Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:26]1[CH:27]=[C:28]([O:36][CH3:37])[C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1)[CH:24]=[CH2:25]>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:30]3[CH:31]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=[C:28]([O:36][CH3:37])[C:29]=3[OH:35])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C=CCc1cc(OC)c(O)c(B(O)O)c1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: C=CCc1cc(OC)c(O)c(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1
Yield: 37 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(5-allyl-2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 5-allyl-2-hydroxy-3-methoxyphenylboronic acid in 37% yield using method F; δH [2H6]-DMSO 13.53,(1H, s), 13.31,(1H, s), 8.35-8.20,(4H, m), 8.16,(2H, d), 7.70,(1H, s), 7.53,(1H, s), 7.09,(1H, d), 6.93,(2H, m), 6.05,(1H, m), 5.14,(1h, d), 5.06,(1H, d), 3.85,(6H, s), 3.40,(2H, d).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:41][C:42]1([O:45]C1)[CH3:43].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C:42]([OH:45])([CH3:43])[CH3:41])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](SCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (83.0 mg, 0.143 mmol), isobutylene oxide (113 mg, 1.56 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=1:1, developed once) to give the title compound as a colorless oil (62.3 mg, 82%).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].ON1C2C=CC=CC=2N=N1.[CH2:36]([NH:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)[CH3:37].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:39]([NH:38][CH2:36][CH3:37])=[O:45])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: CCNC(=O)[C@@H]1CCCN1
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
7.33 g (29.7 mmoles) of Z-Arg(NO2)-OH and 1.034 g of N-hydroxy-benzotriazole are added to a solution containing 3.24 g (22.8 mmoles) of proline ethylamide in 70 ml of THF. The reaction mixture is cooled in an iced water bath and 5.34 g (25.8 mmoles) of DCC dissolved in 50 ml of THF are portionwise added under stirring. The mixture is stirred under cooling with ice for 5 hours, at room temperature for additional 20 hours, then filtered and washed with THF. The filtrate is evaporated under reduced pressure, the residue is dissolved in chloroform and successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each. The chloroformic solution is dried over anhydrous sodium sulfate, filtered, washed with chloroform, then the filtrate is evaporated. The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate, filtered and washed with 30 ml of an 1:2 mixture of THF with ethyl acetate. After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue. The thus-obtained product is filtered, washed with ether and dried under reduced pressure to afford 9.69 g (98% yield) of the aimed compound, m.p.: 125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]1[CH2:15][N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[CH:17]=[CH:18][C:11]2=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]1[CH2:15][N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[O:21])[CH:17]=[CH:18][C:11]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(C)C)C(O)C(F)(F)F)C=C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)C=C3
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 2-(8-ethoxycarbonyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.57 g) in dimethyl sulfoxide (6 mL) and toluene (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g) and dichloroacetic acid (0.43 mL) and the resulting solution allowed to stir for 2 hours. The reaction mixture was poured into ethyl acetate, washed (1N hydrochloric acid, H2O), dried, and evaporated. The resulting material was purified by chromatography, with methanol:dichloromethane (3:97) as the eluent. The resulting solid was recrystallized from ethyl acetate to give the title compound (0.41 g); mp 218°-219° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:15])=[C:12]([OH:11])[CH:20]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Yield: 84.6 %

Procedure:
A mixture of 3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxy-benzoic acid and 6.2 g of dicyclohexycarbodiimide was refluxed for 24 hours and was evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ethyl acetate and excess 4-amino-1H-indole was removed by washing with 2N hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in ether and dried at 50° C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 190° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(O)C.[CH3:14][S-:15].[Na+]>O>[CH3:14][S:15][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: C[S-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 21.4 g of bromoacetophenone is added to 90 ml of ethanol at 0° C., followed by slow addition of a solution of 5 g of sodium thiomethoxide in 25 ml of water. The reaction medium is stirred for one hour at 0° C. and then for 2 hours at room temperature, and is subsequently poured on to 500 ml of ice-water and extracted with twice 200 ml of ethyl ether. The ether phases are combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulphate and then evaporated to dryness. The residue is distilled to give 2-(methylthio)acetophenone.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Fe]>[N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(N2CCOCC2)nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a suspension of 6-morpholin-4-yl-3-nitropyridin-2-amine (200 mg, 0.89 mmol) in acetic acid (3.8 mL) was added iron powder (249 mg, 4.46 mmol). The mixture was stirred at rt for 16 h and then poured slowly into saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with ethyl acetate (3×50 mL), and then the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the desired intermediate (150 mgs, 89%). The crude material was used directly without purification or analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
5-Bromo-2,4-dimethylbenzoic acid (12 g, 52.17 mmol) was added to cooled conc. H2SO4 (48 mL) at −10° C. lot wise. After 10 minutes nitrating mixture {prepared as mixing Conc. HNO3 (6 mL) with conc.H2SO4 (24 mL)} was added drop wise at −10° C. Resulting reaction mass was stirred at −10° C. for 30 minutes. On completion, reaction mixture was poured on ice cold water, solid precipitated was filtered, washed with water and dried under vacuum giving desired compound (13 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](N)=[C:8]([CH2:15][CH3:16])[CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OC(C)(C)C)=O.[BrH:29]>[Cu]Br>[Br:29][C:9]1[C:10]([CH2:12][CH3:13])=[CH:11][C:6]([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][C:8]=1[CH2:15][CH3:16]
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1N
Reactant: Br
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3,5-diethylbiphen-4-ylamine (9.6 g, 0.036 mol) is added to acetonitrile (95 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tert-butyl nitrite (5.7 ml, 0.044 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (2.87 g, 0.02 mol) in hydrobromic acid (2.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×250 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3,5-diethylbiphenyl (4.5 g).
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[N:50][CH:51]=2)[CH:39]=[CH:40][C:41]=1[CH3:42]>>[CH3:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[N:50][CH:51]=2)[CH:39]=[CH:40][C:41]=1[CH3:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)c(C)c4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)nc2)cc1C
Yield: 96 %

Procedure:
The compound of example 398 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 397.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]([O:31][C:32](=[O:46])[CH:33]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35](O)=[O:36])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[C@@H:33]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH2:25][CH3:26])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:10][CH:11]=1)=[O:36])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C(=O)OC(C)(C)C
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)nc(N)n1

Procedure:
(S)-2-tert-Butoxycarbonylamino-succinic acid 4-{4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl} ester 1-tert-butyl ester was prepared according to the method described for Example 64 by using the title compound of Example 44 and 2-tert-butoxycarbonylamino-succinic acid 1-tert-butyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2/[C:13](=[N:16]/[S@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])/[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][S@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[S@](=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: -78 °C

Procedure:
A mixture of (S,E)-N-((3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (0.940 g, 2.95 mmol) from Step A in methanol (20 mL) was cooled to −78° C. in a dry ice/acetone bath. Sodium borohydride (0.335 g, 8.85 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with 3×100 mL of ethyl acetate. The extracts were dried (Na2SO4) and filtered. The solvent was removed in vacuo, and the crude material was chromatographed using a silica gel cartridge (Analogix®, Burlington, Wis., RS-40) with 5-50% acetone/hexanes to give (S)—N-((3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2-methylpropane-2-sulfinamide: 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.11 (m, 5H), 4.85 (d, J=7.0, 1H), 3.90-3.71 (m, 2H), 3.28 (d, J=13.0, 1H), 3.09 (d, J=9.8, 1H), 2.72-2.50 (m, 2H), 2.46 (d, J=9.6, 1H), 2.32-2.12 (m, 2H), 1.82 (td, J=5.5, 12.7, 1H), 1.68-1.60 (m, J=10.6, 2H), 1.35-1.24 (m, 1H), 1.20 (s, J=5.5, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][O:4]1.[H-].[Na+].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[C:9]1([CH2:8][O:1][CH2:2][CH:3]2[CH2:5][O:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCC2CO2)cc1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a stirring solution of (+/−)-2-(hydroxymethyl)oxirane (3.0 g, 40.5 mmol, Aldrich) in dry DMF (40 mL) was added sodium hydride (883 mg, 36.8 mmol, Aldrich). The reaction was stirred for 7 min when benzyl bromide (6.3 g, 36.8 mmol, Aldrich) was added. The reaction was stirred for 2 h and then quenched by the addition of water (50 mL). The reaction was extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 5–20% EtOAc in hexanes) to yield 4.15 g of a colorless oil. MS (ESI) 164 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([CH:25]=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([CH:25]=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCOCc1cc(Br)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCCCC1CCCCN1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-(5-Bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane (590 mg, 1.37 mmol) was dissolved in methylene chloride (11 ml), cooled to 0° C., and treated with 3 ml of trifluoroacetic acid. The reaction mixture was stirred at 0° C. for 20 minutes, then warmed to ambient temperature, and stirred an additional ten minutes. The reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate. The pH was adjusted to about 10 with 1 N sodium hydroxide. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5](O)=[O:6].C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:12])[CH:3]1[CH2:8][C:9](=[O:11])[O:10][C:5](=[O:6])[CH2:4]1
Reactant: O=C(O)CC(CC(=O)O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(C(F)(F)F)CC(=O)O1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Into a 2 liter 3-necked flask equipped with a mechanical stirrer and reflux condenser were added 320 g (1.6 mol) 3-(trifluoromethyl)glutaric acid and 0.775 ml acetic anhydride. The solution was refluxed for 2.5 hours and allowed to cool to room temperature. The majority of the acetic anhydride was removed in vacuo (80° C.) to afford a brown solid which was dissolved in 800 ml of CHCl3 on a steam bath. Following the addition of 200 ml hexanes, a white precipitate began to form. Further crystallization was induced by storage in a refrigerator. The white flocculent solid was filtered and oven dried (50° C., 30 mm Hg) to afford 261 g (89% yield) of the desired product, m.p. 88°-91° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][C:8](=[O:33])[CH2:9][C@H:10]([OH:32])[CH:11]=[CH:12][C:13]1[N:14]([CH:29]([CH3:31])[CH3:30])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)(C)(C)C.[OH-].[Na+:36]>C(O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:29]([CH3:31])[CH3:30])[C:13]=2/[CH:12]=[CH:11]/[C@@H:10]([OH:32])[CH2:9][C@@H:8]([OH:33])[CH2:7][C:6]([O-:34])=[O:5])=[CH:27][CH:26]=1.[Na+:36]
Reactant: CC(C)n1c(C=C[C@@H](O)CC(=O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
To 30 g of ester E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-hept-6-enoic acid tert-butyl ester in 150 ml of ethanol is added under stirring 63 ml of sodium hydroxide solution while maintaining the temperature below 12° C. The solution is stirred for 1 hour, the mixture is concentrated at 25 mm Hg and 45° C., then 220 ml of water are added, destination is continued to a remaining volume of 100 ml , then 280 ml of water are added and the solution is washed with a total of 450 ml of MTBE in 3 portions. The aquous layer is concentrated at 25 mm Hg and 45° C. to a volume of about 200 ml, 150 ml water are added, and the clear aquous solution is lyophylized over 3 days. MS: 433.21
Reaction SMILES: [NH2:1][CH:2](N1C(=O)C2=CC=CC=C2C1=O)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:25]N.[ClH:27]>CO>[ClH:27].[ClH:27].[NH2:25][CH:3]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][NH2:1]
Reactant: NC(CCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: NCC(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Amino-2-benzyloxymethyl-1-phthalimido-ethane (3.0 g, 9.7 mmol) is dissolved in 50 ml dry methanol and hydrazine hydrate (968 mg, 19.3 mmol) is added. After being refluxed for 4 hours, the reaction mixture is stirred for 24 hours at ambient temperature and 50 ml 2N hydrochloric acid was added. The phthalhydrazide is removed by filtration and the 1,2-diamino-1-benzyloxymethyl-ethane-dihydrochloride is purified by recrystallisation from dry ethanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1c(F)cccc1F
Temperature: 4 °C
Yield: 48.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (12.1 g), N,N'-carbonyldiimidazole (12.3 g) and 2-amino-7-chloro-1,8-naphthyridine (8.5 g). The product produced by precipitation in water (6.8 g; m.p. 215° C.) is dissolved in boiling ethanol (450 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-2,6-difluorobenzamide (7.3 g) is produced, m.p. 242° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(Cc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCNCC1)N1CCN(Cc2ccccc2)CC1
Temperature: 24 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 1-benzyl-4-[(1-t-butoxycarbonyl-4-piperidyl)carbonyl]piperazine (115.7 g) in dry dichloromethane (222 ml) was added dropwise over 45 minutes to trifluoroacetic acid (575 ml), maintaining the temperature below 25° C. under an atmosphere of argon. The solution was stirred at 23-25° C. for 1 hour. The solution was evaporated using a bath temperature of 30° C. The residual oil was poured, in portions, into saturated aqueous sodium carbonate solution (770 ml) while maintaining the temperature below 30° C. The aqueous mixture was extracted with dichloromethane (3×575 ml). The dichloromethane extracts were combined, dried (Na2SO4) and evaporated to give 1-benzyl-4-[(4-piperidyl)carbonyl]piperazine (56.2 g, 65% yield) as a white solid;