Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of methyl 5-chloro-2-(4-fluorophenoxy)benzoate (step 1, 2.60 g, 9.26 mmol), tetrahydrofuran (20 mL), methanol (20 mL), and 2 N sodium hydroxide (20 mL) was stirred at room temperature for 3 h. The mixture was poured into 2 N hydrochloric acid (50 mL) and the aqueous mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and evaporated to give 2.41 g (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.11 (1H, d, J=2.8 Hz), 7.43 (1H, dd, J=9.0, 2.8 Hz), 7.14–7.02 (4H, m), 6.80 (1H, d, J=8.8 Hz); MS (ESI) m/z 265 (M−H)−.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.NN.[F:14][C:15](=[C:19]([F:21])[F:20])[CH2:16][CH2:17]N.Br>>[F:14][C:15](=[C:19]([F:21])[F:20])[CH2:16][CH2:17][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NCCC(F)=C(F)F
Agent: Br
Agent: NN
Product: O=C1c2ccccc2C(=O)N1CCC(F)=C(F)F
Yield: 80 %

Procedure:
The compounds of the formula above wherein X, Y, and Z are F and Q is a --CH2N-- derivative are generally prepared by first obtaining the desired trifluoroalkenylamine, which when n equals 1 is 3,4,4-trifluoro-3-butene-1-amine. One method of preparing this compound is disclosed in Example 6 of U.S. Pat. No. 4,952,580, the full text of which is incorporated herein by reference. The present invention provides an improved and novel method of making this compound. Surprisingly, 4-bromo-1,1,2-trifluoro-1-butene, which is commercially available, may be directly converted by first reacting it with a tosylate salt, for example, silver tosylate, a mesylate salt, or other sulfonic acid leaving group. The resulting intermediate, for example, 3,4,4-trifluoro-3-butene-1-tosylate or 3,4,4-trifluoro-3-butene-1-mesylate, is a novel compound. This step is followed by conversion to the phthalimide derivative using a phthalimide salt, such as potassium. Advantageously, this may be accomplished without first isolating the tosylate or mesylate intermediate. The phthalimide is then converted to the desired amine by reaction with hydrazine. This novel process for preparing 3,4,4-trifluoro-3-butene-1-amine has the advantage of having an improved yield compared to the prior reported synthesis method, which is at least partially attributable to avoiding the elimination of hydrogen bromide during the conversion of the bromo compound. N-(3,4,4-trifluoro-3-butenyl)phthalimide is thus produced in greater than 80 percent yield and converted to the desired amine in greater than 85 percent yield. Also, advantageously, when silver tosylate is the reactant chosen to provide the leaving group, the silver ions may be recovered and silver tosylate regenerated.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]([CH2:9][O:10][CH3:11])=O)Cl)=[O:4].[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[CH3:1][O:2][C:3]([C:5]1[S:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:7]=1[CH2:9][O:10][CH3:11])=[O:4]
Reactant: NC(=S)c1ccccc1
Reactant: COCC(=O)C(Cl)C(=O)OC
Solvent: CCO
Product: COCc1nc(-c2ccccc2)sc1C(=O)OC
Yield: 46.8 %

Procedure:
A solution of CH3O2CCH(Cl)COCH2OCH3 (68 mmole, 1.2 eq), prepared according to De Kimpe et al., Synthesis, 188 (1986), in absolute EtOH (75 ml) was treated with thiobenzamide (7.8 g, 56.7 mmole, 1.0 eq) and the resulting brown mixture refluxed under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water twice and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate provided 6.98 g (47%) of title compound as a yellow crystalline solid. 1H NMR (CDCl3): δ 3.6 (s, 3H), 3.9 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][CH:20]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[CH3:18][O:19][CH:20]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][CH:24]=1)[CH2:21][NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(C(CN)OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cccc(C(CNc2cc(C(F)(F)F)nc(-c3cccnc3)n2)OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2,5-dimethoxyphenylethylamine (28 mg, 0.232 mmol) similar to Example 186 and was isolated as an off white solid (35 mg, 54% yield). 1H NMR (CDCl3): 9.59 (brs, 1H), 8.69 (d, J=4.8 Hz, 1H), 7.37 (dd, J=4.8, 8.4 Hz, 1H), 6.76 (m, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.00 (t, 2H), 1.67 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][N:14]2[CH2:15][CH2:16][CH:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:12][CH2:13]2)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)ccc1OC
Yield: 100.8 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole and 0.8 g (2.9 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.91 g (100% of yield) of 5-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O:33]CC)=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C.C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@@:19]([CH2:25][C:26]4[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=4)[O:29][CH2:30][C:31]([O-:33])=[O:32])([OH:24])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40]
Reactant: CCOC(=O)COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])COc1cccc(C[C@]2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of ethyl (R)-{3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (7.8 g) in a mixture of ethanol (50 ml) and THF (50 ml) was added 1N-NaOH solution (15.3 ml) at room temperature. After being stirred for 4 hours at the same temperature, the mixture was evaporated. The residue was washed with diethyl ether to afford sodium (R)-{3-{[2-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-cyclohexen-1-yl]methyl}-phenoxy}acetate(6.7 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C.Cl>C(O)(=O)C>[N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH2:15][N:12]3[C:10]4=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][N:8]=[C:9]4[N:14]=[N:13]3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of the 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (150 mg, 0.451 mmol) in acetic acid, was added 3N HCl (0.1 mL). After the solution was stirred at rt for 2 h, solvents was removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqueous NaHCO3, extracted with DCM. The combined organic layers were washed with NaHCO3(aq) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give a yellow solid of 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (131 mg, 91%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.45 (s, 1H), 8.95 (d, 1H), 8.14 (m, 2H), 7.95 (s, 1H), 7.84 (d, 1H), 7.45 (m, 1H), 6.19 (s, 2H), 2.75 (s, 3H). LCMS (method B): [MH]+=305, tR=2.95 min.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[OH:35])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([C:23]1[CH:24]=[C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[O:35][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:35][C:34]2[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:32][C:33]=2[C:36]([CH3:39])([CH3:38])[CH3:37])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(CCC(=O)OC)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][CH2:17][C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[O:15])=[CH:12][CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:21]1[S:22][C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]2[CH:27]=[CH:28][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)c1Br
Yield: 27 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamidomethyl)-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(4-chlorobenzamidomethyl)thiophene-2-sulphonyl chloride in 27% yield. The crude product was passed through a silica gel column using hexanes/ethyl acetate as eluent. Purification was effected by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 210° C. (dec).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>O1CCCC1>[CH:1]1([NH:6][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NC1CCCC1)Oc1ccccc1
Yield: 81 %

Procedure:
Cyclopentylamine (9.9 ml, 100 mmol) was dissolved in tetrahydrofuran (400 ml); pyridine (8.9 ml, 110 mmol) was added thereto; and the reaction mixture was stirred. The reaction mixture was cooled with ice; phenyl chloroformate (13.8 ml, 110 mmol) was added dropwise for 5 minutes while stirring; and the reaction mixture was stirred at room temperature for 24.5 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in a solvent mixture of hexane:ethyl acetate=5:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (16.6 g, 81 mmol, 81%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:12]([C:17](OC1C=CC([N+]([O-])=O)=CC=1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15].CCN(CC)CC.[CH3:43][C:44]1[CH:73]=[CH:72][CH:71]=[CH:70][C:45]=1[CH2:46][NH:47][C:48]([C@@H:50]1[C:54]([CH3:56])([CH3:55])[S:53][CH2:52][N:51]1[C:57](=[O:69])[C@@H:58]([OH:68])[C@@H:59]([NH2:67])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:49]>CN(C=O)C.C(OCC)(=O)C>[CH3:43][C:44]1[CH:73]=[CH:72][CH:71]=[CH:70][C:45]=1[CH2:46][NH:47][C:48]([C@@H:50]1[C:54]([CH3:56])([CH3:55])[S:53][CH2:52][N:51]1[C:57](=[O:69])[C@@H:58]([OH:68])[C@@H:59]([NH:67][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:49]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@@H](N)Cc2ccccc2)CSC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CSC1(C)C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
HOBt (0.41 g), Boc-Asn-ONp (1.27 g), and Et3N (0.92 ml) were added to a solution of H-Apns-Dmt-NHBzl(2-Me) (1.32 g) obtained in the step 2 of Example 3 in DMF (20 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% NaHCO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from AcOEt/n-hexane to obtain the title compound (1.79 g).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.CN1CCN(C)C1=O.O.C(O[CH:25](OCC)[N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[N:31][N+:32]([O-:34])=[O:33])C>CCOCC>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[CH:25][N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[N:31][N+:32]([O-:34])=[O:33])=[CH:7][CH:8]=1
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Cc1ccc(N)cc1
Solvent: CCOCC
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Product: Cc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
0.05 g of acetic acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.86 g of p-toluidine and 2 ml of 1,3-dimethyl-2-imidazolidinone at 120° C., followed by agitation at the same temperature for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and condensed. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 2.54 g of 1-(4-methylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.[H-].[Na+]>>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH:12]=[N:11][CH:10]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], piperidin-2-one was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a colorless oil. MS: 269.2, 271.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]([C:15]([O:17]C)=[O:16])=[CH:13][CH:14]=1.[OH-].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
To a stirred solution of 83.27A (0.800 g, 2.6 mmol) in THF (7.00 mL) and MeOH (7.00 mL) at 0° C. was slowly added potassium hydroxide (1.4 mL, 2.9 mmol) to maintain the temperature below 6° C. The reaction mixture was then allowed to warm to room temperature and stirred for 19 hours. The reaction was then acidified with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure to yield 83.27B as a colorless solid (0.76 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:13]([O-:16])(=[O:15])=[O:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Na+:17]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)ccc1CBr
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-2-nitrobenzylbromide (50.1 g) and sodium sulfite (27.3 g) in water (200 ml) was heated under reflux for 2.5 hours and cooled to room temperature. The solvent was removed under reduced pressure and ethanol (100 ml) was added to the crude product.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([OH:10])[CH:4]=1.S(OCC)(O[CH2:15][CH3:16])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:10][C:5]1[N:6]=[C:7]([CH3:9])[N:8]=[C:3]([CH2:2][Cl:1])[CH:4]=1)[CH3:16]
Reactant: Cc1nc(O)cc(CCl)n1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(CCl)nc(C)n1

Procedure:
15.8 g (0.1 mol) of 6-chloromethyl-4-hydroxy-2-methyl-pyrimidine, 13 ml (0.1 mol) of diethyl sulphate and 27.6 g (0.2 mol) of potassium carbonate are heated at reflux in 500 ml of acetone for 6 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is taken up in 200 ml of methylene chloride and the methylene chloride solution is washed once with 50 ml of 2N sodium hydroxide and twice with 50 ml of semi-saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residual oil is distilled at 47° C./0.07 mmHg, whereupon the distillate becomes solid. There is obtained 6-ethoxy-4-chloromethyl-2-methyl-pyrimidine, m.p. 29° C.
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])([NH:26][C:27]([C:29]2[N:30]=[CH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:28])[C:16]1=[O:44]>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH2:39][CH2:40][C:41]([O-:43])=[O:42])([NH:26][C:27]([C:29]2[N:30]=[CH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:28])[C:16]1=[O:44].[K+:5]
Reactant: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(CCC(=O)O)NC(=O)c1cc2ccccc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(CCC(=O)[O-])NC(=O)c1cc2ccccc2cn1
Yield: 161.2 %

Procedure:
1.74 g of potassium carbonate, 5 ml of water and 20 ml of acetonitrile were added to 11.47 g of (+)-3-[1-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]propionic acid. After removal of solvent under reduced pressure, the residue was dissolved in 100 ml of acetonitrile was added to the residue under heating, and insolubles were filtered off. The filtrate was concentrated, and the residue was dissolved in 100 ml of acetonitrile under heating. After cooling, precipitated crystals were collected by filtration to afford 10.91 g of (+)-potassium 3-[1-(2-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl]-propionate as a colorless solid. Melting point 275° to 277° C. (decomposed). FAB-MS (m/z): 576 (MK+), 538 (MH+), 192, 39 (base). [α]D25 : +91.8° (c=0.438, methanol).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.O>C1COCC1.[OH-].[Na+]>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][CH:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)C(C/C=C/c1ccc(N(c2ncccn2)C(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (5.63 g) in THF (165 ml), 0.1N aqueous sodium hydroxide solution (165 ml) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water (200 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (4.68 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CCNc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCNc1cc(C(=O)OC(C)(C)C)ccc1N
Reaction time: 8 h
Yield: 91.3 %

Procedure:
3-(2-Ethoxycarbonyl-ethylamino)-4-nitro-benzoic acid tert-butyl ester (1.2 g, 3.55 mmol) was dissolved in ethanol (60 ml) to the solution Pd/C (10%) (300 mg) was added and the reaction mixture was stirred under Hydrogen (1 atmosphere) overnight. The reaction mixture was filtered through celite and evaporated to dryness to give 1 g (91%) of product.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[CH3:6][C:7](=[O:10])[C:8]#[CH:9].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([C:7](=[O:10])[CH3:6])[O:4][N:3]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.1 %

Procedure:
A mixture of dibromoformaldoxime(which was obtained in Example 116) (32.5 g, 160.2 mmol), 3-butyn-one (13.41 g, 197 mmol), potassium carbonate (11 g, 80.1 mmol), and methylene chloride (300 mL) was stirred at ambient temperature for 20 hours. The slurry was then treated with aqueous hydrochloric acid (2 N, 200 mL) and extracted with methylene chloride. The combined organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl acetate/hexanes 5/95) gave a white solid (16.76 g, 56% yield); 1H NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 6.97 (s, 1H).