Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:10].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:19][CH:18]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Oxalyl chloride (0.533 mL, 6.11 mmol) was added dropwise to a stirred suspension of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in DCM (20 mL) under nitrogen. The resulting suspension was stirred at room temperature for 30 mins. DMF (0.05 mL) was added dropwise under nitrogen. The resulting suspension was stirred for 90 mins. A solution of 1-methylpiperazine (0.554 mL, 5.00 mmol) and pyridine (1.211 mL, 14.99 mmol) in DCM (15 mL) was added dropwise at 0° C., over a period of 60 mins under nitrogen. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness to afford the crude product (1.791 g) as a dark orange solid. The solid was redissolved in DCM and washed with NaHCO3. The organic layer was evaporated to dryness to afford methyl 4-(4-methylpiperazine-1-carbonyl)benzoate (0.890 g, 61.1%) as an orange gum, which solidified on standing. Used without further purification.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH3:18][C:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)(O)[O-].[Na+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:18][C:19]1[CH:28]=[C:27]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (0.496 g, 1.609 mmol), methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.466 g, 1.689 mmol), sodium bicarbonate (0.405 g, 4.83 mmol) and tetrakis(triphenylphosphine)palladium (0.186 g, 0.161 mmol) in a 2.0 mL microwave vial was added dioxane (6 mL) and water (1.5 mL). The reaction was capped and placed on a Biotage® Initiator microwave reactor for 30 min at 140° C. The reaction mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.376 g, 0.997 mmol, 62%): 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.10 (dt, J=1.6, 0.7 Hz, 1H), 8.09-8.00 (m, 2H), 7.84-7.78 (m, 2H), 7.44-7.37 (m, 2H), 3.93 (s, 3H), 2.70 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 378 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:10][OH:11])[CH2:8][CH3:9])=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[C:21]([O:23]CC)=O>C1COCC1>[OH:11][N:10]=[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH:8]([CH3:9])[C:21](=[O:23])[C:20]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccncc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
1-(Pyridin-4-yl)propan-1-one oxime (5.3 g, 35.3 mmol) was dissolved in 120 mL of THF and cooled to 0° C. LDA solution (41 mL, 81.3 mmol, 2M in heptane/THF/ethyl benzene) was added dropwise, and the reaction mixture was stirred at 0° C. for 1.5 hour and then warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (24 mL, 177 mmol) and THF (100 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 10% hydrochloric acid. EtOAc (150 mL) was added and solid NaHCO3 was added with vigorous stirring the aqueous layer was basic (pH>8). The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (10-60% EtOAc/hexanes) to give 5.3 g of the title compound. MS: (+) m/z 251.43 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[CH:4][N:3]=1.Cl[C:10]([N+]([O-])=O)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CCO>[C:12]1([C:11]2[C:7]3[C:6](=[O:8])[NH:5][CH:4]=[N:3][C:2]=3[O:1][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc(O)ncn1
Reactant: O=[N+]([O-])C(Cl)=Cc1ccccc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]cnc2occ(-c3ccccc3)c12
Temperature: 60 °C

Procedure:
The title compound was prepared by the method of Dauzonne, D.; Adam-Launay, A. Tetrahedron 1992, 48, 3069-3080. 4,6-Dihydroxypyrimidine 161 (3.3 g, 29.4 mmol) and 160 (5.3 g, 26.7 mmol) were combined in EtOH (absolute, 110 mL) and the mixture was heated at 60° C. for 10 min to dissolve 161. DBU (8.06 mL, 53.9 mmol) was then added drop-wise. After addition of DBU the deep green-brown solution was heated at reflux for 3 h then at 60° C. over night. The deep red solution was then cooled to room temperature and concentrated to a thick red oil. Purification by flash chromatography (SiO2, gradient eluent: CH2Cl2 to 5% MeOH/CH2Cl2) to afford as an orange-red semisolid/oil. This material was triturated with 1.75:1 CH2Cl2/hexanes and solid 162 was isolated by Buchner filtration (−95% pure). Flash chromatography of the mother liquors afforded a second crop of solid 162 (>90% pure). The two crops were combined and concentrated to afford 162 as a pale orange solid (69% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN(CCC2CCN(c3ccncc3)CC2)Cc2ccccc2)cc1
Yield: 53 %

Procedure:
N,N-Dibenzyl-2-(piperidin-4-yl)ethanamine (2.4 g, 7.79 mmol, 1 eq) and 4-bromopyridine HBr (1.97 g, 10.12 mmol, 1.3 eq) were dissolved in n-butanol (30 ml) and DIPEA (3.3 ml, 19.47 mmol, 2.5 eq) and the mixture was refluxed for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was taken up in dichloromethane (100 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 3.5% MeOH in dichloromethane), a white solid was obtained. Yield: 53% (1.6 g, 4.15 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65](O)=[O:66])=[CH:59][CH:58]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[N:24]([C:65](=[O:66])[CH2:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[CH:58][CH:59]=5)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)CCc3ccc(OCc4ccccc4)cc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (prepared as described for Ex. 252) (280 mg, 0.798 mmol) is dissolved in DMF (8 ml) along with HATU (303 mg, 0.798 mmol) and 3-(4-benzyloxy-phenyl)-propionic acid (205 mg, 0.798 mmol). N-Methyl morpholine (0.263 ml, 2.394 mmol) is added and the solution stirred at room temperature for 6 hours. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated. The residue is dissolved in MeOH (20 ml) and dry loaded onto silica (5 g). Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a tan solid; [M+H]+ 589.20, 591.19 for Cl isotopes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[SH:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CC(C)=O>[OH:12][C:10]([CH2:9][CH2:8][S:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:11]
Reactant: O=C(O)CCBr
Reactant: COC(=O)c1ccc(Cl)cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cl)cc1SCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
179.5 g (1.3 mol) of potassium carbonate and, a little at a time, 94.5 g (0.62 mol) of 3-bromopropionic acid were added to a solution of 125.4 g (0.62 mol) of methyl 2-mercapto-4-chlorobenzoate in 1.5 l of acetone, and the reaction mixture was stirred at room temperature for 12 hours. The solvent was distilled off, the residue was taken up in water and the mixture was extracted with diethyl ether. The aqueous phase was then made acidic using concentrated hydrochloric acid, and the resulting precipitate was filtered off with suction and dried. This gave 150 g (88%) of methyl 2-(2-hydroxycarbonyleth-1-yl)thio-4-chlorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:17])[NH:11][NH:12][C:13](OC)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1>[OH-].[K+]>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]2=[O:14])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)NNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A suspension of 4-(3,5-dichlorophenyl)-1-(methoxycarbonyl)semicarbazide (30.3 g, 109 mmol) (Preparation 2) in KOH (54.5 ml, 4M) was heated under reflux for 1 h. After cooling to RT, the insoluble material was discarded and the filtrate acidified to pH 1-2. The precipitate was filtered, washed with water and pentane, and oven dried to yield the above compound as a white solid (27 g, mp=260° C.). 1H NMR (DMSO-d6): 10.80 (2H, s), 7.66 (3H, m).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:19][NH2:20]>C(O)(=O)C>[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:19][N:20]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: NNc1ccncc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Nc1ccncc1F
Yield: 126.9 %

Procedure:
To a stirred solution of phthalic anhydride (1.76 g) in acetic acid (45 ml), 3-fluoro-4-hydrazinopyridine (1.52 g) was added. The reaction mixture was heated under reflux for 1 hr and concentrated in vacuo to give 3.88 g of 2-(3-fluoro-pyridin-4-ylamino)isoindole-1,3-dione. To a stirred solution of 2-(3-fluoropyridin-4-ylamino)isoindole-1,3-dione (3.88 g) in tetrahydrofuran (125 ml) at 0° C., lithium aluminum hydride (2.86 g) was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 1 day. Sodium sulfate decahydrate was added, and the mixture was filtered. The filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel eluting with ethyl acetate. The appropriate fractions were collected and concentrated to yield 1.28 g (37%) of product free base. A portion of the free base was dissolved in methanol, and ethereal hydrogen chloride was added. The precipitate was collected and recrystallized from methanol to yield 0.200 g of product, mp 200-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:26]([CH2:29]C)CC.ClC(OCC)=[O:33].[NH4+].[OH-]>C1COCC1.O>[C:29]([CH:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])(=[O:33])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(N)=O)C1
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 1,4-di(tert-butoxycarbonyl)piperazine-2-carboxylic acid (8.21 g, 24.85 mmol) was dissolved in THF (50 mL) and Et3N (20 mL) at 0° C., ethyl chloroformate (2.8 g, 26.1 mmol) was added dropwise. After stirring at −5-0° C. for 1 h, NH4OH (20 mL) was added and the resulting solution was stirred at room temperature for 1 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N NaOH and brine, dried over Na2SO4 and concentrated in vacuo to give the product (7.5 g, 91.7% yield) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][NH:9][C:10]1[C:11]([NH2:19])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[CH3:21].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:19][C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:31])=[CH:25][CH:24]=1)[CH3:21]
Reactant: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1N
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCC2CCCN2C)cc1
Temperature: 35 °C
Yield: 18 %

Procedure:
N1-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-4-nitro-benzene-1,2-diamine 32 (0.396 g, 1.498 mmol) was dissolved in anhydrous chloroform (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (0.284 g, 1.573 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.455 g, 1.841 mmol) are added quickly as solids and resulting solution heated in an oil bath at 35° C. for 18 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude solid. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow powder 33 2-(4-Ethoxy-phenyl)-N-{2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-5-nitro-phenyl}-acetamide Yield: 0.115 grams (18.0%). 1H NMR (DMSO) δ: 1.31 (t, 3H, J=7.0), 1.43-1.68 (2×m, 4-5H), 1.78-1.91 (m, 2H), 2.01-2.10 (m, 1H), 2.12-2.19 (m, 1H), 2.22 (s, 3H), 2.89-2.99 (m, 1H), 3.19-3.30 (m, 2H), 3.61 (s, 2H), 4.00 (q, 2H, J=6.9), 6.57 (br, 1H), 6.70 (d, 1H, J=9.1), 6.88 (d, 2H, J=8.4), 7.24 (d, 2H, J=8.6), 7.94 (dd, 1H, J=9.1, 2.6), 7.99 (d, 1H, J=2.5), 9.43 (br s, 1H); MS (ESI): 427 (MH+, 100%).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2CCC(OC(C)(C)C)=O)=[CH:22][C:21]=1F)#[N:19]>O1CCCC1>[C:5]([CH2:4][CH2:3][C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:24][C:23]1[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[C:21]([CH:22]=1)[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)CCc1ccccc1COc1ccc(C#N)c(F)c1
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccc(CCC(=O)O)c2)ccc1C#N
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
A solution of dry sodium (RS)-4-hydroxy-4-(2-methylphenyl)butanoate (0.18 g) in dry tetrahydrofuran (50 mL) is treated with sodium hydride and stirred at 60° C. for 15 minutes. tert-Butyl 3-[(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionate (0.2 g) is added and the mixture heated at reflux for 4 hours. After standing at room temperature for 18 hours the reaction mixture is filtered. Ethyl acetate (50 mL) and 1 N hydrochloric acid (50 mL) are added to the filtrate and the organic phase is separated. The organic phase is washed with water (10 mL), dried over magnesium sulphate, evaporated and the residue purified by flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5 v/v). Fractions homogeneous in the required product are combined and evaporated. The residue is dissolved in ether and the solution washed with 1% sodium bicarbonate solution, 0.5 N hydrochloric acid, water, dried over magnesium sulphate and evaporated. The resulting colourless gum is crystallised from a mixture of cyclohexane and ethyl acetate to give (RS)-4-{5-[3-(2-carboxyethyl)benzyloxy]-2-cyano-phenoxy}-4-(2-methylphenyl)butanoic acid (0.12 g) m.p. 136-137° C. [Elemental analysis:- C,71.4; H,6.23; N,2.91%. Calculated:- C,71.0; H,5.75; N,2.96%].
Reaction SMILES: OC(C)(C)C[N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:55]([O:59][C:60]([N:62]1[C@H:66]([CH2:67]N2C=CC(N)=N2)[CH2:65][O:64][C:63]1([CH3:75])[CH3:74])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([N:62]1[C@H:66]([CH2:67][N:4]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:5]2)[CH2:65][O:64][C:63]1([CH3:74])[CH3:75])=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cn2ccc(N)n2)COC1(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 0.98 g, 3.01 mmol) in dichloromethane (15 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (0.64 g, 3.32 mmol), 1-hydroxybenzotriazole (0.45 g, 3.32 mmol) and (R)-4-(3-amino-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.07 g, 1.57 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen and then diluted with dichloromethane, washed with a saturated ammonium chloride solution, water, a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 100% ethyl acetate/hexanes) to afford (R)-4-(3-{(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidin-3-carboxylic acid t-butyl ester (1.00 g, 55%) as a white powder: LR-ES-MS m/z calculated for C30H40ClN5O6 [M]+ 601, observed 602 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C(C)=NC=CC=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1ncccc1Br
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2C)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=340.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: CC(C)Cc1ccc(N)c(C#N)c1
Reactant: NS(=O)(=O)Cl
Product: CC(C)Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-Amino-5-isobutylbenzonitrile (Example 88b) and sulfamoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[C:12]([O:16][C:17]([NH:19][C@H:20]([CH:25]=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@H:25]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)[OH:26])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1cncn1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)c1ncnn1C
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5.3 g of 1-methyl-1,2,4-triazole in 100 ml of tetrahydrofuran under nitrogen at -75° C. was added via syringe 25.6 ml of n-butyllithium. The solution was stirred 1.5 hour at -75° C. and then 6.9 g of N-tert-butoxycarbonyl-L-leucinal in 25 ml of tetrahydrofuran at -75° C. was added. The mixture was stirred 1/2 hour each at -75° C. and at -23° C. the mixture was treated with 10 ml of saturated ammonium chloride and concentrated. The residue in 100 ml of ethyl acetate was washed with 50 ml of each of water, 2N citric acid, 1M sodium bicarbonate and brine and dried. The solution was filtered and concentrated to give 8.41 g (88%) f a colorless oil which partly crystallized. Two recrystallization from iso-propyl acetate afforded 1.85 of (S)2-(tert-butoxycarbonyl)amino-4-methyl-(R)1-(1-methyl-1H-1,2,4-triazol-5 -yl)pentan-1-ol, mp 144°-145° C. [α]D26 -26±1°(c, 1.1, MeOH).