Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC.C(OCC)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
n-Butyllithium (1.6N hexane solution, 108 ml) was added dropwise to a diethyl ether solution (400 ml) of 3-bromopyridine (25.7 g) at −78° C. over 1 hour under nitrogen atmosphere. After stirring for 30 minutes, a diethyl ether solution (100 ml) of diethyl oxalate (28.6 g) was added dropwise thereto at −78° C. over 1 hour. The reaction mixture was further mixed for 30 minutes, allowed to warm to 0° C., and 1N hydrochloric acid (200 ml) was added thereto. After stirring for 30 minutes, sodium bicarbonate was added thereto to neutralize the reaction mixture. The organic layer was separated, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 3-pyridylglyoxylate (13.1 g, yield 45%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[S:36][CH:35]=[N:34][C:33]=3[CH:37]=2)O1>>[S:36]1[C:32]2[CH:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])[C:5]4[N:17]([CH3:20])[CH:18]=[N:19][C:4]=4[CH:3]=3)=[CH:37][C:33]=2[N:34]=[CH:35]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Product: C[C@@H](Oc1nc(-c2ccc3scnc3c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (50 mg, 0.17 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (49 mg, 0.19 mmol), (R)-4-((R)-1-(6-(benzo[d]thiazol-5-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.27 was isolated, following column chromatography.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Br:5][C:6]1[CH:19]=[C:18]2[C:9]([O:10][C:11]3[C:12]([F:23])=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=3[C:17]2=[O:20])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:19]=[C:18]2[C:9]([O:10][C:11]3[C:12]([F:23])=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=3[C:17]2([CH:1]=[CH2:2])[OH:20])=[CH:8][CH:7]=1
Reactant: C=C[Mg]Cl
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of vinylmagnesium chloride (55.9 ml, 89.4 mmol) at −78° C. was added dropwise of a solution of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (8.0 g, 24.76 mmol) in THF (99 mL). After 30 min, the reaction was allowed to slowly warm to rt, then quenched with 240 mL of saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 7-bromo-4-fluoro-2-methoxy-9-vinyl-9H-xanthen-9-ol (8.69 g, 24.76 mmol, 100% yield) as yellow solid.
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11].Cl.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH:29]([NH:31][C:32](=[O:38])[CH:33]([NH2:37])[CH:34]([CH3:36])[CH3:35])[CH3:30])=[CH:26][C:25]=2[CH:39]=1.O>ClCCl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([CH:29]([NH:31][C:32](=[O:38])[C@H:33]([CH:34]([CH3:35])[CH3:36])[NH:37][C:10]([N:9]([CH3:8])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[CH3:30])=[CH:26][C:25]=2[CH:39]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(NC(=O)C(N)C(C)C)c1cc2cc(Cl)ccc2o1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(NC(=O)[C@@H](NC(=O)N(C)c1ccccc1)C(C)C)c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.4 %

Procedure:
0.34 g of N-methylmorpholine and 0.57 g of N-methyl-N-phenylcarbamoyl chloride were successively added to a solution containing 1.1 g of N-[1-(5-chloro-2-benzofuranyl)ethyl]-2-amino-3-methylbutanamide hydrochloride dissolved in 30 ml of dichloromethane, at -15° C. The mixture was allowed to sit and warm naturally to room temperature and then stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residual crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>CCO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN2C(=O)c3ccccc3C2=O)c2ccccc2Cl)CC1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To 4-[1-(2-Chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (302) (1.0 g, 2.15 mmol) in EtOH (5 mL) was added hydrazine (0.67 mL, 21.5 mmol) and the solution was heated at 60° C. for 1 h. The reaction mixture is then taken up in EtOAc (50 mL) and washed with 1N NaOH (50 mL). The organic phase was concentrated to dryness yielding 0.73 g (100%) pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1cccc(Br)c1
Reaction time: 168 h
Yield: 69.7 %

Procedure:
A solution of 2-(3-bromophenyl)acetic acid (2.64 g, 12.28 mmol) in 8:2 benzene/methanol (50 mL) was cooled to 0° C., then treated with the dropwise addition of 2.0 M TMS-diazomethane in hexanes (6.14 mL, 12.28 mmol) over 10 minutes. The mixture was allowed to come to room temperature and stirred for 7 days. The mixture was concentrated in-vacuo, and the residue was purified over silica gel, eluting with 10% ethyl acetate/hexanes to yield the title compound (1.96 g, 8.56 mmol, 69.7% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22]N=CC=4NN=3)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:11]=[N:10][N:9]4[CH:8]=[CH:6][CH:22]=[N:23][C:24]=34)=[O:15])=[CH:11][N:10]([CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1n[nH]c2cncnc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 30 °C
Reaction time: 8 h
Yield: 141.9 %

Procedure:
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo pyrimidine-3-carboxamide (2.0 g, 5.4 mmol), t-butyl-bromoacetate (0.88 mL, 6.0 mmol), and cesium carbonate (2.1 g, 6.5 mmol) were combined and stirred at 30° C. overnight. The mixture was warmed to 65° C. at which time additional carbonate and t-butylbromoacetate was added and stirred 8 hrs. The mixture was cooled to ambient temperature and stirred overnight, then partitioned EtOAc/water. The organic phase was separated, washed with brine, dried (Na2SO4), filtered through silica gel, and concentrated to a solid. The solid was washed with 1:1 EtOAc/hexanes to yield 1.85 g (71%) of tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetate as yellow crystals. LCMS (ESI) m+H=483.0. 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.77 (m, 1H), 8.73 (s, 1H), 8.51 (m, 1H0, 8.38 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.31 (m, 1H), 6.97 (m, 2H), 4.85 (s, 2H), 3.83 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C2C=CC=CC=2)=O)=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:15]([C:9]2[CH:30]=[CH:29][CH:12]=[CH:11][CH:10]=2)[C:16]2[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2ccccc2N)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of lithium aluminum hydride (1.0 g) in THF (40 ml) cooled to 5° C. was added a solution of 4-methoxy-N-(2-phenylamino-phenyl)-benzamide (5.0 g) in THF (30 ml) over a 45 minute period. After complete addition, the reaction mixture was heated to reflux for 1.5 hrs. The solution was cooled to room temperature and excess lithium aluminum hydride was quenched with ethanol until hydrogen evolution ceased. Saturated agueous sodium hydrogen carbonate (100 ml) was added and the resultant solution extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried with sodium sulfate and filtered through a pad of silica. The silica pad was washed with ethyl acetate (500 ml) and the organic fractions were combined. The filtrate was concentrated in vacuo to a brown oil which solidified on standing to give the title compound. (4.78 g). 1H (300 MHz, CDCl3): d 3.79 (s, 3H), 4.27 (s, 2H), 4.52 (br s, 1H), 5.08 (s, 1H), 6.67-6.74 (m,4H), 6.79-6.86 (m, 3H), 7.04-7.24 (m, 6H); TLC (EtOAc/Hex (1:4)): Rf =0.57.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Temperature: 80 °C
Yield: 79 %

Procedure:
A flask containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (1000 mg, 3.23 mmol), 4-(benzyloxy)phenylboronic acid (883 mg, 3.87 mmol), cesium fluoride (1176 mg, 7.74 mmol) and tetrakis(triphenylphosphine)-palladium(0) (224 mg, 0.194 mmol) was flushed with nitrogen. Dimethoxyethane (16 mL) was added and the reaction was heated at 80° C. for 18 hr. The reaction was then partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 30 to 20% methylene chloride) afforded 1055 mg of methyl 3-amino-2-(4-(benzyloxy)-phenyl)-6-bromoisonicotinate as a yellow solid. MS (ESI) m/z 415.1 (M+H). 1H NMR (CDCl3) δ ppm 7.77 (1H, s), 7.55 (2H, d, J=8.55 Hz), 7.31-7.46 (5H, m), 7.06 (2H, d, J=8.55 Hz), 5.95 (2H, br. s.), 5.12 (2H, s), 3.92 (3H, s).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][N:19]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:52]>>[CH2:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[O:20][N:19]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:52])[C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1Cc1cc(-c2cccnc2)on1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2cccnc2)on1

Procedure:
The methods described in Part I of Example 35 were used to treat 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline (0.920 g, 3.00 mmol) with mCPBA (0.808 g of 77% pure material, 3.6 mmol) followed by p-toluenesulfonyl chloride (0.629 g, 3.30 mmol) and concentrated ammonium hydroxide (15 mL) and purify the final product to provide 0.46 g of 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 206-207° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.CC(C)([O-])C.[K+].[C:17](#[N:19])[CH3:18].O>C(Cl)Cl>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: CCOC(=O)c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)c1cccs1

Procedure:
A 67 ml. portion of ethyl 2-thiophenecarboxylate is added to 56 g. of potassium t-butoxide (exothermic). After cooling, 33 ml. of acetonitrile is added and the mixture is stirred and heated on a steam bath for 1.5 hours. A 250 ml. portion of water is added followed by 200 ml. of methylene chloride. The mixture is stirred overnight. The aqueous layer is separated and combined with 42 ml. of concentrated hydrochloric acid. This mixture is extracted with 300 ml. of methylene chloride followed by two 100 ml. portions of methylene chloride. The combined extracts are then washed with 200 ml. followed by 100 ml. of 10% sodium bicarbonate. The extracts are dried over sodium sulfate and passed through magnesol. The filtrate is combined with hexanes and evaporated giving crystals of β-oxo-2-thiophenepropionitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54](=[O:65])[CH2:55][CH2:56][C:57]1([C:62](O)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58]1)([CH3:52])([CH3:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:62]([C:57]3([CH2:56][CH2:55][C:54]([O:53][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58]3)=[O:63])=[O:24])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCC1(C(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Reaction time: 0.17 h
Yield: 124.7 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 5-aminopentylcarbamate (0.683 g, 2.105 mmol) in 15 ml DMF was added HATU (0.800 g, 2.105 mmol), 1-(3-tert-butoxy-3-oxopropyl)cyclopentanecarboxylic acid (0.425 g, 1.754 mmol) in 5 ml DMF, and DIEA (1.532 mL, 8.77 mmol). The solution was stirred for 10 minutes and material purified by HPLC using a gradient of 0-50% acetonitrile in DCM. Solvents were removed under reduced pressure to give 1.2 g crude tert-butyl 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)-pentylcarbamoyl)cyclopentyl)propanoate. The crude material was dissolved in 20 ml DCM and 10 ml TFA was added to remove t-Bu group. Solvent was removed under reduced pressure and material purified by reverse phase chromatography to give 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylcarbamoyl)cyclopentyl)propanoic acid (16 mg, 0.032 mmol, 1.852% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24]C)=[O:23])=[N:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO.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.O.C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:21]=[N:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccccn2)cn1
Temperature: 120 °C
Yield: 23.2 %

Procedure:
In a 5 ml microwave vial were added 2-bromopyridine (0.093 ml, 0.949 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinecarboxylate (300 mg, 1.139 mmol), bis(triphenylphosphine)palladium(II) chloride (133 mg, 0.190 mmol), sodium carbonate (302 mg, 2.85 mmol), 1,2-dimethoxyethane (1.5 ml), ethanol (1.000 ml) and water (0.500 ml). The reaction mixture was heated for 0.5 hours at 120° C. in the microwave. The mixture was diluted with MeOH and filtered through Celite®. The product was concentrated in vacuo then filtered through a 20 g SCX cartridge (washed with MeOH, eluted with 1M NH3 in MeOH) and evaporated in vacuo. The product was triturated with ether and concentrated under vacuo. The product was diluted in DCM then 1 ml of 1M HCl in ether added and the product was concentrated in vacuo then was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated under vacuo to give the title compound (44 mg).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][Si](O[Si](C)(C)C)(C)C.IC>CN(C)C=O>[N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-nitrouracil (10.00g, 64 mmole), 1,1,1-3,3,3-hexamethyldisilazane (40 mL, 190 mmole) and chlorotrimethylsilane(4.0 mL, 0.32 mmole) are heated to reflux for 24 hours. The solution is concentrated under reduced pressure to afford 5-nitrouracil bis (trimethylsilyl) ether. 5-nitrouracil bis(trimethylsilyl)ether (10.0 g, 24 mmole), dimethylformamide (50 mL) and iodomethane (3.0 mL, 49 mmole) are heated in an 80° C. oil bath for 24 hours. Ice water is added, and the mixture is stirred for 30 minutes, then extracted with dichloromethane (3×). The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCCOC(=O)c1c(N)sc2c1CC1CCC2O1
Product: CCCOC(=O)c1c(NC(=O)c2ccccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 34A and commercially available 2-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (DMSO-d6, 300 MHz) δ 0.92 (t, J=7.5 Hz, 3H), 1.64-1.71 (m, 3H), 1.98-2.15 (m, 3H), 2.58 (d, J=17.0 Hz, 1H), 3.11 (dd, J=16.6, 4.4 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 4.69-4.74 (m, 1H), 5.14-5.16 (m, 1H), 7.80-7.94 (m, 4H), 11.40 (br s, 1H); MS (ESI+) m/z 440 (M+H)+. Anal. calcd. for C21H20F3NO4S: C, 57.40; H, 4.59; N, 3.19. Found: C, 57.44; H, 4.47; N, 3.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35]>>[C:34]([NH:33][CH2:32][CH2:31][NH:30][C:24]([C:14]1[C:15](=[O:23])[N:16]([CH2:19][CH2:20][CH2:21][OH:22])[C:17]2[C:12]([C:13]=1[OH:29])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:25])(=[O:36])[CH3:35]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 30.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and N-(2-aminoethyl)acetamide (100 mg, 0.99 mmol) was prepared N-[2-(acetylamino)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 31% yield) as a tan solid after purification by reverse phase HPLC. 1H NMR (methanol-d4/CDCl3) δ 10.18 (br s, 1 H), 8.40 (s, 1 H), 7.56 (s, 1 H), 7.09-7.05 (m, 2 H), 6.94-6.88 (m, 2 H), 4.21 (m, 2 H), 4.04 (s, 2 H), 7.70 (m, 2 H), 3.46 (m, 2 H), 3.33 (m, 2 H), 1.86 (s, 3 H), 1.74 (m, 2 H); MS m/z 457 M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[N:8]2C2CCCCO2)=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:3]=1.Cl.[H-].[Na+].[C:37]([O:40][CH2:41][CH2:42]Br)(=[O:39])[CH3:38]>CO.CN(C=O)C.O>[C:37]([O:40][CH2:41][CH2:42][N:8]1[C:7]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:39])[CH3:38]
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a solution of 2-(1-((2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (328 mg, 0.685 mmol) in methanol (10 mL) was added concentrated HCl (0.15 mL). The resulting mixture was stirred at 50° C. for 18 hours. The reaction mixture was then concentrated to give a yellow paste which was then taken up in DMF (10 mL) and cooled to 0° C. To this cooled solution was then added sodium hydride (60% dispersion, 88 mg, 2.2 mmol). The mixture was stirred at 0° C. for 5 minutes before the addition of 2-bromoethanol acetate (0.2 mL, 1.8 mmol). After 18 hours of stirring at room temperature, the reaction was diluted with water. The aqueous mixture was the extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (10% MeOH in DCM) to give the title compound (110 mg, 26%). LCMS: M+H+=481.2.