Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1C(OCC)=O.ClC1C=CC2SC=C(C)C=2C=1>>[Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][CH:7]=1
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Agent: Cc1csc2ccc(Cl)cc12
Product: Clc1ccc2scc(CBr)c2c1
Yield: 57 %

Procedure:
Using the general procedure of Example 1, Method A, (iv), replacing ethyl-5-chloro-3-methylbenzo[b]thiophene-2-carboxylate with 5-chloro-3-methylbenzo[b]thiophene gave 2.78 g (57%) of 3-bromomethyl-5-chlorobenzo[b]thiophene: mp 126°-128° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([Br:25])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:8]([CH2:15][CH3:16])=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CO[C:28](OC)([CH3:30])[CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:8]([CH2:15][CH3:16])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:22][O:23][C:28]([CH3:30])([CH3:29])[O:24]2)[C:6]=1[Br:25]
Reactant: COC(C)(C)OC
Reactant: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 93 %

Procedure:
3-(2-Allyloxyethyl)-1,5-bis(methoxymethoxy)-2-bromo-4-ethylbenzene (5.0 g, 13 mmol) obtained in Example 33, Step 2 was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (10 mL). To the solution were added 4-methylmorpholine N-oxide (1.9 g, 16 mmol) and a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol (1.0 mL) at room temperature with stirring, and the mixture was stirred overnight. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was further stirred for 2 hours and then extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol. The obtained 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol was dissolved in N,N-dimethylformamide (50 mL), and 2,2-dimethoxypropane (6.4 mL, 52 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added thereto at room temperature with stirring, followed by stirring for 30 minutes. After neutralization with a saturated aqueous solution of sodium hydrogencarbonate, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain 1,5-bis(methoxymethoxy)-3-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-2-bromo-4-ethylbenzene (5.6 g, 93%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:18])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:26](=[O:28])[CH3:27])[C:11]1=[O:17])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(N)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-Amino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (500 mg, 1.98 mmol) in dichloromethane (5 mL) was added triethylamine (220 mg, 2.18 mmol) followed by acetic anhydride (202 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and aqueous 1M HCl. The organic layer was washed with saturated aqueous NaHCO3, brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (40% ethyl acetate/hexane) to afford the title compound as a colourless oil (569 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 0.87 (3H, t), 1.40 (9H, s), 1.91 (1H, m), 2.13 (3H, s), 2.19 (1H, m), 5.38 (1H, dd), 6.26 (1H, t), 6.99 (1H, d), 8.33 (1H, d), 8.43 (1H, br s).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:26])[C:24]=1O)[CH:20]=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][O:14][C:24]3[C:23]([CH3:26])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[CH3:16])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(C2CCCCC2)nc1CCO
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc(C)c1OCCc1nc(C2CCCCC2)oc1C
Reaction time: 2 h

Procedure:
0.400 g of the above prepared 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethanol (1.91 mmol) was dissolved in 10 ml of toluene and treated successively at 0° C. with 0.287 g of 3,5-dimethyl-4-hydroxybenzaldehyde (1.91 mmol), 0.501 g of triphenylphosphine (1.91 mmol), and 0.387 g (1.91 mmol) of DIAD. The cooling bath was then removed and stirring continued for 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with dil. NaOH and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15) delivered finally 0.415 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Yield: 64.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 106 mg 5-bromo-2-oxindole, and 75 μL piperidine in 2 mL ethanol were heated to 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 120 mg (64%) of the title compound as a brown solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([C:16](=O)[CH2:17][CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([CH2:25][C:26]([O:28][CH3:29])=[O:27])(C)C>>[Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([C:16]([CH2:17][CH3:18])=[CH:25][C:26]([O:28][CH3:29])=[O:27])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(=O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Reactant: COC(=O)C[Si](C)(C)C
Product: CCC(=CC(=O)OC)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F

Procedure:
Compound 90.E (mixture of geometric isomers) was prepared from 90.D and methyl (trimethylsilyl)acetate (available from Aldrich) according to the analogous method described in Example 84.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N+:35]([O-])=[CH:34][CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.O.[PH2]([O-])=O.[Na+].[PH2]([O-])=O.[Na+]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccncc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
A suspension of 4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.200 g, 0.00039 mol) and 10% palladium on carbon (0.042 g, 0.00004 mol) in acetic acid (3 mL) was reacted with sodium hypophosphite monohydrate (0.063 g, 0.00059 mol) at 60° C. for 2 hours. Additional 10% palladium on carbon (0.042 g, 0.00004 mol) and sodium hypophosphite (0.045 g, 0.00042 mol ) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the residue was slurried in methanol for 4 hours. The mixture was filtered through Celite® 521, washing with methanol. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 50% isocratic for five minutes, then 50%-100% acetonitrile-0.1M ammonium acetate over 25 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.020 g, 0.00004 mol) as a white solid:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:29][N+:30]1[CH:35]=[CH:34][C:33]([C:36]2C=CC=CC=2C=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[CH:35][N+:30]([O-:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1-c1cc[n+]([O-])cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: [O-][n+]1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1-oxidopyridin-4-yl benzaldehyde. MS (ESI) m/z 484.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10](I)[CH2:9]1)[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 71.8 %

Procedure:
5-Ethyl-3'-iodo-2',3'-dideoxyuridine (432 mg, 0.87 mmole) is dissolved in methanol (40 ml) and triethylamine (0.5 ml) is added along with 10% Pd/C (200 mg). The mixture is then stirred in an atmosphere of hydrogen at room temperature for 30 min. After filtration of catalyst, the filtrate is evaporated to dryness. Purification of the product was achieved on silica gel plates using chloroform-methanol (20:1) to obtain a solid (150 mg, 75%).
Reaction SMILES: [OH-].[K+].[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>O.CCO>[O:15]=[C:13]([CH3:14])[CH2:12][CH:4]1[C:5](=[O:9])[CH2:6][CH2:7][CH2:8][C:3]1=[O:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)CC1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of KOH (2.54 kg, 2.26 kg corrected for assay, 40.2 moles) in water (4.0 L) was added over 30 mins to a solution of cyclohexane-1,3-dione (4.53 kg, 4.51 kg corrected for assay, 40.2 moles) in EtOH (16.2 L), while maintaining the temperature below 30° C. After stirring for 15 mins at r.t., freshly distilled chloroacetone (4.39 kg, 3.83 kg corrected for assay, 41.4 mol) was then added slowly to the mixture, maintaining a temperature of 25-28° C. The resulting slurry was stirred at r.t. for 19 h. Inorganic by-products were then removed by filtration and were washed on the filter with EtOH (4.5 L). The filtrates were combined to provide 2-(2-oxopropyl)cyclo-hexane-1,3-dione as a solution in EtOH. Assay by GC 26.5% w/w; purity by GC: 82.3 area %). This solution was transferred to a reactor and glycine ethyl ester hydrochloride salt (6.41 kg, 6.17 kg corrected for assay, 44.2 moles) was added at r.t. with stirring followed by sodium acetate trihydrate (6.04 kg, 6.02 kg corrected for assay, 44.3 moles). The mixture was diluted with ethanol (28.9 L) then heated under reflux for 2 h. EtOH was removed in vacuo (−0.850 to −0.900 bar) at 30° C. until 40 L of distillate had been collected. After cooling the residue to 0° C., water (15 L) was added, while maintaining a temperature of 0-5° C. After stirring for a further 1 h at this temperature, the solid that separated out was collected by filtration and was then dried in vacuo at 35° C. with a nitrogen bleed to give the title compound as a solid; 6.7 kg; assay by 1H NMR: 86.6% w/w; weight corrected for assay: 5.80 kg (61% over 2 steps); purity by GC: 96.0 area %; m/z: 235 (MH+); 1H NMR: (CDCl3) 1.27-1.32 (3H, t), 2.10-2.17 (2H, m), 2.19 (3H, s), 2.42-2.46 (2H, t), 2.65-2.69 (2H, t), 4.21-4.28 (2H, m), 4.51 (2H, s) and 6.27 (1H, s).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>CCOCC.O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 1.0 M solution of 4-tolylmagnesium bromide in ether (20.5 ml) is added dropwise to a solution of diethyl oxalate (6.5 g) in anhydrous tetrahydrofuran (41 ml) under a nitrogen atmosphere and ice cooling. Five minutes after completing the addition, the mixture is stirred at room temperature for 1.5 hours. To the reaction mixture is added 1 N hydrochloric acid, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 2.99 g (76%) of ethyl 4-tolylglyoxylate.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]([CH2:18][C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: O=c1cc(-c2ccccc2)c2c(O)cc(O)cc2o1

Procedure:
A solution of phloroglucinol (2.00 g) and ethyl benzoylacetate (3.05 g) in ethanol (30 ml) was treated with dry HCl as described in example 1a. The product was recrystallized from ethanol-water (1:1). Yield 3.0 g (75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>OS(O)(=O)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
To a solution of 2-Benzyloxy-6-nitro-phenylamine (I-107, 1.52 g, 0.0062 mol) in acetic anhydride (1.27 g, 0.0125 mol), 4 drops of conc. H2SO4 was added at room temperature and stirred for one minute and then the reaction flak was immersed in an oil bath maintained at 90° C. After 2 minutes, the solidified reaction mixture was taken in water (20 mL) and filtered the solid. Solid was further washed with water (20 mL×2) and dried under high vacuum to afford N-(2-benzyloxy-6-nitro-phenyl)acetamide, I-108 (1.59 g).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>C(OCC)(=O)C.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.[Cu]I>[CH:27]1([C:25]#[C:26][C:2]2[C:3]([F:17])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1
Reactant: C#CC1CC1
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1c(C#CC2CC2)ccc2c1cnn2C1CCCCO1
Temperature: 120 °C
Yield: 56.4 %

Procedure:
In a high pressure tube, a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8 mmol; Intermediate 21), PdCl2(PPh3)2 (3.7 g, 5.35 mmol), CuI (1.0 g, 5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cycles of vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was added under N2 atmosphere. The tube was sealed and the reaction mixture was heated at 120° C. for 63 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether) affording the title compound (4.3 g). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285 (M+H)+.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH3:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12]>[Ni]>[C:2](=[O:3])([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH3:5])[NH2:1]
Reactant: CCCCOCCO
Reactant: NC(N)=O
Agent: [Ni]
Product: CCCCOCCOC(N)=O
Temperature: 135 °C
Yield: 98 %

Procedure:
60 parts of urea are mixed with 177 parts of butylglycol and 3 parts of a cation exchanger which is commercially available under the registered name Lewatit CA 9259 and, having been treated in accordance with Example (1 a), contains nickel, in a stirred apparatus. The mixture is heated to 135° C., whilst stirring. It is then heated for 10 hours at 140° C. After cooling, the mixture is filtered and the excess butylglycol is distilled from the filtrate under reduced pressure. 158 parts of n-butoxyethyl carbamate (corresponding to 98% of theory, based on urea) are obtained. On distillation of the end product in a high vacuum, a residue of only 0.9% by weight is left. The pure butoxyethyl carbamate has a boiling point 118°-120° C. at 0.2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (19 μl, 2 eq) followed by addition of DIEA (65 μl). The resulting solution was stirred at r.t. for 1 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (400 μl) at 60° C. for 1 h before worked up with EA/brine. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (178) (10.5 mg, yield: 35.4%, purity>95%) as off-white solid.
Reaction SMILES: C1(B(O)O)C=CC=CC=1.[CH3:10][N:11]([CH3:35])[C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]([C:24]2[N:25]=[C:26](O)[C:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:32]=3[CH:33]=2)=[CH:14][CH:13]=1.[NH2:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:26]1[N:25]=[C:24]([C:15]2[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]([N:11]([CH3:35])[CH3:10])=[CH:13][CH:14]=2)[CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(O)n2)cc1-c1ccccc1
Reactant: NCCCN
Agent: OB(O)c1ccccc1
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1-c1ccccc1

Procedure:
Treatment of the above intermediate with 2-methylnicotinic acid according to Method A (Example 1) provided the corresponding [1,6]napthyridin-5-ol. Treatment of this with phenylboronic acid using the procedure described in Example 5 provided 7-(6-dimethylamino-biphenyl-3-yl)-[1,6]naphthyridin-5-ol. Conversion to the 5-chloro intermediate using Method B, followed by treatment of this with 1,3-diaminopropane by the procedure described in Method C (Example 3) provided the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.82 (dd, 1H), 8.16 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 1H), 7.63 (dd, 2H), 7.52 (s, 1H), 7.41 (t, 2H), 7.29 (t, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 3.84 (t, 2H), 3.00 (t, 2H), 2.58 (s, 6H), 1.99 (t, 2H); MS (m/e) calculated for C25H27N5 397, found 398.3 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1CC
Yield: 50.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115b) (0.89 g, 2.63 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.25 g of the title compound as a colorless amorphous solid (49%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([Br:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3Br)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (45 mg, 0.157 mmol), NBS (56 mg, 0.314 mmol) in DMF (0.5 mL) was stirred at room temperature for 1.5 h. Following solvent removal, product (20 mg, 34.8%) was collected through silica gel column purification (CHCl3:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, acetone-d6) 7.51 (bs, 2H), 7.21 (s, 1H), 6.98 (s, 1H), 6.06 (s, 2H), 4.13 (s, 2H); MS m/z 366.0 (M+H)+.