Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N+:30]([CH3:34])[C:29]=2[CH:35]=1.C(N(CC)CC)C>CN(C)C=O>[I-:1].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]=[C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=4)[N:10]([CH3:14])[C:9]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8]3)=[N+:30]([CH3:34])[C:29]=2[CH:35]=1
Reactant: Cc1sc2ccc(F)cc2[n+]1C
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=Cc1sc3ccc(F)cc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 436 mg (1.41 mmol) 5-fluoro-2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 3.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]([O:13][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(O)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxyacetate (2.5 g, 9.43 mmol, 1.0 eq), DMAP (115 mg, 0.94 mmol, 0.1 eq) in dichloromethane (30 mL) was added TBDMSCl (2.85 g, 18.91 mmol, 2.0 eq) and triethylamine (5.0 mL, 35.97 mmol, 3.8 eq) at 0° C. After addition, the ice-water bath is removed and the mixture is allowed to reach room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=50:1) to produce ethyl 2-(5-bromothiophen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate (2.5 g, 69.9%). 1H NMR (400 MHz, DMSO-d6): δ 0.03 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.16 (t, J=7.0 Hz, 3H), 4.09-4.15 (m, 2H), 5.56 (d, J=0.8 Hz, 1H), 6.91-6.92 (m, 1H), 7.08 (d, J=4.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>N1C=CC=CC=1>[CH3:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of 3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (38 mg, 0.10 mmol, prepared in Example 13) in pyridine (2 ml) was added methanesulfonyl chloride (18.5 mg, 0.16 mmol, 1.6 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (43 mg, 86%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=O)[N:2]=1.ClC(OCC)=O.[CH3:23][NH2:24]>O1CCCC1.C(N(CC)CC)C>[CH3:23][NH:24][C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:16]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5 g of β-carbolin-3-carboxylic acid in a mixture of 900 ml of tetrahydrofuran and 3.6 ml of triethylamine is boiled under reflux for 15 minutes and cooled to room temperature. Freshly distilled ethyl chloroformate (2.5 ml), dissolved in 100 ml of tetrahydrofuran, is added dropwise with stirring over a period of 11/2 hours. After the reaction mixture has been stirred for an additional 30 minutes, a large excess of methylamine is added. Stirring is continued for one hour, whereafter the mixture is filtered and concentrated to approximately 50 ml under reduced pressure. Addition of water (250 ml) causes the amide to precipitate. The mixture is left at 5° C. overnight, filtered and dried at 60° C. for 15 hours. β-carbolin-3-carboxylic acid methylamide thus formed (4.1 g; 77%) is recrystallized from toluene. The melting point is 275° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(C(F)(F)F)cc12
Product: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
Preparation D3, Step 3: A suspension of 6-(trifluoromethyl)quinazolin-4-ol (10.41 g, 48.4 mmol) in phosphorous oxychloride (100 mL) was heated at reflux for 3 h, during which time a clear, amber solution was observed. The solution was cooled to room temperature, concentrated in-vacuo, and stripped 3× from 150 mL methylene chloride to remove any remaining phosphorous oxychloride. The residue was partitioned between EtOAc and saturated sodium bicarbonate (1:1, 300 mL), and the mixture was stirred until gas evolution ceased. The layers were separated, the organic phase was washed successively with saturated sodium bicarbonate and brine, the combined aqueous phases were extracted with EtOAc (50 mL), and the combined organic phases were dried over sodium sulfate then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25% EtOAc/Heptane, to yield 8.14 g of 4-chloro-6-(trifluoromethyl)quinazoline as a white solid. MS (ES+)=233, 235 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOC(C)=O.CCCCCC>[C:26]1([C:4]2[CH:3]=[C:2]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:25])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: OB(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccccc2)cc1C1=CCCCC1
Yield: 85 %

Procedure:
The title compound was prepared by the procedure of Example 28, step (a) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 19 mg, 0.038 mmol), and phenylboronic acid (5.1 mg, 0.042 mmol). Silica gel chromatography (5-10% EtOAc/hexane) afforded the title compound (16 mg, 85%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.5 Hz), 7.78 (s, 1H), 7.59 (m, 2H), 7.52 (dd, 1H, J=8.5, 2.1 Hz), 7.44 (m, 2H), 7.41 (d, 1H, J=2.1 Hz), 7.33 (m, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.67 (t, 2H, J=8.3 Hz), 2.26-2.36 (m, 4H), 1.75-1.93 (m, 4H), 0.98 (t, 2H, J=8.3 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H34N4O2Si, 499.3 (M+H), found 498.8.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>O1CCCC1>[C:3]([C:5]1[CH:27]=[CH:26][C:8]2[O:9][C:10]([CH3:25])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2oc(C)c(Cc3ccc(-c4ccccc4)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1
Yield: 54 %

Procedure:
5-(Methoxycarbonyl)-2-methyl-3-(4-phenylbenzyl)benzo[b]furan (1.31 g) was refluxed for 1 hr in a mixed solution of a 10% aqueous solution (10 ml) of sodium hydroxide, methanol (10 ml) and tetrahydrofuran (10 ml). The reaction mixture was concentrated and concentrated hydrochloric acid was added to acidify the solution. The precipitated solid was collected by filtration, washed with water and diisopropyl ether and dried to give the objective compound (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([Si](C)(C)C)[N:15]=[N:14]1.[I:22]I>O1CCCC1.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([I:22])[N:15]=[N:14]1
Reactant: II
Reactant: C[Si](C)(C)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc(I)nn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trimethylsilyl-1,2,3-triazole (EP-400842-A1; 1.00 g) in tetrahydrofuran (20 ml) was added silver trifluoroacetate (623 mg) and iodine (716 mg) at -78° C. under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature over 1 hour and then left to stir for a further 16 hours. The reaction was filtered and the filtrate diluted with water (100 ml) and extracted with ether (100 ml), the organic fraction was separarted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica, 100 g) eluted with dichloromethane:hexane (2:1) to give the title compound as a pale yellow crystalline material, m.p. 194-195° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[CH3:26][O:25][C:23]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)=[O:24]
Reactant: COC(=O)Cl
Reactant: CSc1cccc(C2=CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC=C(c2cccc(SC)c2)CC1
Temperature: 0 °C

Procedure:
4-(3-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-pyridine (2 g) and NEt3 (1 g) were dissolved in CH2Cl2 (75 ml) and cooled to 0° C. Methyl chloroformate (0.96 g) dissolved in CH2Cl2 (20 ml) was added dropwise and the reaction mixture was then allowed to reach room temperature. After an additional two hours at room temperature the reaction mixture was washed with 10% Na2CO3 solution, dried (MgSO4), filtered and concentrated by evaporation. The oily residue was chromatographed on a silica column using CH2Cl2:MeOH (19:1 (v/v)) as eluent, 4-(3-methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+45), 248 (89), 129 (83), 128 (bp), 59 (96).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])C#N>C1COCC1>[F:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)Oc1ccc(C#N)cc1F
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)c(F)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (1595 μl, 2.71 mmol) and the solution was stirred for 0.5 h before addition of 3-fluoro-4-isopropoxybenzonitrile (405 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected washing with water to give 3-(3-fluoro-4-isopropoxyphenyl)-6-methoxyisoquinolin-1-ol (520 mg, 70% yield) as a solid after drying. MS: MS m/z 328.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:13].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-3-nitropicolinonitrile (6.84 g, 30 mmol) in dimethylsulfoxide was cooled to −25° C. and treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (60 mL, 60 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. It was quenched with water and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to provide crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CS(O[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])(=O)=O.C([O-])(O)=O.[Na+].O>C(#N)C>[CH2:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)[CH2:17][CH2:16][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: CCCC(CCC)OS(C)(=O)=O
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCNc1ccc(F)c(C)c1
Yield: 349.5 %

Procedure:
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes:ethyl acetate, to give 2.56 g (35%) of a pale yellow oil.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15]([O:19][CH2:20][CH3:21])=[CH:16][CH:17]=[O:18])[CH2:6]1)(=O)C.C(=O)(O)[O-].[K+].O>C(O)C>[CH2:20]([O:19][C:15]([C@@H:14]1[C@:22]2([CH3:31])[C@H:11]([C@H:10]3[C@H:25]([C:24](=[O:30])[CH2:23]2)[C@:26]2([CH3:29])[C@H:7]([CH2:6][C@H:5]([OH:4])[CH2:28][CH2:27]2)[CH2:8][CH2:9]3)[CH2:12][CH2:13]1)=[CH:16][CH:17]=[O:18])[CH3:21]
Reactant: CCOC(=CC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=CC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 34.1 %

Procedure:
A solution of 3α-acetoxy-20-ethoxy-21-formyl-5α-pregn-20-en-11-one (500 mg) in ethyl alcohol (15 ml) was treated with potassium bicarbonate (450 mg) and the mixture was refluxed, under nitrogen, for 7 hours, then poured into water. The product was extracted with methylene chloride, and the extract washed with water, dried and evaporated. Purification of the residue (37 mg) by preparative t.l.c. and crystallisation from methyl acetate/petrol gave title compound (154 mg) m.p. 175°-178°, [α]D - 115.9°, λmax. 258 nm (ε 18,780).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:13]([NH2:23])=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[N:1]1([C:10]2[N:15]=[C:14]3[C:13]([NH:23][C:35](=[O:36])[N:16]3[CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(-c3ccccc3)nc(-n3cnc4ccccc43)nc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To 30 mg (0.078 mmol) of crude 2-(1H-benzo[d]imidazol-1-yl)-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine in 3 mL THF was added CDI (38 mg, 0.233 mmol, 3 equiv.) and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed in vacuo and the residue purified by preparative TLC (silica gel, 5% methanol in methylene chloride) to afford the desired product (9.5 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ, ppm: 9.16 (br s, 1H), 8.68 (d, 1H), 8.06 (br m, 2H), 7.90 (d, 1H), 7.71-7.62 (m, 3H), 7.52-7.33 (m, 3H), 4.82-4.68 (m, 1H), 4.31-4.20 (m, 2H), 3.64 (app t, 2H), 3.01-2.82 (m, 2H), 1.89 (br d, 2H); MS (EI) m/z 413.2 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[OH:14][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O

Procedure:
Tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) and copper(I)iodide (0.095 g, 0.5 mmol) were, added to a solution of ethyl 5-ethynyl-2-hydroxybenzoate (10.5 g, 55 mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol) in tetrahydrofuran (75 ml) and triethylamine (75 ml) at 55° C. After 2 h the solid product was collected with filtration and washed with hydrochloric acid (1M). The material was boiled in formic acid (300 ml) for 15 nun. and filtered. Water (200 ml) was added and the product crystallized upon cooling. Yield 17.3 g (79%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([N:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[C@H:20]([O:35][CH3:36])[CH2:19]2)=[N:9][CH:8]=1>N1C=CC=CC=1>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][N:18]([C:10]2[CH:11]=[C:12]([C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][N:9]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][C@H:20]1[O:35][CH3:36])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Methanesulfonyl chloride (16 μl, 21 mmol) was added to 66 mg (0.14 mmol) of Cis(±)-ethyl 5-amino-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 194) in 3 ml pyridine. After stirring for 1 h, 5 μl more methanesulfonyl chloride was added. Stirred at room temperature overnight. Solvent was removed, and the residue was partitioned between EtOAc and Na2CO3 (aqueous). The EtOAc was separated and washed with water and brine. Drying (MgSO4) and removal of solvent gave 63 mg of product. MS (ES)(MH+): 534 for C21H27Cl2N5O6S, NMR (d6-DMSO): 1.4 (t, 3H), 1.8 (m, 2H) 2.2 (s, 3H), 2.9 (s, 3H), 3.1-3.2 (m, 2H), 3.3-3.5 (m), 3.6 (m, 1H), 4.2-4.3 (m, 2H), 4.4 (q, 2H), 4.7 (m, 1H), 7.1 (s, 1H), 7.2 (d, 1H), 8.2 (s, 1H), 12.2 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[CH2:19][CH3:20]>>[CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)Oc1ccc(CO)cc1
Reactant: CCCBr
Product: CCCOCc1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By the process described in Example 1, p-[(1,5-dimethyl-hexyl)-oxy]-benzyl alcohol is reacted with propyl bromide to give p-[(1,5-dimethyl-hexyl)-oxy]-α-propoxy-toluene (boiling point = 198°- 200°C/1.0 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:28])[CH:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([NH2:46])=[O:45]>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:28])[C@@H:23]5[CH2:27][CH2:26][N:25]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:24]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@@H]1CCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-pyrrolidin-3-yl-amino)-thiazol-4-one (90 mg, 0.17 mmol) in DMF (2 mL) was added potassium carbonate (72 mg, 0.52 mmol) followed by 2-Bromo-acetamide (28 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (80 mg, 80%).
Reaction SMILES: C1(C[O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([O:35][C:12]1[CH:11]=[C:10]([C:9]([OH:8])=[O:36])[CH:15]=[C:14]([O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OC(C)=O)cc(C(=O)O)c1
Yield: 115.2 %

Procedure:
To a stirred and ice bath cooled solution of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy) benzoic acid phenylmethyl ester in 7.5 ml of methylene chloride and 2.8 ml (0.02 mol) of triethylamine was added 0.86 ml (0.012 mol) of acetyl chloride. The reaction mixture was stirred in an ice bath for 1 hour, at room temperature for 2 hours and then was washed with 1N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to a solid. Trituration with methanol and filtration gave 5.17 g (96% yield, mp 55°-56°) of 3-acetyloxy-5-(octadecyloxy)benzenecarboxylic acid.