Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][C:21](=[O:23])[CH3:22])[N:10]=[C:4]2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2cc(Br)ccn2n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc2cc(Br)ccn2n1
Temperature: 50 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
To a solution of 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared using the procedure in WO2006038116) (0.150 g, 0.704 mmol), diisopropylethylamine (0.363 g, 2.81 mmol), catalytic DMAP (0.09 g, 0.07 mmol) in anhydrous THF (4 mL) was added acetic anhydride (0.216 g, 2.11 mmol). The reaction mixture was stirred at 50° C. for 22 h under N2 (g). After cooling to room temperature the mixture was concentrated, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate (40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. Filtration and concentration followed by column chromatography of the residue on silica (95:5 dichlormethane/methanol) afforded N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (0.170 g, 95% yield) as a brown oil. MS (EI) for C8H7BrN4O: 256 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[N+:19]([CH:18]=[C:17]([S:16][CH3:15])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)([O-:21])=[O:20]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 63.4 %

Procedure:
A mixture of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (12.86 g, 60 mmole) [prepared by the procedure described in Belgian Pat. No. 857,388] and 1,1-bis(methylthio)-2-nitroethylene (9.91 g, 60 mmole) [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) and Acta Chem. Scand., 21. 2797 (1967)] in acetonitrile (150 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 15.5 hours. The solvent was removed by evaporation under reduced pressure and the crude product placed on silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined to yield the title compound (12.6 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)N1CCOCC1
Temperature: 130 °C
Yield: 98.6 %

Procedure:
Ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (6.25 g, 18.3 mmol) and morpholine (16.0 g, 184 mmol) were sealed and heated in a high-pressure vessel at 130° C. overnight. An analysis by TLC indicated the reaction was incomplete. Pyridinium p-toluenesulfonate (100 mg) was added, and the reaction was heated for three days at 105° C. and for one day at 125° C. The solution was allowed to cool and then poured into water (100 mL). The resulting solution was extracted with dichloromethane (3×75 mL), and the combined extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was mixed with ethyl acetate (50 mL) and hexane (200 mL) and sonicated. The solvent was decanted away to afford 6.9 g of 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC.[Cl-].[CH2:16]([N+:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1cc[n+](Cc2ccccc2)cc1CC
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC1=C(CC)C(Cc2ccccc2)N(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
The Grignard reagent prepared from magnesium (85.5 g.), benzyl chloride (407 g.) and ether (3020 ml.) was added to the slurry of 1-benzyl-3,4-diethylpyridinium chloride in benzene (2250 ml.). After refluxing the mixture was quenched in ice and ammonium chloride (453 g.). Ammonium hydroxide was added to the mixture. The ether layer was washed with water and concentrated. A solution of sodium borohydride (52 g.) in water (260 ml.) was added to a solution of the residue (712 g.) in ethanol (2 l.). The mixture was stirred, allowed to stand overnight and filtered. The filtrate was concentrated under vacuum. Water and ether were added to the residue. The ether layer was washed with water, dried and concentrated. The residue was distilled under vacuum. The main fractions darkened on exposure to air. Therefore, the sodium borohydride reduction was repeated excluding water. Sodium borohydride (42 g.) was added portionwise with stirring to a solution of the combined main fractions (517 g.) in ethanol (100%, 1 l.). The mixture was stirred for 6 hours, allowed to stand overnight and concentrated. Water and ether were added. The ether layer was washed with water, dried and concentrated. Since the reduction still appeared incomplete, it was repeated using dimethylformamide as the solvent. Sodium borohydride (40 g.) was added portionwise to a solution of the residue in dimethylformamide (1 l.). The mixture was stirred and allowed to stand overnight. Water was added and the mixture was extracted with ether. The ether extracts were washed with water, dried and concentrated. The residue was distilled under vacuum, affording 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (172 g., b.r. 154°-178° C./0.1 mm., mostly at 174° C.).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]3[C:26](=[O:27])[O:25][CH2:24][C:7]=3[CH:8]=2)[O:3]1.Cl>C(O)(=O)C.C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]3[C:26](=[O:27])[O:25][CH2:24][C:7]=3[CH:8]=2)[O:3]1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)OC3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)OC3
Yield: 134.5 %

Procedure:
Ethyl 2-(2,8-dioxo-4-phenyl-6,8-dihydro-2H-furo[3,4-g]chromen-3-yl)acetate (58 mg) was dissolved in acetic acid (2 ml) and concentrated hydrochloric acid (1 ml), and heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the residue, which was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from THF-isopropyl ether to obtain the title compound (72 mg, yield: 92%). Melting point: 226-227° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[O:9][CH2:10][CH2:11][C:4]=12.C(=O)([O-])O.[Na+].[Br:19]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:19][C:8]1[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[C:4]2[CH2:11][CH2:10][O:9][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)c1ccnc2c1CCO2
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)c1c(Br)cnc2c1CCO2
Reaction time: 9 h
Yield: 79.9 %

Procedure:
To a solution of 4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridine (463 mg, 2.40 mmol) in dichloromethane (10 mL) were added sodium hydrogen carbonate (504 mg, 6.00 mmol) and bromine (959 mg, 6.00 mmol) at room temperature, and the mixture was stirred for 9 hr. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (522 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:40])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][Cl:40])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Temperature: 65 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMF is heated to 65° C. to solubilize the starting material. To this solution is added methanesulfonyl chloride (2.77 mL) at room temperature. The reaction is heated at 65° C. for 2 h, then allowed to cool to room temperature. The reaction is poured into H20 (300 mL) to precipitate the product. The solid is filtered and recrystallized from CH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:61]3C=2N=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:61][N:60]([CH3:59])[C@@H:74]1[CH2:78][CH2:77][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:3]=2)[CH2:83]1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethyl-amino)pyrrolidine. MS (ES+) m/e 622.40 (MH+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.Cl[S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O.CN(C)C=O.ClCCl.C(N(CC)CC)C.N1C=CC=CC=1>[S:12]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([OH:3])=[O:10])([C:15]1[CH:23]=[CH:22][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1

Procedure:
N-tosyl-proline derivatives were synthesized as follows. Proline methyl ester hydrochloride was reacted with 4-(chlorosulfonyl)benzoic acid and sodium carbonate in water. The product was converted to the pentafluorophenyl ester by reacting it with pentafluorophenyl trifluoroacetate and pyridine in N,N-dimethylformamide, and purified via flash chromatography. This activated ester was then reacted with the methyl-ester of glutamate (or any of the other amino acids tested) in the presence of triethylamine and dichloromethane, the product purified by flash chromatography, and the methyl esters hydrolyzed with lithium hydroxide in water. The final products were purified via reverse-phase HPLC and lyophilized.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1)C.[C:10]1([C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16](=[O:21])[C:17](=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]2)[C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCOC1=NCCCC1
Product: CC(=O)C(C(=O)c1ccccc1)=C1CCCCN1
Reaction time: 32 h

Procedure:
12.7 g (0.1 mole) of 2-ethoxy-3,4,5,6-tetrahydropyridine and 24.4 g (0.15 mole) of 1-phenyl-1,3-butanedione are mixed and heated together in a nitrogen atmosphere, with stirring, for 32 hours in an oil bath at 100°. The reaction mixture is cooled, and subsequently chromatographed on silica gel with an ethyl acetate/hexane mixture as the eluant. The main fractions are combined and crystallised from ether to obtain 1-phenyl-2-(2-piperidinylidene)-1,3-butanedione in the form of yellow crystals, m.p. 80-81°.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCC(CN2CCOCC2)NC1
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCOCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(4-morpholinyl)methyl]piperidine to give colorless crystals, mp. 194°-195° C. (after recrystallisation from diisopropyl ether and acetonitrile using activated charcoal).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C=O)C>[O:7]([CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CCl)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1Oc1cccc(COc2ccccc2)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
Phenol (0.16 g) and potassium carbonate (0.12 g) were stirred together in DMF (6 ml) under nitrogen at room temperature. After 20 minutes, a solution of methyl 2-(3-chloromethylphenoxy)-3-pyridinylacetate (0.5 g) in DMF was added and stirring continued. Copper-bronze (cat.) was added and the reaction mixture heated at 100° C. for a total of 5 hours. GC analysis indicated complete reaction. The reaction mixture was cooled and filtered, and then poured into water (50 ml). The aqueous mixture was extracted with ether (×3) and the combined extracts washed with dilute sodium hydroxide solution. The ether solution was then dried, filtered and evaporated to give methyl 2-(3-phenoxymethylphenoxy)-3-pyridinylacetate as a yellow oil (0.35 g, 59%), mass spectrum m/e 349 (M+); 1H NMR (CDCl3) inter alia delta 3.69 (3H, s); 3.76 (2H, s); 5.07 (2H, s) ppm, contained with traces of DMF. In a separate experiment, the chloromethyl compound (2.73 g, prepared as above) yielded a further 2.00 g of methyl 2-(3-phenoxymethylphenoxy)-3-pyridinylacetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[N:12][CH:13]=1)#[N:2].CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[N:12][CH:13]=1)#[N:2]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(F)c(C#N)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Solvent: O
Product: N#Cc1cc(COc2cncc([C@@H](CC(=O)O)NC(=O)[C@H]3CCCN(C(=O)CCC4CCNCC4)C3)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (3.2 mg, 10 μmol) as solved in tert.-butanol (0.15 mL) and methanol (0.13 mL) and barium hydroxide octahydrate (7.4 mg, 20 μmol) was added. After stirring for 45 minutes at room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (0.3 mL) and acidified by formic acid (0.9 mL). After 3 hours at room temperature the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 0.8 mg of (3R)-3-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.[H-].[Na+].CS(OC[C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH2:36][CH2:37][O:38][CH2:39][CH:40]=3)=[C:31]([F:41])[CH:30]=2)[CH2:24]1)(=O)=O>CN(C)C=O.CCCCCC>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH2:36][CH2:37][O:38][CH2:39][CH:40]=4)=[C:31]([F:41])[CH:30]=3)[CH2:24]2)=[N:9]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 55 °C
Yield: 50 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (631 mg, 2.43 mmol) in dry N,N-dimethylformamide (10 ml), under a nitrogen atmosphere was added a suspension of sodium hydride (107 mg of a 60% dispersion in oil, 2.67mmol) in hexane followed by 5(R)-methanesulfonyloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (see WO 97/09328; 226 mg, 0.61 mmol) in dry DMF (3 ml). Over a period of 24 hours further batches of sodium hydride totalling (428 mg of a 60% dispersion in oil, 10.7 mmol), were added and the reaction mixture heated to 50-60° C. for 24 h, after which time TLC indicated the formation, of the desired product (Rf 0.34, 50% ethyl acetate/hexane). The majority of the N,N-dimethylformamide was evaporated under hi-vacuum and the product isolated by MPLC (50%THF/Hexane) and then triturated with ether to yield the title compound as a white amorphous solid (63.4 mg, 29%). NMR: 2.42 (m, 2H), 3.45 (m, 2H), 3.81 (m, 3H), 4.15 (t, 1H), 4.21 (d, 2H), 4.90 (m, 1H), 6.01 (d, 1H), 6.09 (m, 1H), 6.53 (t, 1H), 7.31 (dd, 1H), 7.40 (t, 1H), 7.48 (dd, 1H), 8.39 (d, 1H); m/z: ES+ (M+H)=360.
Reaction SMILES: C(S[C:4](=S)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])C.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH2:32]>O>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([CH2:13][CH2:12][C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[NH:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]3[N:25]=2)[CH:19]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCSC(=S)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(Br)cc1CCc1c(Cl)cccc1C1=NC2CCCCC2N1

Procedure:
As shown in Scheme 25, a solution of 187 mg (0.43 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-dithiobenzoic acid ethyl ester in 2.5 mL of trans-1,2 diaminocyclohexane was heated to 110° C. in a sealed pressure tube for 12 hours. The reaction mixture was diluted with water and extracted with methylene chloride twice. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (eluting with 95:5 CH2Cl2/methanol) to give a yellow oil. The oil was treated with methanolic HCl and evaporated to yield 34 mg of product as a pure hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11]Cl)=[O:7])[CH3:2].CC(C)=O.[I-:18].[Na+]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11][I:18])=[O:7])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)CC(=O)COCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)COCCI
Reaction time: 13 h
Yield: 67 %

Procedure:
To a solution of 19 g (91 millimoles) of ethyl-4-(2-chloroethoxy)-acetoacetate (IV) and 380 ml of acetone 134.4 g (910 millimoles) of sodium iodide are added. The reaction mixture is heated to boiling for 13 hours. The inorganic substance is filtered off and the filtrate is evaporated in vacuo. The residual oil is dissolved in dichloro methane, the solution is washed with water, dried and evaporated. The crude product is subjected to fractionated distillation in vacuo. Bp.: 170° C./0.1 Hgmm. Thus 18.3 g of the desired product are obtained, yield 67%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:3]1[C:2]([NH:1][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2CCCC2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
To a stirred solution of methyl 3-amino-2-bromobenzoate (3 g, 13.0 mmol) and cyclopentanone (5.4 g, 64.28 mmol) in methanol (20 mL), acetic acid (1.56 g, 26 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (2 g, 31.7 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material purified by column chromatography to afford methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 36%).