Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.Cl.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C.CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: NCCCBr
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1cc(NCCCBr)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (10 g, 54.5 mmol) in acetonitrile (200 mL) was added triethylamine (22.80 mL, 164 mmol) at 0° C., stirred for 5 min at r.t., and then added dropwise a solution of 3-bromopropan-1-amine hydrochloride (12 g, 68.8 mmol) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred for 1 h at r.t., filtered, and concentrated. Purification via FC afforded the title compound (5.6 g).
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)([C:10](OCC)=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[H][H]>C(O)(=O)C.[Pt]=O>[O:11]=[C:10]1[C:4]([NH:3][CH:1]=[O:2])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][C:16]2=[CH:17][CH:18]=[CH:19][C:20]3=[C:25]2[N:24]1[CH2:23][CH2:22][CH2:21]3
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC=O)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC=O)Cc2cccc3c2N(CCC3)C1=O
Yield: 96.6 %

Procedure:
A mixture of diethyl (formylamino)(8-quinolinylmethyl)malonate (9.2 g, 26.7 mmol) and platinum oxide (0.7 g) in glacial acetic acid (150 mL) was hydrogenated (50 lb initial pressure) for 15 minutes (hydrogen uptake ca. 2 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was partitioned between ethyl acetate and sodium hydroxide solution. The ethyl acetate phase was washed with water, the ethyl acetate was evaporated, and the product was crystallized from ether to give 7.8 g (97%) of ethyl 2,3,6,7-tetrahydro-3-oxo-2-(formylamino)-1H,5H-benzo(ij)quinolizine-2-carboxylate, mp 103°-106° C. Anal. Calcd. for C16H18N2O4 : C, 63.56; H, 6.00; N, 9.27. Found: C, 63.51; H, 6.09; N, 9.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([Cl:16])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(C)C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 2-(4-methoxyphenyl)propanoic acid (synthesized by the process of I. Shiina, et al., Eur J. Org. Chem., 5887-5890 (2008)) (1.20 g, 6.66 mmol) was dissolved in thionyl chloride (6.00 mL, 82.6 mmol) and the solution was heated to reflux for 27 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of 2-(4-methoxyphenyl)propanoyl chloride (16) as a colorless oil. The product was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([NH:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(2-aminoethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (125 mg) in THF (2.5 mL) were added triethylamine (0.134 mL) and acetyl chloride (0.046 ml), and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (121 mg).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)[C:16]2=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:6]=1)C.O[Li].O>C1COCC1.CO.O>[Br:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:40])=[O:3])[C:16]1=[N:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34]
Reactant: CCOC(=O)c1cccc(OCCCn2c(=NC(=O)OC(C)(C)C)n(Cc3cccc(Br)c3)c3ccccc32)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1cccc(Br)c1
Temperature: 40 °C
Yield: 103.4 %

Procedure:
To a solution of 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester (155 mg, 0.25 mmol) in THF (2 ml), MeOH (2 ml) and H2O (1 ml) was added LiOH.H2O (53 mg, 1.27 mmol). The reaction was warmed to 40° C. where it was maintained for 20 h. After this time, the reaction was cooled to rt concentrated under reduced pressure and then partitioned between EtOAc and 1M HCl. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (150 mg, 100%). HPLC-MS 580, 582 [M+1]+.
Reaction SMILES: ClC1C=C(C=CC=1)C(C1C2C=CC=CC=2OC=1C1C=CC(O)=CC=1)=O.C(C1OC1)Br.[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][CH:59]=1)[C:35]([C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]=1[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[O:56][CH2:55]2)=[CH:48][CH:47]=1)=[O:36].[CH:60]([NH2:63])([CH3:62])[CH3:61]>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][CH:59]=1)[C:35]([C:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]=1[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]([OH:56])[CH2:55][NH:63][CH:60]([CH3:62])[CH3:61])=[CH:48][CH:47]=1)=[O:36]
Reactant: O=C(c1cccc(Cl)c1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12
Reactant: CC(C)N
Agent: BrCC1CO1
Agent: O=C(c1cccc(Cl)c1)c1c(-c2ccc(O)cc2)oc2ccccc12
Product: CC(C)NCC(O)COc1ccc(-c2oc3ccccc3c2C(=O)c2cccc(Cl)c2)cc1

Procedure:
Treatment of 3-m-chlorobenzoyl-2-p-hydroxyphenylbenzofuran with epibromohydrin as described in Example 26 followed by reaction of the 3-(3'-chlorobenzoyl)-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran with isopropylamine as described in Example 25 gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:28][C:29]([C:32]([F:35])([F:33])[F:34])=[N:30][N:31]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.69(1H,bs), 9.53(1H,s), 8.91(1H,s), 8.65(1H,dd), 8.11(1H,d), 7.64(2H,d), 7.45(5H,m), 7.15(2H,d), 5.19(2H,s); m/z (M+1+) 464.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1 H), 7.53-7.51 (m, 1 H), 7.42-7.40 (m, 1 H), 3.66 (s, 3 H), 1.69-1.67 (m, 2 H), 1.27-1.24 (m, 2 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](SC)=[N:10][C:9]=2[CH:15]=1.[C:16]1(C)C=CC(S(OC2C(C(C)C)CCC(C)C2)(=O)=O)=CC=1.[C:37]([C:40]1[CH:41]=[CH:42][C:43]([NH:59][CH2:60][CH3:61])=[C:44]([N:46]=[C:47]2[N:51]([CH2:52][C:53]3[O:54][CH:55]=[CH:56][CH:57]=3)[C:50](=[O:58])[CH2:49][S:48]2)[CH:45]=1)(=[O:39])[CH3:38]>>[C:37]([C:40]1[CH:41]=[CH:42][C:43]([NH:59][CH2:60][CH3:61])=[C:44]([N:46]=[C:47]2[N:51]([CH2:52][C:53]3[O:54][CH:55]=[CH:56][CH:57]=3)[C:50](=[O:58])[C:49](=[C:11]3[N:10]([CH3:16])[C:9]4[CH:15]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:6]=[CH:7][C:8]=4[S:12]3)[S:48]2)[CH:45]=1)(=[O:39])[CH3:38]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccco1
Reactant: CSc1nc2cc(OCCCl)ccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(C)CCC2C(C)C)cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccco1

Procedure:
In a manner similar to Example 45, intermediate 5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated with menthyl p-toluenesulfonate and then condensed with the above 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one. MS(ESI): 583 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:10]1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>C(Cl)Cl>[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH:44][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: Cc1ccccc1NN
Reactant: CCCCCCCCC1CC1CCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)NNc1ccccc1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g of dihydrosterculic acid* in 75 ml methylene chloride cooled to -20°, is added dropwise 1.1 g triethyl amine and then dropwise 1.1 g ethyl chloroformate. The reaction mixture is allowed gradually to come to room temperature and stirred for 2 hours. There is then added 1.0 g triethylamine followed by 1.6 g o-methylphenyl hydrazine hydrochloride and the reaction mixture then stirred for 16 hours. Thereafter the reaction mixture is extracted five times with portions of 2 N hydrochloric acid, then once with 2 N aqueous sodium hydroxide and washed extensively with saturated aqueous sodium chloride. The organic phase is then dried over anh. sodium sulphate, filtered and the filtrate evaporated i.v. to dryness to obtain a residue. The residue is then chromatographed over silica gel, with chloroform as the eluent. The desired fractions** are combined and evaporated i.v. to dryness to yield the title product as a waxy solid, NMR; b +0.65(3), b -0.3(1), d 8.0(1), d 6.1(1), s 2.1(3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][O:13]1.Cl>BrCCBr.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:16]2([OH:18])[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1CC(=O)CCO1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1CC(O)(c2cc(F)cc(F)c2)CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A Grignard reagent was prepared from 3,5-difluorobromobenzene (0.772 g), 1,2-dibromoethane (2 drops), magnesium (0.106 g) and THF (5 ml). The mixture was stirred at ambient temperature for 15 minutes and then heated to 50° C. for 15 minutes. The mixture was allowed to recool to ambient temperature and a solution of 2-methyltetrahydropyran-4-one (J. Amer. Chem. Soc., 1982, 104, 4666) in THF (1 ml) was added dropwise. The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained a less polar isomer, (2RS,4SR)-4-(3,5-difluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.25 g, 36%), having the 2-methyl and 4-hydroxy substituents in a trans-relationship.
Reaction SMILES: [CH:1]([CH:21]1[CH2:26][C:25](=[O:27])O[C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH3:28]>>[CH:1]([CH:21]1[CH2:26][C:25](=[O:27])[NH:28][C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: N
Product: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Temperature: 160 °C

Procedure:
In another reaction vessel was placed 570 grams of the above isomerized eicosenyl succinic anhydride. This was heated to 160° C. and ammonia injection started. The temperature rose to 175° C. Ammonia injection was continued at 175° C. until the temperature dropped. Then 30" Hg vacuum was slowly applied to distill out water and ammonia. Additional ammonia was injected to be sure no anhydride remained. There was no further reaction so this ammonia was stripped out at 30" Hg vacuum at 170° C. yielding isomerized eicosenyl succinimide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:18]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
3-Aminophenol (21.8 g, 0.200 mol) and imidazole (34 g, 0.50 mol) were dissolved in DMF (200 mL), the solution was cooled with an ice-water bath, and TBDMSCl (36.1 g, 0.24 mol) was added in one portion. The cooling bath was removed, the reaction mixture was allowed to warm-up to room temperature, and stirred for 1 h. DMF (ca. 150 mL) was evaporated in vacuo at +55° C., the residue was diluted with AcOEt (250 mL), washed with sat. aq. NaHCO3 (twice), water (several times), brine and dried over MgSO4. After evaporation of solvents, the oily residue was dried in vacuo (0.5 Torr) to a constant weight. Purification by column chromatography (gradient elution with hexane to hexane/ether=5/1) afforded compound 2 (Rf=0.24 in hexane/ether=8/1) as a clear oil (34.1 g, 76%). 1H NMR (300 MHz, CDCl3): δ=0.21 (s, 6 H, SiMe2But), 0.99 (s, 9 H, SiMe2But), 3.60 (br. s, 2 H, NH2), 6.18 (m, 1 H), 6.28 (m, 2 H), 6.98 (m, 1 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:20])[C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]1[O:20][C:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[N:7][N:6]=1
Reactant: O=C(NNC(=O)c1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)ccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(-c2nnc(-c3cc(Cl)ccc3Cl)o2)c(F)c1F
Yield: 81 %

Procedure:
By the general method of Part B of Example 2, the reaction of 21.0 g (0.05377 mol) 2,5-dichloro-N′-(pentafluorobenzoyl)benzohydrazide in POCl3 gave a product which was recrystallized from ethanol/water to give 16.59 g (81% yield) of 2-(2,5-dichlorophenyl)-5-(pentafluorophenyl)-1,3,4-oxadiazole (10).
Reaction SMILES: OC([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)CCCCC.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[K+].[CH2:22]([OH:24])[CH3:23]>O>[OH:24][CH:22]([CH:18]1[O:19][CH:17]1[CH2:15][O:14][C:10]1[CH:9]=[CH:8][CH:13]=[CH:12][CH:11]=1)[CH2:23][CH2:9][CH2:8][CH2:13][CH3:12]
Reactant: ClCC1CO1
Reactant: CCO
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(O)C1OC1COc1ccccc1

Procedure:
19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 28.6 g. epichlorohydrin are dissolved in 25 ml. ethanol and heated to the boil. A solution of 6.6 g. potassium hydroxide in 3 ml. water and 25 ml. ethanol is then added dropwise thereto in the course of 15 minutes. The reaction mixture is boiled under reflux for 2 hours, the solvent is then distilled off and the residue is taken up in water. Extraction is carried out with ethyl acetate, the ethyl acetate phase is washed twice with aqueous sodium hydroxide solution and water, dried and evaporated to give 22.4 g. (89% of theory) of the title compound in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COc1cccc(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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1

Procedure:
4-Bromo-1-fluoro-2-nitro-benzene (5 gms.), 3.85 gms. 3-methoxyphenylboronic acid and 22 mL of a 2M aqueous solution of sodium carbonate are suspended in 100 mL of a 1:1 (v:v) mix of toluene and ethanol. The resulting suspension is then treated with 0.8 gms. tetrakis(triphenylphosphine)palladium(0) at room temperature. The reaction mixture is then heated at reflux for 12 h. The reaction mixture is subsequently concentrated in vacuo, and the resulting residue is taken up in ethyl acetate (200 mL). The ethyl acetate solution is then washed successively with water (2×200 mL), and brine (2×200mL). The organic layer is then dried by filtering through phase separator paper and concentrated in vacuo to yield 7.19 gms. of crude product. The crude product is then recrystallized from hot ethanol yielding 4-fluoro-3′-methoxy-3-nitro-biphenyl as a yellow-white solid in the amount of 4.767 gms.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11]C(OCC2C=CC=CC=2)=O)[CH:9]2[CH2:22][CH2:23][CH:6]1[CH2:7][CH2:8]2)=[O:4].[ClH:24]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:24].[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH2:11])[CH:9]2[CH2:22][CH2:23][CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2R,3S)-3-Benzyloxycarbonylamino-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (0.57 g, 1.79 mmol) was dissolved in ethyl acetate (20 mL). 10% Palladium on carbon (60 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (6 mL) and added dropwise with vigorous stirring to a mixture of 4.0 M solution of hydrochloric acid in 1,4-dioxane (1.02 mL) and diethyl ether (10 mL). The desired product began to precipitate as a white solid. The mixture was stirred for 20 min. The precipitate was collected by vacuum filtration, washed with additional diethyl ether (5 mL). The solid was further dried in vacuo for 1 h to afford the desired product, (2R,3S)-3-amino-bicyclo[2,2,2]octane-2-carboxylic acid methyl ester hydrochloride (0.33 g, 1.50 mmol, 84%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.38 (2H, dd, J1=21.2 Hz, J2=13.6 Hz), 1.55-1.63 (5H, m), 1.76-1.89 (3H, m), 3.02 (1H, dd, J1=10.0 Hz, J2=2.4 Hz), 3.47 (1H, bs), 3.65 (3H, s), 7.97 (3H, s). LC-MS (ESI) calcd for C10H17NO2 (free amine) 183.25, found 184.2 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(NCC1CN(C(=O)CO)CCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:4][C:3]=1[O:26][CH3:27].[C:28]([O-])([O-])=O.[K+].[K+].COS(=O)(=O)OC>CC(C)=O.O>[CH3:27][O:26][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OC)c(OC)c2)ccc1O
Yield: 44.5 %

Procedure:
To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (368 mg, 1.0 mmol, 1.0 eq.) in dry acetone (10 mL) were added anhydrous K2CO3 (138 mg, 1.0 mmol, 1.0 eq.) and sulfuric acid dimethyl ester (176 mg, 1.0 mmol, 1.0 eq.) at rt. The reaction mixture was heated under reflux overnight, cooled, diluted with water and extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with H2O, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by silica column chromatography using CH2Cl2 as eluent to provide (1E,6E)-1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (170 mg, 44%).