Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:11]=[C:7]([C:8]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)=[O:10])[C:6]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: N#Cc1cnc(Oc2ccc(F)cc2)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(C#N)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-cyano-2-(4-fluorophenoxy)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.91 (1H, d, J=1.8 Hz), 8.48 (1H, d, J=1.8 Hz), 8.03 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.17–7.12 (4H, m), 4.78 (2H, d, J=5.4 Hz), 3.91 (3H, s); MS (ESI) m/z 406 (M+H)+, 404 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][CH2:10][CH2:11][S:12][CH:13]=1)[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:33]([OH:35])=[O:34])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]([OH:32])=[O:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(C)=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][CH2:10][CH2:11][S:12][CH:13]=1)[C:5]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:33]([OH:35])=[O:34])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]([OH:32])=[O:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CON=C(C(=O)O)C1=CSCCS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)C1=CSCCS1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Ethyl acetate (15 ml.) and 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetic acid (syn isomer) (2.0 g.) were added to the solution at -10° C. to give a solution. On the other hand, a suspension of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.83 g.) in water (40 ml.) was changed to a solution by adding sodium bicarbonate (1.45 g.), and then acetone (40 ml.) was added thereto. After the solution was adjusted to pH7.3, the ethyl acetate solution obtained above was added dropwise thereto over 10 minutes with stirring at -5° to -7° C., during which the pH of the mixture was kept at 6.8 to 7.3 with an aqueous solution of sodium bicarbonate. The mixture was stirred for 1.5 hours at the same temperature. The resultant solution was adjusted to pH7.8 and washed with ethyl acetate (40 ml.). The solution was adjusted to pH6 and washed with ethyl acetate (40 ml.). And the solution was adjusted to pH2 and extracted with ethyl acetate (100 ml.). The extract was washed with a saturated aqueous solution of sodium chloride (60 ml.) and dried over magnesium sulfate. The extract was concentrated in vacuo, and the residue was washed with diethyl ether and collected by filtration to give pale yellow crystals of 7-[2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.4 g.).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[N:7]=1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:6]1[N:7]=[C:2]([OH:1])[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]=2[N:5]=1
Reactant: CO
Reactant: O=C(O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Yield: 63 %

Procedure:
To a solution of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid (3 g, 0.01 mol) in methanol (15 ml) was added catalytic amount of sulphuric acid (0.2 ml) and the solution was refluxed for 2 hrs. The methanol was distilled off, and the residue was washed with sodium bicarbonate solution to give 2 g (63%) of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester as an off-white solid, which was used without further purification. 1H NMR (400 MHz, DMSO) δ ppm=1.73 (m, 4H), 2.6 (m, 2H), 2.78 (m, 2H), 2.83 (m, 4H), 3.37 (s, 3H), 12.18 (s, 1H). LC-MS: [M+H]=293.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl>ClCCl.C(OCC)C>[NH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
tert-butyl 1-(5-(3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (80 mg, 0.132 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (30 mg, 45%) as a yellow-orange solid: 1H NMR (500 MHz, MeOD) δ 9.26 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.20 (dd, J=8.9, 1.9 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.68 (dd, J=9.1, 2.8 Hz, 1H), 7.11 (d, J=9.1 Hz, 1H), 7.04 (m, 2H), 4.54 (s, 1H), 4.02 (d, J=12.7 Hz, 1H), 2.80 (s, 3H), 2.18 (m, 1H), 1.94 (m, 1H), 1.74 (m, 2H); ESI MS m/z 506, [C27H25ClFN5O2+H]+; HPLC 95.2% (AUC), tR=10.84 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(OCC)(=O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: Nc1ccc(O)cc1F
Yield: 95.5 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (2.20 g, 14.0 mmol) in 25 mL ethyl acetate is evacuated under reduced pressure and filled with nitrogen three times. Palladium, 10% by weight on carbon (220 mg) is added. The mixture is evacuated under reduced pressure and filled with nitrogen three times. The mixture is evacuated under reduced pressure and filled with hydrogen. The mixture is stirred under hydrogen atmosphere (balloon) over night. The mixture is then filtered over diatomaceous earth and concentrated to provide the title compound (1.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMF-d7) δ 8.75 (s, 1H), 6.78 (m, 1H), 6.40 (m, 1H), 6.50 (m, 1H), 4.38 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:21]([CH3:36])[CH:20]=1>>[CH3:35][N:33]([CH3:34])[CH:30]1[CH2:29][CH2:28][N:27]([C:22]2[C:21]([CH3:36])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:32][CH2:31]1
Reactant: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 1-(4-amino-5-methoxy-2-methylphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 30).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1cccc(O)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(NC(=O)CCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 3-(3-hydroxyphenyl)-propionic acid (198 mg, 1.19 mmol) in anhydrous THF (5 mL) were added N-methylmorpholine (1.2 equiv.) and isobutylchloroformate (1.2 equiv.) at 0° C. After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (150 mg, 0.99 mmol) in anhydrous THF (1 mL) was added to the reaction mixture. After 5 min the temperature was allowed to warm up to rt and stir overnight. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a yellow oil. Purification by flash chromatography using EtOAc/cyclohexane as eluant and recrystallization from DCM/MeOH/TEA (10/0.4/0.1) gave the title compound as a white solid (32%) in 98.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:6][CH2:5]1)(=O)[CH3:2].[OH2:34].[NH2:35][NH2:36]>CO>[NH2:13][C:12]1[NH:36][N:35]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:34])[CH3:2])[CH2:5][CH2:6]2)[C:11]=1[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O
Reactant: CC(=O)N1CCC(C(OS(=O)(=O)c2ccc(C)cc2)=C(C#N)c2nc3ccccc3s2)CC1
Reactant: NN
Solvent: CO
Product: CC(=O)N1CCC(c2n[nH]c(N)c2-c2nc3ccccc3s2)CC1
Yield: 54.5 %

Procedure:
A mixture of the above prepared toluene-4-sulfonic acid 1-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-2-cyanovinyl ester (140 mg, 0.29 mmol) and hydrazine hydrate (25 mg, 0.5 mmol) in methanol was refluxed overnight. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2:MeOH=20:1 to yield 54 mg (55%) of 1-[4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-piperidin-1-yl]-ethanone. MS (ES+): 342.1 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([NH2:19])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=S)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[OH2:31]>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([NH:19][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH2:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[CH:12]=2)=[O:31])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: COc1ccc(N)cc1OCc1cc(Cl)cc(Cl)c1
Reactant: O
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cc(Cl)cc(Cl)c2)cc1OCc1cc(Cl)cc(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[(3,5-dichlorophenyl)methoxy]-4-methoxyphenylamine (0.596 g, 2 mmol) in dichloromethane (30 mL) was added 3,5-dichlorophenylisothiocyanate (0.408 g, 2 mmol) in one portion. Stirring was continued overnight. Water (100 mL) was added to the mixture, and after extraction and separation of organic layer the solvent was evaporated in vacuo to give a solid, which was triturated with a mixture diethyl ether:hexanes and filtered. Yield 0.273 g (27%). White micro-crystals, m.p. 154-155° C. (dec.); 1H NMR (DMSO-d6, 400 MHz) 9.67 (s, 1H); 9.74 (s, 1H); 7.59 (s, 2H); 7.53 (s, 1H); 7.48 (s, 2H); 7.30 (s, 1H); 7.11 (s, 1H); 7.00 (d, J=8.5 Hz, 1H), 6.92 (dd, J=9.0 and 2.5 Hz, 1H); 5.10 (s, 2H); 3.79 (s, 3H). Anal: Calcd for: C, 50.22; H, 3.21; N, 5.58. Found: C, 50.50; H, 3.45; N, 5.56.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.[S:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CO.CN(C=O)C.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>[OH:27][C:10]([C:23]([F:25])([F:26])[F:24])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([C:34]2[CH:35]=[CH:36][S:32][CH:33]=2)[CH:3]=[CH:4][C:5]=1[O:30][CH3:31])([CH3:28])[CH3:29])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
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: CN(C)C=O
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(-c2ccsc2)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
A mixture of 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.2 g, 0.4 mmol), 3-thiopheneboronic acid (77 mg, 0.6 mmol), sodium carbonate (Na2CO3; 85 mg, 0.8 mmol) in DME-MeOH-DMF (1:1.5:0.5; 3.0 mL) was stirred for 10 minutes and Pd(PPh3)4 (46.2 mg, 0.04 mmol) was added. The mixture was microwaved for 15 minutes at 120° C., cooled to room temperature, and filtered through CELITE® filter aid. The residue was diluted with EtOAc (20 mL) and washed with aqueous NaOH (1.0M, 10 mL), water, and brine, and dried over sodium sulfate, and the volatiles removed in vacuo. The residue was purified by silica gel chromatography and then by reverse phase HPLC to yield 60 mg (30%) of 1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one as a white foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([N:22]1[CH2:30][CH2:29][CH:25]([C:26](Cl)=[O:27])[CH2:24][CH2:23]1)(=O)C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[C:15]([F:31])[CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:31][C:32]1[CH:37]=[C:36]([CH:35]=[CH:34][C:33]=1[F:38])[C:26]([CH:25]1[CH2:24][CH2:23][NH:22][CH2:30][CH2:29]1)=[O:27]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1ccccc1F
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(=O)N1CCC(C(=O)c2ccc(F)c(F)c2)CC1
Product: O=C(c1ccc(F)c(F)c1)C1CCNCC1

Procedure:
Following the procedure for the preparation of 1-acetyl-4(4-fluorobenzoyl)piperidine (U.S. Pat. No. 3,576,810), 1-acetyl-4(3,4-difluorobenzoyl)piperidine is prepared from 1-acetylisonipecotic acid chloride and 1,2-difluorobenzene. The acetyl group is removed by hydrolysis in dilute hydrochloric acid. Basification followed by extraction with a suitable solvent yields the title compound.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=O.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:4]1([C:2]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH2:1])[CH2:6][CH2:5]1
Reactant: CCNCC
Reactant: CC(=O)C1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(C1CC1)N(CC)CC
Reaction time: 5 h
Yield: 38.1 %

Procedure:
A solution of titanium tetrachloride (10.4 g) in n-hexane (30 ml) was added dropwise with stirring to a solution of cyclopropyl methyl ketone (8.4 g) and diethylamine (43.9 g) in n-hexane (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 5 hours, filtered and the filtrate was evaporated to dryness to give 1-cyclopropyl-1-diethylaminoethene (5.3 g) as a pale yellow oil, NMR (CDCl3) d=0.5-0.8(m, 4H), 1.1(t, 6H), 1.4(m, 1H), 3.2(q, 4H), 3.45(s, 1H), 3.5(s, 1 H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[C:7]([I:49])=[C:8]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])=[CH:24][CH:23]=2)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:15]([CH2:14][NH:13][C:10]1[C:9]([I:18])=[C:8]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:26][CH:27]=2)=[O:20])[C:7]([I:49])=[C:6]([NH:5][CH2:4][C:1](=[O:3])[CH3:2])[C:11]=1[I:12])(=[O:17])[CH3:16]
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc2)c1I
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CCCCCCCCCCCCCCC(=O)O)cc2)c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a solution of 4-[[[3,5-bis(acetylmethylamino)-2,4,6-triiodophenyl]carbonyl]amino]-benzenepentadecanoic acid, 1.1-dimethylethyl ester XIe of Example 7b (30 mg, 0.3 mmol) in anisole (1 mL), was added trifluoroacetic acid (10 mL) and the mixture stirred at RT overnight (15 h). The solvents were removed in vacuo, and the residue crystallized from ethyl acetate to furnish pure XIIe as a white amorphous solid (205 mg, yield 70%, purity>98%). Additional product (35 mg, purity 96%) was obtained from the mother liquor for a total yield of 81%.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6].Cl.C[Si](Cl)(C)C.Cl[C:24]([O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25]>C[Si](C)(C)N[Si](C)(C)C.C(Cl)Cl>[CH:39]1[C:40]2[CH:28]([CH2:27][O:26][C:24]([NH:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH:16][C:24]([O:26][CH2:27][CH:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[C:35]4[C:40]3=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:25])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6])=[O:25])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]=2[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](C/C=C/C[C@H](N)C(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(N[C@@H](C/C=C/C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The acid hydrochloride (S,S)-2,7-Diamino-E-oct-4-ene-1,8-dioic acid dihydrochloride (1.59 g, 5.8 mmol) was suspended in hexamethyldisilazane (20 ml) and 1 ml of trimethylsilyl chloride was added. Then the suspension was refluxed overnight. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous methylene chloride. This solution was cooled to 0° C. and a solution of 9-fluorenylmethyl chloroformate (3.10 g, 12 mmol) in methylene chloride was added. The solution was stirred for 1 hour before the cooling bath was removed. The next morning the solvent was evaporated and the residue was dissolved in THF. Then the mixture was quenched with 1N aqueous HCl and the solution was stirred for two hours. The organic solvent was removed and the water phase was extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in methylene chloride and precipitated with ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:31]1[CH:36]=[C:35]([N:37]([CH3:61])[C:38]([N:40]([C:49]2[C:54]([Cl:55])=[C:53]([O:56][CH3:57])[CH:52]=[C:51]([O:58][CH3:59])[C:50]=2[Cl:60])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:39])[N:34]=[CH:33][N:32]=1)[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:28]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni].O>[NH2:28][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:31]1[CH:36]=[C:35]([N:37]([CH3:61])[C:38]([N:40]([C:49]2[C:50]([Cl:60])=[C:51]([O:58][CH3:59])[CH:52]=[C:53]([O:56][CH3:57])[C:54]=2[Cl:55])[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:46])[CH3:47])=[O:39])[N:34]=[CH:33][N:32]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: [Ni]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)-3-nitrophenyl)piperazine-1-carboxylate (149 g, 0.164 mmol) was stirred in THF (1.5 ml) and MeOH (1.5 ml). Five drops of Raney Nickel suspension in water was added. The solution was stirred under hydrogen atmosphere at room temperature overnight. The reaction was filtered through a pad of Celite®. and filtrate was concentrated to give crude title compound which was taken to the next step without further purification. ESI-MS: 877 [M+H]+.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:19]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by cyclopentanecarbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.88-0.97 (m, 3 H) 1.30-1.39 (m, 2 H) 1.51-1.62 (m, 4 H) 1.62-1.70 (m, 3 H) 1.77-1.87 (m, 2 H) 2.16-2.26 (m, 5 H) 2.73-2.86 (m, 1 H) 3.71-3.83 (m, 4 H) 5.84-5.94 (m, 1 H); MS (ESI) m/z 280 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[N:12][C:4]=1[NH2:3])[CH3:15]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A 60% sodium hydride suspension in mineral oil (1.28 g, 32 mMol) was added to a stirring suspension of 2-aminonicotinic acid (4.21 g, 30 mMol) in DMF (50 mL), and the mixture was gently heated until gas evolution was observed. The suspension was stirred at room temperature for 4 hours, after which a homogeneous amber solution was observed. Iodoethane (4.75 g, 30 mMol) was added, and the mixture was allowed to stir overnight at room temperature. The solution was concentrated in-vacuo, the residue was taken up in 9:1 ethyl acetate/hexane (200 mL), washed with water (5×50 mL), and brine (50 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25%–50% ethyl acetate/hexane, to yield 3.6 g of colorless solids as product. NMR (500 MHz, DMSO) δ 8.20 (dd, 1H, J=5 Hz, 2 Hz), 8.06 (dd, 1H, J=8 Hz, 2 Hz), 7.16 (s, 2H), 6.63 (dd, 1H, J=8 Hz, 5 Hz), 4.28 (q, 2 H, J=7 Hz), 1.30 (t, 3H, J=7 Hz). Yield=72%.