Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)O)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoate (9.133 g, 22.6 mmol), 1 M LiOH (40 mL, 40 mmol), MeOH (30 mL) and THF (90 mL) was heated at 60° C. for 14 h. The reaction mixture was concentrated to one-third of its initial volume, diluted with EtOAc (700 mL), and washed with satd citric acid (3×50 mL), and water (3×50 mL) before it was dried (Na2SO4), filtered, and concentrated to give the title compound (6.90 g, 78%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][S:7][CH:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].O>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)c1cscn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of 4-isopropylthiazole (9 g, 71 mmol) in anhydrous THF (100 mL) at −78° C. was added nBuLi (40 mL, 99 mmol). The reaction was stirred for 1 hr and the temperature reached −40° C. The reaction mixture was cooled to −78° C. and tri-n-butyltinchloride (23 g, 71 mmol) was added. The reaction mixture was stirred at room temperature for 48 hrs. Water was added and solvent was evaporated under reduced pressure. The residue was partioned between water and EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 219 as colorless oil in 55% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.88-1.62 (m, 27H), 1.40 (s, 3H), 1.42 (s, 3H), 3.17-3.24 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].C(Cl)(Cl)(Cl)[Cl:21].ClN1C(=O)CCC1=O.CN(C)C=O>ClCCl>[C:16]([O:15][CH2:14][C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:21])[C:2]=2[NH2:1])[C:7]1=[O:12])[CH3:19])(=[O:18])[CH3:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetic acid (R)-2-(5-amino-1-oxo-1H-isoquinolin-2-yl)-propyl ester (20 g, 0.07 mol) in carbon tetrachloride (400 mL, 4 mol) at 60° C. was added a solution of N-chlorosuccinimide (11 g, 0.082 mol) in N,N-dimethylformamide (140 mL, 1.8 mol) in 50 minutes. The mixture was stirred at 60° C. for an additional 15 minutes. The cooled mixture was diluted with dichloromethane (400 mL), washed with sodium bicarbonate (100 mL×3), and concentrated under reduced pressure. The mixture was purified by flash chromatography to afford the desired product as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH2:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH:28][C:10]([CH:8]3[CH2:9][CH:7]3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1
Reactant: O=C(Cl)C1CC1c1ccncc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask was 2-(pyridin-4-yl)cyclopropanecarbonyl chloride (7D, 190 mg, 1.05 mmol) added in Pyridine (2 mL) to give a yellow suspension. 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 213 mg, 0.951 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. The reaction was quenched with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure (3×100 mL). The reaction mixture was filtered and purified by preparatory, 5-95% (10 mM NH4HCO3 (aq)/10 mM NH4HCO3 in 20/80 (v/v) H2O/MeCN). Received 9 mg (3%) of yellow solid. 1H NMR (DMSO-d6) δ: 11.32 (s, 1H), 8.46 (d, J=6.1 Hz, 2H), 7.94-8.06 (m, 2H), 7.88 (s, 1H), 7.53-7.67 (m, 3H), 7.15-7.26 (m, 2H), 6.33 (s, 1H), 2.37 (s, 3H), 1.50-1.66 (m, 2H). ESI-MS: m/z 370.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][Si:9]([CH3:16])([CH3:15])[O:10][C:11]#[C:12][CH2:13][CH3:14]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:7][C:6]1[C:2]([C:14]#[C:13][CH2:12][CH2:11][O:10][Si:9]([CH3:16])([CH3:15])[CH3:8])=[CH:3][S:4][CH:5]=1
Reactant: CCC#CO[Si](C)(C)C
Reactant: Brc1cscc1Br
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCC#Cc1cscc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
Into a 250 mL 4 necked RB flask equipped with a magnetic stirring bar, thermometer, rubber septum, argon inlet and reflux condenser with argon outlet (tubed to a silicon oil bubbler) is added 55.0 g (229 mmol) of 3,4-dibromothiophene, 15.6 g of triethylamine, 9.75 g (68.5 mmol) of trimethylsiloxy-1-butyne, 170 mg of triphenylphosphine, 140 mg of copper iodide and 490 mg of dichlorobis(triphenylphosphine) palladium(II). The mixture is heated with a silicon oil bath to 60° C. under argon with stirring for 2 hrs. The cooled mixture is then concentrated on a rotary evaporator at reduced pressure and the residue taken up in 200 mL of hexanes and washed with 2×25 mL of water and the pentane phase dried over sodium sulfate and then concentrated on a rotary evaporator. The residue was chromatographed through neutral silica gel eluted with 2/1 methylenechloride/hexanes to yield 4.8 g of 3-bromo-4(trimethylsiloxybutynyl)thiophene as a light yellow oil which was used directly to prepare 2-hydroxyethylselenolo[2,3-c]thiophene.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](S(C1SC2C=CC=CC=2N=1)(=O)=O)[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1/[CH:10]=[CH:15]/[CH3:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: CCS(=O)(=O)c1nc2ccccc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C/[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of Boc-D-Prolinal (0.53 g, 2.65 mmol) and 2-(ethyl sulfonyl)-1,3-benzothiazole (1.5 g, 6.62 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 1M Lithium bis(trimethylsilyl)amide in THF (4 mL) and continued stirring for 30 min. Then the mixture was warmed to 0° C. and stirred for an additional 3 hr. Upon completion via LC-MS, the reaction mixture was quenched with 20% ammonium chloride solution and extracted with ethyl ether. The ether layer washed with brine, dried over sodium sulfate anhydrous, filtered and dried in vacuo to yield crude product which was further purified on an ISCO normal phase HPLC using a 100% to 75% gradient of hexane to ethyl acetate as mobile phase. Pure tert-butyl-(2R)-2-[(1E)-prop-1-enyl]pyrrolidine-1-carboxylate was isolated from the combined fractions (0.09 g). 1H NMR (CD3OD, 400 Mhz) 5.51-5.44 ppm (m, 1H), 5.39-5.31 (m, 1H), 4.20-4.12 (m, 1H), 3.38-3.30 (m, 3H), 1.91-1.81 (m, 2H), 1.79-1.66 (m, 4H), 1.425 (s, 9H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=O)C.Cl>O.C(O)C>[N:7]1([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A suspension of ethyl 5,8-dihydro-2-(4-acetyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (1000 g) and concentrated hydrochloric acid (800 ml) in a mixture of water (1200 ml) and ethanol (1000 ml) was refluxed for 8 hours and allowed to stand overnight. The crystals precipitated were collected, washed with ethanol, and dissolved by heating in an aqueous solution (10 liters) of sodium hydroxide (250 g). The solution was filtered, adjusted to pH 7-8 with acetic acid, and allowed to stand overnight while ice-cooling. The crystalline precipitate was collected, washed with water, and dried at 110° C. to give 5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido[2,3-d] pyrimidine-6-carboxylic acid (625 g). m.p. 299-305° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[F-].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@H:33]3[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:34]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A mixture of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (2.0 g; prepared as described in Example 22-preparation of starting materials), tert-butyl-3-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (2.4 g) and cesium fluoride (2.9 g) in dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was evaporated under vacuum and partitioned between methylene chloride and water. The solutions were filtered to remove insoluble solids and the methylene chloride was washed with water, saturated brine and adsorbed onto silica. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 96/4). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yloxy]-7-methoxyquinazoline as a yellow foam (2.9 g, 95%); 1H NMR Spectrum: (DMSO-d6) 1.40 (s, 9H), 2.00-2.32 (m, 2H), 3.20-3.55 (m, 3H), 3.69 (dd, 1H), 3.92 (s, 3H), 5.00-5.20 (m, 1H), 7.20 (s, 1H), 7.20-7.32 (m, 1H), 7.40-7.57 (m, 2H), 7.80 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([N:11]=[N+]=[N-])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]>CC(O)=O.C(Cl)Cl.C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([NH2:11])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(Br)c(N=[N+]=[N-])c(F)c1Nc1ccc(Cl)cc1Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(N)c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 4-azido-5-bromo-2-(2,4-dichlorophenylamino)-3-fluorobenzoic acid methyl ester (2.05 g, 4.72 mmol) in AcOH-CH2Cl2 (10-30 mL) was added Zn dust (1.59 g, 24.3 mmol) at 0° C. The reaction mixture was warmed to room temperature. The resulting mixture was stirred for 1 hour. The reaction mixture was diluted with CH2Cl2, and washed with water, saturated aqueous NaHCO3 (2×), water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography(3 to 5% EtOAc in hexanes) to afford the desired product (1.24 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(OCC)C>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.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.5 %

Procedure:
To a solution of 4-bromobenzenesulfonamide (4.51 g, 19.1 mmole) in toluene (900 mL) at 75° C. was added ethynyl(trimethyl)silane (4 g, 40 mmole), Pd(PPh3)4 (1.3 g, 1.1 mmole), CuI (0.46 g, 2.42 mmole) and TEA (5.7 g, 56 mmole) and the mixture was allowed to cool to room temperature while stirring. Additional Pd(PPh3)4 (1 g, 0.9 mmole) was added and the mixture was stirred at room temperature. After 5 days, ethyl ether was added and the mixture was washed with 10% HCl, H2O, sat. aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo to give 2.93 g (61% yield) of the product: ESHRMS m/z 271.0935 (M+NH4, C11H15NO2SSiNH4, Calc'd 271.0937).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(=O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl 2-fluoro-2-phosphonoacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan (see Example 9, step A) diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:14]([F:26])[CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[F:26][C:14]1[CH:13]=[C:12]([N:7]2[C:8](=[O:11])[C:9]3[S:10][C:2]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:3][C:4]=3[N:5]=[CH:6]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCCN1
Reactant: O=c1c2sc(Br)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1
Product: O=C1CCCN1c1cc2ncn(-c3ccc(OCCN4CCCC4)c(F)c3)c(=O)c2s1

Procedure:
6-Bromo-3-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one was reacted with 2-pyrrolidone by method S. The product with the molecular weight of 442.52 (C22H23FN4O3S) was obtained in this way; MS (ESI): 443 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:4]([C:6]2[C:22]3[C:10](=[C:11]([CH3:25])[C:12]4[N:13]([CH3:24])[C:14]5[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=5[C:20]=4[CH:21]=3)[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Reactant: NCCCN1CCOCC1
Product: Cc1c2ccnc(C(=O)NCCCN3CCOCC3)c2cc2c3cc(O)ccc3n(C)c12
Temperature: 120 °C

Procedure:
0.36 g (1.078 mmol) of the ester obtained in Step A of Example 11 are dissolved in 10 ml of 4-(3-aminopropyl)morpholine under an argon atmosphere. The mixture is heated at 120° C. for 19 hours.
Reaction SMILES: [CH3:1][Si:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH:9]=1.[Br:54]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:51][Si:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][O:45][CH2:44][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:52])[CH3:53])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[C:9]=1[Br:54]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 2.3 mmol) in CH3CN (10 mL) and dichloromethane (10 mL) was added N-bromosuccinimide (0.45 g, 2.5 mmol) portionwise and the resulting mixture was stirred at room temperature for 0.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:12][N:11]=1)=[O:9])C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][C:13]1[CH:12]=[N:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[N:15][CH:14]=1)[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Nc1cnc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
(+/−)-3-({5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (14.6 mg, 28.0 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M NaOH (1 mL, 1 mmol) was added. This was stirred at room temperature for 10 min. The reaction brought to pH 3 with 1 N HCl. The methanol was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give crude product. Purification by reversed-phase HPLC gave (+/−)-3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid (13.8 mg). Analytical LCMS: retention time 3.40 minutes (Waters Atlantic dC18 4.6×50 mm, 5 μm column; 5% acetonitrile/water (0.05% trifluoroacetic acid modifier) linear gradient to 95% acetonitrile/water over 4.0 minutes, hold at 95% acetonitrile/water for 1.0 minute; flow rate 2.0 mL/minute); MS (M+1): 501.3.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.[N+:52]([O-])([OH:54])=[O:53]>C(#N)C>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[C:5]([N+:52]([O-:54])=[O:53])=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(C)c([N+](=O)[O-])c2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 70 °C
Yield: 32.7 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in acetonitrile (1 mL) was added zirconyl(IV) nitrate hydrate (36 mg, 0.16 mmol). The reaction mixture was heated to 70° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through a micro filter and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC (silica gel, 96:4 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (34 mg, 33%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.23 (s, 1H), 12.27 (br s, 1H), 8.19 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.89 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 4.69 (d, J=8.5 Hz, 1H), 4.61 (s, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.49 (dd, J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.35 (m, 1H), 3.28 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.40 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 743 (M+H); HPLC 98.0% (AUC), tR 13.79 min.