Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][NH2:44])[N:38]=[CH:37]1>N1C=CC=CC=1>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([NH:44][CH2:43][CH2:42][CH2:41][C:39]2[N:38]=[CH:37][NH:36][CH:40]=2)=[N:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:30][CH:31]=1
Reactant: CSC(=NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1)NC(=O)c1ccccc1
Reactant: NCCCc1c[nH]cn1
Solvent: c1ccncc1
Product: O=C(N=C(NCCCc1c[nH]cn1)NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1)c1ccccc1
Yield: 58 %

Procedure:
To a solution of the above isothiourea (5.0 g, 9.133 mmol) in dry pyridine (70 ml) was added 3-(1H-imidazol-4-yl)propyl amine (1.26 g, 10.05 mmol) and the resulting mixture was stirred at reflux temperature for 10 h followed by stirring at room temperature for 48 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (600 ml) using a mixture of dichloromethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 3.31 g (58%) of the title compound as an amorphous solid.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10](=[O:19])[NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:34]1[C:43]2[C@@H:42]([NH2:44])[CH2:41][CH2:40][CH2:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(Cl)Cl>[C:5]([O:9][C:10](=[O:19])[NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:44][C@@H:42]2[C:43]3[N:34]=[CH:35][CH:36]=[CH:37][C:38]=3[CH2:39][CH2:40][CH2:41]2)[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: N[C@H]1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N[C@H]2CCCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Acetic acid (2.9 mL, 50.7 mmol), (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (4.32 g, 20.2 mmol) and sodium triacetoxyborohydride (7.56 g, 35.7 mmol) were added to a solution of (S)-5,6,7,8-tetrahydro-quinolin-8-ylamine (2.86 g, 19.3 mmol) in tetrahydrofuran (78 mL) and the mixture was stirred at 25° C. for 3.5 h. The mixture was diluted with methylene chloride (500 mL) and washed with saturated sodium bicarbonate (600 mL). The aqueous layer was extracted with methylene chloride (2×150 mL). The combine organic layers were dried (Na2SO4) and concentrated. The crude mixture of isomers was purified by column chromatography on silica gel with methanol/methylene chloride (4:96) to afford the trans-isomer [4-((5)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (2.01 g, 30%). 1H NMR (CDCl3) δ 1.06-1.39 (m, 4H), 1.69 (s, 9H) 1.65-1.80 (m, 2H), 1.90-2.14 (m, 5H), 2.16-2.25 (m, 1H), 2.29 (bs, 1H), 2.56-2.71 (m, 1H), 2.72-2.88 (m, 2H), 3.43 (bs, 1H), 3.92 (t, 1H, J=6.3 Hz), 4.39 (bs, 1H), 7.04 (dd, 1H, J=7.9, 4.5 Hz), 7.35 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4C(OC(C)(C)C)=O)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:16])([CH3:17])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OC[C@@H]4CCCN4)ccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S)-tert-butyl 2-((2-(5-bromo-2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)pyrimidin-4-yl)benzo[b]thiophen-5-yloxy)methyl)pyrrolidine-1-carboxylate (146 mg, 0.222 mmol) in dichloromethane (5 mL) was treated with trifloroacetic acid (1 mL) and stirred at room temperature for 30 min. The reaction was concentrated in vacuo to yield the title compound as a bright yellow solid (213 mg, quantitative yield). MS (M+H)+ 559/561.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Yield: 69.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 4-fluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 249 mg of 2-[2-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(F)cc2)n1
Yield: 36 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol), using 4-fluorobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (22 mg, 36%) which was obtained as a yellow gum. MS: m/e=485.5 [M+H]+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[O:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]1[O:9][CH2:8][CH2:7][OH:10]
Reactant: OCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: OCCOC1C=CC=CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dihydro-2H-pyran (30.0 g, 0.36 mol), ethylene glycol (310.0 cm3, 5.36 mol) and p-toluene sulphonic acid (ca. 1 mol %, catalyst) were added to dichloromethane (100 cm3) and the mixture stirred at ambient temperature for 18 hours under an inert gas atmosphere. Water (ca. 150 cm3) was then added, resulting in a biphasic mixture. The organic phase (containing the desired product) was collected and the aqueous phase (containing excess ethylene glycol) extracted with further portions of dichloromethane (3×50 cm3). The combined organic phase and washings were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to yield the crude product containing, almost exclusively, the mono-protected alcohol. The desired product was isolated via flash column chromatography (using silica gel 60 and a 3:1 ratio of hexane:ethyl acetate as eluant). Yield=9.10 g (17.3%).
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:3][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: COC(=O)c1cc(O)nc(C)n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)nc(C)n1
Temperature: 0 °C

Procedure:
POBr3 (6.65 g, 23.2 mmol, Spectrochem) was added to a stirred solution of methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate (5.0 g, 29.7 mmol, Preparation #2) in DMF (100 mL) at about 90° C. The reaction mixture was heated at the same temperature for about another 10 min and poured into ice water (500 mL). The solution was neutralized with 10% aqueous sodium carbonate solution (pH 7). This solution was extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (2×100 mL) and brine solution (2×150 mL), and dried over sodium sulphate and concentrated in vacuum. The crude material was purified by silica gel chromatography using 15 to 25% of EtOAc in hexane as the eluent. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford methyl 6-bromo-2-methylpyrimidine-4-carboxylate as an off white solid 5.2 g (75.7%). 1H NMR (400 MHz, DMSO) δ: 8.02 (s, 1H), 4.03 (s, 3H), 2.83 (s, 3H); MS m/z: 231 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([O:26]C(=O)C)[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH:16]=[CH:17][CH:18]([OH:26])[CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(CC1CCCCC1)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of trans-2-(4-cyclohexyl-3-acetoxy-1-butenyl)-5-oxocyclopentaneheptanoic acid methyl ester (265 g), prepared as described in Example 9, in methanol (287 ml) is added a solution of sodium methoxide (prepared from 172 g of sodium and 148 ml of methanol). The reaction mixture is stirred at room temperature for 90 min. then rendered neutral with one equivalent of acetic acid. The solvent is evaporated. The residue is taken up in ether. The ether solution is washed with water, dried and the solvent removed to yield the title compound, νmaxCHCl3 3,450, 1,735 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:30][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)Cc1ccc(N)cc1Cl
Product: CCN(CC)Cc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-diethylaminomethyl-phenylamine (Z35b). The crude product was purified by column chromatography (Alox, neutral, act. II-III, petroleum ether/EtOAc 3:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6](F)[N:5]=1)[CH3:2].C(N(CC)CC)C.O.[NH2:20][NH2:21].NN>O.C(#N)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([NH:20][NH2:21])[N:5]=1)[CH3:2]
Reactant: NN
Reactant: CCOc1nc(F)cc(F)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOc1nc(F)cc(NN)n1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 g of 94 percent purity (0.59 mol) 2-ethoxy-4,6-difluoropyrimidine, 275 mL of acetonitrile, and 107 g of water was prepared and cooled to 10° C. To this was added 68 g (0.67 mol) of triethylamine and then 34 g (0.68 mol) of hydrazine hydrate, slowly with stirring and cooling (at 5° to 10° C). When all of the hydrazine had been added, the mixture was stirred another 15 min with cooling and was then allowed to warm. After a total of 1 hour, the solids that formed were recovered by vacuum filtration and were washed twice with 100 mL portions of water and then with 50 mL of ethanol. The title compound, which was obtained as a white solid melting at 141°-143° C., amounted to 79.7 g (80 percent of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([N:6]([C:13]1[C:18]([C:19](=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:17][CH:16]=[C:15]([CH3:30])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:18]([C:19](=[O:29])[C:20]=1[CH2:21][C:22]1[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[CH:17][CH:16]=[C:15]([CH3:30])[N:14]=2)=[O:31]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1nc(C)ccc1C(=O)CCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cc2ccc(Cl)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-{-3-[3-(6-chloropyridin-3-yl)-propionyl]-6-methyl-pyridin-2-yl}-N-phenyl-oxalamic acid methyl ester in toluene was added MeOH, and the mixture placed in a pre-heated hot bath at 80° C. K2CO3 (0.9 g) was added, which produced an immediate color change. The mixture was cooled to RT, diluted with EtOAc, and washed with LiCl (0.3 wt % aq, 2×). The organic layer was dried over MgSO4, filtered, and concentrated. The product was dissolved in hot EtOAc, and allowed to cool to RT. The resulting precipitate was filtered and washed with EtOAc to provide 3-(6-chloro-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 83) (0.14 g) as a tan solid. M+H=420, mp=220.0-220.5.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:19](Cl)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C[O:32]CC1>>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCCc1ccccc1
Reactant: C1CCOC1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(CCc1ccccc1)Nc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), THF (6 mL), 60% sodium hydride (0.028 mL, 0.688 mmol), hydrocinnamyl chloride (0.131 g, 0.688 mmol). m.p. 191°-193° C.; 1H NMR (250 MHz, DMSO-d6) δ 2.65 (t, 2 H), 2.89 (t, 2 H), 6.86 (s, 1 H), 7.26 (m, 5 H), 7.53 (m, 3 H), 7.84 (m, 2 H), 9.28 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]1([O-])[CH:30]=CC=C[CH:26]=1.[Na+].[Na+]>>[OH:24][C:18]1[CH:23]=[CH:22][C:21]([C:25]([C:13]2[CH:12]=[C:11]([C:8]([CH3:10])([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH3:9])[CH:16]=[CH:15][C:14]=2[OH:17])([CH3:30])[CH3:26])=[CH:20][CH:19]=1
Reactant: [O-]c1ccccc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)c(C(C)(C)c2ccc(O)cc2)c1

Procedure:
1712 g (5.00 mol) of bisphenol A (BPA, Bayer AG) are melted at 190° C. under a nitrogen atmosphere. 20.4 g (0.05 mol) of solid sodium bisphenolate (Na2BPA) are then added. The phenol formed is removed from the resultant melt at a bottoms temperature of 180-190° C. by distillation under a water-jet vacuum (15-20 mbar). The batch preparation is repeated five times and the crude material, from which the phenol has been removed (after separation of a total of 353 g; 3.75 mol of phenol), is combined.
Reaction SMILES: [OH:1]S(O)(=O)=O.[OH-].[Na+:7].[CH2:8]([O:10][C:11](=[O:21])[C@H:12](CCSC)NC(=O)C)[CH3:9].C(OCC)(=[O:24])C>C(O)(=O)C>[C:11]([O:10][C:8](=[O:24])[CH3:9])(=[O:21])[CH3:12].[OH-:1].[Na+:7]
Reactant: O=S(=O)(O)O
Reactant: CCOC(C)=O
Reactant: CCOC(=O)[C@H](CCSC)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)OC(C)=O

Procedure:
To this solution was added with stirring sufficient anhydrous H2SO4 to neutralize the NaOH and render the solution slightly acidic. Under these conditions the N-acetyl-L-methionine was converted to N-acetyl-L-methionine ethyl ester. The remaining ethanol and ethyl acetate (formed from the reaction of residual acetic acid and acetic anhydride with NaOH) was removed by warming the mixture under vacuum. The remaining mixture was slurried with cholorform and filtered to removed sodium sulfate salts. The ester-chloroform solution was then water washed to remove any remaining salts. The resulting ester-chloroform solution was then warmed under vacuum to remove the chloroform. The resulting material was N-acetyl-L-methionine ethyl ester.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:33][C:34](=[NH:53])[C:35]1[CH:52]=[CH:51][C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43][C:37]=2[CH:36]=1>CN(C=O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:33]=[C:34]([C:35]3[CH:52]=[CH:51][C:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43][C:37]=4[CH:36]=3)[N:53]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (Preparation 39) (744 mg, 3.00 mmol), HOBT (446 mg, 3.30 mmol) and EDC (630 mg, 3.30 mmol) were stirred in DMF (28 ml) under argon for 20 minutes. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (915 mg, 3.00 mmol) was added and the mixture stirred at room temperature for 2 hrs before it was heated to 80° C. for 20 hrs. The reaction mixture was partitioned between EtOAc and water and the organic layer washed with aqueous sodium bicarbonate before it was dried in the usual manner and evaporated. The residue was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give the title compound (749 mg, 1.45 mmol). δH (d6DMSO, 400 MHz): 8.40 (1H, dd), 8.31 (1H, d), 7.89 (1H, br.s), 7.86 (1H, dd), 7.58 (1H, d), 7.37 (1H, d), 4.98 (1H, septet), 3.54-3.46 (4H, m), 3.00-2.92 (4H, m), 1.41 (9H, s), 1.36 (6H, d).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([CH3:22])[C:7]1[C:8]([I:21])=[C:9]([C:18](Cl)=[O:19])[C:10]([I:17])=[C:11]([C:15]=1[I:16])[C:12]([Cl:14])=[O:13])=[O:5].Cl.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:25].C(N(CC)CC)C.CN(C)C=[O:47]>>[Cl-:14].[CH2:24]([O:26][C:27]([CH2:28][N:29]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18](=[O:19])[C:9]1[C:8]([I:21])=[C:7]([N:6]([CH3:22])[C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:15]([I:16])=[C:11]([C:12]([OH:47])=[O:13])[C:10]=1[I:17])=[O:36])[CH3:25]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CN(C)C=O
Reactant: COCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1c(I)c(C(=O)O)c(I)c(N(C)C(=O)COC)c1I
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 68.2 g (100 mmol) of N-methoxyacetyl-5-methylamino-2,4,6-triiodoisophthalic acid dichloride (EP 0015867) in 500 ml of N,N-dimethylformamide is mixed with 22.6 g (100 mmol) of iminodiacetic acid diethyl ester hydrochloride (production according to Jongkees, Recl. Trav. Chimys-Bas, 27, 296 (1908)) and 10.1 g (100 mmol) of triethylamine. A suspension results, which is stirred overnight under argon at room temperature. Then, it is concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/ethyl acetate. After concentration by evaporation of the product fractions, a colorless solid is obtained, which is dried in a vacuum.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.Br.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:16](=[O:18])[CH2:17][Br:1])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:5])[CH3:4]
Reactant: CC(=O)OCCc1cc(C(C)=O)ccc1O
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCc1cc(C(=O)CBr)ccc1O

Procedure:
A solution of bromine (0.8 ml, 2.5g) in chloroform (20 ml) was added over 20 min to a stirred solution of 1-[3-[2-(acetyloxy)ethyl]-4-hydroxyphenyl]ethanone (3.26 g ) in chloroform (50 ml) containing a few drops of 45% hydrogen bromide in acetic acid. The red solution was diluted with ER (200 ml) washed with water (100 ml), 8% sodium bicarbonate (100 ml), brine (100 ml), dried and evaporated to give the title compound as an oil which solidified on standing to give a pale pink solid (4.1 g) m.p. 89°-92°. Two recrystallisations from chloroform gave a sample with m.p. 98°-99°.
Reaction SMILES: BrC1C(F)=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:37])[C:32]=2[Br:36])[CH:27]1[CH2:38][C:39]([O:41]C)=O)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>O.CO>[Br:36][C:32]1[C:31]([F:37])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH2:34][CH2:35][N:26]1[C:23](=[O:25])[CH2:24][NH:6][C:39](=[O:41])[CH:38]=[C:27]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1NCCc2c1ccc(F)c2Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL, 1383 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (47.6 g, 138 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (244 g) in water (500 mL). The slightly basic aqueous solution was extracted with AcOEt (3×). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (41.58 g) which was used without further purification. UPLC-MS: MS 302.1/304.1 (M+H+); UPLC rt 0.51 min.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[CH:4]([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13][NH2:14].C=CC>[Pd].C1(C)C=CC=CC=1>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8]
Reactant: COCCN
Reactant: CC1=CCCC(C)C1=O
Agent: [Pd]
Solvent: C=CC
Solvent: Cc1ccccc1
Product: COCCNc1c(C)cccc1C
Yield: 34.6 %

Procedure:
2.0 g (0.0161 mole) of 2,6-dimethyl-cyclohex-2-en-1-one, 50 ml of toluene, 1.8 g (0.024 mole) of 2-methoxyethylamine and 0.5 g of palladium on charcoal (5%) are heated with a starting pressure of 17 bars (7 bars propylene and 10 bars nitrogen) for 10 hours at 180° C. After cooling, the catalyst is filtered off and the filter residue is washed with ether and toluene. The solvent is evaporated off to leave 1.0 g of crude N-(2-methoxyethyl)-2,6-dimethylaniline, from which is obtained, by distillation in high vacuum, 0.4 g (13% of theory) of pure N-(2-methoxyethyl)-2,6-dimethylaniline; b.p. 61°-62° C./ 0.1 Torr.