Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]1([CH3:27])[CH2:15][O:14][CH2:13][CH:12]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:7][C:11]1([CH3:27])[CH2:15][O:14][CH2:13][CH:12]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(O)COCC1NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC1(F)COCC1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.6 %

Procedure:
(Diethylamino)sulphur trifluoride (2.103 mL, 15.92 mmol) was added dropwise to a solution of impure benzyl 4-hydroxy-4-methyltetrahydrofuran-3-ylcarbamate (2.00 g, from Step 4) in dichloromethane (50 mL) at −78° C. After 45 min at −78° C., the mixture was quenched with saturated sodium bicarbonate (100 mL) and allowed to warm to room temperature. After separation of the two phases, the aqueous phase was extracted with dichloromethane (3×50 mL). The combined extracts were dried (MgSO4) and concentrated. The mixture was purified by silica gel chromatography, eluting with 10-50% ethyl acetate in hexanes. None of the fractions were found to be free of impurities. All fractions containing the desired product were combined to give impure benzyl 4-fluoro-4-methyltetrahydrofuran-3-ylcarbamate (597 mg). The mixture was taken to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Cl)c(O)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 46 %

Procedure:
The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=342/344 (Cl) [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:21][O:20][C:5]1[C:6]([O:16][CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=1[CH2:3][CH:2]=[O:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.3 Grams (4.3 mM) of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was dissolved in 15 ml of dichloromethane, then under ice-cooling condition, 1 g of pyridinium chlorochromate was added thereto and the reaction mixture was stirred at a room temperature for 10 hours. After filtration, the filtrate was concentrated under a reduced pressure, and the residue obtained was treated by a silica gel column chromatography (diameter 3 cm×length 15 cm, eluent: 30% ethyl acetate: n-hexane, "Wakogel C-200") to yield 1 g of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde. Colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[N+:30]([O-])=O)=[N:6][CH:7]=1.[Sn](Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[C:11]=2[NH2:30])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2N)CC1
Yield: 58.6 %

Procedure:
In a manner similar to that described in Paragraph A above, N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide (13 g, 26 mmol) was reacted with tin(II) chloride diihydrate (29 g, 130 mmol) in pyridine (100 mL) to afford 7.1 g (60% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6) 10.8 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.6 (d, 1), 7.1 (d, 1), 6.2 (d, 2), 3.3 (m, 4), 2.7 (br, 4), 1.4 (s, 9) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[N:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1csc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc(-c2ccncc2)c1
Temperature: 130 °C
Yield: 52.2 %

Procedure:
5-Pyridin-4-yl-thiophene-3-carboxylic acid ethyl ester (1.4 mmol) was dissolved in 1 M aqueous sodium hydroxide (4 mL) and IMS (5 mL). The mixture was heated by microwave irradiation at 130° C. for 10 minutes, and then filtered. 1 N Hydrochloric acid was added and the resulting precipitate was isolated by filtration washed with water and dried to give the title compound as a white solid (0.15 g). LCMS m/z 205.96 [M+H]+ R.T.=1.51 min. (Analytical Method 5).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:21][CH:22]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 61 %

Procedure:
To a solution of 1-(4-methoxycarbonylbenzoyl)-1,2,3,4-tetrahydroquinoline (22.7 g) in methanol (300 ml) is added 5% aqueous sodium hydroxide solution (150 ml) and the mixture is refluxed for 2 hours. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted hydrochloric acid, extracted with diethyl ether, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting crystal is collected by filtration to give 1-(4-carboxybenzoyl)-1,2,3,4-tetrahydroquinoline (13.2 g) as white powder, m.p. 181°-183° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)(=O)[CH3:2].II.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[N:18]1[C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=2)=[CH:2][N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=12
Reactant: CCOC(=O)Cc1ccc(C(C)=O)cc1
Reactant: Nc1ccccn1
Agent: II
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Yield: 36.8 %

Procedure:
A mixture of 6 g of ethyl 4-acetylphenylacetate, 20 ml of ethanol, 7.5 g of iodine and 5.7 g of 2-aminopyridine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give a reddish brown oil. The oil is column chromatographed over silica gel with chloroform as eluent, and the colorless crystals obtained from the chloroform eluate are recrystallized from a mixture of benzene and petroleum ether to give 3.0 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate melting at 92°-93°C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH2:27])[CH3:26]>CN(C)C=O.CCOCC>[CH2:25]([NH:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH3:26]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCN
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCNCc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
0.66 g (1.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 20 ml of N,N-dimethylformamide. A weak stream of ethylamine gas was introduced at room temperature, the reaction temperature rising to 36°. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. After concentration there was obtained a beige foam which was taken up in ether. There was obtained 0.40 g (59%) of 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as beige crystals; m.p. 166°-168°.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[C:8]([C:15]([O:17]C)=[O:16])[C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.[OH-].[K+:20]>CO>[CH2:1]1[C:6]2[CH:7]=[C:8]([C:15]([O-:17])=[O:16])[C:9]([C:11]([O-:13])=[O:12])=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.[K+:20].[K+:20]
Reactant: COC(=O)c1cc2c(cc1C(=O)OC)COCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc2c(cc1C(=O)[O-])COCC2
Temperature: 49 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
A mixture of dimethyl 3,4-dihydro-1H-2-benzopyran-6,7-dicarboxylate (16.5 g, 0.0659 mol), potassium hydroxide (10.4 g, 0.184 mol) and methanol is stirred for 3 hours at 49° C., cooled to room temperature, and filtered. The filter cake is dried to afford the title product as a cream-colored solid (14.5 g) mp >250° C.
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=N1.CCN(C(C)C)C(C)C.[O:19]1CCC(N)[CH2:21][CH2:20]1.CCOCC>CN(C=O)C>[O:19]1[CH2:20][CH2:21][CH:6]([NH:2][C:7]([NH2:8])=[NH:9])[CH2:5][CH2:4]1
Reactant: N=C(N)n1cccn1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N=C(N)NC1CCOCC1
Reaction time: 72 h
Yield: 78 %

Procedure:
To a stirred solution of 1H-pyrazole-1-carboximidamide hydrochloride (65.2 g, 445 mmol) in DMF (200 mL) at RT under nitrogen was added sequentially DIPEA (103 mL, 593 mmol) and tetrahydro-2H-pyran-4-amine (30 g, 297 mmol; CASRN 38041-19-9) and the reaction was stirred for 3 d. Et2O (100 mL) was added, and the reaction was stirred for 10 min then the reaction was allowed to settle and the ether layer was decanted. This process was repeated 3 times and a solid formed after allowing to settle for 30 min. The solid was filtered off and rinsed with Et2O and dried under high vacuum to afford 35 g, (95% purity, 78% yield) of 1-(tetrahydro-2H-pyran-4-yl)guanidine (24) as a light yellow solid: MS m/z (APCI-pos) M+1=144.1.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:15][CH2:14]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:18]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)N1CCC(OCC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC(=N)N)sc1C(=O)N1CCC(OCC(=O)O)CC1
Reaction time: 2 h

Procedure:
154 mg of tert.-butyl [1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-4-yloxy]-acetate are dissolved in 1.5 ml of dichloromethane and treated with 1.5 ml of trifluoroacetic acid. After 2 hrs. the mixture is evaporated in a vacuum. The residue is dissolved in water and the solution is again evaporated. There are obtained 209 g of mg [1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-4-yloxy]-acetic acid trifluoro- acetate (1:2) as a light hygroscopic foam, MS: 342 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:22]([CH3:24])[C:16]([Cl:15])=[C:17]([OH:18])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(O)c1Cl
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of 16 g (77 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 10.6 g (77 mmol) of ethyl 2-chloroacetoacetate in 150 ml of glacial acetic acid was heated at 100° C. for 17 hours. Upon cooling to room temperature the solid which separated was collected by filtration. The filtrate was diluted with ice water to separate an additional quantity of solid. The solids were combined and dried to yield 14.0 g (60%) of the desired product as a solid, m.p. 258°-260° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:46][O:47][CH2:48][C:49]1[NH:50][CH:51]=[C:52]([OH:56])[C:53](=[O:55])[N:54]=1.CS(O)(=O)=O>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH2:48][C:49]2[NH:50][CH:51]=[C:52]([OH:56])[C:53](=[O:55])[N:54]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: CS(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (60 mg) (0.09 mmol), 20.5 mg (0.13 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 13 mg (0.13 mmol) of methanesulphonic acid are dissolved in 0.6 ml of absolute dimethylacetamide. After stirring at room temperature for 18 hours the mixture is concentrated in a high vacuum at room temperature and the residue is crystallized using ethanol. The product is washed with diethyl ether and dried in a high vacuum at room temperature. There are obtained 26 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -carboxylic acid as a yellow powder. A further 28 mg of yellow crystals of the same compound can be obtained from the mother liquor after concentration.
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:54][S:55]([NH:58][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:40][CH:41]=1)=[O:2])(=[O:57])=[O:56]
Reactant: CS(N)(=O)=O
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)O)cc2)c1=O)C(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)NS(C)(=O)=O)cc2)c1=O)C(=O)C(F)(F)F
Reaction time: 120 h

Procedure:
To a solution of 2-[3-(4-carboxybenzyloxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.387 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.43 g) and 4-dimethylaminopyridine (0.27 g) in dry dichloromethane was added methanesulfonamide; and the reaction mixture was stirred for 5 days. The mixture was diluted with ethyl acetate, washed (three times with 10% aqueous hydrochloric acid, then brine), dried and evaporated before purification by chromatography, eluting with dichloromethane:ethyl acetate:methanol:acetic acid (50:48.9:1.0:0.1), to give the title compound; TLC: Rf =0.38, dichloromethane:ethyl acetate:methanol:acetic acid (50:48.9:1.0:0.1); HPLC: tR =5.38, FR=2, column A, water:acetonitrile (7:3); MS: m/z=651(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:31]1(I)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:31]1([O:30][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH:18]([CH:15]3[CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[CH2:13][CH2:14]3)[CH3:19])[N:29]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 70 °C

Procedure:
A mixture of 2-{1-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-ethyl}-3H-quinazolin-4-one (34 mg, 0.08 mmol), cyclopentyl iodide (18 μL, 0.16 mmol), and potassium carbonate (55 mg, 0.4 mmol) in DMF (1 mL) was heated to 70° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 5.63 (m, 1H), 3.68 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.67 (dd, J=11.2, 1.6 Hz, 1H), 2.81 (quintet, J=7.3 Hz, 1H), 2.28 (t, J=11.8 Hz, 1H), 2.17 (m, 1H), 1.93 (m, 10H), 1.44 (m, 3H), 1.29 (d, J=6.9 Hz, 3H); HPLC ret. time 3.24 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 496.3 (M+1)+
Reaction SMILES: COC(=O)N[C@H](C(=O)[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])CC1C=CC2C(=CC=CC=2)C=1.[C:47]([NH:50][C@@H:51]([CH:55]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])(=[O:49])[CH3:48]>>[C:47]([NH:50][C@@H:51]([CH:55]([C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:52]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:24][O:25][P:26](=[O:27])([OH:28])[OH:29])=[O:53])(=[O:49])[CH3:48]
Reactant: CC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Product: CC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Yield: 30 %

Procedure:
This compound was made as for the preparation of the product of example 3 (step D) with 100 mg of (2S)-2-acetylamino-3,3-diphenyl-propionic acid (this example step A). The final product was obtained in 30% yield (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:16])[CH:3]=1.[OH2:17]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: O
Reactant: Cc1cc(F)ccc1-c1ccccc1C=O
Solvent: CC(C)=O
Product: Cc1cc(F)ccc1-c1ccccc1C(=O)O
Reaction time: 20 h

Procedure:
To a solution of 2.70 g (12.6 mmol) 4′-fluoro-2′-methyl-biphenyl-2-carbaldehyde in 75 ml aceton and 25 ml H2O 3.38 g (21.4 mmol) KMnO4 were added and the mixture stirred for 20 hrs. The solvent was evaporated, the residue treated with 100 ml H2O and 100 ml CH2Cl2 and the pH of the aqueous phase was adjusted to 1 with conc. H2SO4. After filtration through Hyflo, the phases were separated and the aqueous phase washed twice with 100 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 19:1) to give 4′-fluro-2′-methyl-biphenyl-2-carboxylic acid as a colorless solid, MS (EI): 230, (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([NH2:16])[CH3:15].C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:12][NH:16][CH2:14][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-3-quinolinecarboxaldehyde (2.0 g, 10.4 mmol), ethylamine (2M in MeOH, 5.2 mL, 10.4 mmol), and acetic acid (0.65 mL, 11.4 mmol) were combined in MeOH (15 mL) and stirred at room temperature for 30 minutes until all materials were completely dissolved. Sodium cyanoborohydride (1.31 g, 20.9 mmol) was added portionwise over 5 minutes, and the reaction was stirred for 1 hour. The mixture was worked-up with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH3:15])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl trans-4-[(dimethylamino)carbonyl]cyclohexanecarboxylate (20.0 g) obtained in Reference Example 80(1) is dissolved in methanol (100 ml), and thereto is added a solution of sodium hydroxide (7.50 g) in water (40 ml). The mixture is then stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the residue is diluted with ice-water and washed with diethyl ether. The resulting aqueous layer is acidified with 10% hydrochloric acid and extracted twice with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and collected by filtration to give the title compound (15.7 g).