Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1N
Yield: 95 %

Procedure:
The title compound is prepared from 3-amino-4-methyl-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 95% of theory; LC (method 4): tR=1.85 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[CH:10][S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.C1C[O:35][CH2:34]C1>O.CN(C=O)C>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:34]=[O:35])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C1CCOC1
Reactant: CSc1ncnc2sccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CSc1ncnc2sc(C=O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
4-(Methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (1 g) in THF (5 mL) was added to a preformed solution of LDA (BuLi (1.6M in hexanes, 3.8 mL) and di-isopropylamine (0.85 mL)] in THF (20 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C. and then DMF (1.1 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature and stirred for a further 3 hours. The reaction mixture was diluted with water and the; product was extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM afforded the title compound as a white solid (1.17 g, 51%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1ccccc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
4′-Chloro-biphenyl-2-carbaldehyde (6.50 g, 30.0 mmol) was dissolved in CH2Cl2 (75 mL) and methanol (75 mL). The solution was cooled to 0° C. in an ice bath, and then sodium borohydride (1.36 g, 36.0 mmol) was added slowly portionwise. The reaction was allowed to warm gradually to room temperature and stir for 16 hours. The reaction was quenched by addition of 2M NaOH, and the organics were extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over MgSO4 and concentrated to afford (4′-chloro-biphenyl-2-yl)-methanol (6.42 g, 98% yield), which was carried on to the next step without further purification. MS (ES1) m/e (M−H)−: 217.4
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1N)C1CCCCC1

Procedure:
7.1 g. of 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone are dissolved in a 1:1 mixture of benzene and ethyl acetate, and 0.7 g. of palladiumized carbon are added to the mixture. The mixture is hydrogenated at room temperature and 3 atm. hydrogen pressure until the uptake of the calculated amount of hydrogen (this requires about one hour). Thereafter the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. 6.35 g. of crude product are obtained. After recrystallization from isopropanol, 5.8 g. of pure 3-amino-4-(N-ethyl-N-cyclohexylamino)-benzophenone, melting at 106.5°-107.5° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][N:14]2[C:22]3[C:17](=[N:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)OCC[O:9]1>CO.Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:9])[CH2:13][N:14]1[C:22]2[C:17](=[N:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: COc1ccc2c(ccn2CC2(c3ccccc3Br)OCCO2)n1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(ccn2CC(=O)c2ccccc2Br)n1

Procedure:
A solution containing 1.60 g (4.1 mmol) of the compound obtained in Step A in 10 ml of methanol and 20 ml of 18% hydrochloric acid is refluxed for 4 hours. After returning to room temperature and removal of the methanol by evaporation, the mixture is neutralised with a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:5]2[O:6][C:7]([CH3:17])([CH3:16])[C:8]3[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[C:9]=3[C:4]=2[CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(#N)C>[C:31]([O:15][CH2:14][CH:10]1[C:9]2[C:4]3[CH:3]=[C:2]([OH:1])[C:19]([CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:18][C:5]=3[O:6][C:7]([CH3:16])([CH3:17])[C:8]=2[CH2:13][CH2:12][CH2:11]1)(=[O:33])[CH3:32]
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1CO)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)OCC1CCCC2=C1c1cc(O)c(C(C)CCCc3ccccc3)cc1OC2(C)C

Procedure:
A solution of 0.1 mole of dl-7,8,9,10-tetrahydro-2-hydroxy-10-hydroxymethyl-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)-6H-dibenzo[b,d]pyran in 100 ml. of acetonitrile is treated with 0.1 mole of acetic anhydride and the mixture heated for 12 hours under nitrogen. It is then poured onto ice/water and extracted with ethyl acetate (2×100 ml.), the extracts combined, washed with brine and dried MgSO4). Evaporation under reduced pressure followed by silica gel chromatography affords the title product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[C:18]([F:24])[CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][C:15](=[O:25])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:23]2
Reactant: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reaction time: 8 h

Procedure:
A 250 mL flask was charged with 3-(1-benzylpiperidin-4-yl)-8-fluoro-3,4-dihydroquinazolin-2(1H)-one (1.40 g, 4.12 mmol) and methanol (25.0 mL). The suspension was heated with a heat gun to aid in dissolution. The flask was flushed with nitrogen, treated with palladium on charcoal (141 mg, 0.032 equiv.), flushed with nitrogen, then hydrogen, and vigorously stirred under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 0.99 g (97%) as a white solid which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.71 (m, 4H), 2.75 (m, 2H), 3.16 (m, 2H), 4.38 (s, 2H), 4.46 (m, 1H), 6.77 (bs, 1H), 6.81-6.89 (m, 2H), 6.95 (m, 1H). Mass spec.: 250.22 (MH)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[N:15]([CH2:18][CH2:19][OH:20])=[N+:16]=[N-:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:15]([CH2:18][CH2:19][O:20][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[N+:16]=[N-:17]
Reactant: O=C1CCC(=O)O1
Reactant: [N-]=[N+]=NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCOC(=O)CCC(=O)O
Temperature: 40 °C

Procedure:
Succinic anhydride (23.0 g, 0.230 mol) was added into a three-neck round-bottom flask equipped with a condenser and a dropping funnel. Under nitrogen atmosphere and magnetic stirring, freshly distilled methylene chloride (150 mL), DMAP (2.3 g, 19 mmol) and freshly distilled Et3N (46.46 g, 0.460 mol) was sequentially added. After the flask was immersed into an ice-water bath, 2-azidoethanol (20.0 g, 0.230 mol) was added dropwise into the previous solution. The solution was later heated at 40° C. for 48 h, and the reaction mixture was washed successively with 1 M HCl solution (5×100 mL) and deionized water (2×100 mL). The organic phase was dried over anhydrous MgSO4 overnight. After filtering and removal of methylene chloride under reduced pressure, the final product was obtained as a yellow viscous liquid. The yield was: 38.4 g, 90%. 1H NMR (CDCl3, δ, ppm): 4.20 (t, 2H, N3CH2CH2), 3.42 (t, 2H, N3CH2), and 2.61 (m, 4H, CH2CH2COOH).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CC([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.C(N)(C)(C)C>O1CCCC1>[CH2:1]([O:11][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=2)=[CH:27][CH:26]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CC(C)(C)N
Product: CCCCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
To a solution of n-decanol (1.6 g) and 4-methylcarbonyloxy-4'-carboxybiphenyl (2.6 g) in tetrahydrofuran (50 ml) were added dicyclohexylcarbodiimide (1.4 g) and dimethylaminopyridine (0.5 g), followed by stirring at room temperature for 24 hours. Thereto was added tert-butylamine and the mixture was refluxed at 70° C. for 2 hours and hydrolyzed. After the solvent was distilled off, dilute hydrochloric acid was added to make the solution neutral and the solution was extracted with diethyl ether. After the solvent was distilled off, the residue was washed with hexane and recrystallized from water/ethanol (1/9) solution to obtain the titled compound (about 2.3 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH3:17][N:18](C)C=O.N>CCCCCCC>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:17]#[N:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CN(C)C=O
Reactant: COC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Agent: N
Solvent: CCCCCCC
Product: COC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
Into a 300 ml three-neck flask were added compound (E) (20.0 g, 0.061 mol), cuprous cyanide (6.3 g, 0.071 mol) and N,N-dimethylformamide (DMF) (63 ml). The mixture was agitated and refluxed for 6 hours while heating on a mantle heater. After completion of the reaction, the reaction mixture was cooled down to room temperature and a 28% aqueous ammonia (18 ml) was added, followed by agitating the mixture, adding n-heptane (50 ml) for extraction, filtering off an insoluble matter in the n-heptane layer, washing the layer with 6N-HCl (50 ml), further washing with water till the aqueous layer became neutral, concentrating under reduced pressure, recrystallizing the resulting raw crystals from ethanol (10 ml), filtering off and drying to obtain 4-(trans-4'-methyloxymethylcyclohexyl)benzonitrile (F) (6.4 g).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C=O)C>[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:11])[CH3:12])[NH:9][C:33](=[O:32])[C@H:34]([CH3:46])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of L-valine tert-butyl ester hydrochloride (2.1 g, 10 mmole) in DMF (10 ml) was treated with DIEA (1.6 ml. 10 mmole) and benzyloxycarbonyl-L-alanine p-nitrophenyl ester (3.5 g, 10 mmole). After overnight at room temperature, the solution was filtered through a column of neutral Al2O3 (100 g) and eluted with DMF. The solvent was removed in vacuo and the residue filtered through a column of silica gel (50 g) eluted with CHCl3. The resulting oil (3.0 g, 79%) was homogeneous on tlc; Rf (CHCl3) 0.10; Rf (ether) 0.70; Rf (CHCl3 24, CH3OH 1) 0.55.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:24]=2)=[CH:16][CH:15]=1>>[Br-:12].[CH2:1]([N+:7]1[CH:11]=[CH:10][N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][N:24]=3)=[CH:18][CH:19]=2)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1ccnc1
Reactant: BrCc1ccc(-c2ncc(-c3ccccc3)o2)cc1
Product: CCCCCC[n+]1ccn(Cc2ccc(-c3ncc(-c4ccccc4)o3)cc2)c1
Product: [Br-]

Procedure:
The experimental procedure is identical to the procedure for compound la (1-hexylimidazole [2-5] 0.787 g, 5.2 mmol, 2-(4-bromomethyl-phenyl)-5-phenyl-oxazole 1.390 g, 4.4 mmol).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[O:31][CH3:32])[CH2:5][CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.Cl.CN(C1C=CC=CN=1)C.[C:53]([O:57][C:58]([NH:60][C@H:61]([C:66](O)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])=[O:59])([CH3:56])([CH3:55])[CH3:54].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[C:53]([O:57][C:58]([NH:60][C@H:61]([C:66]([O:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[O:31][CH3:32])[CH2:5][CH2:4][CH2:3]1)=[O:67])[CH2:62][CH2:63][S:64][CH3:65])=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(O)c2cc(Cl)ccc21
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.2 %

Procedure:
5-Hydroxy-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g), dimethylaminopyridine (0.83 g) and dimethylaminopyridine hydrochloride (0.72 g) are dissolved in chloroform (15 ml), and thereto are added N-tert-butoxycarbonyl-L-methionine (0.56 g) and dicyclohexylcarbodiimide (0.93 g), and the mixture is stirred at room temperature for 3 hours. To the mixture are added methanol (3 ml) and acetic acid (0.7 ml), and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and to the filtrate is added 5% aqueous sodium hydrogen sulfate solution, and the mixture is extracted with dichloromethane. The dichloromethane layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent is evaporated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=150:1) to give 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.27 g).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C1COCC1.O.[Cl-].[Cl-].[Zn+2].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+:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:13])[CH2:1][CH3:2])=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC[Mg]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 0.5M ZnCl2 in THF (60 mL, 30 mmol) in THF (20 mL) at room temperature was treated with 2M ethyl magnesium chloride in THF (15 mL, 30 mmol) dropwise via syringe, cooled with an ice bath for about 10 minutes, stirred at room temperature for 20 minutes, cooled to 0° C., and treated sequentially with Pd(PPh3)4 (1.73 g, 1.5 mmol) and a solution of 4-nitrobenzoyl chloride (6.12 g, 33 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 40 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with saturated Na2CO3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide 2.17 g (40%) of the desired product. Rf=0.6 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 30.3 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[O:5][C:6]=1[CH3:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:59]=[CH:58][C:46]([O:47][CH2:48][CH2:49][NH:50]C(=O)OC(C)(C)C)=[C:45]([C:60]2[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=2)[CH:44]=1.Cl.CCOCC>ClCCl>[NH2:50][CH2:49][CH2:48][O:47][C:46]1[CH:58]=[CH:59][C:43]([NH:42][C:8]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH:3]=2)=[O:10])=[CH:44][C:45]=1[C:60]1[N:64]([CH3:65])[N:63]=[CH:62][CH:61]=1
Reactant: Cc1cc(C(=O)O)oc1C
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)oc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
4,5-dimethylfuran-2-carboxylic acid (12.65 mg, 1.2 eq), triethylamine (26.21 μL, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 20 minutes. At this time tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg, 75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and the reaction was stirred at room temperature for 18 hr. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid in ether (376 μL, 5 eq) and the reaction was stirred at room temperature overnight. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a pale yellow solid in 47.3% yield. LCMS Ink (%)=355 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (s, 3 H), 2.30 (s, 3 H), 3.11-3.20 (m, 2 H), 3.71 (s, 3 H), 4.16 (t, J=5.31 Hz, 3 H), 6.36 (s, 1 H), 7.10 (s, 1 H), 7.21 (d, J=9.09 Hz, 1 H), 7.49 (d, J=2.02 Hz, 1 H), 7.49 (d, J=2.02 Hz, 1 H), 7.68 (d, J=3.03 Hz, 1 H), 7.84 (dd, J=9.09, 2.53 Hz, 1 H), 7.86-7.98 (m, 2 H), 10.01 (s, 1 H).
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9]C(=O)C)(=O)C.[OH-:13].[Na+].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:8]/[CH:7]=[CH:6]/[CH2:5][O:4][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:22])=[O:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC/C=C/COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
30.0 g (174 mmol) of 1,4-diacetoxy-2-butene (trans/cis=85/15), 150 mL of toluene, and 300 mL of a 50% sodium hydroxide aqueous solution were added into a four-necked flask (1 L), and thereafter, 2.81 g (8.71 mmol) of tetra-n-butylammonium bromide was added thereto as a phase-transfer catalyst. The obtained mixture was stirred at room temperature for 1 hour, and 79.7 g (418 mmol) of 4-toluenesulfonyl chloride was then added to the reaction solution. The obtained mixture was stirred at room temperature for 5 hours, and 480 mL of water and 150 mL of toluene were then added to the reaction solution to facilitate liquid separation. The mixture was stirred, and an organic layer was then separated. A water layer was re-extracted with 150 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 120 mL of water three times, and the resultant was filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure. Thereafter, 60 mL of toluene was added to the residue, and the residue was completely dissolved therein at 60° C. Thereafter, the obtained solution was gradually cooled to 0° C., and it was then stirred for 1 hour. The precipitated crystal was collected by filtration. The obtained crystal was washed with 30 mL of cold toluene, and it was then dried at room temperature, so as to obtain 35.4 g of trans-1,4-di-4-toluenesulfonyloxy-2-butene in the form of a colorless crystal (yield: 51%, trans/cis=100/0). As a result of NMR analysis, the colorless crystal was confirmed to be trans-1,4-di-4-toluenesulfonyloxy-2-butene.