Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][N:27]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:19](=[O:20])[C:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reactant: CNC1CCCCC1
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)N(C)C3CCCCC3)ccc2n1C

Procedure:
In accordance with a procedure analogous to that of Example 130, the above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and N-methyl-cyclohexylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 28m was prepared from compound 2 (75 mg, 0.30 mmol), p-cyanobenzyl bromide (65 mg, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 81.5% (89 mg) yield as a light-yellow solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH:12]([CH:16]([OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>N1C=CC=CC=1>[C:1]1([S:7]([CH2:10][CH2:11][CH:12]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:27][C:13]2=[O:15])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(CCS(=O)(=O)c1ccccc1)C(O)CCCCc1ccccc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(CCCCc2ccccc2)C1CCS(=O)(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 16 h
Yield: 112.2 %

Procedure:
To a solution containing (-)-2-(2-benzenesulfonylethyl)-3-hydroxy-7-phenylheptanoic acid (1 g, 2.56 mmol) in anhydrous pyridine (17 mL) under nitrogen atmosphere at 0° C. is added freshly distilled benzenesulfonyl chloride (0.89 g, 5.13 mmol) via syringe. The resulting dark yellow/orange-colored solution is cooled to -20° C. After 16 hours, the mixture is partitioned between ice/water (100 mL) and ethyl acetate (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×50 mL) and the combined organic extracts are washed successively with water (4×50 mL), brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a yellow oil. The crude product is combined with the product of an identical reaction performed on 1.55 g-scale and chromatographed on silica gel (pet-ether/EtOAc, 4:1) to afford (-)-3-(2-benzenesulfonyl-ethyl)-4-(4-phenylbutyl)-oxetan-2-one (1.07 g, 44%) as a pale yellow oil. TLC analysis [pet-ether/EtOAc, 2:1, Rf (acid)=0.05, Rf (lactone)=0.65]. [α]23D -10.1° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.36-1.80 (m, 6H), 2.16 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 3.16 (m, 1H), 3.35 (m, 1H), 3.79 (m, 1H), 4.56 (m, 1H), 7.16 (m, 3H), 7.28 (m, 2H), 7.69 (m, 2H), 7.79 (m, 1H), 7.91 (m, 2H) ppm. Mass spectrum (EI) m/z 373 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([CH3:11])=[CH2:10].C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C=CC=CC=1>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1.[CH2:10]([CH:3]1[C:4](=[O:5])[O:6][C:1](=[O:7])[CH2:2]1)[C:9](=[CH2:8])[CH3:11]
Reactant: C=C(C)C
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: C=C(C)CC1CC(=O)OC1=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
This method describes an improved method for the synthesis of D,L-2-isobutyl-3-(methoxycarbonyl)-propionic acid (3). Maleic anhydride (750 g, 7.65 moles) was dissolved in hot toluene (500 mL), filtered, and allowed to cool thus producing a finely divided crystalline precipitate. The resulting mixture was further cooled in a refrigerator. 2-Methylpropene was condensed into cold toluene (1 L). The cold maleic anhydride suspension was transferred, with the aid of additional toluene (300 mL), to the glass liner of a Parr 2 gallon stirred autoclave. The 2-methylpropene solution was then added followed by 4-tert-butyl catechol (2 g). The autoclave was sealed and heated, with stirring, to 170° C. over 45 minutes and maintained at that temperature for an additional 9.5 hours. The reaction was then allowed to cool to 60° C. over 7 hours after which, the autoclave was vented. After an additional 1.5 hours, the internal temperature had reached 45° C. and the autoclave was opened. The solvent was removed and the residue was distilled under aspirator pressure through a 10 inch vacuum jacketed Vigreux column fitted with a partial take off head to give unreacted maleic anhydride (139.4 g, 18.6% yield) and β-methallylsuccinic anhydride (765.3 g, 79.8% yield).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[N:30][C:31]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[N:32][CH:33]=1>CN(C=O)C>[F:45][C:42]([F:43])([F:44])[O:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:31]2[N:30]=[CH:29][C:28]([CH2:27][O:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[C:7](=[O:9])[O:8][C:4]=4[CH:3]=3)=[CH:33][N:32]=2)=[CH:40][CH:39]=1
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(CCl)cn2)cc1
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of 6-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (0.093 g, 0.329 mmol) in DMF (4 mL) was add cesium carbonate (0.322 g, 0.988 mmol) and 5-(chloromethyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.1 g, 0.329 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate, and washed with 10% NaOH solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using 20 to 80% ethyl acetate in hexanes to give 6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as an white solid (0.07 g, 39%). LCMS: RT 2.216 min; 529.2 [M−H].
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1.O[CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][CH:25]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1
Reactant: COc1ccc(-n2nc(OC)cc2-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Diethyl azodicarboxylate (0.17 ml) was added dropwise to a suspension of 3-methoxy-1-(4-methoxyphenyl)-5-(4-hydroxyphenyl)-1H-pyrazole (215.6 mg), tert-butyl N-(2-hydroxyethyl)carbamate (352 mg), and triphenylphosphine (286 mg) in THF (3 ml). The mixture was stirred at ambient temperature for 7 hours. Triphenylphosphine (19.1 mg) and diethyl azodicarboxylate (11.5 μl) were added and the mixture stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give tert-butyl (2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:42]([CH:39]3[CH2:41][CH2:40]3)=[O:43])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-[4-(4-Aminomethyl-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5379, Example 379, 100 mg, 0.23 mmol) was dissolved in 5 mL of dry CH2Cl2. To this solution at 0° C. was added triethylamine (0.035 mL, 0.46 mmol) followed by cyclopropanecarbonyl chloride (48 mg, 0.46 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched using H2O. The organic phase was isolated and evaporated under reduced pressure to yield the crude product, which was then purified using reverse phase HPLC. MS: 505.2(M+H−); H1 NMR (DMSO-d6): δ(ppm) 12.41 (s, 1H), 8.58 (s, 1H), 7.82 (d, 2H), 7.57 (d, 1H), 7.31 (dd, 4H), 7.10 (dd, 3H), 5.00 (m, 2H), 4.45 (m, 1H), 4.23 (d, 2H), 3.48 (m, 2H), 2.21 (m, 1H), 1.89 (m, 3H), 1.60 (m, 1H), 0.60 (d, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[CH3:19])=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CN(C)C=O>[CH3:19][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]2[C:9]=1[C:7]1[O:8][CH2:2][C:3](=[O:4])[NH:5][N:6]=1
Reactant: Cc1ccc2nc(C)c(C(=O)NNC(=O)CCl)n2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: Cc1ccc2nc(C)c(C3=NNC(=O)CO3)n2c1
Yield: 16.4 %

Procedure:
A mixture of 21 g of N'-chloroacetyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide and 30 g of potassium carbonate in 200 ml of methyl ethyl ketone and 100 ml of dimethylformamide is stirred with refluxing for 5 hours. After insoluble substances are filtered off, the solvent is distilled off and water is added to the resultant residue. The precipitated crystals are collected by filtration and recrystallized from methanol to give 3 g of 2-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-4,6-dihydro-1,3,4-oxadiazin-5-one as white crystals, melting at 313° C. with decomposition.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1c1cc(C)nc2ccccc12
Temperature: 110 °C
Reaction time: 6 h
Yield: 17.4 %

Procedure:
4-Chloroquinaldine (263 mg, 1.481 mmol), tert-butyl 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (318 mg, 1.231 mmol) and caesium carbonate (885 mg, 2.72 mmol) were mixed with anhydrous toluene (4 ml) in an argon atmosphere. 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (128 mg, 0.221 mmol) and tris(dibenzylideneacetone)dipalladium(0) (67 mg, 0.073 mmol) were added and the resulting mixture was stirred at 110° C. for six hours. Additional 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (128 mg, 0.221 mmol) and tris(dibenzylideneacetone)dipalladium(0) (67 mg, 0.073 mmol) were added and the mixture was stirred at 110° C. overnight. After reaching room temperature the mixture was filtered, the filtrate was evaporated to dryness to give a red oil that was purified by column chromatography (silica, gradient from DCM to DCM/methanol 1:20) to yield 136 mg of a yellow foam (0.214 mmol, 17%). MS (ESI) m/z=400.2 [M+1]+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[CH:16][N:15]=1.[CH3:28][O:29][CH2:30][C:31]1[C:38]([F:39])=[C:37]([F:40])[C:34]([CH2:35]O)=[C:33]([F:41])[C:32]=1[F:42]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:23][CH2:35][C:34]2[C:33]([F:41])=[C:32]([F:42])[C:31]([CH2:30][O:29][CH3:28])=[C:38]([F:39])[C:37]=2[F:40])=[O:22])=[CH:16][N:15]=1
Reactant: Cc1ncc(C(C(=O)O)C(C)(C)C)cn1
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCc1c(F)c(F)c(COC(=O)C(c2cnc(C)nc2)C(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.276 g) in dry dichloromethane (6 cm3) was added to a stirred solution of (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoic acid (0.3 g) and 4-(methoxymethyl)-2,3,5,6-tetrafluorobenzylalcohol (0.33 g) containing a catalytic amount of 4-(N,N'-dimethylamino) pyridine. The stirred mixture was maintained at the ambient temperature for 2 hours, and left to stand overnight. The reaction solution was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel using a 1:1 (by volume) mixture of ethyl acetate and dichloromethane as eluent to give 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-(2-methylpyrimidin-5-yl)-3,3-dimethylbutanoate (0.228 g) as a yellow oil.
Reaction SMILES: O(C)[Na].C[C:5]1(C)OC(=O)[C:8](=[C:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[C:7](=[O:17])[O:6]1>CO>[CH3:5][O:6][C:7](=[O:17])[CH:8]=[C:12]1[CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: CC1(C)OC(=O)C(=C2CCCN2)C(=O)O1
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C=C1CCCN1
Yield: 85.4 %

Procedure:
To a flask containing NaOCH3 (1.21 g, 21.3 mmol) and dry MeOH (50 mL) under nitrogen is added 2,2-dimethyl-5-pyrrolidin-2-ylidene-[1,3]dioxane-4,6-dione (4.5 g, 21.3 mmol) and the contents are refluxed overnight. The reaction is concentrated and the residue is diluted with H20 (50 mL). 1 N HCl is added to obtain a pH of 6 and the mixture is extracted with CHCl3 (3×30 mL). The organic fractions are combined, dried over MgSO4 and concentrated. The crude product is purified by flash chromatography (50% EtOAc/hexanes) to give the title cormpouiid as a white solid (2.57 g, 18.2 mmol). 1H NMR (CDCl3, 300 MHz) 4.49(br. s, 1H), 3.63(s, 3H), 3.62-3.46(m, 2H), 1.75-1.50(m, 2H), 2.11-1.90(m, 2H).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[N:13][C:12]=1N.[OH2:19]>C(O)(=O)C>[Br:10][C:11]1[C:12](=[O:19])[NH:13][N:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]nc(Cl)cc1Br
Temperature: 20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a cooled solution (0-5° C.) of sodium nitrite (5.96 g, 86 mmol, Lobachem) in sulfuric acid (90 mL, 57.6 mmol) was added 4-bromo-6-chloropyridazin-3-amine (12 g, 57.6 mmol, Preparation #26) in acetic acid (300 mL). The mixture was stirred for 1 hr at about 20° C. and water was added (450 mL). The reaction mixture stirred for another 5 h at RT. The reaction mixture was extracted with EtOAc (3×200 mL), dried over sodium sulphate and evaporated on rotovapor. The residue obtained was purified by silica gel column chromatography by eluting with 50% EtOAc in hexane to afford 4-bromo-6-chloropyridazin-3(2H)-one 10 g, (83%) as pale yellow solids; 1H NMR (400 MHz, DMSO) δ 13.527 (s, 1H), 8.203 (s, 1H). MS m/z: 208.8 (M−H)−,
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1([CH2:19][CH2:20][OH:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[Cl:1][C:2]1[C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: O
Product: Nc1cc(N2CCN(CCO)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
To a solution of 4.14 g of 4,5-dichloro-2-nitroaniline and 2.73 g of 1-piperazine ethanol in 20 ml of cyclohexanol, 2.65 g of sodium carbonate was added, and stirred for 14 hours at 150° C. After cooling the reaction liquid to room temperature, water was added thereto, followed by extraction with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=10/1) to provide 5.31 g of the title compound.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17](O)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][C@H:48]([C:70]([NH2:72])=[O:71])[CH2:49][S:50][C:51]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl.C(Cl)CCl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH:47][C@H:48]([C:70]([NH2:72])=[O:71])[CH2:49][S:50][C:51]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-Trp-Pro-OH (76 gm) and triethylamine (18.5 ml) in methylene chloride (850 ml) at about 0° C. to about −10° C., was charged EDC (54.5 gm) and HOBT (28.5 gm). Stirred for 30 minutes and charged H-Cys(Trt)-NH2 (65 gm, obtained from Ex-12) in methylene chloride (750 ml) at same temperature. After completion of the reaction organic layer was subjected to washings with aqueous sodium bicarbonate, aqueous citric acid solution. The separated organic layer was concentrated under reduced pressure and the resultant residue was crystallized in isopropyl ether to obtain Boc-Trp-Pro-Cys(Trt)-NH2 as a white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[BH4-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
To a solution of 10.6 g of 4-(4-chlorobenzoyl)butanoic acid and 1.9 g of sodium hydroxide in 50 ml of water was added under ice-cooling 2.7 g of sodium borohydride portionwise over 35 minutes, and the mixture was stirred at room temperature for 24 hours. The mixture was made acidic with diluted hydrochloric acid under ice-cooling, extracted with ether. The ether extract was washed with water and dried. After removal of the solvent, the residue was recrystallized from a mixture of ethyl acetate-n-hexane to give 7.50 g of 5-(4-chlorophenyl)-5-hydroxypentanoic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:22]=[CH:21][N:20]=[C:19]3[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]4[C:16](=[CH:23][N:24]([CH2:26][CH2:27]OS(C)(=O)=O)[N:25]=4)[C:17]=2[S:18]3)[CH:5]=[CH:6][C:7]=1[F:8].C(N(C(C)C)CC)(C)C.[NH2:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:22]=[CH:21][N:20]=[C:19]3[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]4[C:16](=[CH:23][N:24]([CH2:26][CH2:27][NH:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[N:25]=4)[C:17]=2[S:18]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)OCCn1cc2c(ccc3c2sc2ncnc(Nc4ccc(F)c(Cl)c4)c23)n1
Reactant: CS(=O)(=O)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNCCn1cc2c(ccc3c2sc2ncnc(Nc4ccc(F)c(Cl)c4)c23)n1
Temperature: 80 °C
Yield: 5.1 %

Procedure:
To a stirring solution of methanesulfonic acid 2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-2-yl]-ethyl ester (190 mg, 0.39 mmol) in DMF (3 mL) was added diisopropylethylamine (99 mg, 0.77 mmol) and 2-aminoethylmethylsulfone (143 mg, 1.16 mmol). It was heated to 80° C. for overnight. The crude mixture was diluted with methanol (5 mL) and it was separated by prep HPLC. The prep HPLC fractions were collected and solvent was removed by vacuum. The solid was re-dissolved by ethyl acetate (15 mL) and water (10 mL), sat. sodium carbonate solution (3 mL) was added. The organic layer was separated and dried over sodium sulfate. Evaporation of the solvents gave (3-chloro-4-fluoro-phenyl)-{2-[2-(2-methanesulfonyl-ethylamino)-ethyl]-2H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-6-yl}-amine as a white solid (10.3 mg, 5.1%) 1H-NMR (DMSO-d6) δ 9.25 (bs, 1H), 8.80 (d, 1H), 8.60 (d, 1H), 8.40 (t, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60 (t, 1H), 7.40 (t, 1H), 4.60 (t, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.10 (t, 2H), 2.05 (t, 2H); LCMS RT=2.89 min; [M+H]+=519.2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:36]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([NH2:36])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(N)=O)n1Cc1ccccc1[N+](=O)[O-]

Procedure:
(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared in Example 55, was treated with thionyl chloride and then ammonium hydroxide, as described in Example 54, to give the title compound; mp 183°-185° C.