Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13]>>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([OH:14])=[O:13])[CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OC1CCOCC1
Product: O=C(O)c1cccc(OC2CCOCC2)c1

Procedure:
Prepared from 4-hydroxy-tetrahydropyrane and ethyl 3-hydroxybenzoate. LC-MS (m/z): 245 (M−23 (Na)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][C:21]1[C:22](Br)=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]=[CH:24]2>C1(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)C=CC=CC=1.COCCOC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:22]1[C:21]([CH3:20])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][CH2:26]2
Reactant: Cc1ccc2c(c1Br)C=CC2
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1ccc3ccccc3c1)C=CC2
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To mixed solution of 2-naphthylboronic acid (5 g, 29 mmol) and DME (100 mL), aqueous solution (30 mL) of cesium carbonate (12 g, 36.8 mmol)(30 mL) and 5-methyl-4-bromoindene (4.3 g, 21 mmol), tetrakis(triphenylphosphino)palladium (0.9 g) were added, and heated under reflux. After 16 hours, reaction solution was poured into 1N HCl-ice water to separate organic layer after stirring. Organic layer was washed with saturated solution of sodium chloride after filtering through Celite, and dried over magnesium sulfate, and solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (Silica-gel: produced by Kanto Chemical Co., Inc., hexane) to obtain the desired 4-(2-naphthyl)-5-methylindene (3.9 g, yield: 74%).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29](F)([F:31])F)=C[CH:3]=1.ClC1SC2C=CC([F:43])=C(F)C=2N=1>>[F:43][C:5]1[C:6]2[N:7]=[C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)[S:9][C:10]=2[CH:2]=[CH:3][C:29]=1[F:31]
Reactant: Fc1ccc2sc(Cl)nc2c1F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)c(F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-chloro-4,5-difluoro-1,3-benzothiazole and conducting the Suzuki coupling at 80° C. for 3 h, the title compound was obtained as a yellow solid. MS (ES+): m/z=413.13 [MH+]. HPLC: tR=2.46 min (ZQ3, polar—5 min).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.CN(C)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cncc(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Cl)cncc1Cl
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
Under an argon atmosphere, to a solution of diisopropylamine (33.6 ml, 0.24 mol) in tetrahydrofuran (400 ml) at -65° C. was added a 1.6 M solution of n-butyl lithium in hexanes (156 ml). After 20 minutes later, a solution of 3,5-dichloropyridine (29.6 g, 0.20 mol) in tetrahydrofuran (150 ml) was added dropwise, and the mixture was stirred for 30 minutes. Subsequently, the mixture was treated with dimethylformamide (23.2 ml, 0.30 mol) in tetrahydrofuran (50 ml), and then stirred for one hour under the same conditions. The reaction mixture was poured into a 5% aqueous ammonium chloride solution (1,000 ml) and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, to thereby obtain the title compound (27.2 g, yield 77%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]#[N:26])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:31]O.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]([NH2:26])=[O:31])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OO
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C#N)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C(N)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl)-cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of methanol (1.8 mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium hydroxide (0.150 mL). The resulting suspension was stirred for 72 h at room temperature. The hydrogen peroxide was then quenched with sodium sulfite. The reaction mixture was diluted with 0.5 mL of N,N-dimethylformamide, filtered, and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-2-tert-butyl-1H-indole-7-carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+. Retention time of 1.74 minutes.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[CH:12]=2)[N:7]=1)([CH3:5])[CH3:4].C(C1C(C)=C([O:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C>CN(C)C=O.O>[CH:3]([C:6]1[C:15]([CH3:16])=[C:14]([O:17][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:33])[C:13]2[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[CH:12]=2)[N:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C(C)C)nc2cc(F)c(F)cc2c1O
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(C)C)nc2cc(F)c(F)cc2c1OC(=O)C1CC1
Reaction time: 1 h

Procedure:
3,4-Difluoroaniline (4.5 g) and 6 g of ethyl-2-methyl isovalerylacetate were refluxed in toluene (50 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction mixture was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 246 mg of a mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 10 ml of dimethyl formamide was suspended 20 mg of 60% sodium hydride. Separately, 100 mg of the mixture of 2-isopropyl-3-methyl-4-hydroxy-6,7-difluoroquinoline with 2-isopropyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) was suspended in 20 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 100 mg of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 44.1 mg of 2-isopropyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (compound 34). 1H-NMR data are shown in Table 3.
Reaction SMILES: [N+:1]([O-])(O)=O.[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.CCO.O.[Fe]>[Br:15][C:9]1[C:10]([CH3:14])=[C:11]([CH:12]=[CH:13][C:8]=1[CH:5]([CH3:7])[CH3:6])[NH2:1]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(C)C)c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(N)ccc(C(C)C)c1Br
Temperature: 90 °C

Procedure:
Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in HOAc (60 mL). The mixture is heated 1 hour at 90° C. and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3×60 mL). The combined extracts are washed with 1 N NaOH (3×40 mL) and then water (40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in HOAc (75 mL)/EtOH (75 mL). To this is added Fe powder (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H2O (10 mL) is added dropwise at 0° C. to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H2O (15 mL), and the mixture is stirred for 1 hour at 0° C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl3 (70 mL) at room temperature. The mixture is stirred for 1 hour and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H-indazole. 1H NMR (CDCl3) 8.03 (br, s, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).
Reaction SMILES: [CH3:1][S:2]SC.[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.C(OCC)C>C(#N)C>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CSSC
Reactant: C=CCCCCCC
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCCCCSC
Yield: 64.8 %

Procedure:
The procedure of Example 1 was repeated using dimethyldisulphide (96 mg; 1.02 mmol) and 1-octene (358 mg; 3.19 mmol) in acetonitrile (15 ml) at +1.20 V until 2 coulomb equivalents of charge had been passed. After the addition of water and extraction with diethyl ether, there was obtained 106 mg of methylthio-octane. Mass Spec. m/e 217 (M+) and 44 (100%). I.R. 3300 and 1650 cm-1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[NH:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>[Cu](I)I>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: c1cc[nH]c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2cccc2)c(C)nc1OC
Temperature: 185 °C
Yield: 36.2 %

Procedure:
Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol), sodium hydroxide (84 mg, 2.10 mmol) and pyrrole (72 μL, 1.04 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5 mL) is added then sealed. The first reaction is heated in the CEM Discover microwave at 185° C. (max wattage set to 150 W) for 1 hr. LC/MS shows the reaction is incomplete. The reaction is re-microwaved at 185° C. for a further 1 hr but LC/MS shows no further apparent product formation. The second reaction is microwaved at 185° C. for 1 hr. Further copper iodide (150 mg) is added, the reaction is flushed with N2 and re-microwaved at 185° C. for a further 1 hr. LC/MS shows the reaction is largely complete. The two reactions are combined, diluted with water and extracted with three portions of dichloromethane. The combined organic layers are washed with two portions of 1 M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give a black oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with ethyl acetate:heptane (1:49, increasing to 1:1). Clean fractions containing the product are combined and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-pyrrol-1-yl-pyridine (68 mg, 18% yield) as a yellow-orange oil. MS: m/e=217 (M+H); 1H NMR (CDCl3, δ ppm): 7.26 (1H, s, obscured by CHCl3 in CDCl3), 6.73 (2H, m), 6.30 (2H, m), 3.98 (3H, s), 2.58 (2H, q), 2.27 (3H, s), 1.10 (3H, t).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:31])[C@@H:14]([NH:20]C(OCC2C=CC=CC=2)=O)[CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]>C(O)C.[Pd]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:31])[C@@H:14]([NH2:20])[CH2:15][C:16]([F:17])([F:19])[F:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)N1CCN(C(=O)[C@H](CC(F)(F)F)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCOC(=O)N1CCN(C(=O)[C@@H](N)CC(F)(F)F)CC1
Reaction time: 12 h

Procedure:
To a solution of 170 mg 4-((S)-2-Benzyloxycarbonylamino-4,4,4-trifluoro-butyryl)-piperazine-1-carboxylic acid propyl ester in 20 ml ethanol were added 0.05 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 106 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26]([O:28][C:29]([CH:31]1[CH:36]2[CH:32]1[CH2:33][O:34][C:35]2=[O:37])=[O:30])[CH3:27].Cl>C1COCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH:36]([CH2:35][OH:37])[CH:32]1[C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15])=[O:30])[CH3:27]
Reactant: CCOC(=O)C1C2COC(=O)C21
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(CO)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 600 mg (2.9 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 10 ml of THF was cooled to −78° C. and treated dropwise with 3.2 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To this solution 500 mg (3.2 mmol) of (1SR,5SR,6SR) 2-oxo-3-oxa-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester dissolved in 5m of THF were added portionwise. The mixture was allowed to reach RT and stirred for 10 hrs. The mixture was then poured into a diluted aqueous HCl-solution (ca. 0.2 M) and extracted with AcOEt. The combined organic phases were dried with Na2SO4. Filtration, evaporation of the solvent gave 630 mg (57%) of (1SR,2SR,3RS) 2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester. Orange foam. MS: 373 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23]C3CCCCO3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.Cl>C(O)C>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 8-bromo-7-(4-fluorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (26 g, 52.5 mmol) in ethanol (500 mL) was added concentrated HCl (50 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to half its volume and the product precipitated. The solids were collected and washed with water and ethanol; then dried under vacuum to give 8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (18.1 g, 83.9% yield) as white solid. LCMS retention time 1.243 min; LCMS MH+ 411.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:4]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH:3]=1.CC1(C)C(C)(C)OB([C:53]2[CH:54]=[C:55]([P:59](=[O:64])([O:62][CH3:63])[O:60][CH3:61])[CH:56]=[CH:57][CH:58]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[Si:38]([O:37][C:4]1[CH:3]=[C:2]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([P:59](=[O:64])([O:62][CH3:63])[O:60][CH3:61])[CH:54]=2)[CH:7]=[CH:6][C:5]=1[C@@H:8]1[C@@H:9]([CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10](=[O:18])[N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: COP(=O)(OC)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
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)c(O[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
(3R,4S)-4-(4-Bromo-2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (0.080 g, 0.11 mmol), crude dimethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate (0.054 g total, 0.030 g calculated, 0.096 mmol) and aqueous 2 M potassium carbonate (0.12 mL, 0.24 mmol) were mixed in ethanol (1.0 mL) and toluene (3.0 mL). The solution was deoxygenated by bubbling nitrogen through the mixture for 5 min while stirring. Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added and the reaction was heated for 3 h at 70° C. under an atmosphere of nitrogen. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated by rotary evaporation under reduced pressure. The product was purified by chromatography over silica gel using ethyl acetate-hexane (gradient: 10% ethyl acetate to 80%) to afford dimethyl (3′-{[tert-butyl(dimethyl)silyl]oxy}-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 as a colorless syrup (0.065 g, 84%). 1H NMR (300 MHz, CDCl3) δ 6.9-8.0 (m, 16H), 5.09 (d, J=2.2 Hz, 1H), 4.64 (d, J=6.1 Hz, 1H), 3.79 (d, J=2.4 Hz, 3H), 3.76 (d, J=2.4 Hz, 3H), 3.05-3.15 (m, 1H), 1.8-2.0 (m, 4H), 1.06 (s, 9H), 0.85 (s, 9H), 0.36 (s, 3H), 0.33 (s, 3H), 0.00 (s, 3H), −0.20 (s, 3H) ppm
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(N)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COC(=O)c1cccc2cc(Nc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 90 °C

Procedure:
To a mixture of methyl-6-amino-1-napthoate (300 mg, 1.5 mmol) and 4-chloro-6,7-dimethoxyquinoline (416 mg, 1.8 mmol) in a 20 mL sealed tube was added isopropyl alcohol (6 mL) and trifluoroacetic acid (287 μL, 3.7 mmol). The reaction vessel was sealed and heated at 90° C. for 1 h before being allowed to cool to ambient temperature. To the resulting thick yellow slurry was added isopropyl alcohol (6 mL). The reaction vessel was sealed and heated at 90° C. for 10 h. The mixture was then cooled to 0° C. and filtered. The resulting solid was washed well with cold CH3OH and dried in vacuo to provide the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 389.3 (M+1). Mass Calc'd for C23H20N2O4: 388.42.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>>[Cl:1][C:2]1[N:6]([CH3:17])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(Cl)nc2ccccc21

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (3.0019 g, 19.67 mmol, Sigma-Aldrich Chemical Company, Inc.) in 2.5 M sodium hydroxide solution (19.67 ml, 49.2 mmol, J. T. Baker) at 0° C. was added dimethyl sulfate (3.01 ml, 31.5 mmol, Riedel de Haen AG) dropwise. The reaction was allowed to stir for 1½ h. White precipitate was noted to form. The white precipitate was filtered, washed with water, and dried to give the title compound. LCMS showed product peak at 1.47 min (m+1=167.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3 H) 7.21-7.28 (m, 1 H) 7.28-7.35 (m, 1 H) 7.59 (d, J=3.72 Hz, 1 H) 7.61 (d, J=3.72 Hz, 1 H)
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:31])[CH3:38]
Reactant: CN(C)CCCN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCCN(C)C)cc3)c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
DIPEA (76 μl, 0.6 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), 3-dimethylaminopropylamine (20 mg, 0.2 mmol), HBTU (91 mg, 0.24 mmol) and HOBT (27 mg, 0.2 mmol) in DMF (0.5 ml). The reaction was stirred at room temperature for 16 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml). The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (80:8:1). The product fractions were concentrated under vacuum to give N-[(dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (37 mg, 49%).