Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:9]([C:3]1[C:2]([O:1][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])([O-:11])=[O:10]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(F)(F)F)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
A mixture of 3-hydroxy-2-nitrotoluene (5 g), 2,2,2-trifluoroethyl methanesulfonate (8.7 g), anhydrous potassium carbonate (9 g) and N,N-dimethylformamide (40 ml) was heated, with stirring, on an oil bath at 80° C. for 4 hours, and then at 100° C. for 4 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by a dilute aqueous potassium carbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then filtered through NH silica gel, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and subjected to a silica-gel column chromatography with 5 to 10% ethyl acetate/hexane to yield the title compound (4.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:23]=[N:24][C:25]([N:28]6[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]6)=[N:26][CH:27]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH3:41])[N:9]=2)=[CH:4][CH:3]=1.ClC([O:45][C:46](C)=C)=O.[N:49]1[CH:54]=CC=C[CH:50]=1>>[CH3:50][N:49]([CH3:54])[C:46]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[N:26][C:25]([N:28]6[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]6)=[N:24][CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH3:41])[N:9]=2)=[CH:6][CH:7]=1)=[O:45]
Reactant: Cn1cc(-c2ccnc3[nH]c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: c1ccncc1
Reactant: C=C(C)OC(=O)Cl
Product: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc23)cc1
Temperature: 0 °C
Yield: 27 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-{4-[3-(4-aminophenyl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-2-pyrimidinyl)-1-piperazinecarboxylate (0.326 mmol) in pyridine (8 ml) under argon at 0° C. was added isopropenyl chloroformate (1.31 mmol) portionwise over 3 hours maintaining the reaction temperature at 0° C. The resulting solution was concentrated, purified by reverse-phase. This intermediate was dissolved in THF (10 ml) and dimethylamine (2M in THF, 20 ml) was added. After heating for 2 hours at 50° C., concentration in vacuo provided the title product (27%) as a yellow solid which was used without further purification. ESMS [M+H]+: 623.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[H][H].[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27].Cl>CN(C=O)C.O>[CH3:23][O:24][CH2:25][C:26]([O:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[CH:3]=1)=[O:27]
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: COCC(=O)Cl
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (893 mg, 3.7 mmol) in DMF (20 mL) was added sodium hydride (purity of about 60%, 192 mg, 4.8 mmol, 1.3 eq.), and the mixture was stirred until no more hydrogen was generated. Then, methoxyacetyl chloride (1.07 g, 9.9 mmol, 2.6 eq.) was added thereto, and the mixture was stirred at a room temperature for 50 minutes. To the mixture was added water. The resulting mixture was acidified with concentrated hydrochloric acid, and then the resulting precipitate was separated by filtration and dried to give 4-methoxyacetoxy-1-phenyl-1,8-naphthyridin-2(1H)-one (847 mg, yield 73%).
Reaction SMILES: C(C1[C:4]([C:25](O)=O)=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12](N3C4C(=NC=CC=4)NC3=O)[CH2:11]C2)=NC=1)#N.[C:28]([C:30]1[C:31]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[C:53]4[C:48](=[N:49][CH:50]=[CH:51][CH:52]=4)[NH:47][C:46]3=[O:54])[CH2:41][CH2:40]2)=[CH:32][C:33]([C:36]([OH:38])=O)=[N:34][CH:35]=1)#[N:29].N1C2C(=CC=CC=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:9]1([C:36]([C:33]2[N:34]=[CH:35][C:30]([C:28]#[N:29])=[C:31]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[C:53]5[C:48](=[N:49][CH:50]=[CH:51][CH:52]=5)[NH:47][C:46]4=[O:54])[CH2:41][CH2:40]3)[CH:32]=2)=[O:38])[C:6]2[C:12](=[CH:11][CH:25]=[CH:4][CH:5]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1cnc(C(=O)O)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: N#Cc1cnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(=O)N2CCc3ccccc32)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C

Procedure:
0.11 mg (0.29 mmol) of an isomer mixture of 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylic acid, 34 mg (0.29 mmol) 2,3-dihydro-1H-indole and 90 μL (0.61 mmol) TEA were placed in 1.5 mL DMF. 0.10 g (0.32 mmol) TBTU were added. The reaction mixture was stirred over the weekend at RT. The purification and separation of the isomers were carried out by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:1].[F:12][C:11]([F:14])([F:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:21]([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:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC(F)(F)CCCCCCCCCBr
Solvent: CC#N
Product: FC(F)(F)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A stirred solution of 1-bromo-10,10,10-trifluorodecane (4.75 g) and triphenylphosphine (4.53 g) in acetonitrile (100 ml) was heated under reflux for 3 days. The solution was evaporated under vacuum and the residue was washed with ether, dissolved in toluene and the solution diluted with ether to give the product as a hygroscopic solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[OH:44][C@@H:45]1[C@@H:50]([NH3+:51])[CH2:49][CH2:48][O:47][CH2:46]1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[C:13]([NH:51][C@H:50]1[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]1[OH:44])=[O:15]
Reactant: Nc1c(C(=O)O)cc(Br)c2ccccc12
Reactant: [NH3+][C@H]1CCOC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(C(=O)N[C@H]2CCOC[C@@H]2O)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-amino-4-bromo-2-naphthoic acid (0.644 g, 2.42 mmol) in 10 mL of acetonitrile cooled to 0° C. was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]-phosphonium hexafluorophosphate (1.82 g, 4.12 mmol), O-(7-azabenzotriazol-1yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (0.921 g, 2.42 mmol), (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-aminium chloride (0.310 g, 2.02 mmol), and triethylamine (0.84 mL, 6.1 mmol). The reaction was warmed to rt and stirred for 4 h. The mixture was diluted with ethyl acetate, washed with dilute aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 1-amino-4-bromo-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-2-naphthamide that gave a mass ion (ES+) of 366.9 (81Br) for [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)C2)C1
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture of 3,3-difluoropyrrolidine hydrochloride (200 mg, 1.17 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (284 mg, 1.99 mmol) and triethylamine (295 μL, 221 mg, 2.18 mmol) in DCE (10 mL) was stirred at room temperature for 1 h before the addition of sodium triacetoxyborohydride (745 mg, 3.52 mmol). The resulting mixture was stirred for 72 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-50%) affording 3-(3,3-Difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (193 mg, 63%). 1H NMR (CDCl3, 300 MHz): δ 3.95 (m, 2H), 3.82 (dd, J=8.9, 4.9 Hz, 2H), 3.32 (m, 1H), 2.91 (m, 2H), 2.82-2.63 (m, 2H), 2.33-2.32 (m, 2H) and 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH:29]4[O:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[O:31][CH2:30]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p. =86°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:6]=[CH:7][N+]([O-])=O>C(O)C.C(O)=O.[OH-].[OH-].[Pd+2]>[CH3:16][O:15][C:12]1[CH:11]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:13]=1[OH:14])[NH:17][CH:7]=[CH:6]2
Reactant: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: COc1cc2cc[nH]c2c(OC)c1O
Yield: 14 %

Procedure:
A mixture of 10 g (0. 037 mole) of 3,5-dimethoxy-4-hydroxy-2,β-dinitrostyrene and 10 g of palladium hydroxide on charcoal in 400 cm3 of ethanol and 7 cm3 of formic acid is heated under reflux for 3 hours. After cooling, the reaction mixture is filtered through Celite. The filtrate is evaporated to dryness. The residue is redissolved in dichloromethane and the solution is filtered on silica gel. After distillation of the solvent under reduced pressure and recrystallization from diisopropyl ether, 1 g of the desired product is obtained in the form of a whitish solid (yield =14%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(Cl)(=O)OCC(C)C.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].[Si]([CH:35]=[N+:36]=[N-:37])(C)(C)C>O1CCCC1.C(#N)C>[N+:36](=[CH:35][C:27](=[O:29])[C@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH3:30])=[N-:37]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N,N-Diisopropylethylamine (4.7 mL, 27 mmol) and isobutyl carbonochloridate (3.11 ml, 23.78 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.0 g, 15.9 mmol) in tetrahydrofuran (34.5 ml) at 0° C. and the mixture was stirred at 0° C. for four hours. The mixture was then diluted with acetonitrile (22 mL). TMS-diazomethane (2.0 M in diethyl ether, 15.9 ml, 31.7 mmol) was then added slowly to the mixture at 0° C. The mixture was allowed to stir at 0° C. for 3 hours and was then allowed to warm to room temperature for 14 hours. The mixture was concentrated under reduced pressure and then purified by column chromatography on silica to afford (R)-tert-butyl (4-diazo-3-oxobutan-2-yl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 7.27 (d, J=7.4 Hz, 1H), 6.01 (s, 1H), 3.97-3.87 (m, 1H), 1.37 (s, 9H), 1.13 (d, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[C:6]2[C:7]([CH2:11][OH:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C=O)C>[Si:21]([O:12][CH2:11][C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:13]=2)[CH:10]=[CH:9][CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccn2nc(C(F)(F)F)cc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccn2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
The compound of Example 64 (5.17 g, crude product) was dissolved in DMF (100 mL). To this solution, imidazole (4.89 g) and t-butyldimethylsilyl chloride (4.33 g) were added and the mixture was stirred at room temperature for 1.5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethyl acetate=9:1) afforded the title compound as a yellow oil (3.42 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)C.[AlH4-].[Li+]>C1COCC1>[C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([CH2:5][CH2:4][OH:3])[CH:15]=[CH:14]3)[CH2:18][CH2:19]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CCO)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of [6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-acetic acid ethyl ester (250 mg, 0.68 mmol) in THF (10 mL) was added 1.0 M of lithium tetrahydroaluminate in THF (2 mL, 2 mmol) at 0° C. After stirred at room temperature for 2 hrs, the solution was quenched with ethyl acetate (1 mL), then added Rochelle's salt aqueous (1.5 mL). The solution was stirred for 1 hr, then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. The resulting crude was purified via silica gel column eluted with EtOAc in hexanes from 0 to 60% to give white precipitate (0.17 g, yield: 77%). ESI-MS: 327.20 (M+H)+.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:21]1[C:29]([NH2:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][C:22]=1[NH2:31]>>[NH2:31][C:22]1[N:23]=[C:24]2[C:28]([N:27]=[CH:26][N:25]2[CH:2]([C:4]2[O:5][C:6](=[O:20])[C:7]3[C:12]([C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:3])=[C:29]([NH2:30])[N:21]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1nc(N)c2nc[nH]c2n1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1cnc2c(N)nc(N)nc21
Yield: 31.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1 from 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 50 mg, 0.15 mmol) and 9H-purine-2,6-diamine (34 mg, 0.23 mmol) to give the title compound (19 mg, 31%).
Reaction SMILES: [Na+].[CH:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:5]=[C:4]([S:16]([O-:19])(=O)=[O:17])[CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[CH:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:5]=[C:4]([S:16]([Cl:22])(=[O:19])=[O:17])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc2ccc3c(c2c1)CCCC3
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2ccc3c(c2c1)CCCC3
Temperature: 60 °C

Procedure:
5,6,7,8-Tetrahydrophenanthrene-3-sulfonic acid sodium salt (1 g, 3.68 mmol) is suspended in 5 mL of thionyl chloride. DMF (2 drops) is added and the solution is heated to 60° C. for 30 minutes. After this time, the reaction mixture is concentrated. The residue is triturated with CH2Cl2 and the resulting solid is filtered off. The collected organic solution is concentrated. The crude product is purified by column chromatography eluting with 10% EtOAc/hexanes to give the title compound (0.60 g, 2.3 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH:41][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:22])[CH3:40]
Reactant: CC(N)c1ncco1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.22 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (91 mg, 0.39 mmol). DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.25 ml, 1.43 mmol) and HATU (92 mg, 0.24 mmol). The light yellow solution was stirred at room temperature for 48 h. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 108 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[P:50]([O-:55])([O:53][CH3:54])[O:51][CH3:52].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:34]([O:33][C@H:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:24][CH2:23][C@H:22]1[C:21](=[O:41])[N:20]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:19]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:8]=[CH:7][CH:12]=[C:11]([P:50](=[O:55])([O:53][CH3:54])[O:51][CH3:52])[CH:10]=2)=[CH:18][CH:17]=1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: COP([O-])OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2)cc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate (0.27 g, 0.38 mmol), dimethyl phosphite (0.070 mL, 0.76 mmol) and triethylamine (0.15 mL, 1.08 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, and the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated for 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution was washed successively with 0.5 M hydrochloric acid (20 mL) water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate was obtained as a white foam (0.26 g, 65%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (dt, J=14.2, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.40(d, J=8.5 Hz, 2H), 6.9-7.8 (m, 12H), 4.68 (t, J=5.7 Hz, 1H), 4.64 (d, J=2.4 Hz, 1H), 3.81 (d, J=0.9 Hz, 1H), 3.77 (d, J=0.9 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.2 (m, 4H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H) ppm
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[N:30]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[O:27][CH:28]=3)=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: NCc1coc(C2CC2)n1
Product: O=C(NCc1coc(C2CC2)n1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chlorophenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 2-cyclopropyl-oxazol-4-methanamine (example BH) as starting materials; LC-MS (UV peak area/ESI) 96.5%, 452.0987 (M+H)+.