Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:8]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1cnn(C(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of 4-bromo-1H-pyrazole (0.294 g), (bromomethylene)dibenzene (0.494 g) and triethylamine (0.418 mL) in tetrahydrofuran (5 mL) was stirred at 60° C. for 24 hours. The reaction mixture was concentrated and purified by chromatography on silica gel using 0-20% ethyl acetate/hexanes as eluent to provide the title compound.
Reaction SMILES: CCOCC.[N:6]([C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:10]([O-:12])=O)=[C:7]=[S:8].[C:20]1([NH:26]N)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[C:20]1([N:26]2[C:10](=[O:12])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:13])[NH:6][C:7]2=[S:8])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N=C=S)(C(=O)[O-])c1ccccc1
Reactant: NNc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
4.7 g (20 mmol) of ether 2-isothiocyanato-2-phenylpropionate are dissolved in 40 ml of xylene. 2.16 g (20 mmol) of phenylhydrazine are added and the mixture is heated for 4 hours at reflux. The mixture is cooled to room temperature and a beige solid precipitates. The precipitate is filtered, washed with 5 ml of diisopropyl ether and then dried under vacuum. 4.6 g (yield=77%) of 3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of a beige powder melting at 164° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1.COC1C=C([Li])C=CC=1.[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1.[Cl-].[Na+]>C(OCC)C.CCCCCC>[CH3:24][N:25]1[CH2:30][CH2:29][C:28]([OH:31])([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:27][CH2:26]1
Reactant: COc1cccc(Br)c1
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]c1cccc(OC)c1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(C2(O)CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 159 ml. of n-butyl lithium in 100 ml. of hexane containing 47.7 g. of 3-methoxybromobenzene was stirred at -25° C. for twenty minutes and then was warmed to room temperature at which temperature it was stirred for one hour, thus providing 3-methoxyphenyllithium. The reaction mixture was chilled to 10° C. and stirred while a solution of 50 g. of 1-methyl-4-piperidone in 100 ml. of diethyl ether was added in dropwise fashion over a thirty minute period. Following the completion of the addition, the reaction mixture was stirred for two additional hours, and was then mixed with 50 ml. of saturated aqueous sodium chloride solution. The aqueous solution was extracted several times with diethyl ether, and the ethereal extracts were combined and concentrated to dryness to provide 38 g. of 1-methyl-4-hydroxy-4-(3-methoxyphenyl)piperidine formed in the above reaction.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].[OH-:5].[Ca+2:6].[OH-]>C(O)(=O)C>[C:2]([O-:5])(=[O:3])[CH3:4].[Ca+2:6].[C:2]([O-:5])(=[O:3])[CH3:4]
Reactant: CC(C)=O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
Furthermore, acetone can be synthesized by pyrolyzing cellulose in a wood material to give acetic acid, neutralizing the acetic acid with calcium hydroxide to give calcium acetate, and then pyrolyzing the calcium acetate. Since acetic acid is generated by oxidation of ethanol during the fermentation in the synthesis of bioethanol, the acetic acid can be utilized to synthesize acetone through the same process as above.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1cncc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0° C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.52 (m, 2 H), 7.83 (s, 1 H), 5.45 (t, J=5.8 Hz, 1 H), 4.55 (t, J=5.7 Hz, 2 H). MS m/z 144.1
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1.C([O-])(=O)C.CC#N>CCOC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 35.3 %

Procedure:
5-Nitrophenyl triflate 26 (7 g, 18.7 mmol), palldium (II) acetate (88 mg, 0.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene (430 mg, 0.78 mmol) and hplc grade CH3CN (10 ml) were mixed well in a teflon-linked stainless steel bomb. After adding freshly made, pulverized proton sponge formate (5.1 g, 19.6 mmol), the bomb was sealed and heated at 90° C. for 2 h. The reaction mixture was taken up in EtOAc, passed through a silica gel plug, and then purified on a silica gel column, eluting with 0-30% EtOAc/hexanes to yield 1.5 g (35%) methoxynitrobenzaldehyde acetal 27.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:14](Cl)(Cl)[Cl:15].Cl>[Cl-].[Zn+2].[Cl-]>[Cl:15][P:14]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13]1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: ClP(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2ccccc21
Temperature: 100 °C

Procedure:
700 g (4.12 mol) of o-phenylphenol and 4.1 g of zinc chloride are heated to 180° C. with stirring. 692 g (5.03 mol) of phosphorus trichloride are then added dropwise over 12 hours. Reflux is maintained for a further 5 hours; at the end no further hydrogen chloride is evolved. The excess phosphorus trichloride is distilled off at 120° C. in vacuo, the reaction product is cooled to 100° C. and 966 g of toluene are added. Cooling to room temperature gives a 50% strength solution of 6-chloro-(6H)-dibenz[c,e][1,2]oxaphosphorin in toluene. The 31P-NMR spectrum indicates a purity of 95.5%.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:25]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:38]>O1CCCC1>[ClH:38].[ClH:38].[NH2:8][CH2:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)(=[O:28])=[O:29])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OC(=O)CNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OC(=O)CN)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
272 mg (0.515 mmol) of the compound of Example 60 was added to 10 ml of tetrahydrofuran. 2 ml of concentrated hydrochloric acid was added to the mixture and stirred at room temperature for 3 h. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol to obtain 159 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N1CCN(C2C=C(N[C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])C=CC=2)CC1)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt and using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 476.1 [M+H]+; tR=1.98 min (System 1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:22])[C:11](N2[C@@H](C(C)C)COC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O.S([O-])([O-])=[O:27].[Na+].[Na+]>C1COCC1.O>[C:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:22])[C:11]([OH:12])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](C)CCCc1ccccc1
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
(4S)-3-((2R)-5-Phenyl-2-methyl-1 -oxopentyl)-4-isopropyl-1,3-oxazolidin -2-one (0.25 g, 0.83 mmol), prepared by the method described in J. Org. Chem. 59: 2261, (1994), was dissolved in 4.2 mL of 4:1 THF:H2O, cooled to 0° C. and purged with N2. 30% Hydrogen peroxide (0.34 mL) was added dropwise, followed by a dropwise addition of a solution of LiOH·H2O (31.9 mg, 1.3 mmol) and 1.7 mL H2O. The reaction mixture was stirred at 0° C. for 1 hour, then a solution of sodium sulfite (0.42 g, 3.3 mmol) in 2.5 mL of H2O was added. THF was evaporated in vacuo, and H2O was added to the residue. This mixture was washed with CH2Cl2 (3×). The aqueous layer was cooled to 0° C., acidified with aqueous hydrochloric acid and extracted (5×) with EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (0.11 g) as a colorless oil. 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 3H), 1.50 (m, 3H), 1.60-1.80 (m, 3H), 2.5 (m, 1H), 2.62 (t, 2H), 7.08 (m, 3H), 7.29 (m, 2H). MS (DCl/NH3) m/e 210 (M+NH4)+.
Reaction SMILES: C1C=CC=CC=1.[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=[O:13].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:8]1[S:7][CH:11]=[CH:10][N:9]=1
Reactant: O=Cc1nccs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: c1csc(C2OCCO2)n1
Temperature: 25 °C

Procedure:
A benzene (10 mL) solution of 2-thiazole carboxaldehyde (5.00 g 44.19 mmol), ethylene glycol (7.40 mL, 132.58 mmol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) was refluxed with azeotropic removal of H2O for 3 h and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and the organics washed with sat'd NaHCO3, brine and then dried (MgSO4), filtered and concentrated to provide the title compound as a reddish oil. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=3.1 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 6.13 (s, 1H), 4.16–4.01 (m, 4H).
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Cl:19])[CH:3]=1.[CH2:20]([O:22][CH:23]([N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1)[CH3:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[Cl:19][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH:23]([O:22][CH2:20][CH3:21])[CH3:24])[CH:29]=2)[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1-c1cc(F)cc(F)c1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Product: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A solution of 1-(6-bromo-4-chloro-3′,5′-difluorobiphenyl-2-yl)ethanone (300 mg, 0.87 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 0.96 mmol), and sodium carbonate (280 mg, 2.6 mmol) in 1,4-dioxane (3.0 mL, 38 mmol) was degassed with nitrogen 5 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) degassed with additional nitrogen for 5 mins, and heated at 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (190 mg, 54%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:35]=[C:34]([CH:36]=O)[C:33]([CH3:38])=[N:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[CH3:30][N:31]1[CH:35]=[C:34]([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:12])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)[C:33]([CH3:38])=[N:32]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: Cc1nn(C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (6.83 g, 17.3 mmol) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (3.0 g, 24.2 mmol) were dissolved in dichloromethane (150 ml). Acetic acid (996 μl, 17.3 mmol) was then added and the reaction mixture allowed to stir at room temperature for four hours. Sodium triacetoxyborohydride (5.49 g, 25.9 mmol) was then added and reaction mixture stirred for a further 18 hours. Saturated aqueous sodium bicarbonate solution (300 ml) was then carefully added followed by dichloromethane (100 ml). The organic layer was separated and the aqueous layer re-extracted with more dichloromethane (150 ml). The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified by flash chromatography on silica, eluting with a 5% (v/v) solution of methanol in dichloromethane followed by a rising gradient of 5-10% (v/v) methanol in dichloromethane to afford a clear gum, which was taken up in diethyl ether and evaporated to dryness to afford the title compound (7.61 g, 87%); NMR Spectrum: (DMSO d6) δ 1.43 (s, 9H), 1.69 (m, 4H), 1.98 (m, 2H), 2.10 (s, 3H), 2.56 (m, 1H), 2.92 (m, 2H), 3.26 (s, 2H), 3.70 (s, 3H), 7.15 (m, 2H), 7.40 (m, 3H), 7.52 (m, 2H), 7.87 (d, 2H), 8.60 (s, 1H), 9.73 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[NH:25][C:26](=[NH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21]4[O:22][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=4)=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCO2
Reactant: CCOC(=O)C(=N)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
To a solution of 1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (200 mg, 0.561 mmol) in DCM (5 mL) and water (1 mL) was added ethyl 2-(hydroxyamino)-2-iminoacetate (143.5 mg, 1.086 mmol) and DIPEA (230 μL, 1.317 mmol) to give a pink suspension. The reaction was stirred at 40° C. for 1.5 hours. LCMS analysis of the reaction mixture indicated complete consumption of starting material. The reaction mixture was extracted with DCM (2×10 mL) dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was dissolved in THF (6 mL) and treated with TBAF (0.561 mL, 0.561 mmol). The resulting yellow solution was stirred overnight. LCMS analysis of the reaction indicated consumption of the intermediate. The solvent was removed under reduced pressure. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 30-100% EtOAc. Ethyl 5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carboxylate (120 mg, 0.276 mmol, 49.2%) was isolated as an off-white solid. LCMS (+ESI) m/z=435.0 [M+H]+.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:13][C:12]1[C:7]([Cl:6])=[C:8]2[C:9]([CH:2]=[C:1]([CH3:3])[NH:14]2)=[CH:10][CH:11]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2ccc(Cl)c(Cl)c2[nH]1
Temperature: -20 °C

Procedure:
1 600 ml of 0.5M isopropenylmagnesium bromide in THF are introduced under nitrogen and are cooled to −20° C., 51.2 g of 2,3-dichloronitrobenzene in 250 ml of anhydrous THF are added and the mixture is left stirring for I hour at −20° C. The reaction medium is poured at −20° C. onto 1 liter of saturated NH4Cl solution, the mixture is diluted with Et2O and then the aqueous phase is washed twice with Et2O. The organic phases are combined and are concentrated to dryness. The residue is extracted with DCM and the organic phase is washed twice with water and then with a saturated NaCl solution. It is dried and then evaporated and the residue is chromatographed on [lacuna] a hexane/AcOEt (95/5, v/v) mixture. 24.27 g of the expected compound are obtained, M.p.=70–71° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([OH:19])=O)[C:3]=12.[C:21]1([C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:28]([C:31]#[N:32])[C:29]#[N:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:20])[C:17]([N:36]3[CH2:35][CH2:34][N:33]([C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:28]([C:31]#[N:32])[C:29]#[N:30])[CH2:38][CH2:37]3)=[O:19])[C:3]=12
Reactant: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3c(-n4ccnn4)ncc(F)c23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (70 mg), 2-(phenyl(piperazin-1-yl)methylene)malononitrile (55 mg), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (200 mg) and Hunig's Base (0.1 ml) were combined in 1.5 ml of DMF. The mixture was stirred at room temperature for 16 hours. Then, DMF was removed via evaporation at reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer washed saturated NaHCO3 solution (3×100 ml), and brine (10 ml). The organic phase was dried over anhydrous MgSO4-Concentration in vacuo provided a crude product, which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](B3OC(C)(C)C(C)(C)O3)=[C:11]3[O:12][CH2:13][CH2:14][CH:15]([CH3:16])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[CH:29]=3)=[C:11]3[O:12][CH2:13][CH2:14][CH:15]([CH3:16])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cc(Br)ccn1
Reactant: CC1CCOc2c(B3OC(C)(C)C(C)(C)O3)c(-c3ccc(F)cc3)nn21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCCC3C)ccn1
Temperature: 120 °C
Yield: 23.5 %

Procedure:
150 mg of 2-(4-fluorophenyl)-7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (0.419 mmol, 1.1 eq.) and 87 mg of N-(4-bromopyridin-2-yl)propanamide (0.381 mmol, 1 eq.) are dissolved in 1.5 ml of 1,4-dioxane. To this solution are added 22 mg of bis(tricyclohexylphosphine)-palladium(II)dichloride (0.03 mmol, 0.08 eq) and a aqueous solution of Na2CO3 (5 eq, 0.952 ml). The reaction mixture is flushed for 5 mins with argon and then sealed. Next the mixture is heated for 15 mins at 120° C. in the microwave (CEM Explorer). After cooling, the reaction mixture is diluted with EtOAc and washed with water. The combined organic phase are dried over Na2SO4 and concentrated in vacuo. The crude product is purified by silica gel chromatography (eluent cyclohexane/ethyl acetate). 34 mg (21%) of N-{4-[2-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]pyridin-2-yl}propanamide are obtained.