Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]3[OH:17])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH:10]([O:17][C:22](=[O:24])[CH3:23])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]3=[O:14])[S:8][C:4]=2[CH:3]=1
Reactant: CC1=C(C)C(O)N(c2nc3ccc(F)cc3s2)C1=O
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1C(C)=C(C)C(=O)N1c1nc2ccc(F)cc2s1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
N-(6-fluoro-2-benzothiazolyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (1.39 g) was added to tetrahydrofuran (30 ml) and sodium hydride (0.18 g) at room temperature. The mixture was refluxed for 15 minutes, and then cooled to room temperature. A solution of acetyl chloride (0.79 g) in tetrahydrofuran (10 ml) was added dropwise. After the mixture was refluxed for 3 hours, the solvent was evaporated. The residue was mixed with water, and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The solid residue was washed with a small amount of diethyl ether to give the desired N-(6-fluoro-2-benzothiazolyl)-2-oxo-3,4-dimethyl-5-acetyloxy-2,5-dihydropyrrole (1.42 g). m.p. 180°-183° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@:8]1([O:28][CH3:29])[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[S:6].[O-:30][C:31]#[N:32].[K+]>O>[NH:1]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@:8]1([O:28][CH3:29])[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[S:6])[C:31]([NH2:32])=[O:30]
Reactant: CO[C@@]1(NC(=S)CCCN)C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@@H]21
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: CO[C@@]1(NC(=S)CCCNC(N)=O)C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@@H]21
Yield: 36.6 %

Procedure:
50 mg of 7β-aminoethylthioacetamido-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid obtained in Example 1 was dissolved in 3 ml of water, 30 mg of potassium cyanate was added to the solution, which was then adjusted to a pH between 7.5 and 8.0 and subjected to reaction at room temperature for a period of 6 hours. After the reaction, 7 ml of water was added to the reaction mixture, the pH was adjusted to 6.5, and the mixture was passed through a column of Diaion HP-20, fractions eluted with water and containing the end compound were concentrated and freeze-dried to give 20 mg of 7β-ureidoethylthioacetamido-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[CH:44]=3)(=[O:41])=[O:42])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(OC)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(3-methoxybenzenesulphonylmethyl)benzoate (Intermediate 101) and furan-3-yl boronic acid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1.O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]32)C1

Procedure:
Add t-butyldimethylsilyl chloride (5.49 g, 36.4 mmol), 4-dimethylaminopyridine (0.21 g, 1.74 mmol) and triethylarmine (5.32 mL, 38.14 mmol) to a stirred solution of 3β-hydroxyandrosta-5,15-dien-17-one (M81, 10.00 g, 34.8 mmol) in anhydrous DMF (175 mL) under nitrogen. Stir the resultant suspension at room temperature for 3 days and then pour into rapidly stirred water (750 mL). Filter the resultant suspension and crystallize the white solid to give 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]androst-5,15-dien-17-one (M82).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C)C=O>[C:25]([C:29]1[CH:30]=[C:31]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:32]=[CH:33][CH:34]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Reactant: CC(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3ccc4c(-c5cccc(C(C)(C)C)c5)ccc5ccc2c3c54)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Next, a mixed solution of 4.6 g of 1-bromo-6-(4-methylphenyl)pyrene, 4.9 g of 2-(3-t-butylphenyl)-4,4,5,5-tetramethyl 1,3,2-dioxaborolane, 8.0 g of tripotassium phosphate, 306 mg of PdCl2(dppf).CH2Cl2 and 75 ml of deaerated dimethylformamide was heated with stirring under a nitrogen gas flow at 100° C. for 6 hours. After cooling to room temperature, 100 ml of water was injected, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 4.3 g of 1-(3-t-butylphenyl)-6-(4-methylphenyl)pyrene.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+].O>COCCOC.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>[N:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)Cc1ccc(Br)c2ccccc12
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: O
Solvent: COCCOC
Product: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12

Procedure:
4-Bromonaphth-1-ylacetic acid (J. Org. Chem., 1951, 16, 1588) (1 g, 3.78 mmole) in 1,2-dimethoxyethane (50 ml) was treated with pyridin-4-ylboronic acid (465 mg, 3.78 mmole), sodium hydrogen carbonate (952 mg, 11.3 mmole) and water (10 ml). A stream of argon was bubbled through the mixture for 15 minutes, then tetrakis(triphenylphosphine)palladium (0) (200 mg 0.17 mmole) was added and the mixture heated under reflux for 18 hours. The mixture was then concentrated in vacuo to a gum, which was partitioned between 2M sodium hydroxide solution and dichloromethane. The aqueous layer was separated, adjusted to pH 0 with 6M hydrochloric acid and washed with dichloromethane; then adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane. The dichloromethane extract was dried (Na2SO4) and concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215° C. (465 mg, 46%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[F:9][C:10]([F:20])([F:19])[CH2:11][I+]C1C=CC=CC=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[F:9][C:10]([F:20])([F:19])[CH2:11][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: FC(F)(F)C[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)CNc1ccccc1
Yield: 90.8 %

Procedure:
250 mg (0.573 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate, 107 mg (1.15 mmol) of aniline and 5 ml of methylene chloride were reacted and worked up in the same manner as described in Reference Example 4 to obtain 91.1 mg of N-(2,2,2-trifluoroethyl)aniline as an oily substance. Yield, 92%.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=1[C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[OH:21][C:19]1[CH:20]=[C:15]2[C:16]([C:22](=[O:32])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:1]([CH3:2])[O:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Temperature: 115 °C

Procedure:
Acetic anhydride (3 ml, 30 mmol) was added to a suspension of potassium carbonate (4.0 g, 29 mmol) and 1-(2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1.95 g, 7.5 mmol) in DMF (10 ml), and the resulting suspension heated at 115° C. for ˜90 mins. The mixture was allowed to cool and poured into water (200 ml), to give an off-white precipitate. The solids were removed by filtration and washed with water (100 ml) and diethyl ether (2×40 ml), to give 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one as an off-white powder, dried in vacuo, (1.65 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[CH3:43][N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50]>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([C@@H:45]3[CH2:46][CH2:47][CH2:48][N:44]3[CH3:43])=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)[C@@H]2CCCN2C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and (S)-1-methylpyrrolidine-2-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.03 minutes; C31H39ClN6O3 (579.15); mass spectrum: (M−H)−=578.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (25 g.) is heated with octadecyl bromide (70 g.) in dry hexamethylphosphoramide (100 ml.) containing anhydrous potassium carbonate (30 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (10 ml.). The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides the product of the Example.
Reaction SMILES: C([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[O:20][CH:19]([CH:21]=[CH:22][P:23]([OH:26])([OH:25])=[O:24])[CH:18]([O:27]C(=O)C3C=CC=CC=3)[CH:17]2[O:36][CH3:37])[C:12](=[O:38])[N:11]=1)(=O)C1C=CC=CC=1>[NH4+].[OH-]>[NH2:9][C:10]1[CH:15]=[CH:14][N:13]([CH:16]2[O:20][CH:19]([CH:21]=[CH:22][P:23](=[O:24])([OH:25])[OH:26])[CH:18]([OH:27])[CH:17]2[O:36][CH3:37])[C:12](=[O:38])[N:11]=1
Reactant: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1ccc(NC(=O)c2ccccc2)nc1=O
Agent: [NH4+]
Agent: [OH-]
Product: COC1C(O)C(C=CP(=O)(O)O)OC1n1ccc(N)nc1=O
Yield: 100.9 %

Procedure:
Compound 17.5 (37 mg, 95% yield) was synthesized from compound 17.4 (62 mg, 0.11 mmol) by treating 17.4 with concentrated NH4OH (10 ml) at 45° C. for 30 min. The reaction mixture was concentrated to dryness and purified by C-18 HPLC to afford compound 17.5. 1HNMR (D2O, 300 MHz) δ 7.65 (d, 1H), 6.29-6.45 (m, 1H), 5.96-6.10 (m, 3H), 5.85 (d, 1H), 4.42 (t, 1H), 4.10 (t, 1H), 3.91 (m, 1H), 3.40 (s, 3H), 31PNMR (D2O, 300 MHz): 0.90 ppm. LRMS [M−H]− C11H16N3O7P requires 332.1. Found 331.2.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: OCCc1ccc(OCCCCOc2ccccc2)cc1
Yield: 70.5 %

Procedure:
A mixture of 10.31 g (45 mmol) of 4-phenoxybutylbromide, 6.22 g (45 mmol) of 2-(4-hydroxyphenyl)ethanol and 6.22 g (45 mmol) of pulverized potassium carbonate in 45 ml of isopropanol was refluxed for 24 hours. The resulting mixture was cooled, mixed with water and then extracted three times with ethyl acetate. The combined extracts were washed with water and then with saturated aqueous sodium bicarbonate. They were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on 500 g of silica gel (Merck Si60, 0.04-0.063 mm) using methylene chloride/methanol (98:2) as eluent. The product-containing fractions were evaporated in vacuo to yield 2-[4-(Phenoxybutoxy)phenyl]ethanol in the form of 9.08 g of crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:10][C:11]([CH3:13])=[S:12])[CH:7]([CH3:9])[CH3:8])=[O:4].FC(F)(F)[C@@H](C1C2C(C=C3C=1C=CC=C3)=CC=CC=2)O>OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].CCOCC>[CH3:1][CH:2]([CH3:14])[C:3]([O:5][C@H:6]([O:10][C:11]([CH3:13])=[S:12])[CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O[C@H](c1c2ccccc2cc2ccccc12)C(F)(F)F
Solvent: CCOCC
Product: CC(=S)O[C@@H](OC(=O)C(C)C)C(C)C
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A mixture of 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (125 g) and lipase from Candida rugosa (Sigma-Aldrich) (12.5 g) in pH 7.2 phosphate buffered saline (1 L) was stirred at room temperature. The reaction was monitored by 1H-NMR using the chiral solvating agent (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The reaction was stirred overnight. The reaction mixture was then diluted with ether, and the ether layer separated and filtered through a pad of CELITE® 545 to remove the enzyme. The ether layer was washed with aqueous sodium bicarbonate (NaHCO3) (5 times) and brine, and dried over anhydrous sodium sulfate (Na2SO4). After rotary evaporation to remove the solvent, 30.4 g of the title compound (4) was obtained. 1H-NMR using a chiral solvating agent confirmed the presence of a single isomer. The absolute configuration was determined by derivatization to a compound having known stereochemistry. 1H-NMR (CDCl3): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (septet, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (73 mg, 84%), MS (ISP) m/z=349.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1.[Cl-].[Na+]>O>[N:1]1([CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: ClC1CCCc2cccnc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(c1)CCCC2N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.9 ml of piperidine were introduced into a solution of 2 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride in 5 ml of water and the mixture was stirred for 15 minutes, heated for two-and-a-half hours at 57°±2° C., then cooled to ambient temperature. The medium was saturated with sodium chloride and extracted with ether. The solvent was eliminated under reduced presure to obtain 2.07 g of 8-(1-piperidinyl)-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [CH:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[C:15]([CH:32]5[CH2:34][CH2:33]5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:37]([F:40])([F:39])[F:38])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[CH:1]1([C:6]2[CH:36]=[CH:35][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([CH:32]5[CH2:34][CH2:33]5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:37]([F:40])([F:38])[F:39])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(C1CC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1c(C1CC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (9.2 mg, 0.017 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (2.013 mg, 0.017 mmol) in TFA (1 mL) and the resulting mixture was stirred at room temperature for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was poured into approximately 4 mL of ice water. A precipitate formed and was collected by vacuum filtration. The solid was washed with n-hexane (3×5 mL) and dried (vacuum oven) to give the title compound as a off-white solid (5.5 mg). LCMS m/z=498.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.43 (m, 1H), 0.55-0.64 (m, 1H), 0.74-0.88 (m, 2H), 1.55-1.78 (m, 5H), 1.79-1.89 (m, 2H), 1.94-2.05 (m, 2H), 2.19-2.30 (m, 1H), 2.42-2.48 (m, 1H), 2.69-2.81 (m, 1H), 2.93 (dd, J=15.92, 3.79 Hz, 1H), 120-3.30 (m, 1H), 3.54-3.65 (m, 1H), 3.84-3.94 (m, 1H), 3.97-4.07 (m, 1H), 5.15 (s, 2H), 6.76 (dd, J=8.59, 2.27 Hz, 1H), 7.05 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.59 Hz, 1H), 7.62 (d, J=8.33 Hz, 1H), 7.67-7.77 (m, 2H), 12.28 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]([CH3:21])[CH3:20].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:3][CH:4]([CH3:8])[CH3:5])[CH:10]=1)[C:5]([O:7][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:6])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CI
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)c1cc(OCC(C)C)cc(OCC(C)C)c1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
In 50 ml of N,N-dimethylformamide are suspended 5.0 g of 3,5-dihydroxybenzoic acid, 29.8 g of potassium carbonate and 11 ml of isobutyl iodide. The mixture thus obtained is stirred at 110° C. for 7 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 2.6 g of isobutyl 3,5-diisobutoxybenzoate as a light yellow oily product.
Reaction SMILES: Cl.COC1C=CC(C[C@@H]2NC(=N)[C@@H](C)C2)=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1.C(=O)C1C=CC=CC=1.NC1C=CC=CC=1N>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][N+:28]([O-:30])=[O:29])=[CH:24][CH:25]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Agent: COc1ccc(C[C@H]2C[C@H](C)C(=N)N2)cc1
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O=Cc1ccccc1
Product: COc1ccc(CC[N+](=O)[O-])cc1
Yield: 92 %

Procedure:
Isomer B: (±) (trans) 5-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-imine, monohydrochloride ##STR232## 227 A) 4-Methoxy-b-nitrostyrene (25.0 g, 0.15 mole) was reacted with benzaldehyde (19.1 g, 0.18 mole) and 1,2-diaminobenzene (19.8 g, 0.18 mole) according to the procedure of Chikashita et. al. (Synth. Commun. 1985, 15 (6), 527) to yield methoxy-4-(2-nitroethyl)benzene (25.0 g, 93%) as a yellow oil.