Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][NH:11][CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:12]([NH:11][CH2:10][CH:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:8])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C(NCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 85.7 %

Procedure:
A mixture of N-[2-(t-butyl-dimethylsilyloxy)-2-phenylethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine (4.95 g) [prepared as described in step (a) above] and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 20 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the ethyl acetate was washed with water and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by chromatography through a silica gel column using a 3:1 by volume mixture of cyclohexane and ethyl acetate as the eluant, to afford the title compound (3.26 g) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3([CH3:36])[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:19][CH:18]2[CH3:37])[CH2:5]1.[CH3:38]I>O1CCCC1>[CH3:38][O:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[CH:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3([CH3:36])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH2:19][C@@H:18]2[CH3:37])[CH2:5]1
Reactant: CI
Reactant: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(O)c2cc(C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(N2CCN(C3(C)CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a suspension of sodium hydride (150 mg, 3.75 mmol) in tetrahydrofuran (15 mL) was added a solution of tert-butyl 4-{4-[3-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (92 mg, 0.185 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 1 h before methyl iodide (0.50 mL, 8.05 mmol) was added. The reaction was continuously stirred at room temperature overnight and quenched by addition of 10 mL of water and 10 mL of EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice (2×15 mL). The combined extracts were washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude product (81 mg, 85%) which was used directly for the next step. LC-MS [M+1]=511.3.
Reaction SMILES: C([O:8][C:9](=[O:21])[NH:10][C:11]1C=CC2OCC[O:18][C:13]=2[CH:12]=1)C1C=CC=CC=1.[Li][CH2:23]CCC.[C:27]([O:32][CH2:33][C@H:34]1[O:36][CH2:35]1)(=O)[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CC(=O)OCC>[O:32]1[C:27]2[CH:28]=[CH:29][C:30]([N:10]3[CH2:11][C@@H:12]([CH2:13][OH:18])[O:8][C:9]3=[O:21])=[CH:23][C:35]=2[O:36][CH2:34][CH2:33]1
Reactant: [Li]CCCC
Reactant: CCCC(=O)OC[C@@H]1CO1
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (13.0 g, 45.6 mmol) in THF (220 mL) was cooled to −78° C. before the drop wise addition of n-BuLi (29.5 mL of a 2.36M solution in hexanes, 1.1 eq). The mixture was stirred at −78° C. for 1 h and then warmed to −15° C. At this temperature (S)-glycidyl butyrate (7.37 g, 1.1 eq) was added dropwise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with a sat. aq. NH4Cl and water. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hex/EA 2:1, 1:1) to afford the title intermediate as a grey solid (7.04 g, 62% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH2:36][C:37]#[N:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].CCOC(C)=O>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@:31]([CH2:36][C:37]#[N:38])([OH:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](O)(CC#N)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 2-((1S,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanenitrile, 69b, (0.14 g, 0.26 mmol) in methanol (10 mL) was added sodium methoxide (0.06 g, 0.26 mmol). After stirring at room temperature for 2 minutes, the reaction mixture was diluted into EtOAc and brine. The separated organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford 46 mg of desired product: 1H NMR (300.0 MHz, MeOD) δ 8.65 (dd, J=2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, J=2.0, 2.5 Hz, 1H), 7.98 (d, J=4.1 Hz, 1H), 4.66 (dd, J=8.0, 15.8 Hz, 1H), 2.64 (s, 2H), 2.20 (d, J=12.6 Hz, 2H), 2.01 (dd, J=3.4, 9.8 Hz, 2H), 1.84-1.75 (m, 1H), 1.63-1.47 (m, 2H), 1.33 (dd, J=3.6, 12.4 Hz, 1H) ppm; LCMS RT=2.31 (M+H) 385.45.
Reaction SMILES: [C:1]([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=O)[CH3:2].[Br:13]CCO>>[Br:13][CH2:2][CH2:1][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12
Reactant: OCCBr
Reactant: CC(=O)Sc1ncn2ccsc12
Product: BrCCSc1ncn2ccsc12

Procedure:
The procedure of Synthesis Example 11b) was repeated, except that 990 mg of 7-acetylthioimidazo[5,1-b]thiazole and 0.461 ml of 2-bromo ethanol were used as the starting compounds. Thus, 1.06 g of 7-(2-bromoethyl)thioimidazo[5,1-b]thiazole was prepared.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([BH3-])#N.[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH:15]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[CH:30]=[C:21]([O:20][CH3:19])[CH:22]=[C:23]5[C:28]=4[N:27]=[CH:26][CH:25]=[CH:24]5)[CH2:32][CH2:33]3)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2c(F)ccc3cccnc23)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(C3CCN(c4c(F)ccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(7-fluoroquinolin-8-yl)piperidin-4-one (Step 3, 0.26 g) and 6-methyoxy-8-(1-piperazinyl)quinoline (Example A, Step 4; 0.26 g) in anhydrous methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting mixture was stirred at room temperature under nitrogen for 18 hours. An additional aliquot of sodium cyanoborohydride (0.11 g) was added and stirring at room temperature was continued for another 24 hours. The resulting reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/acetone to give the desired product, which was converted to its trihydrochloride salt in CH2Cl2 using 1M HCl/Et2O to provide 0.12 g of a yellow solid; MS (ES) m/z (relative intensity): 472 (M+H)+ (100).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes propionylchloride (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine (0.18 g, yield: 56%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:3])[C:4]#[CH:5]
Reactant: Oc1ccc2ncccc2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Cu]
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and trifluoroacetic anhydride (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:48])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(SCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[[1-[3-methoxy4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]benzoate (264 mg, 0.482 mmol) in CH2Cl2 (5.2 mL) was added m-CPBA (118.8 mg, 0.482 mmol) at 0° C., and the mixture was stirred at room temp for 1 hr. The mixture was diluted with CHCl3, and quenched with sat. Na2S2O3. The separated organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2 pyrrolidinyl]methylsulfinyl]benzoate as a crude amorphous solid. To a stirred solution of this crude compound in THF (4 mL) and H2O (1mL) was added LiOH (34.6 mg, 1.45 mmol), and the stirring was continued overnight at room temp. The mixture was diluted with CHCl3, washed with 1 N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-CHCl3-MeOH to afford 193.2 mg (73%) 24 as a white crystalline powder. IR (KBr) 3338, 2956, 1708, 1529, 1299, 1207, 1155 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.70–2.06 (m, 4H), 2.24 (s, 3H), 2.90 (dd, J=8.3, 13.2 Hz, 1H), 3.02–3.08 (m, 1H), 3.16–3.25 (m, 1H), 3.41–3.60 (m, 3H), 3.84 (s, 3H), 4.40 (br s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 7.11–7.17 (m, 2H), 7.75–7.81 (m, 3H), 7.98–8.05 (m, 1H), 8.10 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z 550 (M++1), 572 (M++Na); Anal. Calcd for C29H31N3O6S.3/2H2O: C, 60.40; H, 5.94; N. 7.29. Found: C, 60.15; H, 5.82; N, 6.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[O:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([OH:8])=[C:6]([C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(O)c(C(C)=O)cc1Cl
Temperature: 0 °C

Procedure:
Chloro-2,4-dimethoxybenzene (4.94 g, 28.6 mmol) and AlCl3 (4.58 g, 1.2 eq.) were dissolved in 280 ml of CH2Cl2 and cooled down to 0° C. Acetyl chloride (2.03 mL, 1.0 eq.) was slowly added via syringe and the mixture allowed to react for another 3 h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by short flash chromatography (SiO2, hexane/AcOEt=95/5), yielded 4.22 g of the title compound as white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12](C=O)=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:29]1[CH:34]=[CH:33][C:32]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C.[O:53]1CCC[CH2:54]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH:20]([C@@H:54]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[OH:53])[CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[CH:12]=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: FS(F)(F)(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)c1cc(I)c2c(n1)CC1(CC([C@H](O)c3ccc(S(F)(F)(F)(F)F)cc3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 1-iodo-4-pentafluorosulfanyl-benzene. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:56][C@H:57]1[CH2:62][NH:61][C@H:60]([CH3:63])[CH2:59][N:58]1[CH2:64][C:65]1[S:66][C:67]2[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][C:68]=2[N:69]=1>CN(C=O)C.CCOC(C)=O>[CH3:63][C@@H:60]1[CH2:59][N:58]([CH2:64][C:65]2[S:66][C:67]3[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:75])[F:76])=[CH:70][C:68]=3[N:69]=2)[C@@H:57]([CH3:56])[CH2:62][N:61]1[C:19](=[O:21])[CH2:18][O:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:25])[F:23])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: C[C@@H]1CN(Cc2nc3cc(C(F)(F)F)ccc3s2)[C@@H](C)CN1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2nc3cc(C(F)(F)F)ccc3s2)[C@@H](C)CN1C(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of [4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid (172 mg, 0.476 mmol, 2 eq.) in DMF (5 ml) was added EDAC hydrochloride (68 mg, 0.36 mmol, 1.5 eq.), HOBt (55 mg, 0.36 mmol, 1.5 eq.) and 4-methylmorpholine (0.13 ml, 1.2 mmol, 5 eq.). The resulting solution was stirred for 30 min then 2-((2S,5R)-2,5-dimethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzothiazole hydrochloride (87 mg, 0.24 mmol, 1 eq.) was added. The solution was stirred overnight at room temperature and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column with Heptanes—EtOAc to afford 1-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone as a yellow solid (86.1 mg, 53.7%). (CI, m/z): [M+H]+ 674; 1H NMR (400 MHz, CDCl3) δ 1.02-1.53 (m, 10H), 2.18 (br s, 4H), 2.47 (d, J=11.7 Hz, 1H), 2.99 (d, J=8.8 Hz, 1H), 3.23 (br s, 1H), 3.31-3.53 (m, 2H), 3.85-4.13 (m, 4H), 4.20 (br s, 3H), 4.46 (d, J=7.6 Hz, 1H), 6.64 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 8.01 (t, J=8.3 Hz, 2H), 8.21 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26](C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(#N)C.C(N(CC)C(C)C)(C)C.ClC(OC)=O>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-{4-[1-(tert-butoxycarbonyl)cyclopropyl]phenyl}piperazine-1-carboxylate (16.0 mg, 0.0000397 mol) was treated with hydrogen chloride in 1,4-dioxane (4.0 M, 0.20 mL) at rt for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile (1.0 mL, 0.019 mol) and was treated with N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) and methyl chloroformate (5.0 μL, 0.000065 mol). After 30 min, the solvent was evaporated under reduced pressure and the residue was the desired product, which was directly used in the next step without further purification. LC/MS: 361.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH3:18]
Reactant: Cc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(OCC)N(C)C
Product: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-7-methyl-1(2H) naphthalenone was prepared from 7-methyl-1-tetralone (4.8 g, 30 mmol) and N,N-dimethyl-formamide diethyl acetal (15.4 ml, 90 mmol). The crude product was recrystallised from diethyl ether-hexane to give yellow crystals (4.64 g) m.p. 79-82° MS (ES+) 238 (MNa+, 6%), 216 (MH+, 100%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[NH:10]C(=O)C2=O.OO.[CH3:19][OH:20]>>[Cl:14][C:12]1[CH:13]=[C:5]([Cl:4])[CH:6]=[C:7]([C:1]([O:20][CH3:19])=[O:2])[C:11]=1[NH2:10]
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C1=O
Reactant: C[O-]
Reactant: CO
Agent: OO
Agent: [Na+]
Product: COC(=O)c1cc(Cl)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
20 parts of a 30 percent strength by weight solution of sodium methylate in methanol are added to 21.6 parts of 5,7-dichloroisatin in 300 parts of methanol at -10° C., resulting in a dark violet suspension of a bulky precipitate. 7 parts of 50 percent strength by weight hydrogen peroxide solution are then added at -3° C. and thereafter the mixture is stirred for one hour at room temperature. The solution is concentrated and the crystalline residue is mixed with water and filtered off. 17.6 parts (80% of theory) of methyl 3,5-dichloroanthranilate, of melting point 62°-63° C., are obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc2n1C
Yield: 78 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 78% of theory, C26H27N7O4 (501.6) Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =502
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:40][O:41][CH2:42][CH2:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:30])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:46](=[O:47])[CH2:45][O:44][CH2:43][CH2:42][O:41][CH3:40])[CH2:26][CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Reactant: COCCOCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)N1CCC(Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)CC1
Yield: 33.6 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylene chloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 519; melting point 110 to 111° C.