Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (2.3 mL of a 0.31M stock solution, 0.71 mmol) cooled to −78° C. was treated with a solution of 4-methoxycarbonylmethyl-benzoic acid methyl ester (66 mg, 0.31 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.85 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (86 mg, 0.40 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was then stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (50 mL). This solution was extracted into ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester (60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for C17H22O4 (M+) 290.1518, found 290.1518.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([CH:24]=3)[NH2:23])[O:15][N:14]=2)[CH:12]=1>N1C=CC=CC=1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([NH:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=3)[O:15][N:14]=2)[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1
Solvent: c1ccncc1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (20 μL; 0.26 mmol; 1.2 eq.) was added to a solution of Example 69 (83 mg; 0.22 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 16 hours. The solution was then partitioned between water and ethyl acetate. The two phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed (3×) with 0.1M HCl, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography c-hexane/ethyl acetate, 60/40) afforded the title compound as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1.CCN(S(F)(F)[F:28])CC>ClCCl>[F:28][CH2:2][CH2:3][C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCO
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCF
Reaction time: 0.5 h

Procedure:
To a partial suspension of 4-[5-(2-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one (0.180 g, 0.616 mmol) (example 27f) in dichloromethane (10 mL) at 0° C. under nitrogen is added DAST (0.314 g, 1.848 mmol) dropwise. After 30 min, the mixture is diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, water and brine. The combined aqueous phase is back-extracted once with dichloromethane. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1 to 49:1) to afford 4-[5-(2-fluoro-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as an oil. The material is converted to the HCl salt and triturated with methanol, to give a crystalline solid; MS (ESI) m/z 289.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.27 (s, 3 H), 1.59 (s, 3 H), 4.69-4.95 (m, 4 H), 5.73 (br. S., 1 H), 7.16 (s, 1 H), 7.53 (d, J=7.6 Hz, 1 H), 7.63 (br. S., 1 H), 7.71 (td, J=7.6, 1.1 Hz, 1 H), 7.81 (td, J=7.6, 1.3 Hz, 1H), 8.27 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: COC(=O)C1C=CC(N=[N:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:16]=2)=CC=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>[Pt](=O)=O.CO>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:15]1[N:16]=[C:12]([NH2:11])[NH:13][CH:14]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]
Reactant: COC(=O)Cc1c[nH]c(N=Nc2ccc(C(=O)OC)cc2)n1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)Cc1c[nH]c(N)n1

Procedure:
A mixture of 4-(4-methoxycarbonylmethyl-1H-imidazol-2-ylazo)-benzoic acid methyl ester (2 mmol, 604 mg) synthesized above, platinum (IV) oxide (60 mg) and methanol (50 mL) was hydrogenated (60 psi) for two days (another portion of PtO2 was added after one day). Trifluoroacetic acid (TFA) (2 mmol, 0.15 mL) was added to the reaction mixture and it was filtered. The filtrate was concentrated and diluted with water, washed with ether (2×50 mL). Evaporation of the water from the aqueous solution gave the (2-Amino-1H-imidazol-4-yl)-acetic acid methyl ester as a TFA salt. (273.8 mg, 51%). LCMS: 156 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]([OH:18])=[O:17].OS(O)(=O)=O.[CH3:24][CH2:25]O>>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]([O:18][CH2:24][CH3:25])=[O:17]
Reactant: CCO
Reactant: O=C(O)c1cccc2c(Cl)c3ccccc3cc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc2c(Cl)c3ccccc3cc12
Yield: 77 %

Procedure:
10-Chloroanthracene-1-carboxylic acid (37A, 17.3 g, 0.0674 mol), conc. H2SO4 (1.0 mL), and abs. EtOH (500 mL) was refluxed for 3 days using 4Å molecular sieves in a Soxhlet extractor to remove H2O. The solvent was removed and then partitioned between EtOAc and satd. NaHCO3. The solvent was then removed from the organic layer to give 14.86 g (77%) of ethyl 10-chloroanthracene-1-carboxylate, which was used without further purification.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[C:21]([Si:24]([CH3:26])([CH3:25])[O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([CH3:23])([CH3:22])[CH3:20]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCOCCOCCO

Procedure:
Compound 28c was prepared according to the procedure described hereinabove for Compound 6a, using hexaethylene glycol (5 grams, 17.7 mmol), TBDMSCl (1.65 grams, 11 mmol), and imidazole (0.748 grams, 11 mmol) in DMF (26 ml), yielding 1 gram of the product (14% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([CH3:39])[C:31]([C:36](Cl)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>ClCCl>[CH:17]1([N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:39])=[CH:3][CH:4]=2)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(N(C(=O)c2ccc(N)cc2)C2CCCC2)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of N-(4-aminobenzoyl)-N-cyclopentyl-p-anisidine (870 mg) and pyridine (443 mg) in dichloromethane (20 ml) was added o-toluoyl chloride (868 mg) at 0° C. Then the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and diluted with ethyl acetate and the solution was washed with water, IN-hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (SiO2 20 g, ethyl acetate:n-hexane=1:2). The eluent was concentrated and triturated with diethyl ether to give N-cyclopentyl-N-[4-(2-methylbenzoylamino)benzoyl]-p-anisidine (750 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:31]1[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1>C(O)C>[OH:31][C@@H:32]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1)[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(NCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNC(=O)c4ccc(C(F)(F)F)cc4)CC3)ccc2s1

Procedure:
To a solution of N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2 g, 0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml, 1.5 mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (0.09 g, 0.42 mmol). The reaction was heated to 85 degrees for four hours. The mixture was then concentrated in vacuo and purified using preparative thin layer chromatography (10:1 DCM:MeOH) to yield N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=523.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10](N)[CH2:11][NH2:12].[Cl-].[Na+]>C(Cl)(Cl)Cl.O>[NH:9]1[CH2:10][CH2:11][N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: N#Cc1cnc(N)cn1
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1cnc(C2=NCCN2)cn1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
A mixture of 2-amino-5-cyanopyrazine (500.0 mg, 4.163 mmol), ethylenediamine (3.0 mL, 44.88 mmol), and phosphorous pentasulfide (185.1 mg, 0.416 mmol) was placed in a sealed tube and heated at 120° C. for 3 h. At this time, the reaction was poured onto ice. The resulting reaction mixture was diluted with chloroform (50 mL), water (10 mL), and a saturated aqueous sodium chloride solution (20 mL). The layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 5-(4,5-dihydro-1H-imidazol-2-yl)-pyrazin-2-ylamine (327.0 mg, 48.1%) as a white solid which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:26][CH3:27])[C:7]([O:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:9]2[N:8]=[C:7]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[C:6]([CH2:26][CH3:27])=[N:5][C:4]=2[C:1](=[O:3])[NH2:2])=[CH:31][CH:30]=1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Oc2ccc(Br)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 88.9 %

Procedure:
A mixture of tert-butyl {3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]phenyl}carbamate (500 mg), 4-bromophenol (440 mg), potassium carbonate (440 mg), and N-methylpyrrolidone (5 mL) was reacted at 100° C. for 4 hours. The reaction mixture was left to be cooled, and then water-saturated brine (1:1) was added thereto, followed by extraction with ethyl acetate. Then, the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-95:5, hexane:ethyl acetate=7:3-3:7) to obtain tert-butyl (3-{[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (599 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[OH:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCOC.O.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>[CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([C:42]5[CH:41]=[CH:40][CH:39]=[C:38]([OH:37])[CH:43]=5)[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(I)c4)C(=O)O3)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCOC
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(-c5cccc(O)c5)c4)C(=O)O3)ccc2O1
Yield: 45.9 %

Procedure:
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{[(3-iodophenyl)methyl]oxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (300 mg), 3-hydroxyphenylboronic acid (102 mg), tripotassium phosphate (417 mg) and dichlorobis(triphenylphosphine)palladium(II) (100 mg) in dimethoxymethane (10 ml) under nitrogen was heated under reflux for 4 h. The mixture was cooled to 20° and diluted with water (50 ml). The mixture was extracted with EtOAc (2×25 ml) and the combined extracts washed with water (50 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with diethyl ether gave the title compound (130 mg). LCMS RT=3.74 min, ES+ve 593 (MNH4)+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCNC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2 over 0.5 h. The reaction was stirred for 16 h and the volatiles were removed in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound of Step A(4.43 g).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)C.[OH-].[Na+]>O1CCOCC1.CO>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH:13]1[C:14]2[C:19](=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:20][CH2:21][CH:12]1[N:7]1[CH:8]=[CH:9][CH:10]=[N:11][CH:6]1[CH2:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)CC1N=CC=CN1C1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCC2N2C=CC=NC2CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.1 %

Procedure:
To a solution of 1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-acetic acid ethyl ester (1.4 g, 2.75 mmol) in a mixture dioxane/MeOH (4/3) (35 ml) was added dropwise 2M NaOH(aq) (24 ml). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was then concentrated in vacuo, combined with water and AcOEt. The aqueous phase was acidified until pH 1 with 2N HCl, extracted three times with with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled product (1.23 g, 93%) as yellow-green crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:21]1[CH2:20][C:19]2[C:18]3[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:9]([CH3:30])[CH3:8])[CH2:15][CH2:14]4)=[N:29][CH:28]=[N:27][C:26]=3[S:25][C:24]=2[CH2:23][CH2:22]1)(=[O:34])=[O:33]
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CNCC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CN(S(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (30 mg, 0.09 mmol, 1.00 equiv) in 5 mL of anhydrous dichloromethane was added TEA (40 mg, 0.40 mmol, 4.38 equiv) and MsCl (14 mg, 0.12 mmol, 1.36 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (16% CH3CN increasing to 23% in 10 min, up to 100% in 2 min, down to 16% in 2 min); flow rate: 20 mL/min; UV Detection at 254/220 nm. This resulted in 8.0 mg (22%) of 4-([12-methanesulfonyl-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy)-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES): m/z 411 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.59-1.71 (m, 4H), 2.05-2.10 (d, 2H, J=15 Hz), 2.34-2.50 (m, 9H), 2.98 (s, 3H), 3.08 (t, 2H, J=5.7 Hz), 3.06 (t, 2H, J=5.7 Hz), 4.67 (t, 2H, J=1.8 Hz), 5.26 (m, 1H), 8.53 (s, 1H).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].N1C=CC=CC=1>ClCCl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:10][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])[CH:19]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Troc-Cl (0.76 ml, 5.56 mmol) in dry dichloromethane (10 mL) was added dropwise to 2-amino-4,5-dimethoxybenzoic acid 102 (1 g, 5.1 mmol) and pyridine (0.82 ml, 10.1 mmol) in dry dichloromethane (20 ml) at 0° C. The reaction mixture was allowed to stir overnight at room temperature and then washed with dilute HCl (1N, 2×25 ml), water (2×25 ml) and brine (20 ml). The organic phase was dried over MgSO4 and evaporated to yield of crude product (1.6 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].CCCC(C)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Trans-(4-Formyl-cyclohexyl)carbamic acid tert-butyl ester (3.27 g, 14.38 mmol) and aniline (1.98 mL, 15.81 mmol) are dissolved in dichloromethane (60 mL) at room temperature. Sodium triacetoxyborohydride (4.57 g, 21.57 mmol) is added in one portion and the mixture is stirred at room temperature for 2.5 hours. 1N sodium hydroxide solution (20 mL) is added and the mixture is stirred at room temperature for a further 10 minutes. The DCM layer is separated and washed successively with water and saturated brine, dried (MgSO4), filtered and evaporated to give a colourless solid. This is slurried with iso-hexane, filtered and dried to give a colourless solid; [MH+305]
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35](OCC)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)=[CH:21][CH:20]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:83]2[CH:87]=[N:86][C:85]([O:88][CH2:89][CH2:90][O:91][C:92]3[CH:93]=[C:94]([CH2:98][NH2:99])[CH:95]=[CH:96][CH:97]=3)=[N:84]2)C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35]([NH:99][CH2:98][C:94]4[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH2:90][CH2:89][O:88][C:85]5[N:86]=[CH:87][NH:83][N:84]=5)[CH:93]=4)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(OC)cc3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: COc1ccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-methoxyphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 80 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (123.6 mg, 50%).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3,4-dichloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=265 (M+).