Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[OH-].[Na+].O>C(O)CO>[CH3:21][O:20][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3CCCCO3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(C2CCCCO2)c2sc(N)nc12
Temperature: 100 °C
Yield: 79.8 %

Procedure:
To a solution of 2.60 g (8.06 mmol) [4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-carbamic acid methyl ester in 100 ml ethylene glycol was added 100 ml 2 N NaOH and the mixture was heated at 100° C. for 3 h. After cooling to room, the reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (acetone/hexane 1/4-1/2) afforded 1.70 g (80%) 4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 265 (M+H+, 100).
Reaction SMILES: CN(C)C=O.[CH2:6]([O:8][C:9](=[O:26])[CH2:10][N:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][C:13]=1[CH3:19])[CH3:7].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:6]([O:8][C:9](=[O:26])[CH2:10][N:11]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]1[CH:17]=[C:16]([CH2:29][CH2:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(I)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)OC(C)(C)C)ccc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To N,N-dimethylformamide (43 ml) were added the compound (2.03 g, 5.00 mmol) obtained in step A, tert-butyl acrylate (3.20 g, 25.00 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride—dichloromethane complex (1:1) (204 mg, 0.250 mmol), tetra-n-butylammoniumiodide (2.78 g, 7.50 mmol), water (6.9 ml) and triethylamine (6.9 ml), and the mixture was heated at 80° C. for 2 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane). To the obtained colorless oil (1.86 g) in ethanol (23 ml) was added 10% palladium carbon (containing water) (186 mg), and the mixture was stirred at room temperature for 3 hr. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.79 g, yield 88%) as a colorless oil.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]2[CH2:13][CH:4]1[CH:5]=[CH:6]2)=[O:2].C>C(OCC)(=O)C.[Pd]>[CH:1]([CH:3]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]2[CH2:13][CH:4]1[CH2:5][CH2:6]2)=[O:2]
Reactant: COC(=O)C1C2C=CC(C2)C1C=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1C2CCC(C2)C1C=O
Yield: 81.6 %

Procedure:
4 g (0.022 mole) of methyl 2-formyl-bicyclo[2.2.1]hept-5-en-3-yl-carboxylate--see Example 2 above--in 60 ml of ethyl acetate were hydrogenated in the presence of 100 mg of 10% Pd over charcoal at atmospheric pressure and at room temperature. After absorption (about 1 h) of the theoretical quantity of hydrogen, the reaction mixture was filtered and the clear filtrate was concentrated under reduced pressure. The obtained residue was distilled (pressure: 0.06 Torr/bath temperature: 82°-115°) to yield 3.27 g (yield 82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([O:8][CH2:9][C@@H:10]2[C@@H:14]([O:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C@:13]([F:26])([CH3:25])[C:12](=[O:27])[O:11]2)=[O:7])=[CH:4][CH:3]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(OCC)(=O)C.[Cl-].[NH4+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C@@H:10]2[C@@H:14]([O:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C@:13]([F:26])([CH3:25])[C@H:12]([OH:27])[O:11]2)=[O:7])=[CH:28][CH:29]=1
Reactant: C[C@]1(F)C(=O)O[C@H](COC(=O)c2ccc(Cl)cc2)[C@H]1OC(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccc(Cl)cc2)[C@H]1OC(=O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a 1 liter dry round-bottomed flask was loaded ((2R,3R,4R)-3-(4-chlorobenzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl 4-chlorobenzoate (1b, 50.0 g, 113 mmol) and the solid was dissolved in anhydrous THF (200 mL). The solution was cooled to −20° C. Lithium tri-tert-butoxyaluminohydride (1.0 M in THF) (170 mL, 170 mmol) was added via an addition funnel over 20 min and the resulting mixture was stirred for an additional one hour at −20° C. Ethyl acetate (120 mL) was added and the mixture was allowed to warm up slowly to 0° C. Sat. aq ammonium chloride (4.5 mL) was added. The mixture was concentrated under reduced pressure and then diluted with EtOAc (500 mL). Aqueous HCl (3 N, 300 mL) was added to dissolve all solids. After separation, the organic layer was washed with water (2×200 mL), brine (100 mL), and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to furnish an amorphous solid. The solid was dissolved in methanol (169 mL) heated to reflux. After cooling to room temperature, water was added portionwise (37 mL total) until a slightly turbid mixture formed. After standing, the precipitated β-lactol product was filtered and washed with methanol (2×20 mL) and dried (0.2 mmHg, 50° C., 17 h) to 30.5 g (61%) of an off-white solid with an anomeric ratio of β/α>35:1. 1NMR (DMSO-d6): δ 7.95 (m, 2H, arom.), 7.90 (m, 2H, arom.), 7.61 (m, 2H, arom.), 7.51 (m, 2H, arom.), 7.31 (dd, 1H, C1-H, J=5.2 Hz, J=0.8 Hz), 5.50 (dd, 1H, C3-H, J=24 Hz, J=7.2 Hz), 5.19 (dd, 1H, C4-H, J=10.8 Hz, J=5.6 Hz), 4.56 (m, 1H, C5-Ha), 4.42 (m, 2H, C5-Hb and OH), 1.42 (d, 3H, CH3, J=22.8 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.N#N.[H][H]>CO.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Nc1cnc(C2=CCOCC2)cn1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: Nc1cnc(C2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-amine (2.7 g, 15.24 mmol) and Pd—C (10%, Degussa type) (1.6 g, 1.5 mmol) in MeOH (50 mL) was degassed by N2 stream for 15 min. After equipped with hydrogen gas balloon, the reaction mixture was stirred for 15 h at room temperature. The crude product was filtered off through celite pad and washed with EtOAc. The volatile material was concentrated in vacuo yielding 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine and was used for the next step. LCMS (m/z): 180.3 (MH+), 0.28 min.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:11]([C:14]1[CH:15]=[N:16][N:17]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:18]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2cc([N+](=O)[O-])cn2)cc1
Reaction time: 5 h
Yield: 31 %

Procedure:
To 4-tolylboronic acid (544 mg, 4.00 mmol), 4-nitropyrazole (226 mg, 2.00 mmol), copper (II) acetate (545 mg, 3.00 mmol), and 4 Å sieves (1.5 g) in DCM (15 mL), was added pyridine (0.32 mL, 4 mmol) at RT, and stirred for 5 h. The mixture was filtered through Celite, washing with DCM, then evaporated to dryness. The residue was purified by FCC, eluting with 0-30% ethyl acetate in cyclohexane, to give the title compound as a white solid (126 mg, 31%). LCMS (Method 3): Rt 3.93 min, m/z 204.1 [MH−].
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][Si:10]([CH3:13])([Cl:12])[Cl:11].[Cl:14][SiH:15]([Cl:17])[Cl:16]>>[Cl:14][Si:15]([Cl:17])([Cl:16])[CH2:9][Si:10]([Cl:12])([Cl:11])[CH3:13]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](Cl)(Cl)CCl
Solvent: CCN(CC)CC
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 30.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.063 g (0.62 mmol) of triethylamine, 1.0g (6.2 mmol) of (chloromethyl)methyldichlorosilane, and 4.18 g (30.9 mmol) of trichlorosilane were reacted at 200° C. for 24 hrs. The resulting mixture was distilled to give 0.50 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (yield; 31%).
Reaction SMILES: [CH2:1]([N:4]([C:6]([NH:8][C:9]1[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=1)=[O:7])[NH2:5])[CH2:2][CH3:3].[CH2:16]=O.[OH-].[K+]>CO>[CH2:1]([N:4]1[C:6](=[O:7])[N:8]([C:9]2[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=2)[CH2:16][NH:5]1)[CH2:2][CH3:3]
Reactant: C=O
Reactant: CCCN(N)C(=O)Nc1nnc(OC)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCN1NCN(c2nnc(OC)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:33]([CH2:34]O)=[CH:32][C:31]([CH3:36])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:22]([N:29]1[C:33]([CH2:34][Br:20])=[CH:32][C:31]([CH3:36])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(CO)n(Cc2ccccc2)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)n(Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a stirring solution of 1.10 g (4.21 mmol, 1.2 equiv) of triphenylphosphine in 15 mL of CCl4 at -5° C. is added 200 μL (3.86 mmol, 1.1 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 710 mg (3.51 mmol) of (2-Benzyl-5-methyl-2H-pyrazol-3yl) methanol, prepared as in Part C, in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 0.5 h at RT, and then poured into 25 mL NaHCO3 and extracted with Et2O (2×25 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 576 mg of the title compound as a clear oil: 1H NMR (CDCl3, 300 MHz) δ7.32 (m, 3H), 7.19 (m, 2H), 6.16 (s, 1H), 5.42 (s, 2H), 4.32 (s, 2H), 2.31 (s, 3H); low resolution MS (FAB)m/e 265 (M+).
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].Cl.[CH:30]([NH:33][OH:34])([CH3:32])[CH3:31].CC(C)([O-])C.[K+].CCOC(C)=O>C1COCC1.CCN(CC)CC.CO>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:34][NH:33][CH:30]([CH3:32])[CH3:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: CC(C)NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2ONC(C)C)cc(C(C)(C)C)n1C
Temperature: 40 °C
Yield: 18.5 %

Procedure:
To a solution of Example 81C (0.51 g, 1.3 mmol) and N-isopropylhydroxylamine hydrochloride (0.29 g, 2.6 mmol) in THF (20 mL) was added potassium tert-butoxide (0.43 g, 3.8 mmol). The mixture was warmed to 40° C. for 18 hours then concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.11 g, 0.24 mmol, 19% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.97 (t, J=7.3 Hz, 3H) 1.11 (d, J=6.4 Hz, 6 H) 1.33-1.49 (m, 2H) 1.42 (s, 9H) 1.63-1.73 (m, 2H) 3.43-3.59 (m, 1H) 3.75 (s, 3H) 4.28 (dd, J=7.1 Hz, 2H) 6.06 (s, 1H) 7.08 (s, 1H) 7.48 (dd, J=8.6, 1.9 Hz, 1H) 7.68 (d, J=8.8 Hz, 1H) 8.14 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 455 (M+H)+. Anal. calculated for C23H33F3N4O2: Calc: C, 60.78; H, 7.32; N, 12.33. Found: C, 60.87; H, 7.37; N, 12.16.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=2)O1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cn1
Yield: 24 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.0 g) was reacted with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-2-carbonitrile as in General Procedure 4A to give the title compound as a bright yellow solid (24% yield). M.p. 200° C. (dec), LCMS: m/z=364.53 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.46-3.52 (m, 2H), 3.62-3.72 (m, 2H), 4.50 (s, 2H), 5.12 (s, 1H), 6.70 (s, 1H), 6.92-7.00 (m, 2H), 7.03-7.12 (m, 1H), 7.62-7.69 (m, 2H), 7.67 (s, J=3.0 Hz, 1H), 7.75 (m, 1H), 8.73 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(NC1C=C(Cl)NC(C)([N+]([O-])=O)C=1C(OCC)=O)CCC>CO.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCCCN
Agent: CCCCNC1=C(C(=O)OCC)C(C)([N+](=O)[O-])NC(Cl)=C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.5 Mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of n-butylamine are added dropwise. The solvent is then removed in vacuo and 500 ml. of benzene are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting oil is dissolved in 300 ml. of methanol and yields on cooling 110 g. of 4-butylamino-6-chloro-2-methyl-2-nitropyridine-3-carboxylic acid, ethyl ester (70%), m.p. 33°-35° (methanol).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1.O1CCOCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])=[O:8])[N:4]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 25.5 %

Procedure:
0.13 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide was added to a 1,4-dioxane 6 ml solution comprising 0.14 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, followed by reflux with heating for 18 hours. After the reaction liquid was stood to cool, it was poured to water, followed by extraction with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The filtrate was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7/3) to obtain 33 mg of the desired product (melting point: 231 to 233° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[C:15]([O:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[O:20]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
To 3-chloro-4-(trifluoromethyl)phenol (Preparation 16, 110 mg, 0.56 mmol) and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (Preparation 13, 150 mg, 0.56 mmol) dissolved in dimethylsulfoxide (5 ml) was added potassium carbonate (232 mg, 1.68 mmol) and the mixture stirred at 90° C. for 18 hours under nitrogen. The mixture was poured onto ammonium chloride (aq) and extracted with ethyl acetate (3×20 mL), washed with water (3×20 mL) and dried (MgSO4). Purification of the crude product by silica gel column chromatography using 80% Ethyl acetate in heptane furnished the title compound as white solid (12.2 mg, 4.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][C:12]#[N:13].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:11]([C:12]#[N:13])[C:10]1=[O:14]
Reactant: N#CCC(=O)Nc1ccc(F)cc1Br
Reactant: CO/C=C/C(C)=O
Agent: C1CN2CCN1CC2
Solvent: COCCOCCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 29.9 %

Procedure:
A mixture of N-(2-bromo-4-fluorophenyl)-2-cyanoacetamide (5.00 g, 19.4 mmol), (3E)-4-methoxybut-3-en-2-one (2.33 g, 23.3 mmol), 1,4-diazabicyclo[2.2.2]octane (2.18 g, 19.4 mmol) and 2-(2-methoxyethoxy)ethanol (50 mL) was stirred at 130° C. for 5 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50), washed with ethyl acetate-hexane and collected by filtration to give the title compound (1.78 g, 29%) as a pale-brown powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.O=S(Cl)[Cl:25]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([Cl:25])=[O:22])=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of acid 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 6.8 mmol) in SOCl2 (10 mL) was stirred at RT for 2 h under an inert atmosphere. The reaction was concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 95%) as a light yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[CH3:28][N:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/[C:33]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH:20]=1)=[O:34]
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: CN(C)C/C=C/C(=O)O
Product: CN(C)C/C=C/C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 35 %

Procedure:
(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-(dimethylamino)but-2-enoic acid using Method E (35% yield). HPLC: 99%, RT=3.399 min. MS: m/z=466 [M+H]+, RT=3.37 min. 1H-NMR (DMSO-d6) δ 10.52 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 7.48 (t, 1H), 7.43-7.38 (m, 3H), 7.29-7.26 (d, 2H), 7.17-7.12 (m, 3H), 7.05-6.99 (m, 3H), 6.74 (m, 1H), 6.48 (d, 1H), 3.94 (d, 2H), 2.79 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:4]([NH2:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:14]([C:3]([CH2:1][CH3:2])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH2:6])=[O:5])[CH3:15]
Reactant: BrCc1ccccc1
Reactant: CCC(CC)(C(N)=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21 g) in DMF (9.93 mL) was treated with potassium carbonate (0.807 g) and benzyl bromide (0.694 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH3:11])[N:7]=[C:6]([NH:16][CH:17]2[CH2:19][CH2:18]2)[CH:5]=1.[OH-].[Na+].Cl>CO>[CH:17]1([NH:16][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:13])=[O:14])[CH3:11])[N:7]=2)[C:3]([OH:20])=[O:2])[CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(NC2CC2)nc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1cc(C(=O)O)cc(NC2CC2)n1)S(C)(=O)=O
Reaction time: 5 h
Yield: 91 %

Procedure:
Treat a solution of 2-cyclopropylamino-6-(methanesulfonyl-methylamino)-isonicotinic acid methyl ester (261 mg, 0.87 mmol) in methanol (8 mL) with 1 N NaOH (1.3 mL, 1.31 mmol) at room temperature. Stir for 5 h, acidify with 1 N HCl to about pH=3. Extract the reaction mixture with ethyl acetate, dry (sodium sulfate) and concentrate to give the title compound (226 mg, 91%).