95 (t, 2H); LCMS: [M+H] 293.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:9]=[C:8]2[CH:34]=[CH2:35])=[O:4].Br[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]([C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:9]=[C:8]2/[CH:34]=[CH:35]/[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:4]
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(F)c(C(=O)OC)cc12
Reactant: Brc1cccnc1
Product: COC(=O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F

Procedure:
600 mg of 6-fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid methyl ester and 190 μl of 3-bromopyridine were treated in the same manner as described in Example 124, to afford 75 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59](O)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]>CN(C)C=O>[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59]([N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]
Reactant: c1csc(COC2CNC2)c1
Reactant: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cc12
Reaction time: 8 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (61 mg, 0.30 mmol), EDCI (71.5 mg, 0.37 mmol), HOBt (52 mg, 0.37 mmol) and diisopropylethylamine (110 μL, 0.62 mmol) were successively added to a solution of (E)-3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylic acid hydrochloride (70 mg, 0.25 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated, gasified with an aqueous solution of sodium hydroxyde (2N) until pH 12 and finally extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (10 mg, 10%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:21])[C:17]([NH:19][CH3:20])=[CH:18][C:11]=3[O:10][CH2:9]2)=CC=1.FC(F)(F)C(O)=O>>[F:21][C:16]1[C:17]([NH:19][CH3:20])=[CH:18][C:11]2[O:10][CH2:9][NH:8][C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(Cc1ccc(OC)cc1)CO2
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cc1F)C(=O)NCO2
Yield: 72.8 %

Procedure:
To 3-(4-methoxybenzyl)6-fluoro-7-(methylamino)2,3-dihydrobenzo[e][1,3]oxazin-4-one (1 g, 3.5 mmol) added trifluoroacetic acid ((5 mL) and heated the reaction at 80° C. for 4 hr. RP-HPLC showed formation of new peak and disappearance of SM peak. The trifluoroacetic acid was removed under vacuum and the residue suspended in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate was dried, filtered and evaporated to afford 6-Fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one as off-white solid (0.500 g, 72%) after triturating with diethyl ether. RP-HPLC: 1.58 min; ES-MS (M+H)+=198.0; 1H-NMR (CDCl3) δ (ppm): 7.5 (d, 1), 6.4 (s, 1), 6.15 (d, 1), 5.17 (s, 2), 2.91 (s, 3)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:60][C:61]1[CH:66]=[CH:65][C:64]([CH2:67][NH2:68])=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:64]3[CH:65]=[CH:66][C:61]([F:60])=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
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: C[C@@H]1CC[C@H](C(=O)NCc2ccc(F)cc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(4-fluorophenyl)methanamine (60 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (193 mg) as a yellow solid. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: [C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])(=[O:5])[C:2]([CH3:4])=O.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH3:14][O:15][C:16]([CH:17]([NH:18][C@H:2]([C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:4])[CH2:19][CH2:20][S:21][CH3:22])=[O:23]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(CCSC)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 72 h
Yield: 24.1 %

Procedure:
A solution of pyruvoyl-L-proline (185 mg), L-methionine methyl ester (600 mg), and sodium cyanoborohydride (200 mg) in 20 ml of methanol is adjusted to neutrality with dilute methanolic sodium hydroxide. After standing at room temperature for three days the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water to yield 80 mg of product. The nmr spectrum shows OCH3 at 3.95δ, S-CH3 at 2.2δ and CH-CH3 at 1.55 and 1.7δ. The mass spectrogram on silylated material shows the expected molecular ion at 404 m/e.
Reaction SMILES: [Li].[NH3:2].[NH2-].[Li+].C[C:6]1[C:14]2[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[C:12]([C:19](O)=[O:20])[S:11][C:10]=2[CH:9]=[C:8]([O:22][CH3:23])[CH:7]=1>O1CCCC1>[CH3:23][O:22][C:8]1[CH:7]=[CH:6][C:14]2[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[C:12]([C:19]([NH2:2])=[O:20])[S:11][C:10]=2[CH:9]=1
Reactant: COc1cc(C)c2c(OC(C)C)c(C(=O)O)sc2c1
Reactant: N
Agent: [Li+]
Agent: [Li]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COc1ccc2c(OC(C)C)c(C(N)=O)sc2c1
Yield: 66 %

Procedure:
Excess lithium (74 mg, 10 mM) is added portionwise to a -78° C. solution of a catalytic amount of ferric nitrate in 10 mL of liquid ammonia. The dry ice/acetone bath is removed to allow the reaction to warm to reflux. When the gray color of lithium amide remains for 10 minutes, 2 mL of freshly distilled tetrahydrofuran is added slowly followed by a solution of methyl 6-methoxy-3-(-methylethoxy)benzo[b]thiophene-2-carboxylic acid (200 mg, 0.71 mM) in 2 mL of tetrahydrofuran. The ammonia is allowed to evaporate. The reaction solution is diluted with ethyl acetate, washed with aqueous hydrochloric acid, followed by water, then brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crystalline residue is suspended in 1:9 ethyl acetate:hexane, filtered, and dried at 50° C. in vacuo affording 125 mg (66%) of colorless crystals, mp 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:5]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:6])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cccc(Cl)c1F
Product: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1

Procedure:
Prepared according to Method A step B from 3-chloro-2-fluoro-N-methoxy-N-methylbenzamide (2.5 g, 11.5 mmol) and 4-methoxyphenylmagnesium bromide (25 mL, 0.5 M in THF) to give 0.3 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: NCc1ccc(Cl)cc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(Cl)cc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (4-chloro-2-(trifluoromethyl)phenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 591 [M+H]+.
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:38])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[C:9]=2[C:8](=[O:20])[C:7]2[CH:21]=[CH:22][C:23]([O:25][CH:26]3[CH2:31][O:30]C(C4C=CC=CC=4)[O:28][CH2:27]3)=[CH:24][C:6]1=2>O>[OH:30][CH2:31][CH:26]([CH2:27][OH:28])[O:25][C:23]1[CH:22]=[CH:21][C:7]2[C:8](=[O:20])[C:9]3[C:10]4[C:15](=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=4)[NH:16][C:17]=3[C:5]([CH3:4])([CH3:38])[C:6]=2[CH:24]=1
Reactant: CC1(C)c2cc(OC3COC(c4ccccc4)OC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2cc(OC(CO)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Anhydrous ferric trichloride (56 mg, 5 eq.) was added to the dichloromethane (2 mL) suspension of 6,6-dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-13-1, 13 mg, 0.028 mmol), and stirred at room temperature for 1 hr. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (7 mg, 46%).
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH2:19][C@H:18]([NH3+:22])[C@H:17]1[NH3+:23].C(N(CC)CC)C.[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O>ClCCl>[C:36]([O:35][C:33](=[O:32])[NH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C:16]([F:24])([F:15])[C@@H:17]1[NH2:23])([CH3:39])([CH3:38])[CH3:37]
Reactant: [NH3+][C@@H]1[C@@H]([NH3+])CCCC1(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC(F)(F)[C@@H]1N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of (1S,2R)-3,3-difluorocyclohexane-1,2-diaminium bis(trifluoroacetate) (7.5 g, 19.8 mmol) in dichloromethane (100 mL) was added triethylamine (11.1 mL, 79.0 mmol) followed by BOC2O (5.52 mL, 23.8 mmol). The reaction was stirred for 10 hr at ambient temperature. Concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (CDCl3, 500 MHz) 4.76 (br s, 1H); 3.39 (m, 1H); 2.71-2.64 (m, 1H); 2.2-2.1 (m, 2H); 1.7-1.59 (m, 2H); 1.56-1.51 (m, 2H); 1.45 (s, 9H); 1.29-1.21 (m, 2H). 19F NMR (CDCl3, 564 MHz) −100.4-−100.9 (d, 1F); −114.35-−114.87 (d, 1F).