Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl.[C:12]1([O:20][CH3:21])[C:13](=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:14][CH3:15]>>[CH3:15][O:14][C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[O:20][CH3:21])[CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Reactant: COc1ccccc1OC
Agent: Cl
Product: COc1ccc(Cc2c[nH]c(=O)[nH]c2=O)cc1OC

Procedure:
A solution of 5.0 g of 5-hydroxymethyluracil, 150 ml of veratrole and 0.5 ml of concentrated hydrochloric acid was heated at 140° C. for one hour. The precipitate was filtered, washed with ether and recrystallized from hot methanol, 6.85 g, M+ 263.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:28](S(C3C=CC(C)=CC=3)(=O)=O)[CH:27]=[CH:26][C:5]2=[N:6][C:7]=1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:22]=[C:21]([CH:23]3[CH2:25][CH2:24]3)[NH:20][N:19]=2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:28][CH:27]=[CH:26][C:5]2=[N:6][C:7]=1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:22]=[C:21]([CH:23]3[CH2:24][CH2:25]3)[NH:20][N:19]=2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)c(Cl)cc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1nc2cc[nH]c2cc1Cl
Temperature: 100 °C
Yield: 13.1 %

Procedure:
To a solution of N2-(1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (320 mg, 0.58 mmol) in methanol (5 mL) was added an aqueous solution of KOH (2 N, 5 mL). The mixture was heated at 100° C. for 3 h. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc. The extract was washed with H2O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 30 mg (26%) of N2-(1-(6-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as white solid. 1H NMR (500 MHz, CD3OD): δ 11.93 (s, 1H), 11.41 (s, 1H), 9.40 (m, 1H), 7.80 (d, 2H), 7.69 (s, 1H), 6.60 (m, 2H), 6.27 (d, 2H), 5.63 (m, 1H), 1.88 (s, 1H), 1.45 (d, 3H), 0.94 (m, 2H), 0.71 (m, 2H); MS (ESI): m/z=395.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.[H][H]>C1COCC1>[Br:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N(C(=O)CCOCCCBr)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCCOCCCBr)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a stirred solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 3-(bromopropoxy)propionamide (28.2 g, 66 mmol) in THF (300 mL) was added BH3-THF (100 mL, 2.0 M in THF, 200 mmol) and the reaction mixture was refluxed for 48 h. The reaction mixture was then allowed to cool to room temperature and methanol was added dropwise until evolution of hydrogen gas stopped. The mixture was then concentrated under reduced pressure and dissolved in dichloromethane (500 mL). The reaction mixture was washed with 1 N hydrochloride acid (500 mL) and the organic layer removed. The aqueous layer was then made basic to pH 12 using 1 N sodium hydroxide and extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), brine (400 mL), dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The resulting crude product was purified by silica gel chromatography (dichloromethane/methanol/aqueous ammonia: 9/0.5/0.05) to afford 20.5 g of the title intermediate (76% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:32])[CH:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)OS(C)(=O)=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47][NH2:48])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:32])[CH:19]([NH:48][CH2:47][CH2:46][NH:45][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:49])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(OS(C)(=O)=O)c3cccc(Cl)c3)ccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(C(=O)Nc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 60 °C
Yield: 85 %

Procedure:
To a solution of 5-[2-(3-chloro-phenyl)-2-methanesulfonyloxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (1.49 mmol) in dry THF (4 mL) was added pyridine (4.48 mmol, 3 equivalents) followed by followed by a dry THF solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (3 equivalents, ˜0.5 mL/mmol). The resulting solution was refluxed at 60° C. overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using eluting with EtOAc:hexane (60:40) to afford the title compound in 85% yield.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:34]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), ethanamine-HCl (8.51 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention 12.1=min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.049 mmol, 69.8% yield): LCMS=459.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.36 Hz), 7.48-7.85 (7 H, m), 5.10 (1 H, s), 3.28 (2 H, dd, J=7.15, 0.99 Hz), 1.14 (3 H, t, J=7.26 Hz); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[NH2:18][CH2:17][CH2:16][NH:19][C:13](=[S:14])[NH:12][C:10]1[C:9]([CH3:15])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([F:1])[CH:11]=1
Reactant: NCCN
Reactant: Cc1c(N=C=S)cc(F)c2cccnc12
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(F)c2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of 5-fluoro-7-isothiocyanato-8-methylquinoline (0.38 g) in toluene (40 mL) is added dropwise to a solution of ethylenediamine (0.78 g) in toluene (40 mL). A white precipitate is observed after the reaction stirs for 10 minutes at room temperature. The precipitate is filtered and dried in vacuo to afford 7-[N'-(2-aminoethyl)thioureido]-5-fluoro-8-methylquinoline as a white solid.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.C(N1CCCCC1)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@H:49]([O:51][CH3:52])[CH2:48][C@H:47]1[CH:53]=[C:54]([CH3:58])[C:55](=[O:57])[CH3:56])=[O:45])[CH:41]=[CH2:42].C(=O)([O-])O.[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@H:49]([O:51][CH3:52])[CH2:48][C@H:47]1[CH:53]=[C:54]([CH3:58])[C:55](=[O:57])[CH2:56][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])=[O:45])[CH:41]=[CH2:42]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1C[C@H](OC)C[C@H]1C=C(C)C(C)=O
Agent: CCN1CCCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OC)C[C@H]1C=C(C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (2.90 g) and N-ethylpiperidine (1.35 ml) in dichloromethane (15 ml) was added trimethylsilyl trifluoromethanesulfonate (1.95 ml) at -20° C., and the resulting mixture was stirred at 0° C. for 1 hour (Solution A). To a solution of (2S,4R)-1-allyloxycarbonyl-4-methoxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (2.70 g) and N-ethylpiperidine (1.48 ml) in dichloromethane (50 ml) was added trimethylsilyl trifluoromethanesulfonate (2.93 ml) at -20° C. and the resulting mixture was stirred at 0° C. for 1 hour. To this mixture was added dropwise the above obtained Solution A at 0° C. and the resulting mixture was stirred for another 1 hour at 0° C. The reaction mixture was taken up into a mixture of ethyl acetate (300 ml) and water (300 ml) and the mixture was stirred at ambient temperature for 2 hours. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (120 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (3S,4R)-4-[4-{(2S,4R)-1-allyloxycarbonyl-4-methoxypyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (3.24 g).
Reaction SMILES: C1(CO[C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])C=CC=CC=1.[O:36]1[C:40](C(O)=O)=[CH:39][CH:38]=[N:37]1.Cl.C(N=C=NCCCN(C)C)C>CO.C(Cl)Cl.[Pd].CN(C)C1C=CN=CC=1>[O:36]1[C:40]([C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])=[CH:39][CH:38]=[N:37]1
Reactant: O=C(O)c1ccno1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)OCc4ccccc4)CCN32)C(=O)O1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)c4ccno4)CCN32)C(=O)O1
Reaction time: 17 h

Procedure:
To a flask containing 8-[5-(S)-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-1, 2, 4a, 5-tetrahydropyrazino[2, 1-c] [1, 4]benzoxazine-3(4H)-carboxylic acid phenylmethyl ester (EXAMPLE 1, 150 mg, 0.31 mmol) in methanol (5 mL) and methylene chloride (5 mL) is introduced 10% palladium on carbon (70 mg). The mixture is placed under a hydrogen balloon for 17 hours, filtered through celite, and concentrated in vacuo. The residue is dissolved in pyridine (5 mL) followed by the addition of isoxazole-5-carboxylic acid (40 mg, 0.35 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(70 mg, 0.35 mmol). The reaction is stirred under an inert atmosphere for 17 hours, diluted with methylene chloride (20 mL), washed with 1N HCl (20 mL) and saline, dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.42, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, HRMS calcd for C21H23N5O6 : 441.1648. Found: 441.1658.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[B:10]([N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])Cl>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[B:10]([C:2]1[CH2:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)N(B(Cl)C1=Cc2ccccc2C1)C(C)C
Solvent: C1CCOC1
Product: CC(C)N(B(C1=Cc2ccccc2C1)C1=Cc2ccccc2C1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 242 %

Procedure:
This solution was dropped into a solution of 4.11 g (15.7 mmol) of (2-indenyl)(diisopropylamino)chloroborane in 30 ml of tetrahydrofuran at 0° C. After stirring at room temperature for four hours, the solvent was evaporated and the residue was extracted twice with 40 ml of hexane and 10 ml of dichloromethane to obtain 6.47 g (19.0 mmol) of bis(2-indenyl)(diisopropylamino)borane as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.Br[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].O1CCCC1>[Cl-].[NH4+].[Zn]>[CH3:21][C:20]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)([CH3:22])[CH:19]=[CH2:18]
Reactant: CC(C)=CCBr
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(C)(C)C1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.75 h

Procedure:
To a suspension of benzyl 3-oxopyrrolidine-1-carboxylate (4.50 g, 0.0205 mol) and 4-bromo-2-methyl-2-butene (4.75 mL, 0.0412 mol) in 25.0 mL of saturated ammonium chloride and tetrahydrofuran (4.75 mL, 0.0586 mol) was added zinc (2.70 g, 0.0412 mol) at rt. Soon after stirring was started, gas and heat were evolved. After 45 min., the resulting light grey mixture was filtered through celite. Layers of the filtrate were separated and the aqueous layer of the filtrate was extracted with EtOAc. The organic layers were combined, washed with brine, dried and evaporated in-vacuo. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na) 290.2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[C:15](=[N:20]O)([NH2:19])[CH:16]([CH3:18])[CH3:17].[O-]CC.[Na+]>C(O)C>[CH:16]([C:15]1[N:20]=[C:9]([C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([F:1])([F:14])[F:13])[O:11][N:19]=1)([CH3:18])[CH3:17]
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)c1cnccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 0 °C

Procedure:
2 g of methyl 4-trifluoromethylnicotinate and 1.56 g of isobutyramide oxime were initially charged in 15 ml of ethanol and cooled to 0° C. 10 ml of a 1.2 molar sodium ethoxide solution were added dropwise to this solution. The mixture was allowed to warm to room temperature over a period of two hours and stirring was then continued at this temperature until the reaction, according to TLC, had ended. The reaction mixture was concentrated and the residue was taken up in saturated ammonium chloride solution and extracted with diethyl ether. Chromatographic purification of the crude product gave the desired compound as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:5]([N+:20]([O-])=O)[CH:4]=1.Cl[Sn]Cl>C(O)C.O>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-(4-Methoxy-2-nitrophenyl)-4H-chromen-4-one (1.5 g, 5.04 mmol) was dissolved in ethanol (30 mL) and heated at reflux. SnCl2 (4.97 g , 26.23 mmol) was added. The mixture was heated under reflux for 20 min. The reaction mixture was cooled to rt diluted with water, neutralized and extracted with ethyl acetate to give the crude compound. This was purified by column chromatography using 3% MeOH in CH2Cl2 to give 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (790 mg, 58%).
Reaction SMILES: [C:1]([S:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[OH-].[K+].Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][C@H:31]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:32]([N:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:35])=[O:33])[CH:27]=CC=1.Cl>C(O)C>[C:47]([O:46][C:45]([NH:44][C@H:31]([C:32]([N:34]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])=[O:33])[CH2:30][C:26]1[CH:27]=[C:2]([CH:23]=[CH:24][CH:25]=1)[CH2:1][S:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:51])([CH3:49])([CH3:50])[CH3:48]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCl)c2)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)Cc1c(SC(C)=O)[nH]c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(SCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution ethyl 2-(2-(acetylthio)-1H-indol-3-yl)acetate (380 mg, 1.4 mmol) in ethanol (5 ml) was added potassium hydroxide (84 mg, 1.5 mmol). After 10 minutes, (5)-tert-butyl 3-(3-(chloromethyl)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (I-5, 605 mg, 1.4 mmol) was added to the solution. The reaction was stirred for 2 hours and then neutralized with 1N (aq) HCl and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (1-5% MeOH/DCM) to provide the desired product (796 mg, 1.26 mmol), 90%. MS (m/z) 632 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:29]1[N:33](COCC[Si](C)(C)C)[C:32]2[CH:42]=[C:43]([C:46]#[N:47])[CH:44]=[CH:45][C:31]=2[N:30]=1)([C:5]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:11]([CH3:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4].COC(C1N(COCC[Si](C)(C)C)C2C=CC(C#N)=CC=2N=1)(C1C(S(C)(=O)=O)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O)C>>[CH3:1][O:2][C:3]([C:29]1[NH:30][C:31]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][C:32]=2[N:33]=1)([C:5]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:11]([CH3:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:4]
Reactant: COC(C)(c1c(S(C)(=O)=O)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: COC(C)(c1c(S(C)(=O)=O)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Product: COC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(S(C)(=O)=O)cc(C)c2[nH]ccc12

Procedure:
A mixture of (±)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-C. 1H NMR (400 MHz, DMSO-d6) δ 12.51-12.55 (m, 1H), 11.48 (br. s., 1H), 8.32-8.33 (m), 7.80-7.98 (m, 2H), 7.56-7.61 (m), 7.42-7.44 (m), 7.18 (t, J=2.91 Hz, 1H), 5.3 (br. s., 1H), 3.41 (s, 3H), 3.05 (s, 3H), 2.18 (s, 3H). MS (ESI+) m/z 409.1 (M+H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([Cl:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[Cl:16][C:10]1[CH:9]=[C:8]([C:5]2[S:4][C:3]([CH:17]=[O:21])=[C:2]([C:25]3[CH:26]=[CH:27][C:28]([OH:29])=[C:23]([F:22])[CH:24]=3)[C:6]=2[CH3:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1Cl
Reactant: COc1ccc(B(O)O)cc1F
Product: Cc1c(-c2ccc(O)c(Cl)c2)sc(C=O)c1-c1ccc(O)c(F)c1
Yield: 27.6 %

Procedure:
Starting from 2-[3-bromo-5-(3-chloro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.0 g, 2.6 mmol, made in Example 13, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.52 g, 3.1 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.26 g, 51%, m.p. 227-29° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.08, Phe: 1.01, Ala: 1.02, Tyr: 0.97
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].C1(C)C=CC(S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O)=CC=1.O1CCCC1>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dimethylformamide. To the solution was added 0.6 g of about 50 % sodium hydride and the whole was stirred for 20 minutes at room temperature, and then heated up to 90°C. To this was added dropwise a solution of 7.5 g of 2,2,2-trifluoroethyl p-toluenesulfonate and 20 ml of tetrahydrofuran and the mixture was reacted for 2 hours. After the reaction was complete, the solvent was removed from the resulting mixture by distillation, and to the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 3.2 g of 1-(m-nitrophenyl)-3-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 228-229°C.