Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+].[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].[CH3:24]I>O.O1CCOCC1.CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:24])(=[O:22])=[O:21]
Reactant: CI
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(F)cc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Sodium hydrogen carbonate (1.59 g, 18.87 mmol) and sodium sulfite (1.59 g, 12.58 mmol) were heated in water (10 mL) at 70° C. for 5 min. A mixture of 2-bromo-4-fluoro-benzene sulfonyl chloride (1.72 g, 6.29 mmol) in dioxane (15 mL) was added to the base solution and stirred at 70° C. overnight. The solvents were removed in vacuo, DMF (15 mL) and methyl iodide (0.43 mL, 6.85 mmol) were added and reaction mixture stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo, EtOAc (10 ml) added, washed with water (90 ml) and concentrated in vacuo to leave a colourless oil. The resulting oil was purified by flash chromatography (0-10% EtOAc in petroleum ether (40:60) followed by 100% MeOH) to afford 2-bromo-4-fluoro-1-(methylsulfonyl)benzene as an orange oil (1.3 g, 81%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O.CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:25][C:19]([CH2:18][F:17])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CF)C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (2.5 g, 21 mmol) and ethyl 2-(fluoromethyl)acrylate (5.0 g, 21 mmol) in methylene chloride (30 mL) was added TFA (0.15 ml, 2.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. overnight. 20 mL of saturated NaHCO3 aqueous solution and 20 mL of ethyl acetate were added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel with 10% EtOAc-Hexane afforded 1.27 g (4.8 mmol, yield: 23%) of ethyl 1-benzyl-3-(fluoromethyl)pyrrolidine-3-carboxylate: 1H NMR (400 MHz, CDCl3) δ 7.39-7.20 (5H, m), 4.62-4.44 (2H, m), 4.18-4.21 (2H, m), 3.62 (2H, s), 2.81-2.72 (2H, m), 2.60-2.50 (2H, m), 2.22 (2H, s), 1.25 (3H, t, J=6.7 Hz); MS (m/e): 266 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([Cl:10])[N:9]=1)[CH3:13]
Reactant: C1CNCCN1
Reactant: CCN(CC)c1nc(Cl)cc(Cl)n1
Solvent: CCO
Product: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) and N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][F:24]>O.[I-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:22][CH2:23][F:24])[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCF)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a flame dried 50 mL round bottom flask was added 3-bromo-4-hydroxybenzonitrile (1.0 g, 5.05 mmol) followed by 5 mL of dimethyl sulfoxide. Potassium iodide (4.2 mg, 0.025 mmol) and potassium carbonate (1.05 g, 7.58 mmol) were added. The flask was immersed in an oil bath at 85° C. and 1-bromo-2-fluoroethane (0.769 g, 0.45 mL, 6.06 mmol) was added. The reaction was stirred at this temperature for 1 h after which it was cooled to room temperature and diluted with water (10 mL). The resulting solution was extracted with dichloromethane (2×20 mL). The organic layer was then washed with water (3×20 mL) and brine, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to obtain an oil which was purified by silica gel flash chromatography using dichloromethane. Product (1.13 g, 92%) was obtained as a colorless solid. 1H NMR (600 MHz, CDCl3): δ 7.83 (s, 1H), 7.57 (d of d, 1H, J=8.4, 1.8 Hz), 6.94 (d, 1H, J=8.4 Hz), 4.8 (t of d, 2H, J=49, 1.2 Hz), 4.35 (t of d, 2H, J=24, 1.2 Hz). 13C NMR (150 MHz, CDCl3): δ 158.5, 136.9, 132.9, 117.5, 113, 106, 81.5 (d, J=171 Hz), 68.5 (d, J=21 Hz). HRMS: Calc'd for C9H7BrFNO (M+H): 243.9767; Found: 243.9767.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[CH:18]=1
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cn(Cc2ccc(C#N)cc2)nn1

Procedure:
38.9 g of 4-azidomethylbenzonitrile is refluxed in 400 ml of toluene with 42 ml of trimethylsilylacetylene for 5 hours at 120°, combined with another 21 ml of trimethylsilylacetylene, and once again refluxed for 3 hours at 120°. Then the mixture is concentrated under vacuum, yielding 63 g of crude 4-[4-trimethylsilyl-(1,2,3-triazol-1-yl)methyl]benzonitrile. The latter is refluxed with a mixture of 700 ml of glacial acetic acid, 380 ml of water, as well as 110 ml of tetrahydrofuran for 2 hours. For working up purposes, the mixture is poured into sodium bicarbonate solution, extracted three times with dichloromethane, washed neutral with water, dried over sodium sulfate, concentrated to dryness under vacuum, and recrystallized from ethyl acetate/hexane, yielding 32.8 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile as colorless crystals, mp 83°.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13](=[O:36])[C:14]4[C:15]([O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:16]([C:20]3[C:21](C)=[N:22][N:23]([CH3:26])[C:24]=3[CH3:25])[N:17]=[CH:18][CH:19]=4)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CN1C(C)=C(C2N=CC=C3C(=O)C(C4C=CC(C5(NC(=O)OC(C)(C)C)CCC5)=CC=4)=C(C4C=CC=CC=4)OC=23)C=N1.[ClH:79]>>[ClH:79].[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13](=[O:36])[C:14]4[C:15]([O:28][C:29]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:26])[C:24]=3[CH3:25])[N:17]=[CH:18][CH:19]=4)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cc1c(-c2nccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Agent: Cl
Product: Cc1c(-c2nccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 46 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl 1-(4-(8-(1,5-dimethyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted to give the title compound (15 mg, 46%) as an HCl salt. 1H NMR (500 MHz, CD3OD): δ 8.78 (d, J=8.2 Hz, 1H), 8.25 (bs, 1H) 8.15 (d, J=8.3 Hz, 1H), 7.60-7.35 (m, 11H), 3.91 (s, 3H), 2.80-2.78 (m, 2H), 2.65-2.60 (m, 2H), 2.55 (s, 3H), 2.29-2.20 (m, 1H), 2.01-1.91 (m, 1H). LCMS (Method I): RT=4.82 min, [M+F1]+=463.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[C:9]1[S:21][C:20]2[CH2:19][C@@H:18]3[C@H:13]([CH2:14][C@@H:15]([C:23]([N:25]([CH2:38][CH2:39][CH3:40])[C:26](=O)[O:27]C4C=CC([N+]([O-])=O)=CC=4)=[O:24])[CH2:16][N:17]3[CH3:22])[CH2:12][C:11]=2[C:10]=1[C:41]#[N:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][NH2:48]>O1CCCC1>[C:41]([C:10]1[C:11]2[CH2:12][C@@H:13]3[C@@H:18]([CH2:19][C:20]=2[S:21][C:9]=1[N:8]([CH3:43])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:17]([CH3:22])[CH2:16][C@H:15]([C:23]([N:25]([C:26](=[O:27])[NH:48][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])[CH2:38][CH2:39][CH3:40])=[O:24])[CH2:14]3)#[N:42]
Reactant: CCCN(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of 4-nitrophenyl N-{[(4aR*,6R*,8aR*)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]-quinolin-6-yl]carbonyl}-N-propylcarbamate (200 mg) and tetrahydrofuran (3 mL) was added N,N-dimethyl ethylenediamine (0.071 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-6-[({[2-(dimethylamino)ethyl]-carbamoyl}(propyl)amino)carbonyl]-8-methyl-4H,4aH,5H,6H,7H,8H,8 aH,9H-thieno-[3,2-g]quinolin-2-yl]-N-methylcarbamate (160 mg).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc2c1c1c(n2CC2CCCC2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCC1
Yield: 19.3 %

Procedure:
A solution of 9-[(cyclopentyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (730 mg, 2.24 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (560 mg, 2.47 mmol) in 20 mL of toluene was heated at 80° C. for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with CH2Cl2) to afford 140 mg (0.433 mmol; 19%) of 9-[(cyclopentyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow oil which slowly solidified. MS (ES) m/e 324 (M+1), 322 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[NH:23][CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C1COCC1>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[N:23]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22][CH2:21]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 189.8 %

Procedure:
Benzoyl chloride (0.013 g, 0.09 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.09 mmol) and Et3N (0.026 ml, 0.19 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 20 hr, then evaporated in vacuo to give 0.091 g of white solid. Purification by flash chromatography, eluting with EtOAc: MeOH (6:4) gave 0.049 g (98% yield) of white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#Cc1cncn1C
Product: Cc1cc2ccc(C#Cc3cncn3C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-((1-methyl-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)acetic acid (81) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 5-ethynyl-1-methyl-1H-imidazole. 1H-NMR: 400 MHz, (CD3OD) δ: 8.80 (br s, 1H), 7.87 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.58 (m, 5H), 7.48 (s, 1H), 7.33 (d, J=8 Hz, 1H), 5.18 (s, 1H), 3.92 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H28ClN2O3: 487.2; found: 487.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CC(C)([O-])C.[K+].[C:16]1(=[O:20])[O:19][CH2:18][CH2:17]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:18][CH2:17][C:16]([OH:20])=[O:19]
Reactant: Cc1ccc(F)c(O)c1
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(F)c(OCCC(=O)O)c1
Temperature: 25 °C
Yield: 60759.5 %

Procedure:
To a suspension of 2-fluoro-5-methylphenol (1.0 g, 7.9 mmol) in tetrahydrofuran (10 mL) at 0-5° C. was dropwise added potassium tert-butoxide 1N in tetrahydrofuran (8.3 mL, 8.3 mmol), followed by 3-propiolactone (0.55 mL, 8.7 mmol) in one portion. The mixture was warmed to room temperature for 1 hour, then heated at 50° C. for 2 hours. After cooling to room temperature, the mixture was quenched with a saturated solution of sodium hydrogenocarbonate (1 mL) and diluted with water (9 mL). The aqueous layer was washed with ethyl acetate (10 mL), acidified with 1M hydrochloric acid until pH 2 and extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 3-(2-fluoro-5-methylphenoxy)propanoic acid (10a) (0.96 g, 4.8 mol, 60%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:17])[N:8]2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([Cl:18])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:73]=1[N+:79]([O-:81])=[O:80].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:18][C:4]1[N:3]=[C:2]([NH:1][C:72]2[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:73]=2[N+:79]([O-:81])=[O:80])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:17])[N:8]2[CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
To an oven-dried vial was added 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (50 mg of HCl salt, 0.186 mmol, 1 equiv.) in anhydrous toluene (3 mL), then freshly grounded cesium carbonate (85 mg, 0.26 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 20 min, Pd(OAc)2 (12.5 mg, 0.019 mmol, 0.1 equiv.), racemic BINAP (17.3 mg, 0.028 mmol, 0.15 equiv.) and 1-bromo-5-fluoro-2-nitrobenzene (Oakwood) (53 mg, 0.24 mmol, 1.3 equiv.) were added as solids, followed by DIEA (50 μL, 1.5 equiv.). The vial was purged with Ar for 3 min, then closed and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with 5% methanol in methylene chloride, filtered through a Nylon 0.45 μm filter, and the filter repeatedly washed with 5% methanol in methylene chloride. The filtrate was concentrated in vacuo and the resulting residue was purified using preparative TLC (silica gel, 4.25% methanol in methylene chloride) to give the desired product as a yellow solid (45.3 mg, 60% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 10.90 (s, 1H), 8.89 (dd, 1H), 8.45 (dd, 1H), 8.10 (br s, 1H), 6.92-6.83 (m, 1H), 4.75-4.60 (m, 1H), 4.28 (dd, 2H), 3.65 (app t, 2H), 2.82 (tdd, 2H), 1.90 (br d, 2H); MS (EI) m/z 409.1 (MH)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][NH:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:13])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (L)-valine tert-butyl ester hydrochloride (4.94 g, 23.6 mmol) in N,N-dimethylformamide (55 mL) was added triethylamine (3.28 mL, 1 equivalent), and the mixture was stirred for 1 h. The reaction was filtered to remove solid salts, and the filtrate was treated with triethylamine (9.85 mL, 3 equivalents) and ethyl bromoacetate (7.84 mL, 3 equivalents), and the reaction was stirred for 3 h at 25° C. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give 4.48 g (78%) of the product which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH3:45])[CH:9]([CH3:33])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH3:45])[CH:9]([CH3:33])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(CCO[Si](C)(C)C(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(CCO)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-[2-(tert-butyldimethylsiloxy)ethyl]indoline-7-carboxamide (170 mg) in tetrahydrofuran (2 ml) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (270 μl), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using ethyl acetate as eluent to give 114 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(2-hydroxyethyl)indoline-7-carboxamide as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[CH:5]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH:7]=[C:8]([C:11](OC)=[O:12])[C:9]=1[CH3:10])[CH3:2].[NH2:40][CH2:41][C:42]1[C:43](=[O:53])[NH:44][C:45]([CH3:52])=[C:46]([F:51])[C:47]=1[CH:48]([CH3:50])[CH3:49]>>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[CH:5]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH:7]=[C:8]([C:11](=[O:12])[NH:40][CH2:41][C:42]2[C:43](=[O:53])[NH:44][C:45]([CH3:52])=[C:46]([F:51])[C:47]=2[CH:48]([CH3:50])[CH3:49])[C:9]=1[CH3:10])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: Cc1[nH]c(=O)c(CN)c(C(C)C)c1F
Product: CCN(c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1

Procedure:
Hydrolysis of tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate following the similar methods for examples described earlier resulted in a crude corresponding carboxylic acid 5-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid. This acid was then coupled with 3-(aminomethyl)-5-fluoro-4-isopropyl-6-methylpyridin-2(1H)-one following similar methods described earlier. After purification by reverse phase HPLC (ACN-H2O containing 0.1% formic acid), the titled compound was obtained. 1H-NMR (400 MHz, CD3OD) δ ppm 8.33 (d, J=2.6 Hz, 1H), 7.81 (dd, J=2.6, 8.8 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.92 (m, 2H), 3.46-3.56 (m, 9H), 3.34 (m, 2H), 3.07-3.18 (m, 3H), 2.33 (s, 3H), 2.24 (d, J=3.2 Hz, 3H), 1.74-1.77 (m, 2H), 1.62-1.69 (m, 2H), 1.49 (s, 9H), 1.37 (dd, J=1.6, 6.8 Hz, 6H), 0.90 (t, J=6.8 Hz, 3H); MS (ES) (M+H) 705.7.