Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2].B(O)(O)[C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([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)=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:23]=[C:24]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)cc5)c4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
In a vial were placed methyl 6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate (Preparation 3) (56 mg, 0.1010 mmol), p-tolylboronic acid (17.855 mg, 0.1313 mmol), Na2CO3 (32.121 mg, 0.3030 mmol), toluene (1 ml), and water (0.1 ml). The mixture was degassed with Argon for few minutes. Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.005 mmol) was added and the vial was sealed. The mixture was stirred at 100° C. for 24 hours. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 33.1 mg of the title compound as foamy solid (63%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[C:31]2[N:30]=[CH:29][N:28](C(OC(C)(C)C)=O)[C:27]=2[CH:26]=[CH:25][CH:24]=1.[ClH:39]>>[ClH:39].[ClH:39].[N:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][O:14][C:13]3[C:8]([NH:7][C:4]4[S:5][CH:6]=[C:2]([CH3:1])[N:3]=4)=[N:9][CH:10]=[CH:11][CH:12]=3)[C:31]=2[NH:30][CH:29]=1
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc3nc[nH]c23)n1
Yield: 14.1 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 70 mg, 0.338 mmol), potassium carbonate (117 mg, 0.844 mmol) and tert-butyl 4-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate (105 mg, 0.338 mmol) [Moon, M., J. Med. Chem. (1992), 35(6), 1076] were reacted according to the method of Example 3, Steps B and C, to provide 3-((3H-benzo[d]imidazol-4-yl)methoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine dihydrochloride (19.6 mg, 14.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.72 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.61 (t, 1H), 7.09 (dd, 1H), 6.79 (s, 1H), 5.70 (s, 2H), 2.29 (s, 3H). Mass spectrum (apci) m/z=338.1 (M+H-2HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])([CH3:12])([CH3:16])[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-n-hexyl-1,2-dihydropyridine (7.42 g, 23.2 mmol) in 250 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (93 mL, 92.87 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 5.9 g (81% from previous reaction) as a clear colorless oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.85-6.63 (dd, 1H), 5.55 (br s, 1H), 5.23-5.12 (m, 1H), 4.87-4.56 (m, 1H), 1.72-1.25 (m, 19H), 0.89-0.85 (t, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:18]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:18]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3sccc3c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccc3sccc3c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To toluene 1.6 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 79 mg were added ethanol 0.60 mL, water 0.30 mL, 5-bromobenzothiophene 61 mg, sodium hydrogen carbonate 48 mg and tetrakis(triphenylphosphine)palladium(0) 11 mg at room temperature, and it was heated and refluxed for 6 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate. Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoic acid 16 mg of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:5]=[C:6]([CH:18]=1)[O:7][CH2:8][CH2:9][O:10]C1C=CC=CC=1C.C(O)C>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:30])=[O:31])(=[O:22])=[O:21])[CH:5]=[C:6]([CH:18]=1)[O:7][CH2:8][CH2:9][OH:10]
Reactant: Cc1cc(OCCOc2ccccc2C)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
A mixture of 2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxytoluene (480 mg, 1.01 mmol), as prepared in the preceding step, 10% palladium on activated carbon (48.2 mg, ethanol (2 mL) and tetrahydrofuran (9 mL) was stirred at ambient temperature under hydrogen (balloon) for 45 minutes. The mixture was filtered through Celite and the filtrate was concentrated to give the title compound (404 mg, quantitative) as a colorless gum. 1H-NMR (300 MHz, CDCl3) δ8.45 (dd, 1H, J=7.8, 1.4 Hz), 8.13 (dd, 1H, J=7.8, 1.4 Hz), 7.88 (td, 1H, J=7.7, 1.4 Hz), 7.75 (td, 1H, J=7.7, 1.4 Hz), 6.60-6.66 (m, 3H), 3.77-3.98 (m, 4H), 2.25 (s, 3H), 1.95 (t, 1H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H18O7S2: 409.0 (M+Na). Found: 408.7.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:19]([O:18][C:16]([NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:8]1[C:6]([OH:7])=[O:5])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (28 mg, 0.054 mmol) is dissolved in 4 ml Dichloro-methane/Trifluoroacetic Acid; 3:1 and stirred for 5 h at room temperature. The solvent/reagent are evaporated and the remaining oil is co-evaporated from Toluene twice. Flash-chromatography, Hexane/Ethylacetate; 1:1 afforded the desired product: Cal. 460.51, found (M)+ 460.9.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Solvent: ClCCl
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g; 0.0194 mol) in methylene chloride (25 mL) was added to a suspension of activated maganese dioxide (27 g) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered, and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde as an oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1([CH3:22])[CH3:21])=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:21][C:7]1([CH3:22])[CH:8]([CH:9]=[C:10]([C:17]([F:19])([F:20])[F:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(c2ccccc2)C(F)(F)F)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)O
Yield: 36.8 %

Procedure:
21 g (0.067 mol) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester were dissolved in 100 ml of ethanol, a solution of 3.1 g of sodium hydroxide in 75 ml of water was then added and the mixture was heated to the reflux temperature for 4 hours, while stirring. The ethanol was then distilled off under a waterpump vacuum, the residue was taken up in 300 ml of water and the aqueous mixture was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phases were then separated off, dried over magnesium chloride, and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C. under 2 mbar. 7 g (36.8% of theory) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid were then obtained as a very viscous light yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[N:17]1([C:2]2[N:3]=[C:4]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:5]3[S:11][CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1nc2c(c(N3CCCC3)n1)SCCC2
Reactant: C1CNCCN1
Solvent: c1ccccc1
Product: C1CSc2c(nc(N3CCNCC3)nc2N2CCCC2)C1
Yield: 61.1 %

Procedure:
10 g of 2-chloro-4-pyrrolidino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, 10 g of piperazine and 50 ml of benzene were heated at a bath temperature of 70°-80° C. for 4 hours. The solvent was then distilled off and the resulting residue was dissolved in dichloromethane. The solution was washed with water and dried. The solvent was distilled off and the resulting crystals were washed thoroughly with diethyl ether to obtain 7.3 g (61% yield) of 2-piperazino-4-pyrrolidino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[Li]C>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][CH:11]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1C
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxy-4-methyl benzoic acid (3.32 g, 20 mmol) in anhydrous THF (100 mL) was cooled to −78° C. A solution of MeLi (25 mL of a 1.6M solution in diethyl ether, 40 mmol) was added slowly to the reaction flask via syringe over 10 min. The cooling bath was removed, and the reaction mixture was allowed to warm to rt, and was stirred for 1 h at rt. The reaction mixture was quenched with 1N HCl (50 mL) and extracted with diethyl ether (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgSO4), and concentrated to afford 3-methoxy-4-methyl benzophenone as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a nitrogen-saturated solution of 2-amino-3-nitrobenzoic acid methyl ester (Chess GmbH, 50 g, 0.26 mol) in absolute ethanol (800 mL) was added palladium hydroxide (Degussa, 20% w/w on carbon, 58.75% w/w water, 10 g). The slurry was degassed then shaken vigorously under hydrogen (4 atm) at room temperature for 48 h. The catalyst was filtered and the filtrate concentrated in vacuo to afford 2,3-diaminobenzoic acid methyl ester as a dark orange oil that solidified on standing (43 g, 0.26 mol, 100%). (m/z): [M-OCH3]+ calcd for C8H10N2O2 135.05; found 135.3. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 3.74 (s, 3H), 4.80 (br s, 1H), 6.20 (br s, 1H), 6.38 (t, 1H), 6.70 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: [O:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](OC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[O:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1csc(Oc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1csc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
A solution of methyl 2-phenoxythiazole-4-carboxylate (265 mg; 1.12 mmol) in anh. EtOH (6 ml) was treated at rt with NaBH4 (213 mg; 5.64 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 63 h. After concentration to dryness under reduced pressure, water was added, and the resulting mixture was extracted with DCM. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded (2-phenoxythiazol-4-yl)methanol as a colorless oil. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 208.06 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:35][O:34][C:32]([CH2:31][O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)=[O:33]
Reactant: COC(=O)CBr
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To a solution of 0.21 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 1.0 ml of N,N-dimethylformamide were added 0.10 g of methyl bromoacetate and 0.20 g of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. Dilute hydrochloric acid was poured into this reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate. This solution was subjected to silica gel column chromatography to obtain 0.06 g of 3-(methoxycarbonyl)methoxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [present compound 5-17].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.I.[NH:44]1[CH2:48][CH2:47][N:46]=[C:45]1S>C(O)C.CN(C1C=CN=CC=1)C>[NH:46]1[CH2:47][CH2:48][N:44]=[C:45]1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:8]=2)[CH2:3]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: SC1=NCCN1
Agent: CN(C)c1ccncc1
Agent: I
Solvent: CCO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC5=NCCN5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 18 step 2) (30 mg, 0.053 mmol) and 4,5-dihydro-1H-imidazole-2-thiol hydroiodide (24 mg, 0.106 mmol) in absolute ethanol (2 ml) is treated with DMAP (catalytic amount) and TEA (29 μl, 0.212 mmol). The resulting mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 150° C. for 4000 s. The solvent is removed in vacuo and purification of the crude product by preparative HPLC ((30-95% acetonitrile in water −0.1% TFA) affords the title compound. (MH+ 639.63)
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20]C)=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[NH2:1][C:2]1[C:11]([CH2:12][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[OH:20])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1N
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Temperature: 160 °C

Procedure:
(2-Aminoquinolin-3-yl)(2,6-dimethoxyphenyl)methanone (0.19 g, 0.6 mmol) was dissolved in diethylene glycol (10 mL), mixed with hydrazine hydrate (0.19 mL, 6.1 mmol) and pulverized potassium hydroxide (0.27 g, 6.7 mmol) and heated for 2 hours at 160° C. The same amounts of hydrazine hydrate and potassium hydroxide were added two more times and the reaction mixture was stirred for two more hours each time at 160° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCO1
Yield: 85 %

Procedure:
To a stirred solution of 15.5 g. (0.15 mol.) of ethyl glycolate in 60 ml. of methylene chloride, cooled to 5° C., was added 12.6 g. (0.15 mol.) of dihydropyran, followed by 50 mg. of 4-toluenesulfonic acid monohydrate. After the immediate exothermic reaction which ensued had subsided, the methylene chloride solution was washed successively with water, 5% sodium bicarbonate and water. The dried solution was then evaporated to give 23.8 g. (85% yield) of ethyl 2-(2-tetrahydropyranyloxy)acetate as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])=[N+:23]=[N-:24]
Reactant: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a suspension of the 2-(2-aminophenyl)isoindole-1,3-dione (360 mg, 1.5 mmol) in acetic acid (20 mL) and water (4 mL) was added dropwise a solution of sodium nitrite (98 mg, 1.42 mmol) in water (2 mL). The mixture was allowed to stir for 10 minutes and then sodium azide (98 mg, 1.51 mmol) was added. The reaction mixture was stirred for 15 minutes before it was poured into water and was extracted with dichloromethane (3×50 mL). The extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave 373 mg (94%) of 2-(2-azidophenyl)isoindole-1,3-dione as a solid: 1H NMR (300 MHz, DMSO-d6) δ 7.94 (m, 4H), 7.58 (m, 1H), 7.48 (m, 2H), 7.32 (m, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH:33]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCCC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Yield: 67.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.55 g, 1.10 mmol) in ethanol (about 5 ml) was added cycloheptylamine (about 1.80 ml, 14.2 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.4 g) as a colorless solid. Yield: 62%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.52 (d, 1H, J=22.2 Hz), 5.81 (bs, 1H), 4.83-4.77 (m, 2H), 4.48-4.41 (m, 1H), 2.15 (s, 3H), 1.89-1.88 (s, 3H), 1.62-1.11 (m, 16H); ES Mass: [M+1]+ 540 (60%), [M+Na] 562 (100%); IR cm−: 3430, 2924, 2853, 2348, 1753, 1725, 1617, 1451, 1274, 1060, 950, 711. HPLC: 92%.