Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:14]([O:21][CH3:22])[C:13]([CH2:23][CH3:24])=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=CC(C2C(OC)=C(C(C3C=CC=CC=3)=CC=2)C(OC)=S)=[CH:26]1>>[C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:21][CH3:22])[C:13]([C:23]3[CH:24]=[CH:29][O:25][CH:26]=3)=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=S)c1c(-c2ccccc2)ccc(-c2ccoc2)c1OC
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Product: COC(=O)c1c(CS(=O)c2ccccc2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from methyl 3-(furan-3-yl)-2-methoxy-6-phenylthiobenzoate (Intermediate 217).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:31][S:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(SC)cn4)cn3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(Nc2ccc(-c3ccc(C4CCC(CC(=O)O)CC4)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude (4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester was dissolved in THF/MeOH (4:1, 2.5 mL) and to it was added aqueous LiOH (4M, 0.5 mL). The mixture was stirred at room temperature for 18 hours, then was immediately purified via reverse-phase HPLC to yield the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2H) 1.44-1.57 (m, 2H) 1.84 (m, 5H) 2.16 (d, J=6.82 Hz, 2H) 2.50 (m, 1H) 6.91 (d, J=8.59 Hz, 1H) 7.36 (d, J=8.34 Hz, 2H) 7.70 (dd, J=8.59, 2.53 Hz, 1H) 7.91 (d, J=8.34 Hz, 2H) 7.95 (d, J=8.84 Hz, 1H) 8.21 (d, J=2.27 Hz, 1H) 8.33 (dd, J=9.09, 2.53 Hz, 1H) 8.98 (br. s., 1H) 9.64 (br. s., 1H); MS (M+H)+434.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CCCS(=O)(=O)[O-])CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1ccc(C2(CCN3CCC(C(N)=O)(c4ccccc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.55 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (175 mg, 0.73 mmol). Chromatography on silica gel (30 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:10]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.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>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([C:11]3[NH:12][C:13](=[O:14])[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1I
Reactant: C#Cc1cccc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C#Cc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 27.3 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-45, 0.070 g, 0.15 mmol) in DMSO (3.0 mL) was added 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.035 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol). The reaction mass was stirred at 80° C. for 5-6 h. The reaction mass was quenched in water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 2.0% EA:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.92 (s, 3H), 7.29 (t, J=8.4 Hz, 1H), 7.48-7.72 (m, 8H), 12-13 (br s, 1H); MS (m/z): 488.00 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH2:10]([O:9][C:7]([C:6]1[O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[N:1]=[CH:18][N:19]([CH3:21])[CH3:20])=[O:8])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1oc2ccccc2c1N
Product: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 4.2 g (20.0 mmol) of ethyl 3-amino-2-benzo[b]furancarboxylate (EP 187487 A1) in 10 mL of N,N-dimethylformamide dimethyl acetal is heated at reflux temperature for 1.5 hours, then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over sodium sulfate, passed through a pad of diatomaceous earth and concentrated in vacuo. The solid is collected by filtration to provide 3.90 g (75%) of a white solid, mp 89–90° C.;
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O)C.CO.[CH3:31][NH2:32]>>[CH3:31][NH:32][C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:3]
Reactant: CCOC(=O)C(C)CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Reactant: CN
Solvent: CO
Product: CNC(=O)C(C)CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In methylamine (40% in water, 20 ml), 1-[3-(ethoxycarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.50 g, 3.7 mmol) was placed. To this mixture 10 ml of methanol were added, to enhance solubility. The resulting mixture was stirred at room temperature for about 64 hours, after which time the reaction mixture was concentrated in vacuo. The residue was taken up in 200 ml of methylene chloride. The organic fraction was washed once with 200 ml of water. The organic fraction was dried over potassium carbonate and the solvents were removed in vacuo to yield 1.61 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient of methylene chlor ide to a 1:1 methylene chloride:ethyl acetate mixture. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 510 mg (36%) of the desired title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Solvent: COCCOC
Solvent: CO
Product: O=C(O)CCC(CC=Cc1cccc(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
Triton B (1.5 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4-phenyl-7-(m-chlorophenyl)-1,6-heptadien-3-one (22.8 g., 0.056 mole) in glyme (175 ml.), followed by addition of methyl acrylate (5.76 g., 0.067 mole) in glyme (25 ml.). After stirring for 20 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 48 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the sticky yellow solid which precipitates is collected and air-dried, yield 4.5 g., m.p. 65°-105°C. Recrystallization from benzene-petroleum ether (30°-60°C.) followed by several recrystallizations from n-butyl chloride gives material with m.p. 150°-151°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([O:19][CH3:20])[N:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:13]=[C:14]([O:19][CH3:20])[N:15]=[C:16]([C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=4)[CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1nc(Cl)cc(NCc2ccc3occc3c2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCc2ccc3occc3c2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
Argon is bubbled through a mixture of benzofuran-5-ylmethyl-(6-chloro-2-methyoxy-pyrimidin-4-yl)-amine (100 mg, 0.35 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [131 mg, 0.63 mmol, see Example 49(b) step 2], Cs2CO3 (342 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) in ethylene glycol dimethyl ether (1.7 mL) and water (0.3 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 μL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzofuran-5-ylmethyl)-amino]-2-methyoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [50 mg, 34%, Example 93] as a solid. LCMS RT=2.05 minutes, MS: 418 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N:17]3[C:21](=[O:22])[C:20]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]4[C:18]3=[O:27])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(O[Cl:31])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:31])=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(N3C(=O)c4ccccc4C3=O)cccc2c1=O
Reactant: O=P(Cl)(Cl)OCl
Product: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Cl
Reaction time: 0.17 h
Yield: 57 %

Procedure:
3-Butyryl-8-phthalimido-4(1H)quinolone (36 g, 0.1 mol) was heated under reflux in phosphoryl oxychloride (200 ml) for 1 hour. The solvent was evaporated and the residue dissolved in chloroform and poured into a rapidly stirred mixture of ice, water and ammonia then stirred for 10 minutes. The chloroform layer was washed with brine, dried (anhyd. MgSO4), filtered and evaporated to a brown oil. Chromatography (silica gel/5% methanol in chloroform) gave 3-butyryl-4-chloro-8-phthalimidoquinoline as a light brown oil (21.5g, 57%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([C:19]([CH:21]=[CH2:22])=[O:20])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:17][C:19](=[O:20])[CH2:21][CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)CC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 2 (5.0 g, 0.021 mole) was reacted with ethylvinyl ketone (6.3 ml) and triethylamine (1 ml) in methanol (30 ml) by the method of Example 3 to give the title compound, m.p. ca. 76°-79° C. Analysis calc. for C19H30O2S(332.50):
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[CH:18]=1>C(#N)C>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[C:19]([F:26])[C:18]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 47.4 %

Procedure:
To a solution of 1.468 g of morpholine and 3.0 mL of diisopropylethylarnine in 80 mL of acetenitrile was added a solution of 5.019 g of 2,6-difluoro-4-nitrobenzene (trifiuoromethane) sulfonate in 10 mL of acetonitrile. The mixture was heated to reflux for 5 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel column (3 cm tall, 10 cm diam), eluting with 25% ethyl acetate/hexanes (v/v) and then 2% acetic acid/25% ethyl acetate/hexanes to give 1.95 g of an orange oil. This was washed with 5% ethyl acetate/hexanes, and the bright yellow solids air dried, mp 91°-92° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[BrH:14].BrBr>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH2:9][Br:14])[N:7]=1
Reactant: Br
Reactant: CC(=O)c1nc(C(F)(F)F)oc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1oc(C(F)(F)F)nc1C(=O)CBr
Temperature: 80 °C

Procedure:
5.8 g (0.02 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-oxazole are dissolved in 30 ml of glacial acetic acid, and 3 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 80° C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added. After a further 30 minutes the glacial acetic acid is removed. The residue which remains is a dark oil which is reacted further as the crude product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]2.[CH3:20][C:21]1[C:26](O)=[CH:25][CH:24]=[C:23]([CH3:28])[N:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:20][C:21]1[C:26]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]3)=[CH:25][CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCO)ccc21
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCOc3ccc(C)nc3C)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
To a solution of ethyl [(1S)-5-(2-hydroxyethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 249, 50.0 mg, 0.19 mmol) and 2,6-dimethylpyridin-3-ol (46.6 mg, 0.38 mmol) in THF (1.5 mL) were added PPh3 (99.2 mg, 0.38 mmol) and ADDP (95.5 mg, 0.38 mmol). The reaction mixture was vigorously stirred at rt for 24 h, and then directly applied to a silica gel column for purification (1:1 hexanes/EtOAc) to give the product (58.9 mg, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H) 1.72-1.81 (m, 1H), 2.36-2.2.44 (m, 2H), 2.45 (s, 3H), 2.47 (s, 3H), 2.73 (dd, 1H) 2.82-2.92 (m, 2H), 3.52-3.56 (m, 1H) 4.19 (q, 2H), 4.26-4.33 (m, 4H), 6.75 (d, 1H), 6.82 (s, 1H) 6.92 (d, 1H), 7.05 (d, 1H), 7.08 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].CCCCCO.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:14]2[C:13](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:21])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: O=C(O)c1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In a 3 liter, three necked round bottom flask, provided with a mechanical stirrer, reflux condenser and thermometer (to 200° C.) was placed 300 g. (1.25 m.) 1-bromo-4-chloronitrobenzene, 140 g. (1.02 m.) anthranilic acid, and 130 ml. n-amyl alcohol. The mixture was heated in an oil bath. After most of the chemicals were dissolved (80°-90° C.) the stirrer was started. Then, 1.3 gm. copper powder and 140 gm. (1.02 m.) potassium carbonate were added all at once. A yellow voluminous froth formed but no heat of reaction. As the reaction temperature rose from 180° to 120°, a red reaction mixture became more solid and hindered further stirring. The reflux condenser was replaced to distill off the formed water and amyl alcohol. Meanwhile, the temperature of the oil bath was steadily increased and finally kept at 200°-210° for 3 hours. The oil bath was replaced by a steam bath and the excess bromochloronitrobenzene was removed by steam distillation. After removal of bromochloronitrobenzene was completed, the solution was filtered and water added making the total volume of dark red solution about 2.5 liters. The solution was cooled to room temperature overnight, and filtered. Dilute HCl (1:1) was carefully added to the filtrate until it was just acid to Congo red litmus paper. The ochre-colored precipitate was removed by filtration and washed with water (750 ml.). The product was dried in vacuo at 70°. The original dark-red filter cake was digested with hot water several times and then treated as described above to extract all the desired product. Obtained: 247 grams (83% yield) of crude N-(4-chloro-2-nitrophenyl)anthranilic acid; orange granular powder; m.p. 235°-247° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]([NH2:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[OH-]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][C:11]([CH3:17])([CH3:10])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 9 °C

Procedure:
Into a flask, 20 grams of water, 52.3 grams (0.284 mole) of cyanuric chloride and 130 grams of mixed xylenes having a boiling point of 138-141° C. were charged, and 37.5 grams (0.290 mole) of 1,1,3,3-tetramethylbutylamine was slowly and dropwise added into the mixture while maintaining the temperature at 8-10° C. Then, 57.9 grams of 20% aqueous hydroxide solution was slowly and dropwise added into the mixture while keeping the temperature at 8-10° C. After the reaction was complete, the oil (organic) and water phases were separated and the water phase was removed to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine,
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuan (20 mL) under a nitrogen atmosphere was cooled to 0° C. Di-isopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.