Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:27](=O)[CH3:28])[CH:24]=[CH:25][CH:26]=1.C(O)C.[Si](Cl)(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(=CC(=O)c1cccc(Br)c1)c1cccc(Br)c1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2cc(-c3cccc(Br)c3)cc(-c3cccc(Br)c3)c2)c1

Procedure:
1,3-bis(3-bromophenyl)but-2-en-1-one (6.15 g, 16.2 mmol) and m-chloroacetophenone (2.50 g, 16.2 mmol) were added to a 100 mL of three neck round bottom flask. To this flask, dry ethanol (40 mL) was added. The mixture was stirred vigorously, and then silicon tetrachloride (7 ml, 56 mmol) was added slowly. The mixture turned red and stirred 12 hours at room temperature. Then water (10 ml×2) was added and stirred for 20 minutes. Then filter the solution to get grey solid. Washed the solid with NaOH solution (10%), water and acetone separately. Dried the crude product and dissolved in THF (3 ml), then added the THF solution to methanol (100 ml) under stirring vigorously. Get the precipitation by filtration, and then recrystallize the crude product from ethanol and dichloromethane, the fine 1,3-Bis(3-bromophenyl)-5-(3-chlorophenyl)benzene will be obtained. Yield is 3.23 g (C24H15Br2Cl), 40%. 1H NMR (δ, CDCl3) 7.84 (m, 2H), 7.74 (m, 3H), 7.69 (s, 1H), 7.63-7.55 (m, 5H), 7.46-7.36 (m, 4H).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CO>[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:17]=1[C:18]1[O:19][CH:2]=[N:1][C:3]=1[CH3:4]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1F
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1 0.0 g, 47.8 mmol), 2,3-difluoro-4-(trifluoromethyl)benzaldehyde (9.68 g, 46.1 mmol), and K2CO3 (13.1 g, 95.0 mmol) in MeOH (240 mL) was heated to reflux. After 2 hr, the reaction mixture was cooled to ambient temperature, water (700 mL) was added, and the product was extracted with EtOAc (700 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. The crude product was purified by chromatography on silica gel in five batches (Analogix® SF40-240G column, 100% CH2Cl2, 65 mL/min) to afford 7.22 g (60%) of the title compound as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.78-7.69 (m, 1H), 7.68-7.59 (m, 1H), 2.30 (d, J=2.5, 3H). MS (DCI+) m/z 264 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[N:41]1.C(=O)([O-])O.[Na+].O>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
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: O
Solvent: COCCOC
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of ((2S,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 mmol; 1.1 g), 3,5-bis(trifluoromethyl)benzyl bromide (4.3 mmol; 0.78 mL) and sodium hydride (60% dispersion in mineral oil, 4.3 mmol; 0.17 g) in DMF (9 mL) is stirred for 1 hour at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is passed though silica pad (eluent: n-hexane/EtOAc) to give (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a mixture of (2S,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.1 mmol, 1.48 g), tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 490 mg) and 2M aqueous sodium hydrogen carbonate (3.6 mL) in 1,2-dimethoxy-ethane (4 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2, and the combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 74% overall yield for 2 steps); ESI-MS m/z: 615 [M+1]+, Retention time 2.12 min (condition A).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and piperidine (0.14 mL, 1.42 mmol) in THF (20 mL) was stirred at room temperature for 4 hrs. 1,4-Dioxane (20 mL) was added and the mixture was refluxed for 18 hrs. After cooled to room temperature, the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (147 mg, 84%).
Reaction SMILES: COC(=O)/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH2:15][O:16][C:17]([CH3:19])=[O:18]>>[CH2:15]([O:16][C:17]([C@@H:19]1[CH2:4][C@@H:5]1[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:18])[CH3:14]
Reactant: CCOC(C)=O
Reactant: COC(=O)/C=C\c1ccc(Br)cc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 1, but using Z-3-(4-Bromo-phenyl)-acrylic acid methyl ester from Step 1 as starting material Flash chromatography (Hex:EtOAc 85:15) afforded the title compound as a oil.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:13]3[CH:12]=[C:11]4[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=[C:10]4[C:29]#[N:30])=[CH:15][CH:14]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Oc3ccc4c(c3)OCO4)cc12

Procedure:
Prepared in analogy to example 31h from 7-(benzo[1,3]dioxol-5-yloxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 406 (M−H)−.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH:20]([O:22][CH2:23][CH3:24])=[CH2:21]>CCOCC>[CH2:20]([O:22][CH:23]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[CH3:24])[CH3:21]
Reactant: OCCCCCCBr
Reactant: C=COCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: CCOC(C)OCCCCCCBr
Reaction time: 1 h

Procedure:
To a cooled solution of 80 mg of toluenesulfonic acid in 40 ml of ether was fed 20 g (110 mmol) of 6-bromohexanol and 40 ml of ethyl vinyl ether simultaneously by separate additional funnels. The temperature of the reaction mixture was kept at 7° C. or lower during the feeds, which took 1 hour. The reaction mixture was stirred 20 minutes longer, then roughly 1 ml of triethylamine was added. The reaction mixture was washed with water and brine, dried over potassium carbonate, filtered and stripped to give 25.7 g of a pale yellow liquid, which was used without further purification.
Reaction SMILES: O[NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])#[CH:16].CCCCCC>C(O)C>[CH2:20]([O:19][C:17]([C:15]1[N:2]=[C:3]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)[NH:14][CH:16]=1)=[O:18])[CH3:21]
Reactant: C#CC(=O)OCC
Reactant: N=C(NO)c1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 26 h
Yield: 44.1 %

Procedure:
To a solution of N-hydroxy-4-(trifluoromethyl)benzamidine (3.0 g) in ethanol (30 ml) was added ethyl acetylenecarboxylate (1.44 g), and stirred at 80° C. for 26 hours. After the solvent was evaporated, diphenylether (15 ml) was added thereto, and additionally stirred at 180° C. for 5.5 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, and n-hexane was added thereto. The insoluble matter was collected by filtration, washed with n-hexane, and then dried to give 2-[4-(trifluoromethyl)phenyl]-1H-imidazole-4-carboxylic acid ethyl ester (1.84 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([F:12])[CH:8]=[C:7]([OH:13])[C:6]=2[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([O:13][CH3:17])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][CH2:15][OH:16])=[CH:4]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCn1cc(CCO)c2c(O)cc(F)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1cc(CCO)c2c(OC)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
39-2 (318 mg, 1.43 mmol) was dissolved in DMF (5 mL) and then potassium carbonate (236 mg, 1.71 mmol) and methyl iodide (98 uL, 1.56 mmol) were added. The reaction mixture was stirred at room temperature overnight, concentrated under vacuum and then water added. A solid was filtered to afford 39-3 (313 mg, 90%) as a light purple solid. LCMS: calc 326.2. found 327.1 [MH]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5-parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 153.6° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+](C1OC(C=O)=CC=1)([O-])=O.N(C1SC2C=C([C:42]([F:45])([F:44])[F:43])C=CC=2N=1)N>>[F:43][C:42]([F:45])([F:44])[C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2s1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Agent: O=Cc1ccc([N+](=O)[O-])o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(C(F)(F)F)cc3s2)o1

Procedure:
The compound 3g was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (141 mg, 1 mmol) and 2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C. for 2 h (yield 302 mg, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:22])[CH2:20]Br>CN(C)C=O>[CH3:17][N:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:22])[CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CN(C(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 67.5 °C
Reaction time: 3 h

Procedure:
2-Nitrophenol S7 (2.8 g), anhydrous potassium carbonate (4.1 g), and N-methyl-N-phenyl-2-bromoacetamide (4.5 g) were suspended in N,N-dimethylformamide (50 ml), and the resulting suspension was stirred at 65-70° C. for 3 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off, obtaining 5.4 g of the compound S8.
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].C(Cl)(=O)C.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(#N)C>[CH3:3][N:2]([CH3:4])[CH2:1][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]
Reactant: COc1cccc(C(C)=O)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: COc1cccc(C(=O)CCN(C)C)c1
Reaction time: 20.5 h
Yield: 93 %

Procedure:
The Eschenmoser salt was produced by reacting 232 g (2.27 mol, 1 equivalent) tetramethyl diaminomethane with 187 g (2.14 mol, 0.95 equivalent) acetyl chloride in 1200 ml acetonitrile. 328 g (2.17 mol, 0.96 equivalent) 3-methoxyacetophenone were then added within 115 minutes at a temperature of from +3° C. to +11° C. and then stirred at from +20° C. to +25° C. for 20 to 21 hours. The resulting hydrochloride salt of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was filtered out. The residue was suspended in 1600 ml water and 190 ml sodium hydroxide solution (36% by weight) (pH 11-12) and extracted with 1000 ml ethyl acetate. The organic phase was separated off and dried over 50 g sodium sulfate. Once the organic solvent had been evaporated, the free base of the 3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one (II) was obtained as a colorless oil (93% yield, 96% purity ascertained by HPLC).
Reaction SMILES: [CH:1]([N:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][C:4]1(C(OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:2].[Cl-].[Na+].O>CS(C)=O>[CH:1]([N:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:2]
Reactant: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)(C(=O)OCC)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)C1
Temperature: 165 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 5 g of the product of Step B, 0.8 g of sodium chloride, 0.26 g of water and 15 ml of dimethylsulfoxide was stirred for 3 hours at 165° C. and the mixture was returned to ambient temperature followed by filtering, washing and evaporating to dryness to obtain 4 g of product which was purified on silica eluting with a cyclohexane-ethyl acetate (9-1) mixture, then by a cyclohexane-ethyl acetate (7-3) mixture to obtain 3.1 g of the desired product with a Rf=0.5.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]1)(=O)=O.[OH:76][C:77]1[CH:84]=[C:83]([O:85][CH3:86])[CH:82]=[CH:81][C:78]=1[CH:79]=[O:80].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:86][O:85][C:83]1[CH:82]=[CH:81][C:78]([CH:79]=[O:80])=[C:77]([O:76][CH2:5][CH:6]2[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]2)[CH:84]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2cc(OC)ccc2C=O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol), 2-hydroxy-4-methoxybenzaldehyde (16.9 g, 0.11 mol) and potassium carbonate (25.6 g, 0.18 mol) were suspended in DMF (700 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (700 ml), washed twice with 0.5N hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with pure water (300 ml). The solvent was evaporated, and the residue was precipitated with methanol (700 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (73.56 g, 69.8 mmol, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(CCc2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(CCc4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a stirred solution of methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoate (70 mg, 0.13 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at room temperature overnight and then treated with conc. HCl until pH=3-4. The solvent was removed under reduced pressure, the residue was triturated with H2O (3×10 mL) and ethyl acetate (3×10 mL) then dried to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoic acid (35 mg, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.39 (s, 1H), 8.32-8.24 (m, 2H), 7.89-7.84 (m, 3H), 7.52-7.40 (m, 5H), 7.03 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.79 (s, 3H), 3.37 (brs, 4H). LC-MS: 513 [M+H]+, tR=1.67 min. HPLC: 97.30% at 214 nm, 97.09% at 254 nm, tR=5.16 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[IH:12].CS[C:15]1[NH:16][CH2:17][CH2:18][N:19]=1.CS.C(OCC)C>N1C=CC=CC=1>[IH:12].[NH:16]1[CH2:17][CH2:18][NH:19][C:15]1=[N:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: CSC1=NCCN1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: CS
Agent: I
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=c1[nH]c2ccc(N=C3NCCN3)cc2o1

Procedure:
13 g (86.7 millimols) of the compound obtained in step 3 and 22.2 g of 2-methylthio-2-imidazoline hydroiodide are heated to the reflux temperature in 100 cc of pyridine. The reflux is maintained until the evolution of methanethiol has ceased (about 2-3 hours). When the reaction has ended, the cooled mixture is poured into 1.5 liters of diethyl ether. The gummy residue is washed 3 times with 300 cc of diethyl ether and taken up in 100 cc of ethanol. The product is filtered off and recrystallised from methanol. Its melting point is 270°-272° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCc2c(O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2=O
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of 3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (8.20 g, 50.6 mmol) in N,N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in liquid paraffin, 2.22 g, 55.6 mmol) at 0° C. and the mixture was stirred at that temperature for 10 minutes. Then, ethyl bromoacetate (9.29 g, 55.6 mmol) was added and the mixture was further stirred at room temperature for 30 minutes. This reaction mixture was poured in water (80 mL) and extracted with 2 portions of ethyl acetate. The organic layers were pooled, washed with water, dried over anhydrous magnesium sulfate (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane-diisopropyl ether to provide 8.40 g of the title compound. Yield 67%.