Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([S:12][CH3:13])=S.[O:14]1[CH:19]=CSC=[N:15]1.Cl.NO>C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:12][CH2:13][CH2:19][O:14][N:15]=1
Reactant: CSC(=S)c1nc2ccccc2s1
Reactant: C1=CSC=NO1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Product: c1ccc2sc(C3=NOCCS3)nc2c1

Procedure:
Methyl 2-benzothiazolecarbodithioate (37 g, 0.16 mol) was converted to 1,4,2-oxathiazine using hydroxylamine hydrochloride (13.2 g) and triethylamine (33 ml) as described in Example 4. The ethyl acetate extract of the product was washed successively with diluted hydrochloric acid (2N), water, 5% sodium hydroxide and water. Evaporation of the solvent left a solid residue which was recrystallized from ethanol/ethyl acetate to 5,6-dihydro-3-(2-benzothiazolyl)-1,4,2-oxathiazine (18.0 g, mp 150-151° C.) Found C 50.68, H 3.27, N 11.78, C10H8N2OS2 requires C 50.85, H 3.39, N 11.80.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[C:10]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:8].Br[CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].C(O)(=O)C>CN(C)C=O.O>[C:7]([C:9]1[C:10]([CH:25]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:37][N:38]2[C:42](=[O:43])[C:41]3[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]2=[O:48])=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:12][C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:8]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CN1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A dry 40 mL vial charged with a mixture of potassium tert-butoxide (0.110 g, 0.984 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was cooled to −50° C. with an acetonitrile-dry ice bath under nitrogen. To the vial was added a suspension of ethyl 4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate (0.200 g, 0.492 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) dropwise. After 10 min of stirring the resulting black solution, a solution of N-bromomethylphthalimide (0.142 g, 0.590 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise and the mixture was stirred at −52° C.˜−45° C. for 90 min. The reaction was quenched with acetic acid (0.084 mL, 1.5 mmol) and warmed up to r.t. The solution was diluted with water (˜30 mL), and the resulting pale yellow solid was collected by filtration. The crude solid was dissolved in DCM (30 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification on a silica gel column (continuous gradient of EtOAc/hexane 0˜50%) afforded the title product (0.126 g, yield 45.3%). LCMS: (FA) ES+ 566. 1H NMR (400 MHz, d-chloroform) δ: 7.95 (s, 1H), 7.90-7.75 (m, 5H), 7.73-7.63 (m, 2H), 7.50-7.40 (m, 3H), 6.03 (m, 1H), 4.87-4.73 (m, 2H), 4.20-4.10 (m, 2H), 3.82-3.75 (m, 4H), 3.51-3.42 (m, 4H), 1.20-1.13 (m, 3H).
Reaction SMILES: C(=O)C.[C:4]1(=[O:18])[N:8]([CH2:9][CH2:10][CH:11]=[O:12])[C:7](=[O:13])[C:6]2=CC=CC=[C:5]12>>[C:4]1(=[O:18])[N:8]([CH2:9][CH2:10][CH:11]=[O:12])[C:7](=[O:13])[CH2:6][CH2:5]1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC=O
Product: O=CCCN1C(=O)CCC1=O
Temperature: 22 °C
Reaction time: 48 h

Procedure:
Scheme 1 describes in general a process encompassed by the present invention. As set forth in Scheme 1, a DERA aldolase catalyzes two sequential aldol condensation reactions between 3-phthalimidopropionaldehyde and 2 mol of acetaldehyde in the presence of other suitable solvents such as methyl tert-butyl ether (MTBE) and water to yield the protected desired amino-lactol (A). Suitable DERA aldolases include, but are not limited to, DERA 04, DERA 06, DERA 101, DERA 102, DERA 104, DERA 105, DERA 106, DERA107 and DERA 108, preferably DERA 04 and DERA 102. The acetaldehyde is added to the mixture of 3-phthalimidopropionaldehyde and DERA aldolase over a time period between about 7 hours to about 12 hours, preferably about 10 hours. The mixture so formed is further stirred at a temperature between about 15° C. to about 30° C., preferably about 22° C., for a time period between about 20 hours to about 60 hours, preferably about 48 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:22])(=[O:21])[NH2:20])[C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:21])(=[O:22])[NH2:20])[C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCCCC1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1N1CCCCC1

Procedure:
By substituting 3-nitro-4-piperidino-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 279°C (decomp.) after recrystallization from aqueous methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([Br:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)cc(OCc2ccccc2)c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A mixture of 3-(benzyloxy)-5-bromobenzaldehyde (5.05 g), hydroxyl ammonium chloride (1.326 g), sodium bicarbonate (1.603 g), and ethanol (50 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.48 g).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>O.[OH-].[Na+]>[Cl:1][C:2]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Temperature: 82 °C

Procedure:
11 g 2-chlorobenzimidazole are dissolved in 74 ml water and 17.35 ml 30% sodium hydroxide. The mixture is heated to 82° C. and to this they are slowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When the reaction is achieved, the solution is cooled to 20° C. and extracted with methylene chloride. The compound is recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:15][C:16](O)=[O:17]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:3]=1[CH2:15][CH2:16][OH:17]
Reactant: Cc1oc(CCc2ccccc2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(CCc2ccccc2)nc1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
BH3-THF complex (49 mL of a 1.0 M solution in THF) was added dropwise via addition funnel over 50 min to a solution of (5-methyl-2-phenethyl-oxazol-4-yl)-acetic acid (5.05 g, 20.6 mmol) in THF (35 mL). The reaction mixture was stirred at ambient temperature for 3 h, and then quenched with MeOH (12 mL). After heating at 50° C. for 2 h, the reaction mixture was cooled to ambient temperature, and then partitioned between CH2Cl2 and 1N NaOH. The organic phase was washed with brine (1×50 mL), dried over MgSO4 and concentrated to obtain a residue, which was purified by column chromatography (500 mL SiO2, 35% EtOAc/hexanes) to provide 3.99 g (84%) of the desired product as a clear, colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.84 (q, J=5.6 Hz, 2H), 3.06-2.67 (m, 4H), 2.62 (t, J=5.6 Hz, 2H), 2.22 (s, 3H); MS (EI+) 232.19 (M+H); 254.15 (M+H+Na).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:26]3[C:25]([CH3:27])=[N:24][N:23]([CH:28]4[CH2:30][CH2:29]4)[C:22]=3[C:21](=[O:31])[NH:20]2)=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.O.CCOCC.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]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:26]3[C:25]([CH3:27])=[N:24][N:23]([CH:28]4[CH2:30][CH2:29]4)[C:22]=3[C:21](=[O:31])[N:20]2[C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cn1nnc2ccc(Cl)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1ccc3nnn(C)c3n1)C2=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
A flask was charged with 5-chloro-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Step 102.3) (132 mg, 0.782 mmol), 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6) (150 mg, 0.521 mmol) Pd2(dba)3 (47.7 mg, 0.052 mmol), Xantphos (60.3 mg, 0.104 mmol) and Cs2CO3 (340 mg, 1.043 mmol) in dioxane (3 mL) and the resulting mixture was heated up and stirred at 100° C. for 16 hr. The reaction was diluted with EtOAc and water and both phases separated. The aqueous layer was extracted with EtOAc, the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Palladium was removed using a Varian PL-Thiol MP SPE cartridge and the residue was purified by silica gel column chromatography (50% EtOAc/hexane) to afford, after trituration in Et2O, the title product (153 mg, 0.357 mmol, 68% yield) as white solid. tR: 1.20 min (LC-MS 2); ESI-MS: 420 [M+H]+ (LC-MS 2); Rf=0.24 (50% EtOAc/Hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.16 (m, 2H) 1.21-1.35 (m, 2H) 1.95 (d, J=3.6 Hz, 3H) 3.87 (td, J=7.3, 3.6 Hz, 1H) 4.14 (d, J=3.7 Hz, 3H) 6.63 (d, J=3.6 Hz, 1H) 7.26-7.42 (m, 2H) 7.42-7.58 (m, 2H) 8.30-8.48 (m, 1H) 8.54 (dt, J=9.2, 3.2 Hz, 1H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:12][CH2:13][C:14]=2[CH:20]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 81.3 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 87) (591 mg, 2.0 mmol) and chloroacetyl chloride (167 ul, 2.1 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as an off-white solid (585 mg, 81%), MS (ISP) m/e=360.1 [(M+H)+] and 362 [(M+2+H)+].
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]2[C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:4]1=2)[CH3:2].CN(C)CCN(C)C.[I:28][Si](C)(C)C.II>C(Cl)Cl>[CH2:1]([N:3]1[C:9](=[O:10])[CH:8]([I:28])[CH2:7][CH2:6][C:5]2[C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)CCCc2c1ccc([N+](=O)[O-])c2OC
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: CCN1C(=O)C(I)CCc2c1ccc([N+](=O)[O-])c2OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-Ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.0 g) in Methylene chloride (12 mL) was cooled to 0° C. and treated with N,N,N′,N′-Tetramethylethylenediamine (1.7 mL) then treated dropwise with Iodotrimethylsilane (1.6 mL). A white precitate formed in the solution. The mixture was stirred at 0° C. for 30 min, solid Iodine (1.4 g) was added in one portion and the mixture stirred at 0° C. A dark color ensued. After 45 min, the reaction was quenched with 10% Na2S2O3, extracted with dichloromethane. The organic layers were washed with brine, dried (MgSO4), filtered and concentrated. (+/−)-1-Ethyl-3-iodo-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one isolated as an orangish solid (1.30 g, 88%). LC/MS: (M+H)+ found 390.93. Taking on without purification.
Reaction SMILES: [Cl:1][C:2]1[C:20](/[CH:21]=[CH:22]/[CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[CH:19][CH:18]=[C:17]([Cl:35])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>C(Cl)(Cl)Cl.CO>[NH2:24][CH2:23]/[CH:22]=[CH:21]/[C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:35])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C/CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: CN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C/CN)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 8-[2,6-dichloro-3-((E)-3-phthalimido-1-propenyl)benzyloxy]-2-methylquinoline (43 mg) in chloroform (1 ml) was added 2M solution of methylamine in methanol (0.5 ml), and the mixture was stirred in the dark at ambient temperature overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography to give 8-[3-((E)-3-amino-1-propenyl)-2,6-dichlorobenzyloxy]-2-methylquinoline (27 mg) as pale yellow amorphous.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C)=O)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:19][NH2:20]>CCO>[CH3:19][NH:20][C:15]([CH:12]1[CH2:13][CH2:14][CH:10]([C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[CH2:11]1)=[O:17]
Reactant: COC(=O)C1CCC(c2csc(NC(=N)N)n2)C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1CCC(c2csc(NC(=N)N)n2)C1
Reaction time: 60 h

Procedure:
Methyl 3-(2-guanidinothiazol-4-yl)cyclopentane carboxylate (0.40 g.) and a solution of methylamine in EtOH (33% w/v; 15 ml.) was allowed to stand at ambient temperature for 60 hours. The solvent was removed by evaporation in vacuo and the residue was purified by medium pressure chromatography on silica gel using CHCl3 /MeOH/aqueous ammonia (s.g. 0.88) 8:2:0.3 v/v/v as eluant to give N-methyl-3-(2-guanidinothiazol-4-yl)cyclopentane carboxamide (0.27 g.), m.p. 216°-218°.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:13][OH:14])([C:9]([F:12])([F:11])[F:10])([F:8])[F:7].C[O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19]>>[C:18]([CH:17]([O:14][CH2:13][C:6]([C:9]([F:12])([F:11])[F:10])([F:8])[F:7])[OH:16])([F:21])([F:20])[F:19]
Reactant: COC(O)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: OC(OCC(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
This reaction was carried out in the same manner as described in Example 1 using charges of sulfuric acid (175 g), C2F5CH2OH (86.7 g, 0.578 mole) and trifluoroacetaldehyde methyl hemiacetal (Alfa Aesar, 50 g, 90% purity, 0.346 mole). The receiver gained 27.1 g in weight and this solution was used without purification in the next step.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH3:33])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O.C(O)(=O)C>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH3:33])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
200 mg (5.0 mmol, 4.2 eq) of sodium hydroxide are added to a solution of 525 mg (1.19 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-methoxybiphenyl-4-yl]propanoate in 6 ml of a tetrahydrofuran/methanol mixture (8/2). The reaction mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed with water, acidified with acetic acid solution and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the residual oil is chromatographed on silica (7/3 to 1/1 heptane/ethyl acetate). The product is crystallized from pentane and 216 mg of 3-[3′-(3-heptyl-1-methylureido)-2-methoxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=100-101° C.). Yield=42%
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](/[C:29]([OH:31])=O)\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:36][NH:37][O:38][CH3:39].[OH-].[Na+]>O1CCCC1.O.[Cl-].[Na+].O>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](\[CH3:28])/[C:29]([N:37]([O:38][CH3:39])[CH3:36])=[O:31])[CH3:24])=[O:22])[C:17]([CH3:18])([CH3:20])[CH3:19])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNOC
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (473 mg, 1 mmol, WO 99/32509) in tetrahydrofuran (2 mL) is added a solution of N,O-dimethylhydroxylamine hydrochloride (166 mg, 1.7 mmol) in water (2 mL), adjusting the reaction mixture to pH 4.5 by adding dropwise 1.0 N sodium hydroxide solution. To this is added dropwise a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (479 mg, 2.5 mmol) in water (7 mL) over a period of 7 min, maintaining pH 4.5 by using 1.0 N sodium hydroxide solution. The reaction mixture is stirred at room temperature for 2.5 h, adjusting the pH to 6-7. To this is added brine (10 mL) and extracted with dichloromethane. The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated to give 491 mg (95%) of the title compound as a white solid. HRMS (ESI) calcd for C29H48N4O4 (M+H+) 517.3748, found 517.3750.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC)=O)[CH2:12][CH:11]3[CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].CC(O)C>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)C(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC1CNCCC1n1c(=O)[nH]c2cc(Cl)ccc21

Procedure:
A mixture of 26 parts of methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-3-methyl-1-piperidinecarboxylate, 36 parts of potassium hydroxide, 200 parts of 2-propanol and 6 parts of water is stirred and refluxed for 18 hours. The reaction mixture is evaporated and water is added to the residue. The whole is acidified with a concentrated hydrochloric acid solution, while cooling. The free base is liberated in the conventional manner and stirred with trichloromethane for 30 minutes. The layers are separated and the aqueous layer is extracted with trichloromethane. The combined organic phases are dried, filtered and evaporated. The oily residue solidifies on triturating in a mixture of 2,2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 5-chloro-1,3-dihydro-1-(3-methyl-4-piperidinyl)-2H-benzimidazol-2-one; mp. 198.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:33][NH:34][C:35](=O)[CH2:36][CH3:37])=[N:10][N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:35]([CH2:36][CH3:37])=[N:34][N:33]=3)[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccncc3)c(=O)n(Cc3ccc(C(F)(F)F)nc3C)n12
Temperature: 130 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a round bottom flask was added N′-(4-(4-chlorophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridazin-3-yl)propionohydrazide (130 mg, 0.239 mmol) and toluene (5 ml). The reaction was heated at 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1.3 ml) was added and the reaction was stirred at 130° C. for additional 4 hrs. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml). The resulting solution was poured into a separatory funnel and wash with 0.5N NaOH (10 ml), water (15 ml) and saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting 65%-100% EtOAc/Hex to give product 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (80 mg) as off-white solid in 64% yield. HPLC retention time (method A) 2.110 min; LCMS (M+H)=525.2; 1HNMR (CDCl3, 500 Hz): 8.59 (2H, d, J=4.4 Hz), 7.56 (1H, d, J=7.7 Hz), 7.44, (1H, d, J=7.7 Hz), 7.3417 (4H, m), 7.18 (2H, d, J=4.4 Hz), 5.64 (2H, s), 2.82 (2H, q), 2.79 (3H, s), 1.46 (3H, t). 13C-NMR (CDCl3, 500 Hz) 158.3, 154.4, 148.9, 144.0, 140.8, 138.2, 136.2, 133.3, 131.8, 131.6, 129.0, 128.8, 126.8, 125.8, 118.3, 49.1, 22.4, 20.8, 12.3.