Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][CH2:38][O:39][C:40]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][CH3:55])[CH2:51][CH2:52]4)=[CH:46][C:40]=3[O:39][CH2:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 62.2 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 154, step E) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.112 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.32 (d, J=6.78 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.05 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.70, 2.11 Hz, 1H), 7.64-7.71 (m, 2H), 7.40-7.45 (m, 1H), 7.32-7.40 (m, 1H), 7.24 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.91-6.97 (m, 2H), 6.76 (dd, J=8.24, 1.47 Hz, 1H), 6.61 (d, J=5.13 Hz, 1H), 4.24 (q, J=6.71 Hz, 2H), 4.08 (q, J=6.96 Hz, 2H), 2.93 (d, J=10.80 Hz, 2H), 2.38-2.45 (m, J=4.03 Hz, 1H), 2.16-2.27 (m, 2H), 1.91 (d, J=9.71 Hz, 2H), 1.67-1.75 (m, 2H), 1.64 (dd, J=12.00, 2.84 Hz, 2H), 1.38-1.46 (m, 5H), 1.26 (t, J=6.87 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.P(Cl)(Cl)([Cl:16])=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([Cl:16])=[N:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(Br)cnc(Cl)c2c1
Temperature: 66 °C
Reaction time: 3 h

Procedure:
4-bromo-7-chloroisoquinoline 2-oxide (3-7) (1.2 g, 4.64 mmol, 1.0 equiv.) was dissolved in anhydrous CHCl3 (20 mL) and treated dropwise with phosphorus oxychloride (0.649 mL, 6.96 mmol, 1.5 equiv.). The reaction mixture was refluxed at 66° C. LCMS after 3 hours showed only product. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3, and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane, and filtered to afford the product 3-8. LRMS m/z (M+H) 277.9 found, 277.9 required.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:10]([N+:14]([O-:16])=[O:15])=[C:9]([Cl:17])[N:8]=1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1NC1CCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclobutanamine (0.485 mL, 5.68 mmol) in iPrOH (20 mL) was added to a solution of 2,4,6-trichloro-5-nitropyrimidine (1.29 g, 5.65 mmol) in iPrOH (40 mL) at −78° C. dropwise via addition funnel. After complete addition, the mixture was allowed to warm to rt over 30 min, then DIEA (0.940 mL, 5.66 mmol) was added and the mixture stirred at rt for 10 min. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14]Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([CH3:16])[CH:8]=2)[N:3]=1.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O.ClC(Cl)C>C1COCC1>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14][N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([CH3:16])[CH:8]=2)[N:3]=1
Reactant: CC1CCNCC1
Reactant: Cc1cc2c(CCl)c(CO)c(Cl)nc2cc1Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc2c(CN3CCC(C)CC3)c(CO)c(Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of the product of Stage 82.d (16.2 g; 55.7 mmol) in THF (70 ml) is treated with a solution of 4-methylpiperidine (23 ml; 195 mmol). The mixture obtained is agitated at ambient temperature for 2 hours. Water (200 ml) and dichloroethane (200 ml) are added. The organic phase is washed with an aqueous solution of sodium chloride (concentrated to 20% by weight; 100 ml), dried over magnesium sulphate and concentrated under reduced pressure. By crystallization of the residue from diethylether, the product in the title is obtained (18.3 g; 93% yield) in the form of a white crystalline solid (M.p. 170–171,5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([C:9]([O:11][CH3:12])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(OC)(=O)C[SH:32]>ClCCl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([S:32][CH2:24][C:23]#[N:25])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2cc(Cl)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: COC(=O)CS
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc2cc(Cl)ccc2c1SCC#N
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of methyl 6-chloro-3-{ [(trifluoromethyl)sulfonyl]oxy}-1-benzothiophene-2-carboxylate (2.0 g, 5.3 mmol) and triethylamine (890 μL, 1.2 eq), in dichloromethane (45 mL) was cooled to −20° C. and methyl thioglycolate(908 μL, 2.5 eq) was added dropwise via syringe pump over 5 h. The reaction was allowed to warm to room temperature overnight. The solution was diluted with water, and ethyl acetate, washed with water and brine, dried, filtered, evaporated, and flash chromatographed (10-20% ethyl acetate/hexanes) to provide methyl 6-chloro-3-[(cyanomethyl)thio]-1-benzothiophene-2-carboxylate (1.01 g, 64%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (Reference; Bull. Chem. Soc. Japan, vol. 49(7), 1980-1984(1976)) (7.15 g) in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and after adding n-butyllithium (1.6M hexane solution: 46 mL) dropwise thereto, the reaction mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at −78° C., and stirring was continued for 1 hour. The reaction mixture was raised to room temperature, water was added, and then extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (7.1 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (50:1) fraction.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5].[CH2:23]([Mg]Br)[CH3:24].CCOCC>O1CCCC1.[Cl-].[NH4+]>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[O:10][C:6]=1[C:4](=[O:5])[CH2:23][CH3:24]
Reactant: CON(C)C(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C

Procedure:
4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methoxy-methyl-amide (1.0 g, 3.18 mmol) is stirred in tetrahydrofuran (15 mL) at −78° C. Ethyl magnesium bromide, 3M/ether (2.1 mL, 4.14 mmol) is added and the mixture is warmed to room temperature. The mixture is diluted with aqueous saturated ammonium chloride and washed with ethyl acetate (three 50 mL portions). The combined washes are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified over silica eluting with 7:3 hexanes:ethyl acetate to afford 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one as an ivory solid, 0.70 g, 78%. MS (M++1)284.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccsc12
Product: Clc1ccnc2ccsc12
Temperature: 105 °C
Yield: 72 %

Procedure:
A stirred suspension of thieno[3,2-b]pyridin-7-ol (5.0 g, 33.1 mmol) in POCl3 (15 mL) was heated at 105° C. in an oil bath for 4 hrs. The resultant solution was cooled to room temperature and the POCl3 was removed under reduced pressure. The residue was cooled in an ice/water bath and cold water was added. The mixture was made basic with concentrated NH4OH solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated to produce oil, which was purified by column chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, J=4.9 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=[O:4])=[O:3].[F:41][C:42]1[C:43]([S:52][CH3:53])=[C:44](B(O)O)[CH:45]=[C:46]([F:48])[CH:47]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[F:41][C:42]1[C:43]([S:52][CH3:53])=[C:44]([C:11]2[C:12]([C:16](=[O:32])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:19][CH:18]=3)=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]3)[CH:45]=[C:46]([F:48])[CH:47]=1
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: CSc1c(F)cc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (8.8 g, 14.6 mmol) and 3,5-difluoro-2-methylsulfanyl-benzene boronic acid (9.0 g, 42 mmol) and flush with nitrogen. Dissolve solids in degassed dioxane (240 mL). Add 2M sodium carbonate (120 mL) and Pd(PPh3)4 (6.7 g, 5.9 mmol). Plunge into 110° C. oil bath and stir vigorously. After 30 minutes, cool the reaction to room temperature and filter off solids. Partition the filtrate between water and methylene chloride. Wash the organic layer with water twice, dry over sodium sulfate, filter and concentrate. Purify the residue over silica gel, eluting with 1 to 2% methanol in methylene chloride, to yield 8.0 g (90%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=3.18 mm (99%); mass spectrum (ion spray): m/z=612.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].N#N>[Cu].C1CCCCC1>[CH2:21]([O:20][C:18]([CH2:17][O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[O:19])[CH3:22]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(CCCO)OCc1ccccc1
Agent: [Cu]
Agent: N#N
Solvent: C1CCCCC1
Product: CCOC(=O)COCCCC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
65 g (0.33 mol) of benzyl 4-hydroxybutyrate and 260 mg of copper powder are charged to 120 ml of cyclohexane and the mixture is heated to reflux. Then a mixture of 38.7 ml (0.37 mol) of ethyl diazoacetate and 300 ml of cyclohexane are added, whereupon evolution of N2 ensues. The reaction mixture is stirred for 4 hours under reflux and then for 4 hours at room temperature, filtered over a glass fibre filter and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate 4:1, giving benzyl 4-ethoxycarbonylmethoxybutyrate as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][OH:21])=[NH:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](Cl)(=O)[CH3:30].O.CCOC(C)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]4[N:19]=[C:29]([CH3:30])[O:21][N:20]=4)=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)no1
Yield: 65.3 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-hydroxy-2-methyl-benzamidine (i.e product of Step 1, 400 mg, 0.93 mmol) in pyridine (10 mL) was added acetyl chloride (0.13 mL, 0.15 g, 1.85 mmol) via syringe and the mixture was stirred at reflux for 30 min. Water and EtOAc were added after cooling and the aqueous layer was extracted with EtOAc. Combined organic layers were dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel and yielded the title compound (277 mg, 65%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:42])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:26][CH2:25]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH:43]([NH2:46])([CH3:45])[CH3:44].CN1[C:52](=[O:53])[CH2:51]CC1>>[F:42][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:51][C:52]([NH:46][CH:43]([CH3:45])[CH3:44])=[O:53])[CH2:26][CH2:25]2)=[N:20][CH:21]=1
Reactant: CN1CCCC1=O
Reactant: CC(C)N
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cnc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)nc2)c1F
Product: CC(C)NC(=O)CN1CCC(COc2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4-Nitrophenyl 4-[({5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxylate (200 mg) was mixed with NMP (5 ml), and isopropyl amine (0.3 ml) was added thereto, followed by stirring at 70° C. for 6 hours. iPrNH2 (0.3 ml) was added to the reaction mixture, followed by stirring at 70° C. overnight. iPrNH2 (0.4 ml) was added to the reaction mixture, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then a 1 M aqueous NaOH solution and EtOAc were added thereto. The organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.7 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl3) to obtain 4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]-N-isopropylpiperidine-1-carboxyamide (107.4 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[O:8][CH2:9][CH3:10].[CH2:11](O)C>>[OH:8][C:9]1[CH:10]=[CH:11][C:4]([CH:5]=[O:1])=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: CCO
Product: O=Cc1ccc(O)cc1
Temperature: 60 °C

Procedure:
The synthesized emeraldine base oligomer in an amount of 0.2 g was slowly sprinkled over a 250 ml beaker containing 150 ml tetrahydrofuran in a BRANSON ultrasonic bath. The polyaniline solution was then transferred to a 500 ml flask with flux condenser and thermometer adaptor and heated with stirring to 60° C. in a heating bath. A separate solution of 1 g (0.0082 mol) p-hydroxybenzaldehyde in 50 ml absolute ethanol was prepared and slowly added via a dropping funnel to the polyaniline solution. The reaction was allowed to proceed for at least 3 days and then transferring the reaction mixture to a rotovap flask and stripping the solvent. The greenish blue powder was thoroughly ether washed and soxhlet extracted for at least 3 days with ether. The fully washed product was vacuum dried in an oven at 60° C. and characterized by NMR, Infrared, Ultraviolet, TGA, DSC,GPC, EA and x-ray spectroscopy. Reduction with sodium borohydride and lithium hydride was achieved by reflux with the endcapped polymer in dimethylformamide, cooling the mixture, pouring ethanol and then filtering, air drying, recrystallizing in methanol and characterizing the reduced base.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][O:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[N:25][C:2]=2[N:3]=1
Reactant: N=C(N)COCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(F)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 80.2). Light brown solid. MS: m/e=318.1 [M+H+].
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13]>ClCCCl>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: Oc1ccc(OC(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(OC(F)F)ccc1O
Temperature: 0 °C
Yield: 85.9 %

Procedure:
4-(Difluoromethoxy)phenol (500 mg, 3.12 mmol) was dissolved in DCE (3 mL). The reaction mixture was cooled to 0° C. and nitric acid (0.488 mL, 10.92 mmol) was added dropwise over 10 min. The reaction mixture was stirred for a further hour at 0° C., then poured into an ice/water mix (5 g in 5 mL). DCE (10 mL) was added and the layers separated. The organic layer was dried (MgSO4) and evaporated to dryness to give a crude brown oil (550 mg). Material was carried forward without further purification, as no separation between products was found in TLC solvent systems used.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C>[N:34]1([C:32](=[O:33])[CH2:31][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=4)[CH:8]=3)[CH2:2][CH2:3]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)N4CCOCC4)CC3)ncn2)s1
Temperature: 0 °C

Procedure:
2-[(6-Piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carbonitrile 12-3 (0.10 g, 0.35 mmol) and diisopropylethylamine (0.049 g, 0.38 mmol) were dissolved in DMF. After cooling to 0° C., a DMF solution of 4-(bromoacetyl)morpholine 12-4 (0.08 g, 0.38 mmol) was added slowly via addition funnel. The product was purified on a C18 preparative LC column and isolated via lyophilization. Hi-Res MS: calc: 415.1655 found: 415.1663. 1H-NMR (CD3OD): 8.49 ppm (s, 1H); 8.03 ppm (s, 1H); 6.27 ppm (s, 1H); 4.34 ppm (s, 2H); 3.70 ppm (m, 4H); 3.65 ppm (m, 4H); 3.42 ppm (t, 2H); 3.33 ppm (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Na+].[I-:12].C(Cl)(=O)C>C(#N)C>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([I:12])[CH:7]=1)[CH3:9]
Reactant: CC(F)c1ccnc(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: CC(F)c1ccnc(I)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyridine (70 g, 439 mmol, 1.00 equiv), NaI (661 g, 4.41 mol, 10.00 equiv), ACN (700 mL) and acetyl chloride (56 g, 713 mmol, 1.60 equiv) were combined in a 2000-mL 4-necked round-bottom flask. The resulting solution was stirred overnight at 80° C. in an oil bath and then cooled to r.t, diluted with ice aqueous saturated sodium carbonate (500 mL) and extracted with dichloromethane (3×500 mL). The combined organic layer was washed with NaS2O3 (10%, 3×300 mL) and the aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with brine (2×500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (1:10 ethyl acetate/petroleum ether) to afford 4-(1-fluoroethyl)-2-iodopyridine as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:27])[C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cccn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)c(Cl)c2-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-(4-chloro-2-pyrazol-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedure D, 78 mg, 0.2 mmol), N-chlorosuccinimide (67 mg, 0.5 mmol), benzoyl peroxide (2.4 mg, 0.01 mmol), and carbon tetrachloride (4 mL). The vial was sealed and stirred for 18 hours at 80° C. The resultant solution was partitioned between ethyl acetate and water and the combined organics were washed with 1 N HCl, saturated sodium bicarbonate, and brine; dried over magnesium sulfate; filtered; and concentrated in vacuo. The crude product was subsequently purified by flash column chromatography (10-100% ethyl acetate in hexanes) followed by preparative HPLC (10-90% gradient of MeCN:water) to afford the title compound as a white solid: MS (ES) M+H expected 424.1, found 424.1.