Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([N+:31]([O-])=O)[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([NH2:31])[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)Oc1ccc(N)cc1OC(=O)CCCCCCCCC
Yield: 92.2 %

Procedure:
A mixture of 2.9 g of 3,4-bis[(1-oxodecyl)oxy]nitrobenzene and 0.5 g of 10% palladium on carbon in 50 ml of ethyl acetate and 10 ml of THF was stirred in a hydrogen atmosphere at room temperature for 5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to an oil which was crystallized from ethyl acetate-hexane to give 2.5 g (92% yield, mp 44°-46°) of 3,4-bis[(1-oxodecyl)oxy]benzenamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OCC)[O:26]CC)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:4][CH:3]=1.Cl.ClCCl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25]=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
3-[2-(4-Bromophenyl)ethoxy]-N-(2,2-diethoxyethyl)-N-phenethyl-propanamide (Example 10c) 0.72 g) was dissolved in anhydrous dioxane (15 mL) and treated with concentrated hydrochloric acid (10 mL) and stirred for 1 hour. The reaction mixture was then poured into dichloromethane (15 mL), washed with water (2×30 mL) and brine (30 mL). The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.54 g) as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:12][NH2:13]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:13][CH3:12])=[O:11])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CN
Reactant: Nc1cc(Br)cnc1C(=O)O
Solvent: CN(C)C=O
Product: CNC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-Amino-5-bromopyridine-2-carboxylic acid (500 mg, 2.30 mmol) and N′,N-carbonyldiimidazole (410 mg, 2.53 mmol) were stirred in DMF (5 mL) at 40° C. for 2 hours. After cooled to room temperature, methylamine (2.0 M in THF, 2.3 mL) was added thereto and further stirred at room temperature for 1 hour. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1 to 4/1) to obtain the intended compound (4.99 g, 94%) as a milky white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH2:3][C:4]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6])#[N:2]
Reactant: NCc1ccccn1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: N#CCC(=O)NCc1ccccn1
Reaction time: 5 h

Procedure:
To a solution of 6.8 g of cyanoacetic acid in 200 ml of acetonitrile was added a solution of 8.65 g of 2-aminomethylpyridine in 50 ml of acetonitrile, and to the resulting suspension there was added rapidly (with stirring) a solution of 18.5 g of dicyclohexylcarbodiimide in 50 ml of acetonitrile. After stirring 5 hours and standing overnight, the suspension was filtered. The filtrate was evaporated, and the crude residue was triturated with ether-ethyl acetate to give crystals, m.p. 78°-80°. Recrystallization from toluene yielded the 2-(cyanoacetylaminomethyl)-pyridine, m.p. 81°-82°.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[NH3:36]>CO>[C:20]([C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:13]2[C:12]3[CH:23]=[C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][C:11]=3[NH:10]/[C:9]/2=[N:8]\[C:6](=[O:7])[C:5]2[CH:34]=[CH:35][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:16]1)(=[O:21])[NH2:36].[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:36][C:5]([CH3:34])([CH3:4])[CH2:6][OH:7])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Solvent: CO
Product: CC(C)(CO)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Product: NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Yield: 40 %

Procedure:
The title compound was prepared from cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride and 1 M ammonia in MeOH using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (19.5 mg, 40% yield). MS, m/z (C26H30FN5O3): calcd, 479.2. found, 480.2 [M+H].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]1[O:12][C@@H:11]1[CH2:13]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[C:1]1([O:7][CH2:13][C@@H:11]2[O:12][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(OC[C@H]2CO2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of phenol (336 mg) in anhydrous N,N-dimethylformamide (16 mL) was added sodium hydride (60% in mineral oil, 190 mg). The mixture was stirred for 1 h and (2S)-(+)-glycidyl 3-nitrobenzene sulfonate (1.0 g) in N,N-dimethylformamide (5 mL) was added. The mixture was heated to 60° C. and stirred for 30 min. The reaction was allowed to cool to room temperature, water (100 mL) was added and the mixture was extracted with 2:1 hexane:ethyl acetate (2 times 40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to supply the crude product. Purification by silica gel chromatography (eluting with 10:1 hexane: ethyl acetate) afforded the title compound (474 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([F:9])[C:5](=[O:8])[CH2:6][CH3:7].[CH2:11](O)[CH2:12][OH:13].B(F)(F)F.CCOCC>C1CCCCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([F:9])[C:5]1([CH2:6][CH3:7])[O:13][CH2:12][CH2:11][O:8]1
Reactant: OCCO
Reactant: CCC(=O)C(F)C(=O)OC
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC1(C(F)C(=O)OC)OCCO1
Temperature: 25 °C

Procedure:
2-Fluoro-3-oxopentanoic acid methyl ester (2.21 g, 14.9 mmol), ethylene glycol (4.15 mL, 74.5 mmol), and BF3.Et2O (0.189 mL, 1.49 mmol) were mixed in cyclohexane (10 mL). The mixture was heated to reflux for 5 h, and allowed to cool to rt. The mixture was diluted with EtOAc, and washed with brine, water, aq. sat. NaHCO3, and brine again. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as an oil (1.88 g, 52%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.ClCCCl>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:18][CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:20]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
0.73 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (b) above] was dissolved in 1.53 ml of anisole, and 7.25 ml of trifluoroacetic acid and 0.25 ml of trifluoromethanebulfonic acid were added dropwise, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 90 minutes, after which 1,2-dichloroethane was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The resulting residue was washed by repeated decantation, in turn, with hexane and with diethyl ether. The residue was diluted with ethyl acetate and was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 420 mg of the title compound, in the form of an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:25]=1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](Cl)=O)=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][O:31][C:30]4[CH:36]=[CH:37][C:27]([F:26])=[CH:28][CH:29]=4)[CH2:16][CH2:17]3)[C:9]3[CH:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:25]=1
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: CC(C)c1ccc2c(c1)C(N1CCNCC1)Cc1ccc(F)cc1S2
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCN(CCOc3ccc(F)cc3)CC1)Cc1ccc(F)cc1S2
Reaction time: 12 h

Procedure:
A solution of 2.6 g of 3-fluoro-8-isopropyl-10-piperazino-10,11-dihydrodibenzo(b,f)thiepin in 15 ml of chloroform was stirred and treated dropwise with 1.7 g of 4-fluorophenoxyacetyl chloride and the mixture allowed to stand for 12 hours. It was then diluted with chloroform, washed with a 5% sodium hydroxide solution and water, dried with potassium carbonate, filtered and evaporated. The oily residue (3.7 g, 100%) was the crude 3-fluoro-10-[4-(4-fluorophenoxyacetyl)-piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin which was used in this state for further work.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[O:26]C.Cl.N1C=CC=CC=1>>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]([F:13])([F:14])[F:15])=[C:3]([OH:2])[CH:8]=1)([O-:11])=[O:10].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[OH:26]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Br)c(O)c1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Temperature: 210 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 2-methoxy-4-nitro-1-(trifluoromethyl)benzene and 1-bromo-2-methoxy-4-nitro-benzene (16 g, crude) was added pyridine hydrochloride (100 g, 860 mmol) and the reaction mixture was stirred at 210° C. for 40 min. Then the mixture was poured into ice-water and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and purified by silica gel column chromatography (5% EtOAc in petroleum as eluant) to afford 5-nitro-2-(trifluoromethyl)phenol and 2-bromo-5-nitrophenol (10 g, crude). 1H-NMR (300 MHz, CDCl3) δ 7.86-7.80 (m, 3H), 7.72-7.63 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][O:14][CH3:15])[CH:6]=1)C.C(O)(=O)C>C(O)C.O.[OH-].[Na+]>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)c1ccc(C)c(OCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COCOc1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Methoxymethoxy-4-methyl-benzoic acid ethyl ester (4.5 g, 20 mmol) was dissolved in a mixture of ethanol (50 mL), water (20 mL) and 1 N aqueous sodium hydroxide solution (30 mL) and stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure to remove most of the ethanol. The resulting aqueous solution was acidified by adding acetic acid (2.5 g, 41.6 mmol). White precipitate was formed. After standing for another 30 minutes, the precipitate was collected by filtration, washed with water and dried to give crude 3-methoxymethoxy-4-methyl-benzoic acid as a white powder. (Yield 3.82 g, 97.0%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1N
Solvent: O
Solvent: CO
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.C1(C)C=CC=CC=1.C([O:32]CC)C>>[Cl-:1].[C:11]([CH2:10][CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[NH3+:12])([OH:21])=[O:32]
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: CCOCC
Agent: Cl
Solvent: Cc1ccccc1
Product: [Cl-]
Product: [NH3+][C@H](c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
A suspension of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E, 29 g, 91 mmol) in 5 M hydrochloric acid (91 mL, 453 mmol) was brought to reflux. After 2 h, TLC indicated complete consumption of starting material to the ring opened product (elution with 75% ethyl acetate in hexanes; Rf starting material=0.5, Rf product=0.0). The reaction contents were co-distilled with toluene (4×100 mL) then brought to dryness. Solids were suspended in diethyl ether (100 mL), filtered, and washed with ether (100 mL). The white crystalline solid was brought to dryness under high vacuum to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)CCNS(=O)(=O)c1ccc(O)cc1
Product: CC(C)CCNS(=O)(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-hydroxy-N-(3-methyl-butyl)-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (11%, light yellow oil). HPLC-MS m/z=377.2 (M+1), Rt: 4.32 min.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]5([C:43]#[N:44])[CH2:42][CH2:41]5)[CH:35]=4)[CH:29]=[CH:30][CH:31]=3)=[N:21][N:20]2[CH:46]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN1CCCC1=O>[C:43]([C:40]1([C:36]2[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=2)[C:33]([NH:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]3[N:20]([CH:46]=[C:17]([NH:16][C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[N:18]=3)[N:21]=2)=[O:45])[CH2:41][CH2:42]1)#[N:44]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6cccnc6)cn5n4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of nicotinic acid (54 mg, 0.438 mmol) in tetrahydrofuran (3 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (64 μL, 0.734 mmol), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue and N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol) were dissolved in N-methylpyrrolidone (3 mL), and the mixture was stirred at room temperature for 14 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0) to give the title compound (100 mg, 53%) as a pale-green powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=O)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].ClCCl.C(N(CC)CC)C.P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+]>ClC1CC(C(C)C)CCC1(Cl)C>[CH3:1][O:2][C:3]([C:4]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[S:13](=[O:14])(=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]=1[C:24]1[CH:32]=[C:31]([O:33][CH3:34])[C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)=[O:35]
Reactant: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(=O)c1cc(OC)c2c(c1)OCO2
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(c2cc(OC)c3c(c2)OCO3)c2ccccc2S(=O)(=O)N1c1ccccc1C
Temperature: -60 °C
Reaction time: 18 h

Procedure:
To a dry 100-mL flask was added {[2-(7-methoxy-benzo[1,3]dioxole-5-carbonyl)-benzenesulfonyl]-o-tolyl-amino}-acetic Acid Methyl Ester (2.0 g, 4.2 mmol), dry 4 angstrom molecular sieves (8 g), and Ti(TfO)2Cl2 (0.56 g, 0.48 mmol). The flask was cooled to −60° C. and dichloromethane (45 mL) was added. A solution of triethylamine (1.35 g, 9.73 mmol) in dichloromenthan (18 mL) was added. The mixture was warmed to 5° C. over 2 hours, followed by refrigeration at 0° C. for 18 hours. The mixture was poured in to 50-mL ammonium phosphate buffer solution (pH 7), stirred 20 minutes, and filtered. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to an oil. The oil was chromatographed on 150 g silica gel eluted with a mixture of ethyl acetate and hexane (40:60). The appropriate fractions were evaporated in vacuo, and the residue was evaporated to a foam, 1.02 g, 53%. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:6]2[S:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28]N(C=O)C>Cl>[N:22]1([CH2:21][CH2:20][N:2]2[N:3]=[C:4]([CH3:28])[C:5]3[CH:9]=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[S:7][C:6]=3[S:1]2(=[O:14])=[O:15])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CN(C)C=O
Reactant: ClCCN1CCOCC1
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NN=C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC1=NN(CCN2CCOCC2)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
The product from step C Example 1 (2.83 g, 10.07 mmol) was dissolved in DMF (40 mL). Sodium hydride (1.2 g, 30.21 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then chloroethylmorpholine hydrochloride salt (3.74 g, 20.14 mmol) was added. The mixture was warmed to 70° C. and stirred for 1h. DMF was evaporated under high vacuum. The residue obtained was diluted with 1N-HCl (50 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was neutralized with aqueous solution bicarbonate and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate fractions were dried over MgSO4 and evaporated to provide a solid, repeated recrystallization from ethyl acetate-hexane yielded 1.35 g, (71%). mp: 160°-162° C. 1H NMR (DMSO-d6): δ: 2.38 (3H, s, CH3); 2.50 (4H, m, 2CH2N); 2.64 (2H, t, CH2); 3.50 (4H, m, 2CH2O); 4.01 (2H, t, CH2); 7.94 (1H, 1s, CH); 8.22 (2H, s, NH2 exchangeable). Analysis calculated for C12H18N4O5S3 -0.15 Ethyl acetate: C, 37.12; H, 4.74; N, 13.74. Found: C, 37.10; H, 4.79; N, 13.90.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C>[ClH:1].[ClH:1].[CH3:27][N:26]1[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:29])[N:18]=[C:17]1[S:16][CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:9](=[O:10])[C:8]2[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][N:43]3[CH2:44][CH2:45][CH:40]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:41][CH2:42]3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCC(N6CCCCC6)CC5)cc4)cc3)n(C)c(=O)c12
Product: Cl
Yield: 137.5 %

Procedure:
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (375 mg) and 4-piperidinopiperidine (434 mg) in DMF (5 ml) was stirred at 100° C. for 7 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was recovered by filtration and dried to provide the title compound as colorless solid (368 mg).