Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.14 g, 0.4 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.088 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.045 g, 31%). MS (ISP) 363.1 [(M+H)+]; mp 206-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[N:17][CH:18]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Cl)cn1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cn1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-amino-5-chloro-pyridine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:18])CO)[CH:13]=1>O>[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:2])[OH:18])[CH:13]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)CO
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and 44 L of deionized water. To the agitated mixture was added 8.5 kg of ice. This was stirred until all the ice melted and the mixture temperature was 1.4° C. To this was added methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 19 (2.73 kg, 6.62 mol) via a powder addition funnel. The mixture was allowed to warm to rt and the slurry was stirred for 16 h. A sample was monitored by 1H NMR and showed the disappearance of starting material. The mixture was filtered and the cake washed with 20 kg of deionized water. This was repeated until a negative starch/iodide paper result was obtained (4×20 L washes). The solids were dried in a vacuum oven at 45-55° C. to provide methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 20 (2.176 kg, 88%) as a mixture with the corresponding aldehyde form 21. Purity was determined to be 99.5% by HPLC. 1H NMR (300 MHz, acetone-d6) δ 8.12 (s, 1H), 7.49-7.30 (m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23 (m, 1H), 5.20 (s, 2H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:32][OH:33])([CH2:30][OH:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=1)(C)(C)C.O1CCOCC1.[ClH:41]>C(Cl)Cl>[ClH:41].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:27])([F:28])[F:29])[CH:12]=1)([CH2:30][OH:31])[CH2:32][OH:33]
Reactant: CCCCCCCCOc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 9-7 (490 mg) was dissolved in methylene chloride (5 ml), dioxane containing hydrogen chloride (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (350 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[C:18]1([C:24]2[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][C:27]([C:28]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:29])=[CH:34][CH:35]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-phenyl-N-methoxy-N-methylbenzamide.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 14) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 2H), 1.55-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.92 (s, 3H), 2.85-3.30 (m, 2H), 3.50-3.65 (m, 2H), 3.70-3.90 (m, 3H), 6.61 (dd, J=8.8, 2.9 Hz, 1H), 6.70-6.80 (m, 2H), 6.88 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H); MS (ES) m/z: 571.0 (MH+); HRMS Calcd. for C25H39N4O7S2 (MH+): 571.2261. Found: 571.2279.
Reaction SMILES: [H][H].O.[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([N+:17]([O-])=O)[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]>[Fe].C(O)(=O)C>[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([NH2:17])[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]
Reactant: [H][H]
Reactant: COc1c(Cl)cc(NC(C)=O)c(OC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc(NC(C)=O)c(OC)c1N
Temperature: 80 °C

Procedure:
253 g of powdered iron which had been reduced with hydrogen were added to 760 ml of water containing 13 ml of acetic acid and which had been previously heated to 80° C., and then 0.46 mole (126.5 g) of 5-acetamido-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step was added gradually, with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 15 minutes. After cooling, the reaction mixture was centrifuged. The iron slurries after being separated from the liquid phase were extracted with ethyl acetate. The ethyl acetate phase which was washed with water and then dried over sodium sulphate was diluted with 100 ml of a 7N hydrochloric acid solution in absolute ethanol. The expected product, which precipitated n the form of hydrochloride, was thoroughly drained. It was dissolved in the minimum amount of water. After neutralization, the expected product precipitated. Recrystallized from alcohol, it melted at 113° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OC(Cl)(c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-fluorobenzoyl)benzoic acid (5 g, 20.4 mmol) followed by thionyl chloride (2.97 mL, 40.9 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature. Removal of the solvent gave 3-chloro-3-(4-fluorophenyl)-3H-isobenzofuran-1-one as a colourless oil (5.35 g, 20.4 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O.N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>O.CO>[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCC1=O
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: CO
Product: CC1CCCCC1Nc1ccccc1
Yield: 37 %

Procedure:
In a 100-mL flask, the following mixture is heated at reflux for 30 h: 9.3 g aniline, 11.2 g 2-methylcyclohexanone and 12 g benzotriazole. Then, 200 mL of methanol and 5 g of NaBH4 in portions are added to the mixture, which is then heated at reflux for 30 min. The solution is allowed to cool, and 100 mL of water are added to the mixture, which is extracted with 2×100 mL diisopropyl ether. The organic phase is recovered, dried over magnesium sulfate and reduced to dryness. In this manner, 7 g of the desired amine are produced.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].CN(C1C=CC=CN=1)C.O>C(OCC)(=O)C.[Pd]>[NH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[C:17]([CH3:18])=[O:19]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2cc(NC(C)=O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methyl 5-nitrobenzofuran-2-carboxylate (13, 0.5 g, 2.26 mmol, made from 5-nitrobenzofuran-2-carboxylic acid, Trans World Chemicals, Inc.) was dissolved in ethyl acetate (40 mL) and 5% Pd/C (30 mg) was added. The reaction mixture was hydrogenated for 1 h at room temperature at a pressure of 60 lb/inch2. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in acetone (10 mL) and was used without further purification. Acetic anhydride (0.86 mL, 9.1 mmol) and dimethylaminopyridine (20 mg) was added. The solution was stirred for 1 h at room temperature. Water (20 mL) was added and the mixture was extracted with ethyl acetate (40 mL×5). The solution was dried using sodium sulfate and solvent was removed in vacuo. A grey powder 9 was obtained (321 mg, 61% yield). An analytical sample was recrystallized in ethyl acetate. mp: 158°-159° C. 1H NMR (DMSO-d6, ppm): 10.03 (s, 1 H, NH), 8.19-8.18 (d, 1 H, J=1.6 Hz, Ar--H), 7.76-7.75 (d, 1 H, J=1.1 Hz, Ar--H), 7.65-7.63 (d, 1 H, J=9.0 Hz, Ar--H), 7.55-7.52 (dd, 2 H, J=2.3, 8.9 Hz, Ar--H), 3.89 (s, 1 H, OCH3), 2.07 (s, 3 H, CH3CO), Anal. (C12H11 NO4), C, H, N.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl

Procedure:
To a solution of trichloroacetyl chloride (160.7 mmoles) in ethyl ether (26 ml) there is added, dropwise over a period of 3 hours, a solution of pyrrole (149 mmoles) in ethyl ether (83 ml). After stirring for a further hour, a solution of potassium carbonate (94 mmoles) in water (39 ml) is added dropwise. The phases are separated and the organic phase is dried over sodium sulphate and filtered. Active carbon is added to this organic phase. After stirring for 5 minutes, the organic phase is filtered and evaporated to dryness to yield the title product.
Reaction SMILES: [Cl-].[CH2:2]([P+](CCCC)(CCCC)CCCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)C1C=CC=CC=1.[CH3:30][SiH:31]([Cl:33])[Cl:32]>>[CH2:2]([CH2:30][SiH:31]([Cl:33])[Cl:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Cl-]
Solvent: ClCc1ccccc1
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 240.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.26 g (0.79 mmol) of benyltributylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 2.73 g (23.7 mmol) of methyldichlorosilane were reacted at 200° C. for 2 hrs. The resulting mixture was distilled to give 0.39 g of benzylmethyldichlorosilane (yield; 24%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:25]=[C:24]([NH:26][C:27]3[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:25]=[C:24]([NH:26][C:27]3[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1
Reactant: Cc1cc(Nc2nc(Nc3ccc(NC(=O)OC(C)(C)C)cc3)nc3ccccc23)[nH]n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nc(Nc3ccc(N)cc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-60, 100 mg, 0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) was stirred for 2 hours at room temperature. The solvents were removed in vacuo and the residue triturated in aqueous K2CO3. The resulting solid was collected by filtration and washed with diethyl ether to afford IIc-66 (69 mg, 90%) as an off-white solid, mp 164–167° C.; 1H NMR (DMSO) δ 2.24 (3H, s), 6.33 (1H, br s), 7.12 (2H, d), 7.48 (3H, m), 7.58 (1H, d), 7.86 (1H, t), 8.64 (1H, d), 10.86 (1H, br s), 11.46 (1H, s); IR (solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H)+
Reaction SMILES: CCCCCCCCC.[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:39]1CCCC1>>[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][CH2:20][CH2:21][OH:39])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C=CCC(CCCCCCCCCCCCCCCCC)OCc1ccccc1
Solvent: CCCCCCCCC
Product: CCCCCCCCCCCCCCCCCC(CCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a 33 ml solution of a 0.5M solution of 9-borabicyclo[3:3:1]nonane in tetrahydrofuran was added dropwise, under nitrogen, a solution of 6.0 g of 4-benzyloxy-1-heneicosene in 30 ml of dry tetrahydrofuran. After stirring at room temperature for 3 hours, the reaction was quenched by successive addition of 9 ml of ethanol, 3 ml of 6N sodium hydroxide and 6.5 ml 30% hydrogen peroxide. The reaction mixture was heated at 50° for 90 minutes and then allowed to stand at ambient temperature overnight. Upon standing, the reaction mixture separated into aqueous and organic phases. The aqueous phase was saturated with potassium carbonate, and the organic phase was separated, washed with 15 ml of 10% solution of sodium sulfite and 20 ml of saturated solution of sodium chloride, dried over potassium carbonate, and concentrated. The residue was taken up in a mixture of 20% diethyl ether/hexane, filtered and concentrated to an oil. Flash chromatography of the oil on silica gel using hexane/diethyl ether (2:1 by volume) as the eluent gave 4.88 g (78%) of 4-benzyloxyheneicosan-1-ol.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH2:21][O:22][C:23]([CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1)=[O:24].Cl.C(N(C(C)C)CC)(C)C.[F:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>>[F:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([N:27]2[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:26]2)=[O:48])=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CNCCC1=O
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCC1=O
Yield: 84.4 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 4-piperidone-3-carboxylate hydrochloride (200.4 mg; 0.97 mmol), diisopropylethylamine (360 μl; 2.08 mmol) and 4-fluorobenzoyl chloride (114 μl; 0.97 mmol), giving ethyl 1-(4-fluorobenzoyl)4-oxo-3-piperidinecarboxylate (240.2 mg) as a thick, light yellow oil without further purification. MS m/z (positive ion) 348 (25), 316 (M+Na+; 75), 294 (MH+; 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([OH:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]([O:20][C:21](=[O:24])[CH2:22]Br)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][O:15][C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[N:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Oc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
123 mg (2.82 mmol) of sodium hydride (55% in mineral oil) were added to 500 mg (2.56 mmol) of 4-(4-fluoro-phenyl)-thiazol-2-ol in 15 ml of DMF. After stirring at room temperature for 30 min, 549.6 mg (2.82 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated to give 762 mg of a mixture of title compound and N-alkylated product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH2:8][NH:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[CH:7]=[CH:8][N:9]=2)=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccc(CC(=O)NCC(O)c2cccc(OC)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCc1ccc(Cc2nccc3cc(OC)ccc23)cc1
Yield: 15.8 %

Procedure:
Phosphorus oxychloride (1.6 ml) was added to a solution of the compound of Example B145 (600 mg, 1.7 mmol) in acetonitrile (15 ml), and the mixture was stirred under reflux for 1 hour 30 minutes. The mixture was cooled on ice, made alkaline with a 5% aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (82 mg).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[CH:4]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)C=CC=CC=1.NC1C=NC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:19][CH2:18]2)[CH:4]=1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Agent: Nc1cccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methyl-2-(3-piperidin-4-ylidenemethyl-phenoxy)-pyridine hydrochloride (530 mg, 1.5 mmol, from Step 5), pyridin-3-yl-carbamic acid phenyl ester (402 mg, 1.88 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridine) and triethylamine (0.836 mL, 6.0 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):DCM) to afford the desired product (429 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.35 (s, 3H) 2.45 (td, J=5.82, 0.99 Hz, 2H) 2.57 (td, J=5.81, 1.11 Hz, 2H) 3.51-3.57 (m, 2H) 3.61-3.67 (m, 2H) 6.44 (s, 1H) 6.73-6.80 (m, 1H) 6.90-6.95 (m, 2H) 6.97 (dt, J=5.18, 0.61 Hz, 1H) 7.08 (d, J=8.02 Hz, 1H) 7.30-7.42 (m, 2H) 7.91 (ddd, J=8.38, 2.58, 1.45 Hz, 1H) 7.98 (d, J=5.24 Hz, 1H) 8.16 (dd, J=4.81, 1.40 Hz, 1H) 8.58 (d, J=2.51 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:29][CH:26]([CH3:28])[CH3:27])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and isopropylamine (5 ml) in 20 ml of ethanol was placed into a high-pressure reaction apparatus and heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 40:1) to give the desired product as a light yellow solid. MS: 454; 1H NMR (DMSO-d6, 300 MHz): δ 10.28 (brs, ½H, NH, D2O exchangeable), 9.62 (brs, 1H, NH, D2O exchangeable), 9.31 (brs, ½H, NH, D2O exchangeable), 8.57 (s, 1H, OH, D2O exchangeable), 7.88 (brs, 1H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 3.85 (m, 1H, CH), 1.20 (d, 6H, J=6.3 Hz, 2×CH3).