Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([C:33]([F:36])([F:35])[F:34])[C:28]([O:31][CH3:32])=[N:29][CH:30]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CNCC3)C1
Reactant: COc1ncc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)(C)O
Product: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
To a glass flask was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 23) (6.331 g, 15.86 mmol), 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (intermediate 1) (4.465 g, 17.442 mmol), sodium tert-butoxide (2.29 g, 23.78 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.726 g, 0.793 mmol), di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine (0.297 g, 0.951 mmol) and anhydrous tert-butanol (30 mL). The flask was flushed with a stream of nitrogen for 15 sec and capped. The mixture was heated with stirring for 4 h under reflux. The mixture was allowed to cool to rt and partitioned between EtOAc (100 mL) and water (20 mL). The biphasic mixture was filtered the through a celite pad. The organic layer was separated and concentrated in vacuo to give crude (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow foam (7.46 g, 95% yield).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[N:20]=[CH:19][N:18]=1>C1COCC1.CC(C)([O-])C.[K+]>[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:14][CH2:13]2)[N:20]=[CH:19][N:18]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a solution of 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (3.65 g, 17 mmol) and 4,6-dichloro-5-methylpyrimidine (2.83 g, 17 mmol) in THF (70 mL), 1M potassium-t-butoxide in THF (16 mL, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. The crude mixture was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1 v/v) to provide 4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine as a solid (4.15 g, 71%). Exact mass calculated for C15H20ClN5O2337.13, found 338.2 (MH+).
Reaction SMILES: CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:53][C:54]([F:77])([C:73]([F:76])([F:75])[F:74])[C:55]([C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][O:69][CH2:70][O:71][CH3:72])[CH:63]=1)=[CH:56][C:57]([O:59][CH2:60][CH3:61])=[O:58].C(O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]Cl.C(O)C>[F:53][C:54]([F:77])([C:73]([F:74])([F:75])[F:76])[CH:55]([C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][O:69][CH2:70][O:71][CH3:72])[CH:63]=1)[CH2:56][C:57]([O:59][CH2:60][CH3:61])=[O:58]
Reactant: CCOC(=O)C=C(c1cccc(COCOC)c1)C(F)(F)C(F)(F)F
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)CC(c1cccc(COCOC)c1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
Under a nitrogen atmosphere, copper (I) chloride (73.7 mg), sodium tert-butoxide (71.5 mg) and BINAP (463 mg) were stirred in toluene (12 mL) at room temperature for 10 min, and to the reaction mixture were successively added polymethylhydrosiloxane (1.67 mL), ethyl 4,4,5,5,5-pentafluoro-3-(3-((methoxymethoxy)methyl)phenyl)pent-2-enoate (1.37 g) and tert-butanol (854 μL) at room temperature. The reaction mixture was stirred at room temperature for 16 hr, ethanol (5 mL) was added at room temperature, and the mixture was filtered through celite. To the filtrate was added saturated aqueous ammonium chloride solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was filtered through NH silica gel to give a crude product (366 mg) of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])(=[O:4])=[O:3].[Se](=O)=[O:17]>>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[C:10]2=[O:15])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc2c1CCCC2=O
Reactant: O=[Se]=O
Product: CS(=O)(=O)c1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-methanesulphonyl-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-methanesulfonyl-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>O1CCCC1>[CH2:1]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 143.6 %

Procedure:
A solution of N-benzyl-4-methoxybenzenesulfonamide (15.00 g, 36.06 mmol) in tetrahydrofuran (90 ml) was added to a suspension of sodium hydride (60% oil suspension 1.47 g, 36.78 mmol) in tetrahydrofuran (90 ml) and stirred for 50 minutes at room temperature. Then the suspension, with ethyl bromoacetate (6.00 ml, 54.09 mmol) added thereto, was stirred for 14 hours at room temperature. After the reaction, the mixture, with water (100 ml) added thereto, was extracted with ethyl acetate (100 ml×3). The organic layer was dried over sodium sulfate, and then the solvent was evaporated out. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give ethyl 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetate (18.82 g, 96%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([NH:24][C:25]1[CH:37]=[C:36]([CH:38]=[CH2:39])[CH:35]=[CH:34][C:26]=1[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:16]([NH:24][C:25]1[CH:37]=[C:36](/[CH:38]=[CH:39]/[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)[CH:35]=[CH:34][C:26]=1[C:27]([OH:29])=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: COc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
0.060 mL of 3-iodoanisole, 0.16 g of cesium carbonate, 24 mg of tetrabutylammonium bromide and 39 mg of polymer supported di(acetato)dicyclohexylphosphino palladium(II) were added to 2.0 mL of toluene solution containing 80 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated, and the solvent was evaporated under reduced pressure after washed with 10% citric acid aqueous solution. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2-(benzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][N:51]=3)[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][N:51]=3)[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 5-chloropyridin-2-amine (112 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was heated to reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer collected and evaporated. The crude material was used without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:11]=[CH:10][C:9]=1[OH:20].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:11]=[CH:10][C:9]=1[O:20][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=1
Reactant: Oc1ccc(Cn2cccn2)cc1Cl
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Cn3cccn3)cc2Cl)cc1
Yield: 94.8 %

Procedure:
To a mixture of potassium carbonate (298 mg), 2-chloro-4-(1-pyrazolyl)methylphenol (300 mg) and anhydrous N,N-dimethylformamide (200 ml) was added dropwise an anhydrous N,N-dimethylformamide solution (2 ml) of 4-chlorobenzyl chloride (232 mg) at room temperature under stirring. This mixture was then stirred at the same temperature for 12 hours, and poured into ice-cooled saturated aqueous ammonium chloride solution, which was extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 454 mg of 2-chloro-1-(4-chlorobenzyloxy)-4-(1-pyrazolyl)methylbenzene (compound 4). Yield, 95%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](OC)(OC)([O:21][CH3:22])[CH2:18][CH2:19][CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:21][CH3:22])[CH2:18][CH2:19][CH3:20])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCCC(OC)(OC)OC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCCC(OC)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthobutyrate
Reaction SMILES: C1(C#C)C=CC=CC=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24](Cl)[CH2:23][C@H:22]1C=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].OS([O-])(=O)=O.[K+]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cl)C[C@H]1C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6.9 ml (62.9 mmol) phenylacetylen in 120 ml THF was treated at −25° C. with 39.3 ml (62.9 mol) n-butyllithium (1.6M in hexane). The reaction was kept at −25° C. for 20 min, then dropped to a solution of 2.94 g (12.6 mmol) crude (2S,4S)-4-Chloro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 100 ml THF which was cooled to −25° C. After 45 min the reaction was neutralized with 100 ml of an aqueous 10% KHSO4 solution. The mixture was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated 10% NaCl, dried (Na2SO4), evaporated and purified by flash-chromatography on silicagel (toluene/acetonitrile 195:5 to 9:1) to give 0.58 g (14%) of (2S,4S)-4-Chloro-2-((R) or (S)-1-hydroxy-3-phenyl-prop-2-ynyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 336 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12.[H-].[Na+].Br[CH2:29][CH2:30][OH:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([CH2:29][CH2:30][OH:31])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: OCCBr
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1CCO
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (0.0041 M) of 11b-(2-chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo [3,2-d][1,4]benzodiazepin-6(7H)-one in 30 ml of dry N,N-dimethylformamide was treated with 0.34 g (0.008 M) of a 57% dispersion of sodium hydride in mineral oil with stirring under nitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added and the reaction was heated to 90° for 3 hr. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloromethane which was then washed with 50 ml of water, 25 ml of a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether, and recrystallized from a mixture of dichloromethane and methanol to give the product as pale yellow prisms, m.p. 185°-190° (dec.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(NCc2ccc3c(c2)OCO3)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(1,3-benzodioxol-5-yl)methanamine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.32-7.49 (m, 5H), 6.64 (d, 1H), 6.31-6.38 (m, 2H), 6.25-6.29 (m, 1H), 5.91 (s, 2H), 4.05 (d, 2H), 3.83 (t, 2H), 3.67 (t, 2H), 3.35 (s, 3H); Mass Spectrum: M−H+ 415.
Reaction SMILES: [F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.FC(C1C=CC=CC=1F)CO[C@H]1CC[C@H](N)CC1.CS[C:39]1[N:44]=[C:43]([OH:45])[N:42]=[C:41]2[NH:46][N:47]=[CH:48][C:40]=12>CC(O)C.O>[F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:39]2[N:44]=[C:43]([OH:45])[N:42]=[C:41]3[NH:46][N:47]=[CH:48][C:40]=23)[CH2:7][CH2:6]1
Reactant: N[C@H]1CC[C@H](OC[C@H](F)c2ccccc2F)CC1
Reactant: CSc1nc(O)nc2[nH]ncc12
Agent: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Solvent: CC(C)O
Solvent: O
Product: Oc1nc(N[C@H]2CC[C@H](OC[C@H](F)c3ccccc3F)CC2)c2cn[nH]c2n1

Procedure:
From trans-4-[(2R)-2-fluoro-2-(2-fluorophenyl)ethoxy]cyclohexanamine, the resolved product of Example 11, Step 8, and 4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-6-ol [R. K. Robins, J. Am. Chem. Soc. 79, (1957), 6407-15] in refluxing 2-propanol/water for several days: MS (m+1)=390.4; 1H NMR (400 MHz, CDCl3-CD3OD) 8.2 (s, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 7.4 (dd, 1H), 7.2 (t, 1H), 7.1 (t, 1H), 5.85 (dd, JHF=47 Hz, 1H), 4.2 (m, 1H), 3.75 (m, 2H), 3.4 (m, 1H), 2.7 (m, 1H), 2.1 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: C(O)CO.[CH:5]([CH:7]1[CH2:9][C:8]1([C:14]([O:16]C)=[O:15])[C:10]([O:12]C)=[O:11])=[CH2:6].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C=CC(O)=CC=1)O>CO>[CH:5]([CH:7]1[CH2:9][C:8]1([C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])=[CH2:6]
Reactant: C=CC1CC1(C(=O)OC)C(=O)OC
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Oc1ccc(O)cc1
Solvent: OCCO
Solvent: CO
Product: C=CC1CC1(C(=O)O)C(=O)O
Temperature: 185 °C

Procedure:
Ethylene glycol (0.2 mols) and dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (0.2 mols) were combined with 0.1 gms dibutyltin diacetate and 0.1 gms hydroquinone. The temperature was gradually raised to 185° C. over a 3 hour period and then maintained for an additional 41/2 hours during which time about 3.2 gms methanol was collected. The temperature was then reduced to about 80° C. and a vacuum (0.1 mm Hg) pulled on the system to remove final traces of volatile products. The resulting light viscous oil (38.5 gms) contained some monomeric product but consisted primarily of oligomeric products of up to about 5 repeating units. A portion of the product containing 5% benzoin isobutyl ether was spread on a glass plate and upon irradiation with an ultraviolet light source provided a transparent, tack-free, resilient polymer film. Similar products are obtained when 2-vinylcyclopropane-1,1-dicarboxylic acid is esterified with ethylene glycol and diethylene glycol.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[OH-].[Li+]>C1COCC1>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][C:3]([OH:27])=[O:2])[CH2:12][CH2:11]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)CC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)CC(=O)O)CC2)cc1OC1CCCC1

Procedure:
In the same manner as Example, 8, 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-3-oxo-propionic acid methyl ester (6.7 mmol, 2.5 g), aqueous lithium hydroxide (1.0M; 8.4 mmol, 8.4 mL) in THF (70 mL) afforded the title compound as an off-white solid, mp=122°-123° C. (6.0 mmol, 2.16 g, 89%).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])(=O)C1C=CC=CC=1.C(SCCC(N[C@H](C(O)=O)C)=O)(=O)C1C=CC=CC=1>>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]
Reactant: CC(C)C[C@H](NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: C[C@H](NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)CCS)C(=O)O

Procedure:
By substituting N-(3-benzoylthiopropanoyl)-L-leucine (6.46 g.) for the N-(3-benzoylthiopropanoyl)-L-alanine in the procedure of Example 2, 2.75 g. of N-(3-mercaptopropanoyl)-L-leucine are obtained, m.p. 131°-132°. This material is recrystallized from acetonitrile.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15]C(C)(C)C)=[O:14])[CH:9]=2)[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc2nc(C(F)(F)F)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 2-trifluoromethylquinoline-6-carboxylate (2 g, 7 mmol) in dichloromethane (50 mL), cooled to 0° C., was added trifluoroacetic acid (5.18 mL, 67.2 mmol) and the reaction mixture allowed to warm to room temperature and stirred for 36 h. The reaction mixture was concentrated under reduced pressure and the crude product obtained triturated with heptane (4×10 mL) to give 2-trifluoromethylquinoline-6-carboxylic acid (1.58 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, d), 8.24 (1H, d), 8.42 (1H, dd), 8.73 (1H, d), 8.78 (1H, d). LCMS: Retention time: 1.38 min. MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[CH:9]2[CH2:13][CH:14]=[CH:15][CH2:16][CH:8]12.C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:11]1[C:10](=[O:12])[CH:9]2[CH2:13][CH:14]=[CH:15][CH2:16][CH:8]2[C:7]1=[O:17])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)C2CC=CCC12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1C(=O)C2CC=CCC2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Ethyl chloroformate (0.18 ml, 1.89 mmol) was added dropwise to a stirred solution of 1,2,3,6-tetrahydrophthalimide (0.22 g, 1.45 mmol) and triethylamine (0.23 ml, 1.67 mmol) in dimethylformamide (2 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 4 h. Methyl alcohol (1 ml) was added, diluted with chloroform (20 ml) and washed with water (3×10 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum to give N-ethoxycarbonyl-1,2,3,6-tetrahydrophthalimide (yield 82%).