Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=[C:2]([CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][N:5]([C@@H:18]([CH2:23][CH:24]=C)[C:19]([O:21][CH3:22])=[O:20])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([N:5]1[CH2:4][CH2:3][C:2]([CH2:26][CH2:27][CH3:28])=[CH:24][CH2:23][C@H:18]1[C:19]([O:21][CH3:22])=[O:20])(=[O:8])=[O:7])([O-:17])=[O:16]
Reactant: C=CC[C@@H](C(=O)OC)N(CCC(=C)CCC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCCC1=CC[C@@H](C(=O)OC)N(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (250 mg, 0.295 mmol) was added to a solution of 2.42 g (5.89 mmol) of the title compound produced in step (iii) of Example 47 in methylene chloride (295 ml), and the mixture was heated under reflux for one hr. The reaction solution was cooled to room temperature, and the solvent was removed under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give 1.84 g (yield 82%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 83.2 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (382 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (309 mg) as yellow crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][OH:8].O[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[I:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1nn(C)c(CO)c1I
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C)c(COc2ccc(C(F)(F)F)cc2)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of (4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methanol (75 mg), 4-hydroxybenzotrifluoride (48 mg), 40% diisopropyl azodicarboxylate (90 mg, toluene solution), triphenylphosphine (117 mg) and tetrahydrofuran (3.0 mL) was stirred at a room temperature overnight. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=90:10 to 50:50), so as to obtain the title compound (34 mg) in the form of a light yellow solid.
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:25]3[C@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@H:20](O)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:18][CH2:19][C@@H:20]([F:8])[C@@H:21]3[C@H:25]2[CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reactant: FS(F)(F)N1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 4 h

Procedure:
A solution of 3.5 cm3 of morpholinosulphur trifluoride in 50 cm3 of dichloromethane is added to a solution, cooled to +5° C., of 9.4 g of (3aR, 4S, 7aR)-7,7-diphenyl-2-tert-butyloxycarbonyl-4-perhydroisoindolol in 250 cm3 of dry dichloromethane. The reaction mixture is stirred for 4 hours at +5° C. and then diluted with 300 cm3 of dichloromethane, washed with 250 cm3 of an aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 42 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 120 cm3. Fractions 13 to 17 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from cyclohexane. 2.55 g of (3aR, 7R,7aR)-4,4-Diphenyl-7-fluoro-2-tert-butyloxycarbonylperhydroisoindole are obtained in the form of white crystals; melting point 202° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][C:22]=1[F:39])[CH2:2][CH2:3][CH3:4].Cl.[NH2:41][O:42][CH:43]([CH3:45])[CH3:44].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12]/[C:13](=[N:41]\[O:42][CH:43]([CH3:45])[CH3:44])/[C:14]([CH3:15])([CH3:16])[CH3:17])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][C:22]=1[F:39])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)ON
Reactant: CCCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(C/C(=N\OC(C)C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
A mixture of 6-butyl-3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one (0.15 g), 2-(aminooxy)propane hydrochloride (0.63 g) and pyridine (5 mL) was stirred at 100° C. for 16 hr. The mixture was allowed to cool to room temperature, and the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.036 g, 22%).
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN[CH2:8][C:9]1[C:10]([N:16]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:17][CH:18]2[CH2:20][CH2:19]2)=[N:11][C:12]([F:15])=[CH:13][CH:14]=1.C(=O)(O)[O-:35].[Na+].N#CBr>CO>[CH:18]1([CH2:17][N:16]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:10]2[C:9]([CH:8]=[O:35])=[CH:14][CH:13]=[C:12]([F:15])[N:11]=2)[CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: Fc1ccc(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(N(CC2CC2)CC2CC2)n1
Agent: N#CBr
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc(F)nc1N(CC1CC1)CC1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-6-fluoro-pyridin-2-yl}-bis-cyclopropylmethyl-amine (302 mg, 0.64 mmol) stirred in methanol (10 mL) was added sodium bicarbonate (139.6 mg, 1.24 mmol). After stirring at room temperature for about 15 minutes, cyanogen bromide (237.5 mg, 1.12 mmol) was added and the solution was allowed to stir at room temperature for about 4 hours. The solution was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and then concentrated under vacuum to give the title compound as an orange oily product (284 mg, yield: 87%) and was used as is without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:35])([F:34])[F:36])[N:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCc3ccccc3)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (1.2 g, 1.6 mmol) in DMF (16 mL) was added benzyl bromide (0.27 g, 1.6 mmol) and NaHCO3 (0.67 g, 8.0 mmol). The reaction was then heated to 60° C. for 2 h, cooled to RT, and stirred for 12 h. The precipitate was filtered, washed with EtOAc and the filtrate concentrated in vacuo. The residue was partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-dibenzyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as the white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[F:17][C:16]1([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:3]=1)[O:8][CH2:9][CH2:10]2
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncnc1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 55 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.1) with pyrimidin-5-ylboronic acid yielded the title compound (55% yield) as a pale yellow solid. MS (ISP): m/z=333.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:22]=2>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1cnc2cc(-c3ccccc3)ccc2c1
Product: c1ccc(-c2ccc3cc(COc4ccc(CCCn5ccnc5)cc4)cnc3c2)cc1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 3-chloromethyl-7-phenylquinoline to give 3-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-7-phenylquinoline. The yield was 59%. Recrystallization from ethanol gave colorless prisms, mp 135-136° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)c(C)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c(C)c1Cl

Procedure:
14.1 g of the compound from (e), 10.7 g of ethyl orthoformate and 12.3 g of acetic anhydride are boiled for 2 hours. The volatile components are then removed by distillation first in a water-pump vacuum and then in a high vacuum at a bath temperature of 130° C. 14 g of the title compound remain (oil).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([NH:49][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of of 2-bromo-4-methylthiazole-5-carboxylic acid (9.00 g, 40.0 mmol) in anhydrous tetrahydrofuran (140 mL) was added N,N-diisopropylethylamine (20.76 mL, 121.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.87 g, 56.0 mmol). The reaction mixture was stirred at ambient temperature for 0.5 hours and 1-hydroxybenzotriazole (7.60 g, 56.0 mmol) and benzyl amine (6.00 g, 56.0 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 hours, then concentrated to half volume in vacuo, diluted with dichloromethane (400 mL), and washed with water (400 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid in 70% yield (8.89 g): mp 92-94° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.41-7.23 (m, 5H), 5.94 (br s, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 311.0 (M+1), 313.1 (M+3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>CN(C)C(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Fc1ccnc(C(F)(F)F)c1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 20 °C
Yield: 79.5 %

Procedure:
A cold (−5° C.), de-gassed solution of 4-aminophenol (41.6 g, 0.38 mol) in N,N-dimethylacetamide (250 mL) was treated with potassium tert-butoxide and stirred while warming to 20° C. A solution containing 4-fluoro-2-trifluoromethylpyridine (60 g, 0.36 mol) in dimethylacetamide (150 mL) was slowly added and the mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo and the residue was added to vigorously stirred water (1 L). The precipitated solids were collected by suction filtration and washed with isopropanol/ether (1:1) followed by ether and hexane. The yellow tan solids were dried to afford 72.8 g (79%) of product. 1H NMR (DMSO-d6) δ 5.20 (s, 2H, —NH2), 6.62 (m, 2H), 6.86 (m, 2H), 7.04 (dd, 1H, J=5.6, 2.4 Hz), 7.24 (d, 1H, J=2.4 Hz), 8.54 (d, 1H, 5.7 Hz). MS ES 255 (M+H)+, calcd 255, RT=1.66 min.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NNc1ccc(N)cc1

Procedure:
1-Acetyl-2-(4-nitrophenyl)hydrazine (12.7 g, 0.065 mole) and 10% palladium/charcoal (catalytic amount) was suspended in absolute ethanol (300 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased (theoretical uptake 15.6 psi-actual uptake was 17 psi).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]C#N)=[CH:12][C:11]=1[F:19].Cl.[C:21](=[O:24])(O)[O-:22].[Na+].C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:21]([OH:22])=[O:24])=[CH:12][C:11]=1[F:19]
Reactant: O=C([O-])O
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 0.7 gm. of the above crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile and 30 cc. of concentrated hydrochloric acid is heated on the steam bath for 1 hour. The reaction mixture is then filtered through a sintered glass filter into ice water and the resulting precipitate collected to give 0.65 gm. of crude product. The crude acid is stirred with 50-60 cc. of saturated sodium bicarbonate solution, a small amount of charcoal is added, and the mixture is then filtered. The filtrate is acidified with concentrated hydrochloric acid and the resulting precipitate collected and dried to give 4-(benzoxazol-2-yl)-3-fluorophenylacetic acid, m.p. 207°-211° C. dec.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.[NH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[CH2:4]([CH2:3][C@H:2]([NH2:1])[C:15]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:17])[CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Product: NCCCC[C@H](N)C(=O)NCC(=O)O

Procedure:
Lys-Gly-Amp was synthesized by a similar method except the amino acid starting material was Boc-Lys(Boc)-OSu and the starting drug conjugate was Gly-Amp (see Gly-Amp synthesis).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].C(N(C(C)C)C(C)C)C.[Br:35][CH2:36][C:37](Br)=[O:38]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]1[C:37](=[O:38])[CH2:36][Br:35])[CH3:3]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)COc1ccc(F)cc1C1NCCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(F)cc1C1c2ccccc2CCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution under N2 of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (2.0 g, 5.2 mmol, 1.0 eq.) in DCM (13 mL), N-ethyldiisopropylamine (2.7 mL, 15.6 mmol, 3.0 eq.) was added. A solution of bromoacetyl bromide (0.5 mL, 5.7 mmol, 1.1 eq.) in DCM (5 mL) was added dropwise. The cooling bath was removed and the brown solution stirred at r.t. for 2 hours. The solution was diluted with AcOEt (170 mL), washed with sat. aq. NaHCO3 soln. (1×90 mL), with sat. aq. NaCl soln. (1×90 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cncn1

Procedure:
Using general procedure 4 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.125 g, 0.47 mmol) and 1,2,4-triazole (0.036 g, 0.52 mmol) gives the title compound (recrystallized from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)[CH:6]=1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Reactant: Clc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cnn(CCCN2CC=C(c3ccccc3)CC2)c1
Temperature: 100 °C
Yield: 86 %

Procedure:
A solution of 2.05 g (20 mmol of 4-chloropyrazole in dimethylformamide is added dropwise to a suspension of 1.0 g of NaH in dimethylformamide. The white suspension is heated for 30 minutes at 100° C. Cooling is carried out and 4.7 g (20 mmol) of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in dimethylformamide, are added. Heating is carried out at reflux for 2 hours. Evaporation to dryness is then carried out and the residue is extracted with chloroform, washed with water and dried with sodium sulfate. The resulting crude product is purified by chromatography on silica gel. 5.2 g (17.2 mmol) of 4-chloro-1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1H-pyrazole are obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[N+:8]([CH3:10])[CH:7]=[CH:6]1.[Cl-].CO.[F-:14].[K+]>O>[F-:14].[CH2:4]([N+:5]1[CH:6]=[CH:7][N:8]([CH3:10])[CH:9]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCn1cc[n+](C)c1
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCC[n+]1ccn(C)c1
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
10.3 grams of [BMIMCl] prepared as described above were added to a mixture of 28 mL methanol and 0.06 mL water. After complete dissolution of the [BMIMCl], 5.0 grams of dry potassium fluoride (KF) were added, and the reaction mixture was stirred at 22° C. for 20 minutes. The mixture was filtered. 4.4 grams of KF was added to the filtrate, and the mixing continued for additional 20 minutes. After filtration, the methanol was evaporated under vacuum at room temperature, and the mixture was then filtered and centrifuged. The resulting yellowish liquid was determined by elementary analysis to be the titled compound [BMIMF] in 94% yield.