Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.[C:24](Cl)(=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(Cl)(Cl)Cl>[CH2:40]([C:41]1[N:16]([CH2:15][CH2:14][CH2:13][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: Nc1ccccc1NCCCn1ccnc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCn1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Triethylamine (0.72 ml) was added to a solution containing N-[3-(1H-imidazol-1-yl)propyl]-1,2-benzenediamine (1.000 g) in chloroform (10.0 ml), and then stearoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.85 ml) was added to a solution containing the residue (2.149 g) in ethanol (22 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.273 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.657 g) as yellow solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[C:9]([CH:10]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[NH:14][C:12](=O)[CH2:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:2]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]1[C:20]2[CH:19]=[C:18]3[O:21][CH2:22][O:23][C:17]3=[CH:16][C:15]=2[NH:14][C:12](=[S:33])[CH2:11]1)[CH3:1]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOc1ccccc1C1CC(=O)Nc2cc3c(cc21)OCO3
Solvent: Cc1ccccc1
Product: CCOc1ccccc1C1CC(=S)Nc2cc3c(cc21)OCO3
Yield: 57.1 %

Procedure:
FQI-1 (200 mg, 1.0 equiv) was weighed into a dry reaction vial under an atmosphere of nitrogen. Dry toluene (4.3 mL) was added, followed by Lawesson's reagent (416 mg, 1.6 equiv). The vial was tightly sealed and the reaction was heated to reflux overnight. After cooling, the solvent was removed in vacuo and the residue was purified by flash column chromatography (gradient of 20% to 70% ethyl acetate in hexanes). Fractions which contained product were pooled to give 120 mg of an impure red oil which was recrystallized from dichloromethane/hexanes to give Compound X as white needles (40 mg, 19%). 1H NMR (400 MHz, CDCl3) δ=9.69 (br. s., 1 H), 7.20 (ddd, J=2.9, 6.0, 8.3 Hz, 1 H), 6.89-6.82 (m, 3 H), 6.46 (d, J=3.1 Hz, 2 H), 5.93 (d, J=1.2 Hz, 2 H), 4.54 (dd, J=6.4, 7.8 Hz, 1 H), 4.10-4.02 (m, 2 H), 3.42 (dd, J=7.8, 17.0 Hz, 1H), 3.23 (dd, J=6.4, 17.0 Hz, 1 H), 1.40 (t, J=7.0 Hz, 3 H). ESI-MS (M+H+) m/z=328.
Reaction SMILES: Cl.NO.[CH2:4]([O:6][C:7](=[O:23])[C:8]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[CH:9][N:10](C)C)[CH3:5].C([O-])(=O)C.[Na+].C(OCC)C>CO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[N:10][O:22][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:23])[CH3:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)c1cnoc1-c1ccc(Cl)c(Cl)c1
Yield: 52.4 %

Procedure:
Hydroxylamine hydrochloride (0.7 g.; 0.01 mol.) was added to a mixture of ethyl-2-(3',4'-dichlorobenzoyl)-3-di-methylaminopropenoate (3.16 g.; 0.01 mol.) and sodium acetate (0.82 g.; 0.01 mol.) in 25 ml. of diethyl ether and 15 ml. of methanol. The resultant mixture was stirred at 25° C. for 16 hours until the reaction was complete. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in chloroform, extracted with water, dried over magnesium sulfate and concentrated in vacuo. Recrystallization with ethanol yielded ethyl-5-(3',4'-dichlorophenyl)-4-isoxazolecarboxylate as a white solid (1.5 g.; 52.4% yield) having a melting point of 108°-110° C. and the following analysis:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C@@:12](O)([CH:13]=[CH:14][C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C(O)=O.[C:48](=[O:53])([O:51]C)[O:49][CH3:50]>>[C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][C@@H:14]([O:53][C:48]([O:49][CH3:50])=[O:51])[C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@@]12C
Reactant: COC(=O)OC
Agent: O=C(O)C(Cl)Cl
Product: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of 50 mg of dichloroacetic acid, and the mixture was heated in an atmosphere of argon gas for 12 hours. The reaction mixture-was then worked up in the same manner as Example 132 to give 90 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:6][CH2:7][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CCCC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl butyrate (49 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2].Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Reactant: BrCc1ccccn1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(C)c1
Yield: 39 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethyl-2-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 10a) and 2-(bromomethyl)pyridine hydrobromide. Yield 39%. 1H NMR (300 MHz, dMSO): δ 1.17-1.22 (t, 3H), 2.46 (s, 3H), 2.60-2.64 (dd, 2H), 4.50 (s, 2H), 7.14-7.18 (m, 2H), 7.27-7.29 (m, 1H), 7.47-7.49 (d, 1H), 7.58 (bd, 1H), 7.72-7.77 (m, 1H), 8.50-8,51 (d, 1H). MS(M+H, 311).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[C:3]=1[O:26][CH2:27][CH3:28].[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[C:3]=1[O:26][CH2:27][CH3:28]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5 dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-125, 1.2 g, 2.65 mmol) and diisobutylaluminum hydride (1 M in methylene chloride, 6.35 mL, 6.35 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([CH3:13])[CH:15]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(C)c(C#N)c(Nc2cccc(C)c2)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile (500 mg, 2.51 mmol) in DMF (6 mL) were added 3-methylaniline (322 mg, 3.01 mmol) and diisopropyl ethylamine (712 mg, 5.52 mmol), and the reaction mixture was stirred 70° C. for 1.5 h. The mixture was cooled and concentrated, and the residue was dissolved into EtOAc (30 mL) and washed with water (10 mL). The ethyl acetate extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (silica gel, hexane/EtOAc, 0 to 100%) to give the product (650 mg, 96% yield).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([P:12]([CH3:15])(=[O:14])O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.N1C=NN=N1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:45]([O:52][C:53](=[O:56])[CH2:54][NH2:55])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.S(=O)(=O)(O)[O-].[K+]>N1C=CC=CC=1.O>[CH2:45]([O:52][C:53](=[O:56])[CH2:54][NH:55][P:12]([CH:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1)([CH3:15])=[O:14])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CP(=O)(O)C1CC(c2ccccc2)=NO1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: c1ccncc1
Product: CP(=O)(NCC(=O)OCc1ccccc1)C1CC(c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.1 g (5 mmol) of 3-phenyl-2-isoxazolin-5-yl(P-methyl)phosphinic acid are dissolved in 20 ml of pyridine and, while cooling in ice, 1.5 g (7 mmol) of mesitylsulfonyl chloride and 0.5 g (7 mmol) of tetrazole are added, and the mixture is then stirred at room temperature for 30 minutes. 1.7 g (5 mmol) of glycine benzyl ester toluenesulfonate are added, and stirring at room temperature is continued with the course of the reaction being followed by thin-layer chromatography. After the reaction is complete, water and half-concentrated potassium bisulfate solution are added to pH 2, the mixture is extracted three times with dichloromethane, and the organic phase is washed with water, dried and concentrated. The pure product is obtained with a melting point of 132° to 135° C. by chromatography on silica gel with dichloromethane/methanol mixtures as mobile phases.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH:15]=O)=[CH:10][N:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([CH:15]=[CH2:1])=[CH:10][N:9]=1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cnc(Cl)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a cooled 0° C., stirred slurry of methyltriphenylphosphonium bromide (10.0 g) in toluene (200 mL) was added potassium t-butoxide (3.07 g) portionwise to produce a yellow slurry. After 1 hr, the reaction mixture was cooled to −20° C. and 2,3-dichloro-5-formylpyridine (2, 4.0 grams, 22.72 mMol) which dissolved in tetrahydrofuran (6 mL) was added dropwise to produce a purple colored slurry. The reaction mixture was warmed to 0° C. and stirred for additional 1 hr. Then the reaction mixture was treated with saturated aqueous brine (150 mL) and diluted with ethyl acetate (200 mL). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography column eluting with a gradient of ethyl acetate (0-10%)/hexanes to afford 2.77 g of the desired product 3 (70%). 1H NMR (400 MHz, CDCl3) δ 8.30 (1H, d, J=2.19 Hz), 7.80 (1H, d, J=2.19 Hz), 6.63 (1H, dd, J=10.96, 17.80 Hz), 5.86 (1H, d, J=17.80 Hz), 5.45 (1H, d, J=10.96 Hz). LC/MS (M+1): 174.
Reaction SMILES: S(O)(C)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([S:15][CH2:16][C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]1[C:8]2[C:7]([F:6])=[CH:12][C:11]([O:13][CH3:14])=[CH:10][C:9]=2[S:15][CH:16]=1
Reactant: COC(=O)CC(=O)CSc1cc(F)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: COC(=O)Cc1csc2cc(OC)cc(F)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
MsOH (13.68 mL) was added dropwise to methyl 4-((3-fluoro-5-methoxyphenyl)sulfanyl)-3-oxobutanoate (2.87 g) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was poured into iced water and extracted with EtOAc. The organic layer was separated, washed successively with water, saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (900 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[CH:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1>C(O)C.Cl.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C=Cc2ncccc2C(=O)O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCc2ncccc2C(=O)O)cc1
Yield: 89 %

Procedure:
9.56 g of 2-(p-methylstyryl)nicotinic acid was dissolved in 190 ml of ethanol and 3.3 ml of concentrated hydrochloric acid. To the solution was added 1.00 g of 5% palladium-carbon (catalyst), and the mixture was subjected to hydrogenation at 40° C. at atmospheric pressure. The reaction mixture was filtered to remove the catalyst, and the filtrate was subjected to distillation under reduced pressure to remove the solvent. To the resulting residue was added 100 ml of water and the mixture was adjusted to pH 5.0 with a 10% aqueous sodium hydroxide solution. The resulting crystals were collected by filtration and dried to obtain 8.58 g of 2-(p-methylphenethyl)nicotinic acid. It was recrystallized from ethanol to obtain 7.72 g of colorless crystals having a melting point of 172°-173° C.
Reaction SMILES: [Na].F[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.O.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[F:13][C:14]([F:18])([F:17])[CH2:15][O:16][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 10.1 g (0.44 mol) of sodium was dissolved in 200 ml of 2,2,2-trifluoro ethanol in 300 ml of a three-necked flask, to which 40 ml (0.38 mol) of p-fluoronitro benzene was dropped and refluxed for 4 hours. After cooling to a room temperature, water was poured (about 1 liter), and precipitated solids were washed with water and dried, to obtain p-(2,2,2-trifluoroethoxy) nitrobenzene (yield: 62%; and melting point: 76.5° C.).
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][NH:8][C:7](=[O:12])[N:6]=1)[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.N1C=CC=CC=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([S:4][C:5]1[C:10]([F:11])=[CH:9][N:8]([C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)[C:7](=[O:12])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCSc1nc(=O)[nH]cc1F
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
This material was prepared by the procedure described in J. Org. Chem. 2006, 71, 9183-9190. To a stirred suspension of dry Cu(OAc)2 (1.02 g, 5.64 mmol), 4-(allylthio)-5-fluoro-pyrimidin-2(1H)-one (700 mg, 3.76 mmol), thiophen-3-ylboronic acid (962 mg, 7.52 mmol), and activated 3 Å molecular sieves (2 g) in dry CH2Cl2 (30 mL) was added pyridine (595 mg, 7.52 mmol) at room temperature. The mixture was stirred for 24 h at ambient temperature in the presence of air. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered through a pad of Celite, and washed with water (50 mL) in the presence of ethylenediaminetetraacetic acid (EDTA; 700 mg, 2.4 mmol). The colorless organic phase was dried over MgSO4 and was concentrated in vacuo. The residue was purified by normal phase chromatography (isocratic, 2:1 petroleum ether:EtOAc) to afford 4-(allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (290 mg, 29%) as a yellow solid: mp 125-127° C.; 1H NMR (301 MHz, DMSO-d6) δ 8.52-8.35 (m, 1H), 7.81 (s, 1H), 7.69-7.55 (m, 1H), 7.32 (d, J=3.5 Hz, 1H), 6.05-5.81 (m, 1H), 5.36 (d, J=16.9 Hz, 1H), 5.18 (d, J=9.8 Hz, 1H), 3.89 (d, J=6.4 Hz, 2H); ESIMS m/z 269 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25].[CH3:27]C(C)([O-])C.[K+].IC>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:23][CH3:27])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25]
Reactant: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN=C(NOC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 16 h
Yield: 25.3 %

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.5 g) in anhydrous THF was stirred at 0-5° C. and potassium tert-butoxide (0.13 g) and lodomethane (0.081 ml) added. After three hours further potassium tert-butoxide (0.068 g) and iodomethane (0.08 ml) were added at 0-5° C. The mixture was stirred at this temperature for 16 hours, evaporated and the residue purified by chromatography on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-N′-methyl-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.13 g), m.p. 139-142° C. Compound 50.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a stirred solution of 1-bromo-4-methoxy-2-nitrobenzene (2.32 g, 10 mmol) in 75 mL of dichloromethane at 0° C. was added BBr3 solution (1 M in DCM, 12 mL, 12 mmol) dropwise. The solution was allowed to warm to room temperature and stirred for 16 h. GC/MS showed starting material still left so another 12 mL of BBr3 solution was added and the reaction mixture refluxed for 4 h. The reaction mixture was cooled in ice and quenched with water. After washing successively with saturated NaHCO3(aq) and brine, the organic layer was dried over MgSO4, filtered and evaporated. The resulting yellow solid was flash chromatographed (25% EtOAc/hexane) to give 1.5 g of product in (69%) yield as a pale yellow solid: MS (EI) m/z 218 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:13])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cc(Cl)n1
Solvent: Cc1ccccc1
Product: Cc1cc(CCl)cc(Cl)n1

Procedure:
2.2 1.14 g of (2-chloro-6-methylpyridin-4-yl)methanol are initially introduced in 50 ml of toluene, and 1.05 ml of thionyl chloride are slowly added dropwise with ice cooling. The mixture is boiled under reflux overnight. After cooling, the solvent is removed, giving 2-chloro-4-chloromethyl-6-methylpyridine as brown oil (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CC(C)[C@@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](CO)C(C)C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (R)-2-amino-3-methylbutan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=461.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:7]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[N:15][CH:16]=2)[CH:8]=1.[Cl:33][C:34]1[N:39]=[C:38](Cl)[C:37]([Cl:41])=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:29]([O:28][C:26]([NH:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:36]2[C:37]([Cl:41])=[CH:38][N:39]=[C:34]([Cl:33])[N:35]=2)=[CH:8][C:7]=1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:14]=[N:15][CH:16]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CN)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Yield: 41.5 %

Procedure:
To a solution of tert-butyl [5-(2-{5-(aminomethyl)-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.81 g, 1.8 mmol) and 2,4,5-trichloropyrimidine (0.45 g, 2.4 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.30 g, 9.37 mmol). The resultant mixture was stirred overnight at 45° C. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water, and then dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (0.44 g, 40%). LCMS for C28H35Cl2N6O4 (M+H)+: m/z=589.1, 591.1.