Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1cc(F)ccc1C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoic acid (42.7 g) and triethylamine (64.8 ml) were dissolved in dichloromethane (250 ml) at 0° and this solution was added to the dichloromethane solution of 2'-(2-chloroacetyl)-5'-fluoro-N-methylformanilide over a period of hour whilst maintaining the temperature below 5° with ice/water bath cooling. After stirring for 1 hour at 5°, the mixture was heated under reflux under nitrogen for 16 hours. Further triethylamine (16 ml) was added and the mixture heated under reflux for a further 16 hours. The mixture was allowed to cool to ambient temperature, washed with water (2×250 ml) and dried over magnesium sulphate. Evaporation of the solvent gave the novel compound 2-[4-fluoro-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate, m.p. 93°-95°.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][C:5]([C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([CH3:8])[O:4]1.[CH3:21][C@H:22]1[CH2:27][C@@H:26]([CH3:28])[CH2:25][NH:24][CH2:23]1>CCOCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([C:5]2([CH3:8])[O:4][CH:3]([CH2:2][N:24]3[CH2:25][C@H:26]([CH3:28])[CH2:27][C@H:22]([CH3:21])[CH2:23]3)[CH2:7][CH2:6]2)([CH3:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Solvent: CCOCC
Product: C[C@@H]1C[C@H](C)CN(CC2CCC(C)(C(C)(C)COc3ccc(Cl)cc3)O2)C1
Yield: 45 %

Procedure:
16 g (0.044 mole) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl]-5-methyl-tetrahydrofuran are stirred together with 11 g (0.097 mole) of cis-3,5-dimethylpiperidine at a bath temperature of 140° C. for about 14 hours. The resulting reaction mixture is taken up in ether, washed several times with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60/ether-petroleum ether 1:1). 7.8 g (45% of theory) of 5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl]-2-(cis)-(3,5-dimethylpiperidin-1-ylmethyl)-5-methyl-tetrahydrofuran of refractive index nD20 =1.5049 are obtained.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7](OC)=[O:8]>CO>[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7]([NH:1][NH2:2])=[O:8]
Reactant: NN
Reactant: COC(=O)CCC(C)C
Solvent: CO
Product: CC(C)CCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under nitrogen, a sclution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49°-51° C.; NMR (CDCl3) δ 0.89 (d, J=7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ 0.81- 0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[OH-].[K+].Cl[C:12]1[N:13]=[C:14]2[CH:20]=[N:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]2=[N:16][CH:17]=1>CS(C)=O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:12]2[N:13]=[C:14]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[N:16][CH:17]=2)=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1cnc2c(cnn2-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2cnc3c(cnn3-c3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
In 3 ml of dimethyl sulfoxide were dissolved 2.00 g (0.0115 mole) of p-bromophenol and 0.5 g (0.009 mole) of potassium hydroxide, and 1.00 g (0.0043 mole) of 5-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was maintained at 100° C. for 2 hours. The post treatments were conducted in the same manner as described in Example 39, and the resulting residue was recrystallized from hexane to obtain 1.41 g (the yield was 89%) of 5-(4-bromophenoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless scaly crystal.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.[Br-].C([Zn+])CC.Cl>Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: C1CCOC1
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC[Zn+]
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen stream, 2,6-dichloroimidazo[1,2-b]pyridazine (0.50 g, 2.66 mmol) and bis(triphenylphosphine)nickel(II) dichloride (0.17 g, 0.27 mmol) were added to tetrahydrofuran (5.0 ml), and a solution of n-propylzinc bromide in tetrahydrofuran (0.5 M, 7.98 ml, 3.99 mmol) was added dropwise over 10 minutes to the mixture under ice-cooling. The reaction mixture was stirred for 10 minutes under ice-cooling, and warmed to room temperature and stirred for 2 hours at room temperature. Cold water (50 ml) was added to the reaction mixture which was then acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, a saturated saline, an aqueous saturated sodium bicarbonate solution and a saturated saline in this order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as white crystals. The yield was 0.43 g (82.7%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C.[Cu]I>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Oc1ccccc1
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(Oc2ccccc2)c1
Yield: 11.4 %

Procedure:
To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were sequentially washed with water (2×50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7]2[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[CH3:19][N:17]1[CH:18]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([NH:6][C@H:4]3[CH2:3][C@H:2]([NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:5]3)[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=2)[CH:15]=[N:16]1
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N4-((trans)-3-aminocyclobutyl)-N2-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (87 mg, 0.2 mmol) was dissolved in DCM (5 mL). DIPEA (53 μL, 0.3 mmol) was added and the reaction was cooled to 0° C. Acryloyl chloride (16 μL, 0.2 mmol) was added via a 10 μL syringe and the reaction was allowed to stir at 0° C. for 1 hr. The reaction was concentrated and purified via flash chromatography eluting with a gradient of 1%-20% EtOH in DCM. The fractions containing the product were pooled and dried down to afford the title compound as a tan solid (confirmed to be product by LCMS). This tan solid was taken directly to the final step.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-])=O)[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>CO.[Ni]>[NH2:10][C:6]1[CH:5]=[C:4]([F:13])[C:3]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:2]([F:1])[C:7]=1[O:8][CH3:9]
Reactant: COc1c([N+](=O)[O-])cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: [Ni]
Solvent: CO
Product: COc1c(N)cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 14 h

Procedure:
To a solution of the product of Example 52B (600 mg, 1.6 mmol) in methanol (100 mL) was added Raney Nickel (60 mg) and the mixture was stirred under hydrogen for 14 hours. The catalyst was filtered off and the filtrate was concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 100/1 dichloromethane/methanol to provide the title compound. MS: 344 (M+H+),
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N>ClCCl.CO>[Cl:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(Cl)cccc32)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxylate from Step B (2.17 g, <6.17 mmol) was dissolved in dichloromethane (10 mL) and trifluoacetic acid (5 mL) was added at room temperature. After 5h, additional trifluoacetic acid (5 mL) was added and the reaction stirred overnight. To this solution was added 2.0 M ammonia in methanol, the mixture was filtered and the volatiles removed in vacuo. The crude product was purified by chromatorgraphy (silica gel, 1 to 25% methanol containing 1% NH3 in methylene chloride gradient elution), which gave the title compound (1.12 g). MS 352.2 (M+1).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:3]\[CH2:4][NH:5][C:6](=[O:16])[CH2:7][P:8](=[O:15])([O:12]CC)[O:9]CC>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:3]\[CH2:4][NH:5][C:6](=[O:16])[CH2:7][P:8](=[O:9])([OH:15])[OH:12]
Reactant: CCOP(=O)(CC(=O)NC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CNC(=O)CP(=O)(O)O
Yield: 46.9 %

Procedure:
Diethyl [2-[(E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylamino]-2-oxo-ethyl]phosphonate (0.325 g, 0.81 mmol) was deprotected in a similar fashion as that described in Step 2 of Example 2. The reaction mixture was diluted with toluene, then evaporated. This process was repeated two more times. The final residue was treated with diluted hydrochloride acid (0.1N) and extracted with ethyl acetate. The extract was washed with water three times, then dried and filtered. Evaporation of the filtrate afforded the title compound (0.14 g, 0.38 mmol, 47%) as a amorphous powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OCCl)c1ccc(Cl)c(Cl)c1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.32 g of chloromethyl 3,4-dichlorobenzoate was added, and the mixture was stirred at 70° C. for 6 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.23 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3,4-dichlorobenzoate (present compound (41)).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[C:49]([CH3:57])=[N:50][N:51]([CH2:54][CH2:55][OH:56])[C:52]=1[CH3:53]>C(Cl)Cl.O>[OH:56][CH2:55][CH2:54][N:51]1[C:52]([CH3:53])=[C:48]([NH:47][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[C:49]([CH3:57])=[N:50]1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: Cc1nn(CCO)c(C)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2c(C)nn(CCO)c2C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (550 mg, 2.71 mmol) in DCM (15 mL), TBTU (1.303 g, 4.06 mmol) and DIPEA (1.39 mL, 8.12 mmol) was added. After stirring for 40 min at rt, 2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethanol (420 mg, 2.71 mmol) dissolved in DCM (5 mL) was added to the solution and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM and water, the organic layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (DCM/MeOH 92:8) yielded the title compound as a white solid. LC-MS conditions A: tR=0.70 min, [M+H]+=341.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15]([N:28]1[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]1)=[O:17])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42, 50 mg, 0.15 mmol) in DMF (3 mL) was added 3-(S)-hydroxypyrrolidine (13.9 mg, 0.16 mmol), HOBt (20 mg, 0.15 mmol) and DIPEA (51 μL, 0.29 mmol). After 5 min, EDCI (36 mg, 0.19 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol/dichloromethane (4:96) gave the title compound as a white solid. m/z (ES+)=413 [M+H]+; RT=3.20 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1)=O.O.[NH2:14][NH2:15]>CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:14][NH2:15])=[O:2])[CH:10]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)ccn1
Solvent: CO
Solvent: O
Product: COc1ccnc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
4-Methoxypyridine-2-carboxylic acid methyl ester (17.6 g, 0.105 mol) was dissolved in methanol (100 ml) and cooled to 0° C. before adding hydrazine hydrate (21 ml) dropwise over 10 min. The mixture was then refrigerated at 4° C. for 16 h. The resulting solid was filtered, washed with cold methanol and dried to afford 4-methoxypyridine-2-carboxylic acid hydrazide (14.3 g, 81%) as a white powder. 1H NMR (360 MHz, CDCl3) δH 3.89 (3H, s), 4.55 (2H, br s), 7.12 (1H, dd, J 3 and 6), 7.50 (1H, d, J 3), 8.42 (1H, d, J 6), 9.79 (1H, br s).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:24][C:25](=[O:35])[NH:26][O:27]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:24][C:25]([NH:26][OH:27])=[O:35])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1)NOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1)NO
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a 500 ml round bottom flask under N2 was added (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-2-pyridinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (15.2 g, 31.8 mmol) in methanol (220 mL), followed by Pearlman's catalyst (3.17 g, 4.5 mmol). The mixture was degassed and hydrogenated using a H2 balloon. After 4 hours, LCMS indicated completion of the reaction. The mixture was kept under N2 in a refrigerator overnight. The clear solution on the top was decanted and filtered through 4 Acrodisc CR 25 mm Syringe Filters. The catalyst on the bottom was washed thoroughly with methanol (2×30 mL) and filtered. The combined filtrates were concentrated to dryness to provide (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-2-pyridinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (11.84 g, 30.6 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.05-1.23 (m, 2H) 1.37-1.68 (m, 5H) 1.70-2.00 (m, 4H) 2.20-2.33 (m, 1H) 2.44 (d, J=9.09 Hz, 1H) 3.11-3.24 (m, 1H) 3.29-3.37 (m, 1H) 3.81-3.93 (m, 1H) 4.96-5.08 (m, 1H) 7.11 (s, 2H) 7.73-7.83 (m, 1H) 8.08 (d, J=8.34 Hz, 1H) 8.25-8.35 (m, 1H) 8.30 (d, J=4.80 Hz, 1H). LCMS: [M+H]+: 388.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:35]4[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=4)[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccc(F)cc3)cc2)cc1)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NOCCOc1ccc(CC(Oc2ccc(F)cc2)C(=O)O)cc1)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The target compound (1.13 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 3 using ethyl 3-[4-[2-[[1-(4′-fluoro-4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(4-fluorophenoxy)propionate (1.44 g) obtained from Reference example 4 and an aqueous sodium hydroxide solution (1N, 5.0 ml).
Reaction SMILES: Br.[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:22]=4[C:21](=O)[O:20]C3=O)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CN(C)C=O>[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:22]=3[C:21]([NH2:34])=[O:20])[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1oc(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cccc([N+](=O)[O-])c12
Reactant: [NH4+]
Agent: Br
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1c(NCCCCN2CC=C(c3ccccc3)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione hydrobromide (410 mg) in dimethylformamide (4 ml) was added 28% ammonium hydroxide (1 ml) on an ice-bath, and the mixture was stirred for 1 hour at room temperature. The mixture was poured into ice-water, extracted with ethyl acetate, and the extracts were washed with water and brine. After dryness with magnesium sulfate and evaporation of the solvent, 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6nitrobenzamide was obtained as an amorphous (300 mg).
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[N+:7]([CH3:10])([O-:9])=[O:8].CN(C)C(N(C)C)=N.O>C(#N)C.C(O)(=O)C>[N+:7]([CH2:10][CH2:2][CH2:1][C:3](=[O:4])[CH2:5][CH3:6])([O-:9])=[O:8]
Reactant: C=CC(=O)CC
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.6 %

Procedure:
A! Ethyl vinyl ketone (25 g, 0,297 mole) was slowly added to a solution of nitromethane (80 ml, 1.48 mole) and 1,1,3,3-tetramethylguanidine (3.7 ml, 0.029 mole) in acetonitrile (180 ml) while maintaining the room temperature by cooling with ice. The reaction mixture was stirred for 48 hours at room temperature, then added with water (70 ml), and the pH was corrected to 5 by acetic acid. The solvent was evaporated under vacuum and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with chilled water (100 ml) and anhydrified over sodium sulfate, then the solvent was evaporated under vacuum to give 42 g of crude 6-nitrohexan-3-one which was used as such in the next step.