Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Br)#[N:2].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1>C(OCC)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: N#CBr
Solvent: CCOCC
Product: COc1ccc(NC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyanobromide (0.6 eq) in diethyl ether, a solution of 4-methoxy phenyl amine (1.0 eq) in diethyl ether was added and the reaction mixture was stirred at room temperature for 2 h. Salt separated out was filtered and the filtrate was concentrated to afford the desired 4-methoxy-phenyl-cyanamide in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a solution of ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylate (D104) (38.7 mg, 0.071 mmol) in Tetrahydrofuran (THF) (10 mL), Ethanol (2 mL) and Water (1 mL) was added sodium hydroxide (56.9 mg, 1.423 mmol). The reaction mixture was stirred at room temperature overnight (16 h). Sodium hydroxide (56.9 mg, 1.423 mmol) was added again. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 2N HCl solution till pH ˜6.0. The organic solvent was removed. Then the mixture was extracted with EA/THF. The combined organic layers were concentrated. The residue was re-dissolved in THF/water and then purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylic acid (E73) (10 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.78 (2H, m), 1.94 (1H, m), 2.12 (2H, d), 2.55 (1H, m), 3.08 (4H, m), 3.29 (3H, m), 3.49 (3H, m), 3.66 (2H, d), 4.87 (1H, dt), 7.29 (1H, t), 7.40 (1H, d), 7.49 (1H, m), 7.93 (1H, m), 8.04 (1H, dd), 8.16 (1H, d), 9.51 (1H, br. s.), 12.59 (1H, br. s.). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H34ClN3O3S requires 515.2. found 516.2 (M+H+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(S)(S)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[F:45][C:44]([C:42]([OH:48])=[O:43])([F:47])[F:46]
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Reaction time: 0.5 h

Procedure:
To Boc-Leu-DTrp-βAla-OEt (760 mg) obtained in Example 29-(1) was added 20% ethanedithiol/TFA (25 ml) at 0°~5° C. The reaction mixture was stirred at 0°~5° C. for 30 min, and concentrated under reduced pressure. Toluene was added to the residue and the solution was again concentrated under reduced pressure. These procedures were repeated 3 times. The resulting residue was dissolved in ether (5 ml). Addition of hexane (ca. 10 ml) caused precipitation. Filtration of a precipitate, followed by drying in vacuo gave Leu-DTrp-βAla-OEt.TFA (781 mg) as a pale yellow solid. To the solid (781 mg) was added sat. NaHCO3. Extraction with chloroform, followed by drying the organic layer over MgSO4, and concentration of the resulting solution under reduced pressure, gave the product (479 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(5,7-difluoro-quinolin-6-yl)-methanol (Stage 182.4, 3.0 g, 8.65 mmol) was dissolved in DCM (87 mL) and Dess-Martin periodinane (4.40 g, 10.38 mmol) was added. The RM was stirred for 3 h at rt. The solvent was removed and the residue was then taken up with EtOAc and washed with 2.5 M NaOH and with brine. The organic layer was then dried over Na2SO4 and the solvent was removed to give the title compound as a brown solid (tR 1.2 min (conditions 2), MH+=345).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([OH:25])[CH:11]=2.[CH2:29](I)[CH3:30].[H-].[Na+].CN(C)C=O>C(OCC)(=O)C>[CH2:29]([O:25][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[CH:3]=1)[C:18]1[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]2=1)[CH3:30]
Reactant: CCI
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(O)ccc3n2Cc2cccc(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Add N-[9-(3-fluoro-benzyl)-6-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (175 mg, 0.46 mmol), ethyl iodide (72 mg 0.46 mmol), and sodium hydride (60% suspension in mineral oil, 37 mg, 0.92 mmol) to dimethylformamide (1 mL) and stir at room temperature overnight. Dilute the reaction with ethyl acetate, wash with water (2×), dry over sodium sulfate, and concentrate. Recrystallize from ethyl acetate/hexanes to obtain the title compound (107 mg, 57%): MS (ES): m/z (M+1); 1H NMR (CDCl3): δ 7.28 (m, 1H), 7.11 (d, 1H), 6.98 (s, 1H), 6.97 (m, 1H), 6.82 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 5.58 (broad s, 1H, NH), 5.22 (s, 2H), 4.44 (m, 1H), 4.09 (q, 2H), 3.15 (dd, 1H), 2.60-2.81 (m, 3H), 2.33 (m, 1H), 2.15 (m, 2H), 1.45 (t, 1H), 1.18 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[CH3:13][C:10]([CH3:14])([CH:9]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[O:8][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]#[N:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)C(O)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(c2ccncc2)C(C)(C)C#N)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 37.3 %

Procedure:
Triethylamine (1.57 ml, 11.3 mmol) was added to a solution of 3-hydroxy-2,2-dimethyl-3-(4-pyridyl)propionitrile (1.00 g, 5.67 mmol) in dichloromethane (20 ml) at room temperature. Further, p-toluenesulfonyl chloride (1.30 g, 6.80 mmol) was added to the mixture, and the whole was warmed at 50° C. with stirring for three days. The reaction mixture was allowed to stand and then concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 699 mg (37.4%) of 2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile as a pale yellow solid.
Reaction SMILES: I(O)(=O)(=O)=O.[C:6]([O:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[O:28]C1CCCCCCCC)(=[O:8])[CH3:7]>O.O1CCOCC1>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:28])(=[O:8])[CH3:7]
Reactant: CCCCCCCCC1OC1CCCCCCC=COC(C)=O
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCCCCCCCCC=O
Temperature: 25 °C

Procedure:
To a solution of 31 g (0.11 moles) of crystallic periodic acid (HIO4, 2H2O) in 50 ml of water a solution of 25 g (0.076 moles) of 9.10-epoxy-octadecen-1-ol acetate in 220 ml of dioxane is added in 10 minutes. The reaction mixture is stirred at room temperature for a night, then poured onto water. The aqueous suspension is extracted twice with a total amount of 500 ml of petroleum ether, washed with water, dried with magnesium sulfate, the solvent is distilled off, and the residue is distilled in vacuo, under argon. The nonanal forming as a side-product is the first to distille over (b.p.: 80°-85° C., 9.75 g, 90%). The 9-acetoxy-nonanal distils over at 160°-162° C.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5](I)=[C:4]([CH3:11])[C:3]=1[CH3:12].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([C:24]#[C:23][C:20]3[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)=[C:4]([CH3:11])[C:3]=2[CH3:12])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Cc1c(C)c(I)c(C)c(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1ccc(C#Cc2c(C)c(C)c(C#Cc3ccc(CCCC)cc3)c(C)c2C)cc1

Procedure:
8.1 g (20 mmol) of 1,4-diiodo-2,3,5,6-tetramethylbenzene, 7.5 g (47.3 mmol) of 4-n-butylphenylacetylene, 2 g (2.9 mmol) of bis(triphenylphosphine)palladium(II) chloride and 550 mg (2.9 mmol) of copper(I) iodide are initially introduced in 100 ml of triethylamine, and the mixture is heated under reflux for 3 h. The batch is then cooled, water and MTB are added, and the phases are separated. The organic phase is washed with saturated ammonium chloride solution and with sodium chloride solution and evaporated in a rotary evaporator, and the residue obtained in this way is purified by column chromatography (SiO2, heptane); the further purification is carried out by recrystallisation from isopropanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:36][CH2:37][S:38][CH3:39])[C@@H:18]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:19]([O:21]CC1C=CC(OC)=CC=1)[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:36][CH2:37][S:38][CH3:39])[C@@H:18]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)OCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CCC[C@H](CCSC)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of (2S,6R,7R,8S)-methyl 2-((tert-butoxycarbonyl)amino)-7-isobutoxy-8-((4-methoxybenzyl)oxy)-6-(2-(methylthio)ethyl)nonanoate (536 mg, 0.941 mmol) and 0.85 mL H2O in CH2Cl2 (9.4 mL) at 0° C. (icewater bath) was added DDQ (214 mg, 0.941 mmol). The resulting dark mixture was stirred at 0° C. for 3 h, then another portion of DDQ (41 mg, 0.180 mmol) were added and the reaction was stirred for 1 h. The reaction was quenched with sodium hydroxide (NaOH; 1.3 ml of 1M aqueous, 1.3 mmol) and stirred for 10 min. The reaction was then diluted with H2O (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a red oil which was purified by column chromatography on SiO2 (5→35% acetone/hexanes gradient) to furnish the title product as a clear, colorless oil (353 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 5.02 (d, J=8.0 Hz, 1H), 4.31 (d, J=5.2 Hz, 1H), 3.95-3.83 (m, 1H), 3.74 (d, J=1.6 Hz, 3H), 3.36 (dd, J=8.5, 6.3 Hz, 1H), 3.22 (dd, J=8.5, 6.6 Hz, 1H), 3.05 (dd, J=5.6, 3.9 Hz, 1H), 2.58 (ddd, J=14.0, 8.7, 5.3 Hz, 1H), 2.47 (ddd, J=12.8, 8.3, 7.4 Hz, 1H), 2.10 (s, 3H), 1.96-1.68 (m, 4H), 1.68-1.49 (m, 3H), 1.45 (s, 9H), 1.39 (s, 4H), 1.21 (d, J=6.3 Hz, 3H), 0.91 (dd, J=6.7, 1.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.36, 155.36, 84.83, 79.93, 79.24, 68.10, 53.20, 52.27, 38.01, 33.20, 33.05, 32.76, 30.90, 29.21, 28.83, 28.33, 22.83, 19.52, 19.46, 19.11, 15.43; ESIMS m/z 450.4 ([M+H]+), 472.4 ([M+Na]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16](N)[CH2:17][NH2:18].[S]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:14]1[NH:18][CH2:17][CH2:16][N:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CC(c1ccccc1)c1ccccn1
Reactant: NCCN
Agent: [S]
Product: c1ccc(C(C2=NCCN2)c2ccccn2)cc1
Temperature: 125 °C

Procedure:
Under a nitrogen atmosphere, carefully reflux (bath temperature of 125° C) a mixture containing 19.4 g. of 2-pyridylbenzyl cyanide, 6.6 g. of ethylene diamine and 0.2 g. of sulphur for 5 hrs. Cool the reaction mixture and under a nitrogen atmosphere dissolve the residue in 300 ml. of benzene, and water wash, dry (over anhydrous potassium carbonate) and filter the benzene solution. Concentrate the filtrate to a small volume whereupon the product crystallizes. Filter the crystals to yield 2-[α-(2-pyridyl) benzyl]-imidazoline, m.p. 134°-136° C. The maleate salt, m.p. 132°-135° C, is prepared from maleic acid and is crystallized from isopropanol.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[CH3:29][N:30]([CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33]
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol as light yellow oil, MS: 409 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22]C2C=CC=CC=2)=[O:20])[C:3]=1[Cl:29].CO.C[O-].[Na+]>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:29]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Reaction time: 24 h

Procedure:
Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (3.00 g, 6.83 mmol) was added to CH3OH (35 mL). Sodium methoxide (25 wt % in CH3OH; 1.9 mL, 8.2 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir for 24 h. Water (50 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove most of the CH3OH. The mixture was extracted with EtOAc (2×40 mL), and the combined organic layers were washed with water (40 mL) and satd sodium chloride (40 mL). Concentration of the volatiles under reduced pressure provided methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a pale yellow solid (2.04 g, 88% purity by LC area).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCc1ccc(OCCO)cc1
Reaction time: 48 h

Procedure:
5 g p-hydroxyphenylacetonitrile were dissolved in 250 ml methylethylketone. 7 g of 2-bromoethanol and 23 g potassium carbonate were added thereto. The mixture was stirred for 48 hours under reflux. At the end of the reaction the potassium carbonate and the produced potassium bromide were filtered. The precipitates were washed with acetone and the acetone wash was added to the reaction mixture. The clear solution was reduced to about 10-15 ml. It was then taken up in ether and shaken with 1/100 N sodium hydroxide.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:30])[C:5]=2[CH:14]=1)(=[O:19])[NH2:20]
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(N)=O)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(N)=O)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
564 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxamide were dissolved in 20 ml of dichloromethane at room temperature and 540 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated to give a solid which was recrystallized from isopropanol to yield 164 mg of 2-(6-carbamoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 248-250° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:18](O)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.N1C=CC=CC=1>[C:19]1([C:18]2[O:1][N:2]=[C:3]([N:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]3)[N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (7 g, 28.6 mmol) in anhydrous DCM (150 mL) was added benzoic acid (3.49 g, 28.6 mmol) followed by diisopropyl carbodiimide (DIC, 3.6 g, 28.6 mmol). The reaction mixture was stirred at RT for 8 hours and filtered. The filtrate was evaporated and the residue obtained was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried and the solvent was evaporated. The residue was purified by chromatography using petrol ether/EtOAc (9/1) as eluent to afford 5 g (53%) of the title compound as a solid. TLC-Pet ether/EtOAc (9/1): Rf=0.7). HPLC purity: 96%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH2:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1CCOCC1>O.Cl>[NH2:16][CH2:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:17])[CH:7]=2)=[N:9][CH:10]=1
Reactant: C1COCCO1
Reactant: Cc1cc(CN)cnc1-c1ccnc(F)c1
Agent: Cl
Solvent: O
Product: Cc1cc(CN)cnc1-c1cc[nH]c(=O)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a mixture of (2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methanamine 66-1 (65 mg, 0.30 mmol) in dioxane (0.6 mL) and H2O (0.2 mL) was added a few drops of aqueous concentrated HCl solution. The mixture was stirred at 90° C. for 10 hours, and then concentrated to dryness by rotary evaporation to give 4-(5-(aminomethyl)-3-methylpyridin-2-yl)pyridin-2(1H)-one 66-2 as yellow solid.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:23]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)[N:25]=2>CN1CCCC1=O>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:22]2[N:23]([CH2:44][C:45]([F:46])([F:48])[F:47])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:25]=3)[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)C1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μg, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: COc1ccc(B(O)O)cc1
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+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94.2 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (100 mg, 0.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (20 mg, 0.017 mmol) and 4-methoxyphenylboronic acid (60 mg, 0.39 mmol), followed by 2 M Na2CO3 (0.35 mL, 0.70 mmol). The mixture was heated to reflux for 4 hr, and was then quenched with water and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 15:1) to give the title compound (102 mg, 94%). mp: 155-158° C.