Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.N1C=CC=CC=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1>O1CCCC1>[NH2:12][C:9]1[N:10]=[CH:11][C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([NH:1][C:29]([C:28]3[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=3)=[O:30])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccc(Cl)c(N)c2)cn1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2Cl)n(C)n1
Yield: 10 %

Procedure:
In the same manner as in Reference Example 3 and using 5-(3-amino-4-chlorophenoxy)pyridin-2-amine (2.01 g, 8.55 mmol), pyridine (725 μL, 8.98 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (1.42 g, 8.98 mmol) and tetrahydrofuran (50 mL) as starting materials, the title compound (306 mg, 10%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:14])[C:3]=1[I:13]
Reactant: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (4.9 g, 15 mmol), triphenylphosphine (5.5 g, 21 mmol), and methanol (0.91 mL, 22 mmol) in tetrahydrofuran (44 mL) at 0° C. was treated with diisopropyl azodicarboxylate (4.1 mL, 21 mmol) dropwise and stirred at 20° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and poured into water. The organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (5%-30%) gave the desired product (4.1 g, 79%). LCMS for C9H8Cl2IO2 (M+H)+: m/z=344.9, 346.9. Found: 344.9, 346.7.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[NH:11][O:10][C:9](=[O:12])[C:8]=2[CH:13]=1)([OH:3])=[O:2].[C:17](=O)([O-])[O-].[Na+].[Na+].COS(OC)(=O)=O.S(=O)(=O)(O)O>>[CH3:17][N:11]1[C:7]2[C:6]([C:14]([OH:16])=[O:15])=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:13][C:8]=2[C:9](=[O:12])[O:10]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(C(=O)O)c2[nH]oc(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cn1oc(=O)c2cc(C(=O)O)cc(C(=O)O)c21

Procedure:
Crude 1C is dissolved in a slight excess of aqueous sodium carbonate solution and treated with a 10% excess of dimethylsulfate. The reaction is warmed on a steam bath under nitrogen with swirling until the solution becomes homogeneous. The warm reaction mixture is immediately made acidic with concentrated sulfuric acid and allowed to cool. The precipitate which forms on cooling is collected, dried and used directly in the next step. Mass spectrum, m/e 237 (m+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[C:33]([F:36])([F:35])[F:34].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:26]([C:27]2[C:28]([C:33]([F:36])([F:34])[F:35])=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:37])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Reactant: CON(C)C(=O)c1cccnc1C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-3-methoxy-bromobenzene (2.0 g, 6.82 mmol) in tetrahydrofuran (50 mL) at −78° C. under argon was added 2 N butyllithium solution in hexanes (3.75 mL, 7.5 mmol) dropwise. The resulting mixture was allowed to stir for one hour, whereupon a solution of N-methoxy-N-methyl-2-trifluoromethyl-nicotinamide (1.76 g, 7.5 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was then allowed to reach room temperature over two hours, then poured onto cold 2 N aqueous hydrochloric acid (150 mL). The mixture was extracted with diethylether, and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 2:1) to give (4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridin-3-yl)-methanone, 1.72 g (65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](OC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a THF solution (0.5 M) of methyl (2E)-3-(4-bromophenyl)acrylate (1 eq.) was added, at 0° C., lithium aluminum hydride (1.0 M THF solution, 1 eq.) dropwise over a period of for 3 h. The reaction mixture was then warmed slowly to RT over 1 h. At 0° C., the reaction was carefully quenched with freshly-deoxygenated H2O. The organic layer was separated and washed with cold 10% aq. HCl. The aqueous washes were combined and back-extracted with ether. The organic extracts were then washed further with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo to reveal a yellow oil. Purification by way of full vacuum distillation afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[ClH:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:16]1[N:17]=[N:18][C:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Temperature: 100 °C
Yield: 98.8 %

Procedure:
18.0 g 6-(3-methoxy-4-n-propoxyphenyl)-3[2H]pyridazinone are suspended in 63.6 g phosphorus oxytrichloride. The mixture is stirred at 100° C. until a clear solution has formed and the evolution of HCl stops. The solution is cooled to about 50° C. and poured onto 1 kg of ice, while stirring constantly, whereupon a crystalline precipitate forms immediately, this being filtered off with suction and washed free from acid with water, dilute sodium bicarbonate solution and again with water. Drying in vacuo gives 19.1 g (98.8%) of the title compound of m.p. 129° C., and of m.p. 132° C. after crystallization from cyclohexane.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:6][C:5]=1[NH:24][C:25](=[O:33])[CH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)=[CH:6][C:5]=1[NH:24][C:25](=[O:33])[CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(C(F)(F)F)cc1)CC2
Agent: [Ni]
Solvent: CO
Product: Nc1cc2c(cc1NC(=O)CCC1CCCC1)CCC2Nc1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a solution of N-[6-nitro-1-(4-trifluoromethyl-phenylamino)-indan-5-yl]-3-cyclopentyl-propionamide (200 mg) in 20 ml of methanol was added a catalytic amount of Raney Nickel. The resulting mixture was hydrogenated under regular pressure at room temperature for 4 hours. The reaction mixture was filtered through celite and washed with methanol. The filtrate was evaporated to dryness in vacuo and the residue was purified by column (hexane/EtOAc, 3:1) to give a white solid product in a quantitative yield. 1H-NMR (DMSO-d6): δ 9.01 (s, 1H, NH, exchangeable with D2O), 7.36 (d, 2H, J=8.4 Hz), 7.05 (s, 1H), 6.78 (d, 2H, J=8.4 Hz), 6.66 (d, 1H, NH, J=8.4 Hz, exchangeable with D2O), 6.31 (s, 1H), 4.88 (q, 1H, J=8.4 Hz), 4.69 (brs, 2H, NH2, exchangeable with D2O), 2.77 (ddd, 1H, J=15.3, 8.4, 3.6 Hz), 2.67 (m, 1H), 2.42 (m, 1H), 2.29 (t, 2H, J=7.5 Hz), 1.73 (m, 4H), 1.56 (m, 4H), 1.48 (m, 2H), 1.07 (m, 2H). MS: 432 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 99.2 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (obtained as described in Example 25, Step A, 300 mg, 0.745 mmol) was treated with 1 M NaOH following the procedure described in Example 71, Step B, using citric acid instead of hydrochloric acid giving (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid (287 mg, 99%). The resulting product was treated with NH2OTHP according to the procedure described in Example 71, Step C, giving (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of the THP and BOC protecting groups following the procedure described in Example 71, Step C gave (E)-3-{3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide hydrochloride (109 mg) as a white solid.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@@H]2C3C(O)=C4C(=O)C5C(O)=CC=CC=5C(=O)C4=CC=3[C@@H](C(OC)=O)[C@@](O)(C)C2)C[C@H](N(C)C)[C@@H]1O[C@@H]1O[C@@H](C)[C@@H](O[C@@H]2O[C@@H](C)C(=O)CC2)[C@@H](O)C1.C[C@@H]1O[C@@H](O[C@H]2[C@@H](N(C)C)C[C@H](O[C@@H]3C4C(O)=C5C(=O)C6C(O)=CC=CC=6C(=O)C5=CC=4[C@@H](C(OC)=O)[C@@](O)(C)C3)O[C@H]2C)C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3.C[C@@H]1O[C@@H](O[C@@H:123]2[C:128]3[C:129]([OH:144])=[C:130]4[C:137](=[O:138])[C:136]5[C:139]([OH:143])=[CH:140][CH:141]=[CH:142][C:135]=5[C:133](=[O:134])[C:131]4=[CH:132][C:127]=3[C@@H:126]([C:145]([O:147][CH3:148])=[O:146])[C@@:125]([OH:153])([CH2:149][C:150]([CH3:152])=[O:151])[CH2:124]2)C[C@H](N(C)C)[C@@H]1O[C@@H]1O[C@@H](C)[C@@H](O[C@@H]2O[C@@H](C)C(=O)CC2)[C@@H](O)C1.C[C@@H]1O[C@@H](O[C@H]2[C@@H](N(C)C)C[C@H](O[C@@H]3C4C(O)=C5C(=O)C6C(O)=CC=CC=6C(=O)C5=CC=4[C@@H](C(OC)=O)[C@@](O)(CC(C)=O)C3)O[C@H]2C)C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3>>[CH3:152][C:150]([CH2:149][C@:125]1([OH:153])[C@H:126]([C:145]([O:147][CH3:148])=[O:146])[C:127]2[CH:132]=[C:131]3[C:133](=[O:134])[C:135]4[CH:142]=[CH:141][CH:140]=[C:139]([OH:143])[C:136]=4[C:137](=[O:138])[C:130]3=[C:129]([OH:144])[C:128]=2[CH2:123][CH2:124]1)=[O:151]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Agent: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Agent: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Product: COC(=O)[C@@H]1c2cc3c(c(O)c2CC[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Reaction time: 12 h

Procedure:
A 500 ml Erlenmeyer flask with 100 ml of vegetative culture of Streptomyces galilaeus OBB-111, obtained by a process analogous to that described in Example 1, containing auramycin A, auramycin B, sulfurmycin A and sulfurmycin B, was allowed to stand at room temperature for 12 hours and extracted with 200 ml of a solvent mixture of chloroform and methanol (1:1, v/v). The chloroform layer was separated, concentrated in vacuo and chromatographed by thin layer chromatography (toluene/methanol=20:1, v/v). The bands containing 7-deoxysulfurmycinone and 7-deoxyauramycinone were scraped off, extracted with chloroform and concentrated in vacuo to dryness to give 1.4 mg of pure 7-deoxysulfurmycinone and 1.2 mg of pure 7-deoxyauramycinone, respectively.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:16][CH2:17]1
Reactant: CC1(C)CCN([C@H]2CC[C@@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CCN(C2CCC(N)CC2)CC1

Procedure:
0.7 g (1.8 mmol) cis-dibenzyl-[4-(4,4-dimethyl-piperidin-1-yl)-cyclohexyl]-amine are placed in 14 ml of methanol, 0.14 g palladium/charcoal (10%) are added and the mixture is hydrogenated at 50 psi and 20° C. Then the catalyst is suction filtered and the mother liquor is concentrated by evaporation. Yield: 0.3 g
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:17][N:18]([CH:20](OC)OC)[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[C:10](\[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)/[C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: CCc1ccc(C(=O)Cc2ncc[nH]2)cc1
Product: CCc1ccc(C(=O)/C(=C/N(C)C)c2ncc[nH]2)cc1

Procedure:
1 mmol of 1-(4-ethylphenyl)-2-imidazolylethan-1-one was heated to 80° C. in N,N-dimethylformamidedimethyl acetal for six hours and concentrated in vacuo to obtain (2E)-3-(dimethylamino)-1-(4-ethylphenyl)-2-imidazolylprop-2-en-1-one.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[S:20][C:8]2[S:9][CH2:10][C:11](=[O:19])[N:12]([CH2:13][C:14]([O:16]CC)=[O:15])[C:7]=2[CH:6]=1)(=[NH:4])[NH2:3].[CH]Cl>>[ClH:1].[C:2]([C:5]1[S:20][C:8]2[S:9][CH2:10][C:11](=[O:19])[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:7]=2[CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)CN1C(=O)CSc2sc(C(=N)N)cc21
Agent: Cl
Agent: [CH]Cl
Product: N=C(N)c1cc2c(s1)SCC(=O)N2CC(=O)O
Temperature: 80 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
A mixture of 6-amidino-1-ethoxycarbonylmethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine hydrochloride (0.15 g) and cHCl (1.5 ml) was stirred at 80° C. for 7 hours. The reaction mixture was evaporated in vacuo. The resulting oil was dissolved with water, and lyophilized to give 6-amidino-1-carboxymethyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b]-[1,4]thiazine hydrochloride (90.6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14]([OH:16])=O)[CH2:10]2)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>Cl.CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:13][CH2:12][CH:11]1[CH2:10][CH:9]([C:14](=[O:16])[NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[F:31])[CH2:8]2)=[O:5])[CH3:2]
Reactant: NCc1ccccc1F
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(C(=O)NCc1ccccc1F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.9 %

Procedure:
A mixture of 100 mg of 8-aza-bicyclo[3.2.1]octane-3,8-dicarboxylic acid 8-ethyl ester, 0.056 g of HOBt, 0.074 g of EDC, 0.073 mL of triethylamine, 100 mg of 2-fluorobenzylamine and 5 mL of DMF was stirred at room temperature for 24 h, diluted with 50 mL of 1N HCl and extracted into 3×25 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of saturated sodium carbonate and dried over magnesium sulfate. Removal of solvents under reduced pressure gave 150 mg of a resin.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[C:10]1(=[O:20])[O:15][C:13](=[O:14])[CH:12]2[CH2:16][CH2:17][CH:18]=[CH:19][CH:11]12>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[C:10]([OH:15])(=[O:20])[CH:11]1[CH:19]=[CH:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:9])=[O:14]
Reactant: O=C1OC(=O)C2CCC=CC12
Agent: C=CC=CCCC(C)O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Product: O=C(O)C1C=CCCC1C(=O)O

Procedure:
In a 1 liter glass autoclave equipped with a thermometer, a condenser, a nitrogen gas inlet and a stirrer, 378 g. (3.0 mole) of 2, 7 - octadienol - 1, 152 g. (1.0 mole) of tetrahydrophthalic anhydride, 100 ml. of xylene and 0.5g. of zinc acetate 2 - hydrate were charged. In accordance with the process of Reference Example 1, 388 g of the di-(2, 7 - octadienol - 1) ester of tetrahydrophthalic acid was obtained as the product.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[NH:10][C:9](=O)[N:8]=1.P(Br)(Br)([Br:32])=O>[OH-].[Na+]>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=[C:9]([Br:32])[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1nc(Oc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cccc(Oc2cc(Oc3cccc(C(F)(F)F)c3)nc(Br)n2)c1

Procedure:
4,6-Bis(3-trifluoromethylphenoxy)-pyrimidin-2-one (4.0 g, 0.0096 mol) and POBr3 (100g) were heated at 140° C. for 48 hours. The mixture was then poured onto a mixture of 2N NaOH (500 ml) and ice. The product was extracted into diethyl ether, dried using Na2SO4, filtered and concentrated under reduced pressure. The product was obtained by column chromatography (3:1, hexane: ethyl acetate) and recrystallization (ethyl acetate/hexane). Yield: 1.0 g (22%); melting point 126°-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CC(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 92.7 %

Procedure:
Methyl 4-hydroxyphenylacetate (6.00 g, 36.11 mmol) was dissolved in acetone (72 ml), and potassium carbonate (7.49 g, 54.16 mmol) and 4-fluorobenzyl chloride (6.47 ml, 54.16 mmol) were added thereto. After being refluxed for 24 hours, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}acetate (9.18 g, 93%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[C:39]([Cl:41])[CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:37]2[CH:36]=[C:35]([Cl:34])[CH:40]=[C:39]([Cl:41])[CH:38]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
Triphenylphosphine (786 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (603 mg), 3,5-dichlorophenol (489 mg) and diethyl azodicarboxylate (522 mg) in tetrahydrofuran (15 mL) at room temperature. After stirring at room temperature for 14 hr, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to give the titled compound (815 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.75 (m, 2H), 1.90 (m, 2H), 3.37 (m, 2H), 3.66 (m, 2H), 4.44 (m, 1H), 6.80 (d, J=1.5 Hz, 2H), and 6.95 (s, 1H); mass spectrum (EI+) m/e 345 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([CH3:32])[C:11]([NH:13][CH:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[NH:16][C:15]2=[O:31])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][C:41](=[O:44])[CH2:42]Br>CN(C=O)C>[CH3:39][O:40][C:41](=[O:44])[CH2:42][N:16]1[C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:20][CH:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:32])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:15]1=[O:31]
Reactant: COC(=O)CBr
Reactant: C[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(NC(=O)C(C)Cc2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-1,4benzodiazepin-3-yl)propanamide (1.0 g) was dissolved in DMF and treated with cesium carbonate (2.1 g) and bromoacetic acid methyl ester (200□l), then left to stir at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water and the organic layer washed (water, brine), dried (magnesium sulphate) and evaporated in vacuo. Purification by flash silica chromatography afforded {3-[3-(3,4-Dichlorophenyl)-2-methyl-propionylamino]-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([O:30]C(=O)C)=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([OH:30])=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2O)=C(C)C1=O
Yield: 63.3 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-methoxyaniline (0.040 g, 0.0834 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) to obtain the titled compound (0.025 g, 0.0528 mmol, 69%).