Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:31])([F:30])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:31])([F:30])[F:6])=[N:9][N:10]=4)[N:13]=3)[CH2:22][CH2:21]2)=[CH:29][CH:28]=1)=[O:4]
Reactant: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of chloroacetyl chloride (140 mg, 1.24 mmol) in DCM (2 mL) was added dropwise to a stirred suspension of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (obtained as described in Example 615) (375 mg, 1.03 mmol) and pyridine (164 mg, 2.07 mmol) in DCM (3 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The resulting precipitate was collected by filtration, washed with DCM (2 mL) and dried under vacuum to give 2-chloro-N-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (418 mg, 92%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=O)[N:8]([CH3:17])[CH2:7][C:6]=12.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[S:27])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(Cl)ncn2-c2ccccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1Cc2c(Cl)ncn2-c2ccccc2C1=S

Procedure:
3.71 g (15 mmol) of 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 10 ml of toluene are heated to boiling under reflux for 4 hours together with 3.03 g (7.5 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The solution is washed with water and evaporated. By chromatography on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-thione of melting point 197.5°-198.5°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CS(O[CH2:19][C:20]1[S:28][C:27]2[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=2[CH:21]=1)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:19][C:20]2[S:28][C:27]3[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=3[CH:21]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)CC1
Yield: 50 %

Procedure:
Potassium carbonate (26.5 mmol) and N-methylpiperazine (6.36 mmol) was added to a solution of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) in toluene (30 ml). The reaction mixture obtained was heated under reflux for 16 hours. The reaction temperature was then reduced to 25° C. and the reaction mixture was diluted with ethyl acetate. The reaction mixture was washed with water and saturated sodium chloride solution and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the crude product obtained was purified by column chromatography (5% methanol in methylene chloride). The desired product was obtained in a yield of 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N:22]=[C:23]=[O:24])[C:3]=1[CH3:25].C(N(CC)CC)C.[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][C:23]([O:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:24])[C:3]=1[CH3:25]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N=C=O
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 45.4 %

Procedure:
3-(4-Chloro-6-fluoro-2-isocyanato-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.4 mmol) and triethylamine (0.14 g, 1.4 mmol) were dissolved in toluene (15 ml) and the solution was treated with phenol (0.13 g, 1.4 mmol). Solution was stirred for 0.3 hr at ambient temperature and water was added. Product was extracted with ethyl acetate. Removal of the solvent followed by column chromatography on silica gel (eluent, methylene chloride) afforded the title compound (0.3 g).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:14]N1C(=O)CCC1=O.O>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[I:14][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Oc2ncccn2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Ic1ccc(Oc2ncccn2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 2-phenoxypyrimidine (int AY) (4.03 g, 0.0234 mol) and N-iodosuccinimide (10.52 g, 0.0468 mol) in trifluoroacetic acid (40 mL) and trifluoroacetic anhydride (8 mL) was heated at reflux for 4 hours. The mixture was allowed to cool to ambient temperature and water (75 mL) was added. The mixture was extracted with three times with 50 mL. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate (50 mL), twice with 10% aqueous sodium thiosulfate (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude solid was purified by flash column chromatography on silica gel using n-heptane/ethyl acetate (3:1) as an eluent to give 2-(4-iodophenoxy)pyrimidine as a light yellow solid (3.49 g, 0.0117 mol): 1H NMR (CDCl3, 400 MHz) 8.57 (d, 2H), 7.73 (d, 2H), 7.07 (t, 1H), 6.98 (d 2H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.45.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][O:14]C2CCCCO2)=[C:4]([C:8](=[O:12])[CH2:9][O:10][CH3:11])[CH:5]=[N:6][CH:7]=1>C(O)C>[Cl:1][C:2]1[C:3]([CH2:13][OH:14])=[C:4]([C:8](=[O:12])[CH2:9][O:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: COCC(=O)c1cncc(Cl)c1COC1CCCCO1
Solvent: CCO
Product: COCC(=O)c1cncc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-2-methoxy-ethanone (0.14 g, 0.46 mmol) in ethanol (15 mL) p-TsOH monohydrate was added. After stirring overnight at RT, solvent was evaporated and the residue was purified by flash chromatography on silica gel with EA/hexane to provide the title compound as a colourless oil. MS (m/z): 216.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([OH:12])=O.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:12]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)C#Cc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 0° C. slurry of 3-(2-fluorophenyl)prop-2-ynoic acid (151 g, 0.92 mol) in CH2Cl2 (3L) was added DMAP (118 g, 0.96 mol, 1.05 equiv), followed by sarcosine ethyl ester hydrochloride (148 g, 0.96 mol, 1.05 equiv), and NMM (233 g, 2.3 mol, 2.5 equiv). The resulting clear solution was allowed to warm to room temperature and was maintained for 17 h. The reaction mixture was washed with a 2N HCl solution (4×500 mL). The aqueous layers were combined and the mixture was adjusted to pH 2 using conc. H2SO4, then back-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with a 10% H2SO4 solution (2×500 mL), dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (174 g, 72%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.61; 1H NMR (CDCl3; of rotomeric mixture) δ 1.27 (t, J=7.2 Hz, 3H), 3.07 (s, 1.4H, N—CH3), 3.36 (s, 1.6H, N—CH3), 4.17-4.27 (m, 3.2H), 4.41 (s, 0.8H, N—CH2), 7.06-7.17 (m, 2H), 7.37-7.58 (m, 2H); 13C NMR (CDCl3; of rotomeric mixture) δ 14.00, 14.03, 33.5, 37.2, 48.0, 52.5, 61.3, 61.5, 83.6, 84.3, 85.7 (d, JC−F=9.9 Hz, 1C), 108.9 (d, JC−F=15.5 Hz, 1C), 109.1, (d, JC−F=15.5 Hz, 1C), 115. (d, JC−F=10.4 Hz, 1C), 115.6 (d, JC−F=10.4 Hz, 1C), 124.2, 132.0 (d, JC−F=7.8 Hz, 1C), 132.1 (d, JC−F=7.8 Hz, 1C), 134.10, 134.15, 154.6, 163.3 (d, JC−F=254.4 Hz, 1C), 168.1, 168.5; HPLC ES-MS m/z (rel abundance) 264 (MH+, 75%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:28])[C:18]([S:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[CH2:21]([S:20][C:18]1[C:17]([Cl:28])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a mixture of 1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (57.0 mg, 0.127 mmol), THF (2 mL), and water (0.67 mL) was added LiOH.H2O (27.0 mg, 0.654 mmol). The mixture was stirred for 18 h at 23° C. The reaction mixture was concentrated under reduced pressure, water (3 mL) was added and the mixture acidified to pH=3 with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (39.0 mg, 80%). MS (ESI/CI): mass calcd. for C18H13ClN4O2S, 384.0; m/z found, 385.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.86 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.39 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.1 Hz, 1H), 4.29 (s, 2H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.[OH-].[Na+]>[N+:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=1)([O-:17])=[O:16]
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc([N+](=O)[O-])ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
N-(4-methoxybenzyl)-4-nitropyridin-2-amine (Int-21, 27.8 g, 0.11 mol) and anisole (13 mL, 0.12 mol) were dissolved in trifluoroacetic acid (112 mL) and heated at 80° C. for 2 h. The reaction mixture was allowed to cool to rt and concentrated. Trituration of the resulting residue with EtOAc and hexanes produced a light yellow solid that was isolated via filtration. The filtrate was allowed to stand overnight and a second crop of crystals was obtained. The combined batches of solids were dissolved in 1N NaOH (250 mL) and extracted with EtOAc (2×250 mL). The combined organic solutions were dried over magnesium sulfate, filtered and concentrated to give 4-nitropyridin-2-amine as an orange solid (10.2 g, 67%). LCMS: (FA) ES+ 140; 1H NMR (400 MHz, CD3OD) δ ppm 8.15 (dd, J=5.7, 0.6 Hz, 1H), 7.23 (dd, J=2.0, 0.6 Hz, 1H), 7.20 (dd, J=5.7, 2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH3:11]>>[CH3:10][C:11]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: Cc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and acetic acid (0.15 ml) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (9:1) to give the pure product (0.25 g, 85%) as a light brown solid. 1H NMR (300 MHz, CDCl3): 8.14 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz), 2.73 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22](=[O:23])[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:27][CH:26]=1
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccc([N+](=O)[O-])cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(4-nitrophenoxy)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 395 mg of the title compound (85%) as a yellow solid in 97.3% purity by HPLC (Rt: 5.76, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)(O)[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:37])[N:20]=1)[CH2:17][CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:26][CH:27]=[C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:22]=[C:21]([CH3:37])[N:20]=1)[CH2:17][CH3:18]
Reactant: CCN(c1nc(C)cc(N2CCC(O)(c3ccco3)CC2)n1)c1ccc(C(C)C)cc1Br
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1nc(C)cc(N2CC=C(c3ccco3)CC2)n1)c1ccc(C(C)C)cc1Br
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A solution of 48 mg of methanesulfonyl chloride in 0.5 ml of dichloromethane was added dropwise under ice-cooling to a solution of 104 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(furan-2-yl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine, 85 mg of triethylamine, and 13 mg of 4-dimethylaminopyridine in 1 ml of dichloromethane, followed by stirring for 15 minutes and then at room temperature for 2 hours. The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The extract was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to give 70 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(furan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22]O.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:21][CH2:22][N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH3:24]
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO
Reactant: CC1CCCN1
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCN1CCCC1C

Procedure:
2-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-oxazol-2-yl}-phenoxymethyl)-pyridine is prepared in a manner substantially similar to Example 53 from 2-{5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol and 2-methylpyrrolidine. MS (m/e): 378.3 (M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH3:15])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[OH-].[Na+]>CC#N.O>[CH3:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[C:2]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[N:3]=1
Reactant: CNc1nc(Cl)nc(-c2ccccc2)n1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(-c2ccccc2)nc(N2CCC(C(=O)O)CC2)n1
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-N-methyl-6-phenyl-1,3,5-triazin-2-amine (10.0 g, 45.3 mmol, 1.00 equiv) dissolved in 1:1 CH3CN:H2O (60 mL) was cooled (0° C.), and 4-piperidinecarboxylic acid (11.7 g, 90.6 mmol, 2.00 equiv) was added. The pH of the reaction mixture was adjusted to 9-10 by treating with 1 N NaOH. The pH was maintained at 9-10 for 24 hours (product formation monitored by LCMS). The mixture was diluted with water, and filtered to provide the crude product (filtered solid was washed with additional water). The resulting solid was purified by HPLC to afford 9.1 g of the title compound. MS (ES+): m/e 314.2 [M+H]+.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([CH2:8][NH2:9])[OH:7]>>[OH:7][CH2:6][CH2:8][NH:9][CH2:1][CH:2]([OH:3])[CH2:4][OH:5]
Reactant: NCCO
Reactant: OCC1CO1
Product: OCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
The commercially available glycidol (0.17 mol, 11 ml) was added dropwise to stirred ethanolamine (1 eq, 1.4 mol, 84.3 ml) at 0° C. Once addition was complete the reaction was allowed to warm up to room temperature, while stirring overnight. The product was then distilled (Ethanolamine first distilled at 60° C. at 1 Torr, and the desired product at 170° C. at 1 Torr). The product was obtained a clear oil that cooled to a clear viscous syrup (0.122 mol, yield=72%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]O>>[OH:11][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:12])=[O:7])[NH2:1]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CO
Product: COC(=O)c1ccc(N)cc1O

Procedure:
A solution of 4-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) in MeOH (15 mL) and concentrated sulfonic acid (1 mL) was refluxed overnight. The reaction mixture was quenched with NaHCO3 aqueous solution (60 mL) and EtOAc (60 mL). The organic layer was separated, dried, evaporated to give 3-hydroxy-4-methoxycarbonylaniline.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[F:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([F:48])=[C:26]([NH:25][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 78.2 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (150 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (140 μL, 1.6 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (240 mg, 77%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:24][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cccc(C(F)(F)F)c2)o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Yield: 56.4 %

Procedure:
To a solution of 5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370B) (1.0 g, 4.4 mmol) was added NBS (0.784 g, 4.4 mmol) and benzoyl peroxide (0.100 g, 0.41 mmol). The mixture was refluxed for 1 h and the solids were filtered. The filtrate was concentrated and purified by radial chromatography (0-20% EtOAc-hexanes gradient) to afford the title compound (0.760 g, 56% yield): MS (ES) m/z 306 (M+1) and 308 (M+1, isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)nc23)cc(C)n1
Yield: 46.1 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (97 mg, 46%). MS (ISP) 421.1 [(M+H)+]; mp 271° C.
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]([CH:28]=[N:29][NH:30]C(=O)CN1C(=O)C2C(=CC=CC=2)C1=O)[C:14](=O)[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])=[O:5].FC(F)(F)C(O)=O>>[F:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:2]([F:1])[C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH:28]=[N:29][N:30]=[C:14]1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:18]2[C:17]1=[O:26]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 7, 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide is heated to 100°-110° C. with trifluoroacetic acid to give 2',6'-difluoro-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.