Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:36])[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:35])[CH3:36])=[O:8])[CH3:2]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one HCl salt (88.0 mg, 0.407 mmol) in DMSO (2.4 mL) was added PyBOP (244 mg, 0.470 mmol) and hunig base (164 ul, 0.939 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1+5% triethylamine). The crude compound was dissolved with DMSO, diluted with water. The precipitated solid was collected and triturated with ethylacetate/TBME/hexane to give the titled compound as a white solid (80.0 mg, 51% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.03-7.10 (m, 1H), 6.04 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.49-3.55 (m, 1H), 3.09 (q, J=6.8 Hz, 2H), 2.81-2.84 (m, 2H), 2.70-2.78 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.86-1.89 (m, 2H), 1.68-1.71 (m, 4H), 1.22 (d, J=6.4 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 507.2, [M+Na] 529.2; HPLC 97.7% purity.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](O)=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)CN(C)C)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 5) in DCM (0.15 M), DIPEA (4 eq.), dimethylglycine (3 eq.) and HATU (2 eq.) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and HCl (1N) and the 2 phases separated. The aqueous phase was extracted with DCM (twice). The combined organic phases were then washed with a saturated aqueous solution of NaHCO3 and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The crude was used in the next step without further purification; MS (ES+) m/z 492 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH2:9][C@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([O:6]CC)=[O:5])C.C[Si](I)(C)C>C(Cl)Cl>[P:4]([CH2:9][C@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(C[C@H]1CCN[C@@H](C(N)=O)C1)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC(=O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 278 mg of cis-4-diethylphosphonomethyl-2-piperidinecarboxamide in 5 ml of methylene chloride to which is added 0.43 ml of trimethylsilyl iodide is stirred at room temperature for 16 hours. The mixture is evaporated to dryness, the residue is dissolved in water, and the solution is evaporated to dryness. A solution of the resulting solid in ethanol is treated with 0.21 ml of propylene oxide to yield cis-4-phosphonomethyl-2-piperidinecarboxamide, m.p. 295°-298° dec.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3)c2)cn1)c1ccco1

Procedure:
This compound was prepared by method C using compound 12a and furan. HRMS (ESI+): m/z=315.1138 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][OH:8])[O:5][CH:6]=1.[H-].[Na+].I[CH3:12]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][CH3:12])[O:5][CH:6]=1
Reactant: OCc1cc(Br)co1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.062 g (4-bromo-furan-2-yl)-methanol in 10 ml dimethylsulfoxide was added 0.288 of sodium hydride (55%) in oil and 0.56 ml of iodomethane and the reaction mixtures was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated; the organic phase was washed with citric acid (10% in water), water, satd. sodiumbicarbonate and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel to yield 0.731 g of a light yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].Cl[C:28]([O:30][CH:31]=[CH2:32])=[O:29]>ClCCCl>[CH:31]([O:30][C:28]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)=[O:29])=[CH2:32]
Reactant: C=COC(=O)Cl
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: C=COC(=O)N1CC(C(=O)OCC)C(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A stirred solution of 1-benzyl-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (9.56 g, Reference Example 6) in 1,2-dichloroethane (25 ml), at 25° C. and under an atmosphere of argon, was treated dropwise with vinyl chloroformate (2.5 ml). The resulting mixture was heated at reflux for 20 hours then evaporated (40° C. and 2.7 kPa). The residue was subjected to flash chromatography on silica (0.045-0.020 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (50:50, v/v) affording the title compound (8.38 g) as a white solid. 1H-NMR [500 MHz, (CD3)2SO]: δ 1.07 (m, 3H); 3.35 to 3.70 and 3.70 to 4.00 (2 m, 6H); 4.03 (m, 2H); 4.54 and 4.56 (2 d, J=6 Hz, 1H); 4.79 and 4.85 (2 d, J=14 Hz, 1H); 7.16 (dd, J=14 and 6 Hz, 1H); 7.69 (d, J=8 Hz, 2H); 8.23 (d, J=8 Hz, 2H). MS (EI): 334 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([NH:13][CH:14]2[CH2:16][CH2:15]2)=[O:12])=[CH:4][CH:3]=1.CO>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH:14]3[CH2:16][CH2:15]3)[C:11](=[O:12])[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCC(=O)c1ccc(Cl)cc1)NC1CC1
Agent: Cl
Solvent: CO
Product: O=c1[nH]cc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1525 mg (6.035 mmol) of N-[2-(4-chlorophenyl)-2-oxoethyl]-N′-cyclopropylurea from Example 113A are suspended in 25 ml of concentrated hydrochloric acid, treated with 25 ml methanol and stirred for one hour at room temperature. The reaction mixture is evaporated to dryness and the residue purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1, then 50:1). 1300 mg (90% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C@@H:16]2[C@@H:20]([OH:21])[CH2:19][CH2:18][NH:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[CH:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1.CCCCC>[C:23]([C@@H:26]1[N:17]2[CH2:18][CH2:19][C@H:20]([OH:21])[C@H:16]2[C:14](=[O:15])[N:13]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)C=O
Reactant: N#Cc1ccc(NC(=O)[C@H]2NCC[C@@H]2O)c2ccccc12
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2[C@@H](O)CCN21
Yield: 81.8 %

Procedure:
A suspension of 30D (40 mg, 0.14 mmol) and pivalaldehyde (30 μl, 0.27 mmol) in a mixture of dry benzene (0.5 ml) and dry pentane (5.0 ml) was refluxed for 20 hr with a Dean-Starke receiver, after which additional pivalaldehyde (30 μl, 0.27 mmol), dry benzene (0.5 ml) and catalytic toluenesulfonic acid was added (Ref: Org. Lett. 2 (18) 2781-2783, (2000)). The reaction mixture was refluxed for another 25 hr, evaporated to dryness and dried in vacuo. Purification using automated flash chromatography (10 g silica gel column, EtOAc/hexane gradient) gave the title compound (single diastereoisomer) as a white foam (40 mg, 81.8%). MS (ES): m/z 350 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][CH2:10]3)[CH:2]=1.S(Cl)([Cl:20])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:20][CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[C:12]1=[O:16]
Reactant: O=C1CCc2cc(-c3cccnc3)ccc21
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccc(-c3cccnc3)cc2CC1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.22 g of 5-pyridin-3-yl-1-indanone are dissolved in 160 ml of dichloromethane and, at 0° C., a solution of 1.34 ml of sulfuryl chloride in 40 ml of dichloromethane is added dropwise over the course of 15 minutes. After stirring at 0° C. for 30 minutes and then at room temperature for 60 minutes, 50 ml of a saturated sodium bicarbonate solution are slowly added. The organic phase is separated off, washed with water, dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel with 50/1 dichloromethane/methanol. 2-Chloro-5-pyridin-3-yl-1 indanone with a melting point of 103-105° C. is obtained (in addition to 2,2-dichloro-5-pyridin-3-yl-1-indanone with a melting point of 109° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([O:18][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CCN1CCC(O)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)OC2CCN(CCc3c(C)[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
To a suspension of 5 g. (0.02 mole) of 2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole) of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018 mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. The mixture was stirred under anhydrous conditions for 24 hours, then treated with 25 ml. of water and stirred an additional hour. The chloroform layer was separated, dried over magnesium sulfate and evaporated on a rotating evaporator to a viscous oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31]>>[OH:31][CH2:30][C@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)[C@@H](N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](CO)C(C)C)cn2)CC1
Yield: 73 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-3-methyl-1-butanol. Then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:24][NH2:25]>CC(O)=O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[NH:24][NH:25][C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(=O)[nH][nH]c(=O)c3cc2C1
Temperature: 125 °C

Procedure:
A mixture of 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.17 g, 0.5 mmol) and hydrazine hydrochloride (0.05 g, 0.7 mmol) in glacial HOAc (10 mL) was refluxed at 125° C. for 4 h. The reaction was cooled, concentrated, and converted to an HCl salt. The resulting solid was recrystallized from EtOAc/MeOH to give a white solid. This white solid was further purified via reverse phase chromatography eluting with H2O/MeOH (95:5). The resulting product was converted to an HCl salt and recrystallized from hot MeOH to give 134 as a white solid (m.p.>300° C.).
Reaction SMILES: [CH3:1][C@H:2]([CH2:32][CH2:33][NH:34][CH2:35][N:36]=[N:37][N+:38]([O-:40])=[O:39])[C@H:3]([NH:12][C:13](=[O:31])[C@H:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@@H:15]([N:17]([CH:25]=[O:26])[O:18]C1CCCCO1)[CH3:16])[C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1>C(O)(=O)C>[CH3:1][C@H:2]([CH2:32][CH2:33][NH:34][CH2:35][N:36]=[N:37][N+:38]([O-:40])=[O:39])[C@H:3]([NH:12][C:13](=[O:31])[C@H:14]([CH2:27][CH:28]([CH3:29])[CH3:30])[C@@H:15]([N:17]([CH:25]=[O:26])[OH:18])[CH3:16])[C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C(=O)Nc1nccs1)[C@H](C)CCNCN=N[N+](=O)[O-])[C@H](C)N(C=O)OC1CCCCO1
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)Nc1nccs1)[C@H](C)CCNCN=N[N+](=O)[O-])[C@H](C)N(O)C=O
Temperature: 40 °C
Yield: 106 %

Procedure:
(2R,3S)-3-(Formyl-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)butanoic acid [(1S,2R)-2-methyl-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide (30 mg, 0.049 mmol) is dissolved in 2 mL of 80% acetic acid and heated at 40° C. for 20 h. Concentration in vacuo, trituration with dichloromethane/ether, and collection of the product provides 26 mg of (2R,3S)-3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)butanoic acid [(1S,2R)-2-methyl-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[S:9](=[O:33])[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(O)cc1)c1sc2ccccc2c1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: O=C(C1=C(c2ccccc2)c2ccccc2S1=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
The product from Example 3 (5.0 g.; 0.0151 mole) and 2.8 g. of m-chloroperbenzoic acid were dissolved together in chloroform. The mixture was allowed to stand at room temperature for about 3 days. The solution then was washed twice with aqueous sodium bicarbonate solution, then with water, and was dried over magnesium sulfate. The solution then was concentrated to dryness. Thin-layer chromatography (TLC) run on the crude product revealed the presence of the starting material, some sulfone, and the desired product. The mixture was slurried in hot benzene, allowed to cool, and filtered to obtain 2.6 g. of a material having m.p. 140°-145° C. TLC on this product indicated some sulfone was still present. The solid was slurried in benzene, warmed, and filtered while hot. The collected solid then was slurried in benzene containing a small amount of ethanol, heated, and allowed to cool. The title compound (1.3 g.) crystallized out and was collected by filtration. TLC of this product indicated the presence only of traces of the sulfone contaminant. The melting point of the product was 215° C. The product was dried in vacuo at 120° C. overnight to further remove any solvent which might be present.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([CH3:21])=[O:20]>C1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:18][C:19](=[O:20])[CH3:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Solvent: c1ccccc1
Product: CC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]-pyridine-3-carbaldehyde (0.50 g) and acetonylidenetriphenylphosphorane ##STR11## (0.82 g) in benzene (6 ml) was refluxed for 4 hours and then the solvent was evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the object compound, were combined and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3-buten-2-one (trans isomer) (0.21 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:16][C@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O[C@H]1CCOC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1O[C@H]1CCOC1

Procedure:
Prepared analogously to I.1 from 2-chlor-3-nitropyridine and (S)-tetrahydro-furan-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Br)cc1
Yield: 96 %

Procedure:
A mixture of 3-[5-(4-bromophenyl)-4-isoxazolyl]propionic acid (5.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-bromophenyl)-4-isoxazolyl]propionate (5.03 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 58–59° C.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[C:28]([C:31](O)=[O:32])[CH:29]=2)[NH:24][C:23](=[O:35])[C:22]=1[C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[C:28]([C:31](=[O:32])[N:2]([O:3][CH3:4])[CH3:1])[CH:29]=2)[NH:24][C:23](=[O:35])[C:22]=1[C:36]1[CH:37]=[C:38]([CH3:43])[CH:39]=[C:40]([CH3:42])[CH:41]=1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 81.1 %

Procedure:
To a solution of N,O-dimethylhydroxylamine (1.14 g in 50 mL dry methylene chloride) was added 1.5 mL triethylamine followed by 4-[2-(1 -tert-butoxycarbonylpiperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid (EXAMPLE 4.1, Step F, 1.35 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.35 g) and 4-dimethylaminopyridine (400 mg) and the mixture stirred at room temperature. After 36 hours, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel (ethyl acetate) to give the title compound (1.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[N+:31]([O-:33])=[O:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
2-hydroxy-5-methyl-3-nitroacetophenone (200 mg, 1.02 mmol), 4-benzyloxy-3-nitrobenzaldehyde (300 mg, 1.16 mmol) and 3 equivalents of sodium hydroxide (120 mg) were introduced into 80% aqueous ethanol solution and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution was acidified by 2N hydrochloric acid solution and diluted with water. The resulting solid was filtered, washed with large amount of water and methanol, and then dried to give 430 mg (Yield 97%) of the title compound as a yellow solid.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].Cl.[CH3:22][O:23][C:24](=[O:31])[C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:28]([CH2:27][CH2:26][C:25]([C:24]([O:23][CH3:22])=[O:31])([CH3:30])[CH3:29])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: COC(=O)C(C)(C)CCN
Agent: Cl
Product: COC(=O)C(C)(C)CCN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 90 %

Procedure:
In analogy to the procedure described in Example 12D, (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 12C) and 4-amino-2,2-dimethyl-butyric acid methyl ester, hydrochloride (intermediate 27) gave the titled compound in 90% yield as light yellow oil. MS: 377.21 (MH+).