Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[7-(3-Methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 115, was dissolved in anhydrous dioxane together with piperazine (0.5 mmol) and the mixture was stirred at 100° C. overnight and then concentrated in vacuo, then diluted with water and extracted with DCM. The DCM extract was washed with water thrice, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 4-[7-(3-piperazin-1-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. This (0.05 mmol) was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.1 mmol) followed by methanesulfonyl chloride (0.1 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MEOH, neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), which was prepared as described in Example 66a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain 14.3 mg (45%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.13 (s, 1H), 8.04 (d, 1H), 7.35-7.22 (m, 4H), 6.88 (d, 2H), 6.33 (s, 1H), 4.31-4.13 (m, 4H), 3.89-3.80 (m, 4H), 3.74-3.56 (m, 3H), 3.20-3.03 (m, 6H), 2.61-2.38 (m, 11H), 2.22-1.88 (m, 6H). LC/MS (ESI): 638.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[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.Cl.[Cl:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1.C(N(CC)CC)C>C(O)C>[ClH:18].[CH3:27][C:23]1[N:22]=[C:21]([CH2:20][CH2:19][N:12]2[CH2:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:14][CH2:13]2)[CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: Cc1cccc(CCCl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(CCN2CC=C(c3cccc(C(F)(F)F)c3)CC2)n1
Yield: 36.4 %

Procedure:
By operating as described in Example 1, 5.7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are reacted with 5.2 g of 2-(2-chloroethyl)-6-methylpyridine hydrochloride in the presence of 7.5 ml of triethylamine in 60 ml of ethanol at reflux for 18 hours to obtain 3.5 g of 1-[2-(6-methyl-2-pyridyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride; m.p. 207°-210° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (582 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (421 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 106–107° C.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>CC#N>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CC(F)(F)F)CC4)cn3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 in 3 mL of CH3CN was added DIEA (32 mL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol). The resulting mixture was then stirred at rt for 1 h, heated at 85° C. for 1 h. CH3CN was then evaporated under reduced pressure and the residue was taken up in 2 mL of DMF. To the reaction mixture was then added DIEA (32 μL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol), and heated at 85° C. for 2 h. LC-MS indicated that the reaction was complete. Purification by reverse phase HPLC yielded N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide (40 mg, 74%) as a white solid. LC-MS (ESI) m/z 597 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.36 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.85 Hz, 1H), 7.81 (d, J=8.85 Hz, 2H), 7.67 (dd, J=2.83, 8.85 Hz, 1H), 7.42 (d, J=8.85 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.65 (td, J=3.93, 8.15 Hz, 1H), 4.57 (s, 2H), 3.23 (q, J=10.24 Hz, 2H), 2.80-2.96 (m, 2H), 2.62 (t, J=9.42 Hz, 2H), 1.97 (br. s., 2H), 1.60-1.76 (m, 2H), 1.34 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[OH-].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:23]([N:7]1[C:8]2[C:4](=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=2)[CH:5]=[CH:6]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 4-[methyl(methylsulfonyl)amino]-1H-indole-6-carboxylate (0.437 g) in DMF (15 mL) was added potassium hydroxide (0.087 g) and iodobutane (0.34 mL). The mixture was heated to 70° C. for 6 h. then stirred at room temperature for 72 h. The mixture was partitioned between water and ethyl acetate, the layers were separated and the organic layer washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol (5 mL) to which was added 1N NaOH (2 mL) and the mixture heated to 50° C. for 1 h. The mixture was cooled to room temperature and poured into water and washed with ether. The aqueous layer was acidified to pH 4 with 1N HCl and the product extracted into ethyl acetate which was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 0.377 g of the title compound: 1H NMR (CDCl3) δ 0.973, 1.38, 1.87, 3.01, 3.45, 4.21, 6.71, 7.36, 7.82, 8.18.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.N12CCCN=C1CCCCC2.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([S:42]([CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:44])=[O:43])[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cc1onc2c1c(=O)n(C1CCCN(S(=O)(=O)Cc3ccccc3)C1)c1cccc(Cl)c21
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a 0° C. suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in ethanol (5 mL) add 1,8-diazabicyclo[5.4.0]undec-7-ene (42 μL, 0.28 mmol). Stir the solution for 10 mins. To the solution add α-toluene-sulfonyl chloride (21 mg, 0.11 mmol) and stir the reaction at 0° C. under nitrogen for 30 minutes. Quench the reaction with 1N HCl, concentrate, and extract with 20% isopropanol/chloroform (×2). Wash the combined organic layers with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.4% methanol/chloroform) to give 37.9 mg of the title compound as a white solid, 72% yield. 1H NMR: consistent with structure. MS (ion spray) 472 (M+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1CBr
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1oc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (3.0 g) in methanol (30 mL) was added sodium methoxide (0.8 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (1.9 g, 77%) as an oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>>[CH:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N1CCC(C(N)=O)CC1
Yield: 94.1 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 2-iodopropane (3.10 mL, 31.2 mmol) of potassium carbonate and (2.15 g, 5.6 mmol) according to the procedure used for Example 8 (Step A) to give 2.5 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH2:11])[CH2:9][CH3:10]>C(Cl)Cl>[CH2:8]([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:9][CH3:10]
Reactant: CCCN
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 ml (50 mM) of ethyl bromoacetate were added dropwise to a solution of 20.5 ml (250 mM) of n-propylamine in 50 ml of CH2Cl2 at 0°. The reaction mixture was then warmed to room temperature and stirred for 1 hour, then concentrated to remove volatiles through a short path distillation head at atmospheric pressure. The residual liquid was taken up in ether and washed with saturated aqueous NaHCO3. The layers were separated and the ether layer was washed once with brine then dried over anhydrous MgSO4. The ether was removed to yield 7.16 g of ethyl N-(n-propyl)glycinate as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C@@H:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][C@@H:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1
Reactant: N[C@H]1CN2CCC1CC2
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)N[C@H]2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 25.6 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8.0 mmol) in anhydrous tetrahydrofuran (4 mL) and anhydrous N,N-dimethylformamide (4 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.9 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of (R)-3-aminoquinuclidine (1.54 g, 12.2 mmol) in anhydrous tetrahydrofuran (4 mL) was added, and the mixture was stirred at room temperature for 18 hours, warmed to 55°±5° C. for three hours, and concentrated in vacuo. The residue was partitioned between 3.0N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol, and the organic layer was separated. The aqueous solution was extracted with toluene (50 mL) containing some 2-propanol, and the combined organic solution was concentrated in vacuo. The residue was washed with water to remove most of the imidazole, then dried azeotropically with toluene, taken up in tetrahydrofuran, and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, taken up in warm acetone, and filtered. After a few hours, a solid had crystallized, and this was collected and dried in vacuo to afford (following second crop) 1.05 g (26%) of colorless solid; mp 101.5°-104° C., [α]D22 +6.50° (C=1 in methanol).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]>C(Cl)(Cl)Cl>[Cl:4][C:8]1([C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:6])[CH:11]=[CH:10][S:9]1
Reactant: COC(=O)c1sccc1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(Cl)SC=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulphuryl chloride (0.11 mol) was added to a stirred solution of methyl 3-hydroxythiophene-2-carboxylate (0.1 mol) (C. Corral, J. Lissavetzty; Syntheses (1984), 847) in anhydrous chloroform (50 ml). After stirring at room temperature for 4 hours the solvent was removed under reduced pressure and the residue used crude in the following preparations (m.p. 70°-71° C., hexane).
Reaction SMILES: [C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][N:15]([CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:27])[CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)N(c1ccccc1)[C@H]1CCNC[C@H]1OC
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@H]1CCN(C(C)c2ccccc2)C[C@H]1OC
Yield: 61.8 %

Procedure:
cis-N-Phenyl-N-(3-methoxy-4-piperidinyl)propanamide (8, 0.5g, 1.9 mmol) from Example 6, phenylethyl bromide (0.40g, 2.2 mmol) and 2.76g (I9 mmol) of potassium carbonate in 100ml of acetonitrile were heated to reflux overnight. The reaction solution was concentrated under vacuum and the crude residue was purified by chromatography (silica gel; ethyl acetate) to yield 0.43g (62%, Rf 0.326) of pure cis-N-phenyl-N-(1-phenylethyl-3-methoxy-4-piperidinyl) propanamide (I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[NH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CNc1ccccc1-c1cccc(F)c1
Reactant: CN1CCNCC1
Solvent: COCCOC
Product: CN1CCN(C(=N)Nc2ccccc2-c2cccc(F)c2)CC1

Procedure:
A mixture of 3'-fluoro-2-biphenylylcyanamide (4.1 g) and N-methylpiperazine (1.9 g) in 1,2-dimethoxyethane (30 ml) was heated at 90°-95° C. for 4 hours to yield N-(3'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine (m.p. 117°-118° C.) which was recrystallised from hexane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:14].[Na+]>C(Cl)Cl>[I:14][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [I-]
Reactant: CCOC(=O)CCCCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCCI
Yield: 69.2 %

Procedure:
Mix ethyl 4-chlorobutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound (89 g); bp 64° C.@0.5 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:30][C@H:31]([CH3:36])[C:32]([OH:35])([CH3:34])[CH3:33])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:27]3[CH2:29][CH2:28]3)(=[N:17]S(CC[Si](C)(C)C)(=O)=O)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[C:3]([NH:30][C@H:31]([CH3:36])[C:32]([OH:35])([CH3:33])[CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:27]3[CH2:28][CH2:29]3)(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](Nc1nc(Nc2ccc(S(=O)(=NS(=O)(=O)CC[Si](C)(C)C)C3CC3)cc2)ncc1Br)C(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(Nc2ccc(S(=N)(=O)C3CC3)cc2)ncc1Br)C(C)(C)O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
50 mg of (RS)-S-[4-({5-bromo-4-[(R)-(2-hydroxy-1,2-dimethylpropyl)amino]-pyrimidin-2-yl}amino)phenyl]-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]-sulfoximide is dissolved in 1 ml of tetrahydrofuran and mixed with 0.3 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture is stirred for 3 days at 50° C. and purified by flash chromatography (dichloromethane-dichloromethane/ethanol 9:1). 10 mg (28% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[H-].[Na+].[CH3:24]OS(OC)(=O)=O.Cl>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:5]/[O:6][CH3:24]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.71 g, 0.0025 mole) was dissolved in dried tetrahydrofuran (10 ml), followed by the addition of 60% sodium hydride (0.13 g, 0.033 mole). Then, the mixture was stirred at room temperature for 20 minutes and to this was added dropwise a solution of dimethylsulfate (0.44 g, 0.0035 mole) dissolved in dried THF (2.5 ml) under ice cooling, followed by stirring for 1.75 hours under ice cooling. After completion of the reaction, water was added to the reaction mixture which was adjusted to pH 1 with conc. hydrochloric acid. The mixture was extracted twice with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.61 g, yield: 81.3%) as a colorless oil.
Reaction SMILES: C([O:4][CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)/[C:9](=[CH:16]/[C:17]2[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])/[C:8]1=[O:24])[CH3:6])(=O)C.C(#N)C>C(O)=O>[CH3:22][C:21]1[CH:20]=[C:19]([CH3:23])[NH:18][C:17]=1/[CH:16]=[C:9]1\[C:8](=[O:24])[N:7]([CH:5]([OH:4])[CH3:6])[C:15]2[C:10]\1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Solvent: O=CO
Solvent: CC#N
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(C)O)c3ccccc32)[nH]1
Yield: 90 %

Procedure:
Alternatively, (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1-(1-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (4b) was prepared in >90% yield by treating 1-{(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}ethyl acetate (4a) (500 mg) with aqueous acetonitrile (10 mL) and formic acid (200 mg) overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc2ncc(Cl)n2n1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine 41 (6.53 mmol) was dissolved in chloroform (12 mL) and N-chlorosuccinimide (6.53 mmol) added under N2. After stirring for 16 h, the mixture was partitioned between saturated sodium hydrogensulfate solution (25 mL) and chloroform (12 mL). The organic layer was removed, washed with water (2×), dried and concentrated to provide 3,6-dichloroimidazo[1,2-b]pyridazine 5 (1.05 g, 85%) as an orange solid; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=9.5 Hz, 1H), 7.74 (s, 1H), 7.12 (d, J=9.5 Hz, 1H). 3,6-Dichloroimidazo[1,2-b]pyridazine 5 (150 mg, 0.8 mmol) and the desired amine (1 mL) were heated in a sealed tube for 16 hr at 120° C. Upon cooling the reaction mixture was concentrated and purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) to provide the desired product 6.