Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[H-].[Na+].Cl.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:11]1)[CH3:2]
Reactant: CCOC(=O)C=CCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a solution of 7-hydroxy-hept-2-enoic acid ethyl ester (99.9 g, 0.58 mol) in tetrahydrofuran prepared in the previous step, cooled with ice-water bath, was added sodium hydride (4.80 g, 0.12 mol, 60%) in two portions. The mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was neutralized with a 1 M aqueous hydrochloric acid solution (pH ˜5.0-6.0). Water (1 L) was then added and the mixture was extracted with ethyl acetate (3×1 L). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with hexanes/ethyl acetate (3×800 mL, hexanes/ethyl acetate=10/1, v/v). The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated and the crude product was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 10% ethyl acetate/hexanes) to afford (tetrahydro-pyran-2-yl)-acetic acid ethyl ester (77.1 g, 77% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[OH:13][CH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)cc(CO)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (3.0 g, 12.2 mmol) in dioxane (27 mL) is added cesium carbonate (4.0 g, 12.2 mmol), potassium carbonate (34 g, 24.4 mmol), and palladium(0)tetrakis(triphenylphosphine) (704 mg, 0.61 mmol), followed by trimethyl boroxine (1.7 mL, 12.2 mmol). The reaction mixture is refluxed for 5 h, cooled to room temperature, and then partitioned between water and ethyl acetate. The organic layer is washed with water, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 181.2 [M+H]+.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:14][C:15]1[C:16]([NH:21][NH2:22])=[N:17][CH:18]=[CH:19][CH:20]=1.O1CCCC1>C(O)(=O)C>[Cl:14][C:15]1[C:16]([N:21]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]([CH3:12])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: NNc1ncccc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)nn1-c1ncccc1Cl
Yield: 15.8 %

Procedure:
A mixture of 1.34 g of ethyl 2-methoxyimino-4-oxopentanoate, 1.23 g of 3-chloro-2-hydrazinopyridine, 25 ml of tetrahydrofuran and 50 ml of acetic acid was heated to reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with methyl t-butyl ether two times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of ethyl 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C.CCO>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1ccc(C(F)(F)F)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and 4-trifluoromethylbenzaldehyde (0.35 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give beige solid 0.58 g, in 94% yield, mp: 260.5° C. 1H NMR (CD3OD) δ 8.35 (s, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.70 (d, 2H), 6.87 (d, 2H). 13C NMR (CD3OD) δ 167.0, 163.0, 147.7, 1139.6, 131.0, 129.1, 126.7, 126.6, 124.5, 116.4. Anal. Calcd for C15H11F3N2O2. ¼H2O: C, 57.60; H, 3.54; N, 8.95, F; 18.22. Found: C, 57.71; H, 3.77; N, 8.67, F; 18.43.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:7][C:6]=1[CH3:16]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:14]([NH2:15])=[N:2][NH:3][C:12]=2[NH2:13])=[CH:7][C:6]=1[CH3:16]
Reactant: NN
Reactant: Cc1cc(C(C#N)C#N)ccc1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2c(N)n[nH]c2N)ccc1Cl
Temperature: 70 °C

Procedure:
Hydrazine monohydrate (0.312 mL, 6.4 mmol) was added to a solution of the product from Example 47A (512 mg, 2.69 mmol) in CHCl3 (25 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles) and the mixture was heated at 70° C. under nitrogen for 22 hours, then cooled to room temperature. The mixture was concentrated under vacuum to provide the title compound as a beige solid. MS (DCI/NH3) m/z 223/225 (M+H)+.
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14](=[O:47])/[C:15](/[N:20]1[CH:23]([S:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]1=[O:46])=[C:16](/[O:18][CH3:19])\[CH3:17].COC(=O)/C(/N1C(SS(C2C=CC(C)=CC=2)(=O)=O)C(NC(=O)COC2C=CC=CC=2)C1=O)=C(\OC)/C>O1CCCC1.C(Cl)Cl>[CH3:12][O:13][C:14]([C@@H:15]1[N:20]2[C:21](=[O:46])[C@@H:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:23]2[S:24][CH:17]=[C:16]1[O:18][CH3:19])=[O:47]
Reactant: COC(=O)/C(=C(\C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Agent: COC(=O)/C(=C(/C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12

Procedure:
302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to a solution of 534 mg (1 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel using toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8.25 μ, followed by pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90 and 7.10 μ, in the form of colourless foams.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.CO[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=1>>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][N:9]=[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20]2)=[CH:5][CH:4]=1
Reactant: COC1=NCCCCC1
Reactant: NCCc1ccc(Cl)cc1
Agent: Cl
Product: Clc1ccc(CCN=C2CCCCCN2)cc1
Reaction time: 72 h

Procedure:
A slurry of 15.9 g (0.08 mole) of p-chlorophenethylamine hydrochloride in 25 ml of O-methylcaprolactim is allowed to stand at room temperature 3 days with occasional stirring with a glass rod. The mixture is then cooled and the resulting solid is collected, washed with ether and recrystallized from methanol-acetone to give 2-(p-chlorophenylethylimino)hexahydroazapine hydrochloride.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH3:28])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br.O>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:10]3[C:11]([CH3:13])=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:8]([CH3:28])[CH:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(O)c(OC)cc23)cc1C
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N-ethyl-N′-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}urea, 76 mg), potassium carbonate (138 mg), and 1,2-dibromoethane (0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N′-ethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.044 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 72 mg (yield 73%) of the title compound.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH3:31][NH2:32]>O1CCCC1.O>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:32][CH3:31])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CN
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in tetrahydrofuran (5 ml) and treated with a solution of methylamine in water (40% w/v; ml) and the resulting mixture stirred at ambient temperature for 18 h. The title compound (55 mg; 60%) was obtained as a brown powder by filtration, washing with water and drying at 40° C. under reduced pressure. 1H NMR (250 MHz; CD3OD) δ: 2.84 (3H, s), 5.89 (2H, s), 6.76 (1H, d), 6.85-7.80 (5H, m), 7.82 (2H, d), 8.00 (2H, d), 8,49 (1H, br); m/z (ESMS): 399 [M+HM]⊕.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]3([C:18]4[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=4[C:11]=2[CH:10]=1)[CH2:17][O:16]3>ClCCl>[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]([F:7])([CH2:17][OH:16])[C:18]3[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=3[C:11]=2[CH:10]=1
Reactant: F
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2c(s1)C(F)(CO)COc1ccc(Br)cc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
HF-pyridine (70%) (2 mL) was added dropwise to a stirred solution of ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-oxirane]-2-carboxylate (600 mg, 1.57 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. After being stirred for 1 h at 0° C. the reaction was quenched with brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give 270 mg (43%) of the titled compound as a off-white solid; LC-MS (ES, m/z) 402, 404 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:18]2[S:19][CH2:15][CH2:16][N:17]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(N)cc1
Reactant: S=C=NCCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(NC2=NCCS2)cc1
Temperature: 50 °C

Procedure:
A 2 liter, 3-neck round bottom flask fitted with magnetic stirrer, addition funnel, argon gas inlet and thermometer was charged with 4-hexylaniline (65.0 g, 0.367 m) dissolved in 500 ml reagent toluene. To this stirred solution, was added dropwise a solution of β-chloroethylisothiocyanate (53.5 g, 0.441 m, 1.2 eq.) in 175 ml toluene at room temperature. No significant exotherm was noted. After the addition was completed, the reaction mixture was warmed to 50° C. for 19 hours. The reaction was cooled to room temperature and the toluene removed on the rotary evaporator to give an orange, semi-solid residue which was stirred with 900 ml diethyl ether (Et2O). The resulting slurry of off-white solid was cooled in an ice water bath and the solid filtered, washed with cold Et2O, and dried (filter suction, desiccator) to give the slightly impure hydrochloride salt of the desired aminothiazoline. The HCl salt was neutralized by adding the salt to a cold, stirred solution of sodium hydroxide (14.7 g, 0.367 m) in 1200 ml water layered with Et2O. After neutralization, the ether layer was separated and the aqueous layer was extracted with Et2O four times. The combined Et2O extracts were washed with water twice and with a saturated NaCl solution once, dried (MgSO4), and evaporated under vacuum to afford 90.0 g of crude, freebase product as a waxy, off-white solid. The crude material was recrystallized from 900 ml hexane to give 73.0 g (76%) product in two crops as small, off-white platelets. m.p. 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N+:6]([O-])[O:7][N:8]=[C:4]2[C:3]=1[Cl:12].P(OCC)(OCC)OCC>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][O:7][N:8]=[C:4]2[C:3]=1[Cl:12]
Reactant: [O-][n+]1onc2c(Cl)c(Br)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: Clc1c(Br)ccc2nonc12
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
The crude 5-bromo-4-chlorobenzo[c][1,2,5]oxadiazole 1-oxide (3.2 g, 12.8 mmol) was stirred in 50 ml ethanol, treated with triethyl phosphite (3.2 g, 19 mmol) and heated to reflux for 5 h. After cooling, the volatiles were removed by rotary evaporation, the residue was taken up in 75 mL dichloromethane and stirred with 20 mL bleach solution for 20 min. The organic phase was washed with 10 mL saturated NaCl, dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography on silica to give the title compound as an orange solid (1.5 g, 50%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=9.4 Hz, 1H), 7.59 (d, J=9.3 Hz, 1H); EIMS m/z 232.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[C:5]([NH:22][C:23](=[O:33])[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]1)([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:6](=[O:14])[NH:7]2.[OH-:36].[K+]>CC(O)(C)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:5]2([NH:22][C:23](=[O:33])[CH2:24][N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]3)[C:4]3[C:8](=[CH:9][C:10]([C:12]([NH2:13])=[O:36])=[CH:11][C:3]=3[C:2]([F:1])([F:34])[F:35])[NH:7][C:6]2=[O:14])=[CH:20][CH:19]=1
Reactant: CCN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(C#N)cc(C(F)(F)F)c32)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(C(N)=O)cc(C(F)(F)F)c32)CC1
Yield: 60.4 %

Procedure:
0.16 g of the product obtained in Example 4, 0.47 g of potassium hydroxide and 7 ml of t-BuOH are placed in a round-bottomed flask equipped with a magnetic stirrer. The mixture is left to react at 50° C. for 5 hours. The resulting mixture is filtered through Celite and washed with THF. The filtrate is evaporated under vacuum and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 100 mg of an oil are obtained, which oil is purified by flash chromatography, eluting with 8/2 ethyl acetate/methanol. 10 mg of white solid are isolated.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[O:37])[CH:25]([F:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([OH:6])=[O:37])[CH:25]([F:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(F)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)C(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of sodium chlorite (274 mg; 3.03 mmol; 5 eq.) and sodium dihydrogen phosphate (291 mg; 2.42 mmol; 40 eq.) in water (4 mL) was added dropwise to a solution of 2-methyl-but-2-ene (0.5 mL) and 3-fluoro-4-(2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (196 mg; 0.61 mmol; 1 eq.) in 1,4-dioxane (4 mL) and the resulting mixture was stirred a room temperature for 3 hours. The dioxane was evaporated in vacuo and the pH made acidic with 1M HCl. The solution was extracted with ethyl acetate (2×), washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (205 mg, 100%) as a yellow oil. UPLC/MS: (MS−) 338.2 ([M−H]−).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Biphenylcarbonyl chloride (8 g) was suspended in chloroform (30 mL). This was added dropwise to a stirred solution of N,O-dimethyl hydroxylamine hydrochloride (5.2 g) and triethylamine (13.5 mL) in chloroform (80 mL) at 0° C. After addition was complete, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The organic phase was separated, washed with water and dried over MgSO4. Evaporation gave an oil, purified by flash column chromatography (ethyl acetate:light petroleum, 1:1) to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 33.8, 61.1, 126.7, 127.2, 127.9, 128.9, 132.8, 140.2, 143.4 and 169.7. δH (CDCl3, 250 MHz): 3.38 (3H, s), 3.59 (3H, s), 7.37-7.48 (3H, m), 7.61 (4H, m) and 7.77 (2H, d, J 8.5).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH2:15])(=[O:4])[CH3:3].[N:16]#[C:17][NH2:18]>O.Cl>[C:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH:15][C:17]([NH2:18])=[NH:16])(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1N
Reactant: N#CN
Agent: Cl
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 157.5 %

Procedure:
A mixture of 108 (100 mg, 0.43 mmol) and cyanamide (27 mg, 0.65 mmol) was mixed and heated at 85-100 C. with stirring for 15 minutes. The liquid mass was cooled to room temperature, dissolved in hot water (0.7 mL), and acidified with 1-2 drops of conc. HCl. The thick solid which separated was filtered and dried to give crude 113 (160 mg). This was recrystallized from 5% HCl to give the pure hydrochloride salt of 113 (50 mg, 52%): mp 284-287 C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>C(#N)C.C(OCC)(=O)C>[C:22]([O:25][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 74.6 %

Procedure:
A solution of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (100 mg, 0.292 mmol) and sodium acetate (159 mg, 1.168 mmol) in acetonitrile (5 mL) was heated in microwave at 140° C. for 7.5 min. The dark-yellow solution was diluted with ethyl acetate (25 mL), washed with water (20 mL), dried over sodium sulphate and the solvent evaporated to afford 2-oxo-2-(3-(quinoxalin-2-yl)phenylamino)ethyl acetate (70 mg, 74% yield). LCMS calculated for C18H15N3O3 (M+H): 322.33. found 322. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.3 (1H, br.), 9.51 (1H, s), 8.52 (1H, m), 8.15-8.20 (2H, m), 8.08-8.10 (1H, m), 7.82-8.00 (3H, m), 7.55-7.60 (1H, m), 4.70 (2H, s), 2.15 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH:13][CH2:14][CH3:15])=[CH:5][C:6]([N:9]([O:11][CH3:12])[CH3:10])=[N:7][CH:8]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>N1C=CC=CC=1>[CH2:14]([NH:13][C:4]1[C:3]([CH2:2][NH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:8][N:7]=[C:6]([N:9]([O:11][CH3:12])[CH3:10])[CH:5]=1)[CH3:15]
Reactant: CCNc1cc(N(C)OC)ncc1CCl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Yield: 85.7 %

Procedure:
5-(Chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (4.3 g, 18.7 mmol, from Example A19) and 4-fluoro-3-nitro-phenylamine (3 g, 19 mmol) were combined in pyridine (50 ml) by the method of Example A4 to provide N4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine (5.6 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1 H), 7.63 (s, 1 H), 7.34-7.29 (m, 1 H), 7.23-7.21 (m, 1H), 7.02-7.6.98 (m, 1 H), 6.84 (s, 1 H), 6.06 (s, 1 H), 4.18 (d, J=3.2 Hz, 2 H), 3.71 (s, 3 H), 3.31 (s, 3 H), 3.32 (q, J=7.2 Hz, 2 H), 1.18 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 350.1 [M+H]+.