Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:4]([C:17]([OH:19])=O)[CH2:3]1.C(=O)(O)[O-].[K+].[H][H].Cl>[Ni].C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[C:8]3[C:9]([NH:14][C:17](=[O:19])[CH:4]2[CH2:3]1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: [H][H]
Reactant: CN1CCN(c2ccccc2[N+](=O)[O-])C(C(=O)O)C1
Agent: [Ni]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: CN1CCN2c3ccccc3NC(=O)C2C1

Procedure:
A mixture of 3.5 g. (0.0135 mole) of 4-methyl-1-(o-nitrophenyl)piperazine-2-carboxylic acid, 2.5 g. (0.025 mole) of potassium bicarbonate, 110 ml. of water, 110 ml. of ethanol and 21/2 teaspoons of Raney nickel is hydrogenated in a Parr apparatus for 12 hours at an initial hydrogen pressure of 47 p.s.i. The catalyst is filtered and the filtrate is acidified with dilute hydrochloric acid. The mixture is then basified with sodium hydroxide and extracted with ethylacetate. The extract is dried and concentrated to give 2.3 g. of product. This is treated with 1 equivalent of hydrogen chloride in ethanol. After standing and cooling, filtration gives 2.4 g. of product, as the hydrochloride salt, m.p. 272°-275°. Recrystallization of the salt from ethanol-water gives 1.75 g., m.p. 284°-285° dec.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH:17]1([CH2:16][NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:28]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)=[O:29])[CH2:19][CH2:18]1
Reactant: NCC(=O)N(CC(=O)NCC1CC1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)NCC2CC2)c2ccccc2)c1
Yield: 75 %

Procedure:
The procedure is analogous to that described in Example 1, but 0.9 g of 2-(2-amino-N-phenylacetamido)-N-cyclopropylmethylacetamide and 0.45 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 1 g of N-cyclopropylmethyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 168° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:40])[C:19]([C:35]([O:37]CC)=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[C:16]([CH3:41])[C:15]=2[F:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Li+].[OH-].C1COCC1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:40])[C:19]([C:35]([OH:37])=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[C:16]([CH3:41])[C:15]=2[F:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(F)c(C)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1

Procedure:
A solution of Example 1E (332 mg) in 1M LiOH (3 mL) and THF (7 mL) was stirred at ambient temperature for 18 hours, diluted with dichloromethane, washed with 1M HCl, and dried (Na2SO4), filtered, and concentrated.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C(OCC)C>[CH3:8][C:7]1[C:2]([B:14]([OH:19])[OH:15])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: Cc1cccnc1B(O)O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A 100-mL, 3-necked round-bottom flask was charged with 2-bromo-3-methylpyridine (1.00 g, 5.81 mmol) and diethyl ether (30 mL). A solution of isopropylmagnesium chloride (2 M in THF, 8.0 mL, 16.0 mmol) was added dropwise with stirring at 0° C., and the resulting solution stirred for 3 h at 0° C. Triisopropyl borate (2.6 g, 13.8 mmol) was added, and the solution stirred for 1 h at room temperature. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 3-methylpyridin-2-ylboronic acid (0.730 g, 92%) as light yellow oil. MS (ESI, pos. ion) m/z 138 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[C:1]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH2:11][OH:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)c1n[nH]cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1nn(CO)cc1Cl
Temperature: 130 °C
Reaction time: 7 h
Yield: 111.2 %

Procedure:
The mixture of 0.62 g of 3-t-butyl-4-chloro-1H-pyrazole, 0.24 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 0.82 g of 3-t-butyl-4-chloro-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[O:12].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:12][CH:18]=1
Reactant: NC(=O)c1ccc2ccccc2c1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc3ccccc3c2)n1
Yield: 68 %

Procedure:
In substantially the same manner as in Reference Example 31, 2-naphthalenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(2-naphthyl)oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 116-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:26]2([CH3:27])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[CH2:9][C@@H:8]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)=[O:4].CC(C)=[O:36].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O.S(=O)(=O)(O)O>CC(C)=O.O.C(O)(C)C>[CH3:1][O:2][C:3]([O:5][C@@H:6]1[C@@:26]2([CH3:27])[C:10](=[CH:11][CH:12]=[C:13]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH:18]([C:20]([OH:36])=[O:21])[CH3:19])[CH2:9][C@@H:8]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)=[O:4]
Reactant: CC(C)=O
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1

Procedure:
In 5 ml of acetone was dissolved 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde and the solution was stirred with ice-cooling. Then, Jones' reagent prepared by mixing chromic acid with concentrated sulfuric acid and diluting the mixture with water in accordance with the method of K. Bowden et al. (J. Chem. Soc., p. 39, (1946)) was added dropwise to the above solution until the red color of the reagent would be persistent. After the excess reagent was decomposed with isopropyl alcohol, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated to give 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20]C(=O)C)[CH:14]=2)=[N:10][C:9]=1[C:24]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[N:26][N:25]=1.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH2:20])[CH:14]=2)=[N:10][C:9]=1[C:24]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[CH:27]=[N:26][N:25]=1
Reactant: CC(=O)Nc1cc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(N)cc1-c1nc(-c2nncn2COCC[Si](C)(C)C)c(-c2ccccc2Cl)o1
Yield: 62.1 %

Procedure:
A mixture of N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.42 g, 0.80 mmol), EtOH (25 mL) and aqueous NaOH (1M, 3 mL) was allowed to stir at reflux for 5 h. The reaction mixture was concentrated and the residue was washed with hexane. Diethyl ether was added and the mixture was filtered. The filtrate was concentrated to give 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-amine (0.24 g, 62%) which was used in the next step without purification. LCMS (AA): m/z=483 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Yield: 90.3 %

Procedure:
A solution of 45.1 (385 mg) in ethanol (12 mL) and ethyl acetate (10 mL) was stirred with 10% Pd—C (50 mg) under a hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered and concentrated to provide 45.2 (350 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:34](OC(=O)C)([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [8-chloro-2-ethyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1.COCCOC>CCOC(C)=O.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>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:19]2[CH:20]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)cc(-c2cncnc2)nc1C
Temperature: 90 °C
Yield: 85 %

Procedure:
To a solution of 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester (0.30 g, 1.40 mmol) and 5-pyrimidine boronic acid (0.522 g, 4.21 mmol) in argon-degassed DME/2 M Na2CO3 (4:1, 12.5 ml) was added Pd(PPh3)4 (162 mg, 0.14 mmol) and the mixture heated to 90° C. overnight. The reaction was cooled, diluted with EtOAc (25 ml) and H2O (15 ml). The aqueous layer was extracted with EtOAc (2×10 ml) and the combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 3:2) to afford 2,4-dimethyl-6-pyrimidin-5-yl-nicotinic acid ethyl ester (306 mg, 85%). 1H NMR (CDCl3) δ 1.43 (t, 3H, J=6 Hz), 2.44 (s, 3H), 2.64 (s, 3H), 4.47 (q, 2H, J=6 Hz), 7.44 (s, 1H), 9.26 (s, 1H), 9.32 (s, 2H).
Reaction SMILES: N#N.[S:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2O)[CH:5]=[CH:4]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>CC(OC)(C)C.C(Cl)(Cl)Cl>[Cl:21][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:5]=[CH:4][S:3][C:11]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ccnc2ccsc12
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Product: Clc1ccnc2ccsc12

Procedure:
A 2-L, 3-neck, rb flask equipped with a mechanical overhead stirrer, a 250-mL addition funnel, and a thermocouple w/N2-inlet adapter was charged with thieno[3,2-b]pyridin-7-ol (144 g, 952 mmol), chloroform (700 mL) and anhydrous N,N-dimethylformamide (100 ml, 1297 mmol). The heterogeneous mixture was cooled in an ice bath with stirring, then oxalyl dichloride (166 ml, 1905 mmol) was added dropwise via the addition funnel. Towards the end of the addition, the exotherm had diminished so the remaining reagent was added more quickly, which resulted in rapid off-gassing and the eruption of a portion of the contents out of the vessel. Upon complete addition, the mixture was allowed to stir out for 2 h, at which point LC-MS analysis indicated only about 10% conversion to the desired product (71556-13-A). The ice bath was removed, and the mixture was heated to reflux with a mantle. The heterogeneous mixture quickly turned homogeneous upon reaching temperature, and LC-MS indicated complete conversion after 1 h @reflux (71556-13-B). After standing at ambient temp over the weekend, an orange solid had formed from the dark brown supernate. The mixture was cooled in an ice bath, then diluted with MTBE (800 mL), resulting in the exothermic precipitation of copious amounts of a dense, mustard-brown solid. The solid was isolated by vacuum filtration and washed with MTBE until the filtrate was colorless to yield the solid and a cloudy, bright orange filtrate. The solid product was then carefully partitioned between DCM (1 L) and sat'd aq. NaHCO3 (1 L). The phases were mixed and the light brown aqueous layer was back extracted with DCM (500 mL). The combined organic layers were washed with sat'd brine, then dried over anhydrous Na2SO4. MTBE (500 mL) was added, then concentrated by about 200 mL, then hexane (500 mL) was added to form a dark brown precipitate. The mixture was further concentrated by 100 mL, then cooled in an ice bath. The mixture was then filtered and washed with hexane/MTBE (200 mL). The filtrate was then concentrated to dryness to yield the title compound as a light brown oil that crystallized to a dark rust colored, oily solid (97.7 g, 60.5% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])=[CH:3][CH:2]=1.[H][H].O>C(O)(=O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)CN1C(=O)CC(c2ccncc2)C1=O
Agent: [Rh]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CC(C2CCNCC2)C1=O

Procedure:
2.8 g of [3-(4-pyridyl)-2,5-dioxopyrrolidin-1-yl]acetic acid are suspended in 160 ml of acetic acid and hydrogenated in an autoclave at 100° C. and a hydrogen pressure of 150 bar for 24 h using 100 mg of 5% rhodium on carbon as a catalyst. The catalyst is then filtered off and the filtrate is concentrated to dryness in vacuo. The product thus obtained is taken up in a little water and freeze-dried.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.[OH:22][NH2:23]>N1C=CC=CC=1>[CH2:1]([C:5]12[CH2:17][CH2:16]/[C:15](=[N:23]\[OH:22])/[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CC/C(=N\O)C(C)=C1c1ccc(O)cc1C2
Temperature: 60 °C

Procedure:
A solution of 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (60 mg, 0.22 mmol) and hydroxyl amine hydrochloride (77 mg, 1.11 mmol) in anhydrous pyridine (0.5 mL) was stirred under a nitrogen atmosphere at room temperature for 4.3 hours and then heated in an oil bath at 60° C. for 30 minutes. The reaction mixture was evaporated under vacuum to an oil which was taken up in EtOAc (10 mL), washed with 1N HCl (2×6 ml), water (6 mL) and brine (6 ml), dried over MgSO4, filtered, and evaporated under vacuum. The residue was lyophilized from benzene (3 mL) to afford (3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one oxime as an amorphous solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 172.9 %

Procedure:
CF3COOH (5 mL) was slowly added at 0° C. to a solution of tert-butyl 4-(5-((2S,5R)-6-(benzyl-oxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperazine-1 carboxylate (723 mg, 1.5 mmol) in DCM (20 mL). The mixture was stirred at 0° C. for 3 hrs, then, the solvent was concentrated to afford (2S,5R)-6-(benzyloxy)-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (997 mg) as a brown oil, which was used directly in the next step. ESI-MS (EI+, m/z): 385.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CS(C)=O>[F:7][C:8]1[CH:13]=[C:12]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
Potassium carbonate (3.46 g, 25.0 mmol) and 2,4-difluoronitrobenzene (7.95 g, 50.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (4.91 g, 50.0 mmol) in DMSO (80 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×2). An organic layer was washed with water (100 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(3-fluoro-4-nitrophenyloxy)-5-methylpyrazole (1.52 g, yield: 12.8%) [mp: 80-83° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.33 (d, J=0.5 Hz, 3H), 5.77 (d, J=0.5 Hz, 1H), 6.96-7.03 (m, 2H), 8.06-8.13 (m, 1H), 10.03 (br s, 1H)] and a yellow solid of 3-(5-fluoro-2-nitrophenyloxy)-5-methylpyrazole (0.97 g, yield: 8.2%) [mp: 95-97° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.31 (s, 3H), 5.77 (s, 1H), 6.90 (ddd, J=2.7, 5.8 and 9.1 Hz, 1H), 7.01 (dd, J=2.7 and 9.6 Hz, 1H), 8.03 (dd, J=5.8 and 9.1 Hz, 1H), 9.86 (br s, 1H)].
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].CO.[C:36](OC)(OC)(OC)[CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:36][C:37]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:7]([C:13]4[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CNC(=O)OC(C)(C)C)cc4)nc3ccn12
Temperature: 100 °C

Procedure:
To a stirred solution of 16-2 (5 g, 11.3 mMol) in 20 mL of 3:1 toluene:methanol was added trimethyl orthoacetate (1.8 g, 15.3 mMol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.6 mMol). The reaction was heated to 100° C. in a microwave reactor for 35 minutes. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified using normal phase flash chromatography to yield 17-1 as a solid. LC/MS (M+1) calculated: 466.6 observed: 466.2
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[CH:8]=2)[CH:3]=1.C([Li])(C)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1>O1CCCC1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:30])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]4([CH3:17])[O:16][CH2:15][CH2:14][O:13]4)[CH:8]=3)[CH:3]=2)[CH:24]=1
Reactant: O=Cc1cccnc1
Reactant: CC1(c2ccc3cc(Br)ccc3c2)OCCO1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(c2ccc3cc(C(O)c4cccnc4)ccc3c2)OCCO1
Yield: 63 %

Procedure:
A solution of 4.5 g of 2-bromo-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene in 30 ml of tetrahydrofuran was cooled to -78° C. under nitrogen, and 14.0 ml of 2.2M t-butyl lithium added dropwise. A solution of 1.64 g of 3-pyridinecarboxaldehyde in 15 ml of tetrahydrofuran was added over a period of 10 minutes, and the temperature was allowed to rise to -20° C. during the next 30 minutes. The reaction was quenched with 30 ml of water and the mixture extracted with methylene chloride. The organic layer was dried over sodium sulfate and solvent removed under reduced pressure to give a solid that was recrystallized from methylene chloride/diethyl ether to give 3.1 g of 2-[(3-pyridyl)hydroxymethyl]-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, m.p. 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.N1C=CC=CC=1>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc2cc(Br)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Yield: 40 %

Procedure:
8.00 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine in 275 ml of tetrahydrofuran is initially introduced in a flask. 1.66 g of sodium hydride (60% in paraffin oil) are added in portions with ice-cooling. 7.00 ml of 2-trimethylsilylethoxy-methyl chloride is subsequently added dropwise at about −30° C., and the mixture is stirred at 25° C. under nitrogen until the pyridine has reacted completely (HPLC check, about 4 hours). The cooled reaction solution is added to about 200 ml of water and extracted three times with EA. The combined organic phases are dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 34 min.), giving 5.30 g of 6-bromo-2-methyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazo[4,5-b]pyridine as white solid (yield 40%, content 99%); MS-FAB (M+H+)=343.1; Rf (polar method): 2.59 min.