Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([OH:3])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C:1]([C:4]2[C:5]3[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1Cl
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-carboxy-2-oxindole (200 mg, 1.13 mmol) and 3-chloro-4-methoxyphenylamine (178 mg, 1.13 mmol) in dimethylformamide (15 mL) at room temperature was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 997 mg, 2.26 mmol) followed by 4-dimethylaminopyridine (206 mg, 1.69 mmol). The mixture was stirred at room temperature for 72 hours. The reaction was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (100 mL), water, 2N hydrochloric acid (100 mL), water (3×200 mL) and brine. It was then dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate to give 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)-amide as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:18]1([CH2:17][C:16]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH2:13][CH2:14][O:15]1
Reactant: OCCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C)OCCc2nc(-c3ccc(Cl)cc3)sc21
Reaction time: 20 h

Procedure:
A mixture of the starting material of formula II, 2-(4-chlorophenyl)-4-(β-hydroxyethyl)thiazole (24.0 g, 0.1 mole, described in Example 1), ethyl acetoacetate (19.5 g, 0.15 mole) and p-toluenesulfonic acid hydrate (38.0 g, 0.2 mole) in toluene (1000 ml) is heated at reflux temperature, with water separation, for 20 hr. The mixture is evaporated under reduced pressure and the residue is triturated with petroleum ether. The residue is dissolved in a mixture of aqueous sodium bicarbonate solution and ether. The organic solution is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 6,7-dihydro-4-methyl-2-(4-chlorphenyl)-4H-pyrano[4,3-d]thiazole-4-acetate (IV, R1 = Cl, R2 = CH3, A= COOCH2CH3 and n= 1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([O:12]C)=[CH:6][C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O>ClCCl>[NH2:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(O)c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.2 %

Procedure:
To a solution of 15.65 g (87.83 mmol) of 2-amino-4,5-dimethoxybenzonitrile in 440 ml of dry dichloromethane was added dropwise at -78° C., 66.0 g (263.5 mmol) of boron tribromide. The mixture was stirred overnight while the mixture was allowed to warm to room temperature. After the addition of 180 ml of water, the resulting precipitate was filtered off and dried in vacuo (37.6 g). The crude material was dissolved in 570 ml of methanol, 0.5 ml of concentrated hydrochloric acid was added and the mixture was refluxed for 1 hour. Evaporation to dryness yielded 18.75 g of 2-amino-4,5-dihydroxybenzonitrile as the hydrobromide salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
A mixture of 2,4-Dichloro nitro benzene (0.25 g, 1.3 mmol), 4-Acetamido thiophenol (0.26 g, 1.43 mmol) and cesium carbonate (0.466 g, 1.43 mmol) in DMF (3 mL) was heated 2.5 hr at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum. The residue is purified by silica gel column chromatography eluting with CH2Cl2/methanol leaving the title compound as a yellow solid (0.25 g, 63%).
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]O.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7]
Reactant: O=C(O)C1=CCC1
Reactant: OCCCCCl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCCCl)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
Cyclobut-1-enecarboxylic acid (2.04 mmol, 200 mg) was dissolved in 1.5 mL dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (4.08 mmol, 345 μL) was added. The temperature of the solution was raised to rt, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 4-chlorobutanol (1.36 mmol, 148 mg) and triethylamine (2.72 mmol, 379 μL) were dissolved in 1.0 mL dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The CH2Cl2 solution was concentrated by rotary evaporation, and then purified by flash column chromatography (60% CH2Cl2/pentane) to yield 21 as a colorless oil (98 mg, 38%). 1H-NMR (500 MHz, CDCl3) δ 6.73 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.43 (m, 2H), 1.81 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 162.27, 146.69, 138.71, 63.31, 44.58, 29.31, 29.20, 27.20, 26.20.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]=[N+:15]=[N-:16])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]([CH2:13][C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])=[N+:15]=[N-:16]
Reactant: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)CN=[N+]=[N-]

Procedure:
((1S)-1-Azidomethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (9.64 g, 39.78 mmol) was treated with TFA (30 mL) in DCM (150 mL) for 3 hrs, the mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with aqueous 1 M K2CO3, dried with Na2SO4 and concentrated to a yellow liquid (4.55 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[CH:8]=[C:9]([C:12]([O:14]C)=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[CH:8]=[C:9]([C:12]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[OH:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c2nccc(Br)c2c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Reaction time: 3 h

Procedure:
Into a 1000-mL 3-necked round-bottom flask, was placed methyl 4-bromo-8-methoxyquinoline-6-carboxylate (13 g, 43.90 mmol, 1.00 equip), tetrahydrofuran (500 mL), and (4-chlorophenyl)magnesium bromide (220 mL, 5.00 equip). The resulting solution was stirred for 3 hr at reflux temperature. The reaction was then quenched by the addition of water (400 mL). The resulting solution was extracted with ethyl acetate (3×300 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to yield (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 490 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:7][CH:8]=1.[C-:13]#[C-:14].[Na+].[Na+].N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:13]#[CH:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCCBr)c1
Reactant: [C-]#[C-]
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCc1cccc(OC)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2ncccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NaH (0.594 g, 14.84 mmol) was suspended in THF (10 mL), and 3,5-dimethylpyrazole (1.091 g, 11.35 mmol) was slowly added and stirred for one hour at room temperature. 2-Chloropyrimidine (1 g, 8.73 mmol) was slowly added to the mixture and refluxed for three hours. Completion of the reaction was confirmed by TLC, and then water (5 mL) was added to the mixture. The solvent was distilled off and the residue was extracted with ethyl acetate twice. The organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate) to give 1.05 g of the title compound (yield 69%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[OH-].[Na+]>CCO.O>[NH2:30][C:28](=[O:29])[CH2:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH2:25][CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A mixture of 200 mg (0.5 mmol) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 4 mL of 1N NaOH in 10 mL of EtOH was stirred for 1.5 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 5 with 1N HCl, extracted with EtOAc, the EtOAc solution washed with brine and dried (MgSO4). The solvent was evaporated at reduced pressure, the residue stirred with ether/MeOH and the insoluble material filtered to give 120 mg (61% yield) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid, mp, 196-199° C.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.O1CCCC1>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 0.5 h

Procedure:
A solution of n-butyl-lithium (15% w/w, 36 ml, 0.05 mole) in hexane was added portionwise to a stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mole) in dry tetrahydrofuran (50 ml.) at 0° under nitrogen. After the addition the solution was stirred for 0.5 hour to give a dark red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:14][C:15]1[C:16](F)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:14][C:15]1[C:16]([O:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: Oc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
3-chloro-4-(trifluoromethoxy)phenol (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55° C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:31][C:32]#[N:33])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=4[CH3:27])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:31]([CH2:1][CH3:2])[C:32]#[N:33])=[CH:10][CH:9]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.3 %

Procedure:
Potassium t-butoxide (908 mg, 8.09 mmol) was added to a stirred solution of [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (1.41 g, 3.68 mmol) and ethyl iodide (1.43 g, 9.20 mmol) in tetrahydrofuran (18 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.20 g, 2.92 mmol, 79%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[C@@H:23]([CH3:27])[CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(OCc5ccccc5)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reaction time: 72 h
Yield: 19.9 %

Procedure:
(11S)-3-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (770 mg, 2.05 mmol) was dissolved in 200 mL of ethanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 430 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) for 3 days. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol and the combined filtrates were concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 30-50% CMA/CHCl3) gave an off-white solid. Recrystallization from acetonitrile and methanol gave (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (110 mg) as a white powder. mp>250° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.49 (br s, 1H), 7.81 (d, J=8.9 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.80 (dd, J=8.9, 2.5 Hz, 1H), 6.42 (s, 2H), 5.05 (d, J=15.4 Hz, 1H), 5.00 (m, 1H), 4.91 (d, J=15.4 Hz, 1H), 4.10 (m, 2H), 1.52 (d, J=6.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 156.7, 152.3, 147.0, 144.2, 132.2, 125.0, 121.6, 112.4, 110.1, 108.2, 68.8, 65.1, 50.3, 19.2; MS (ESI) m/z 271 (M+H)+. Anal. calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 61.99; H, 5.05; N, 20.62.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH3:9].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCO
Reactant: Nc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCNc1ccccc1
Yield: 83 %

Procedure:
200 parts of aniline, 50 parts of ethyl alcohol and 10 parts of triphenyl phosphite are heated for 10 hours at 250° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, excess aniline and unconverted alcohol are distilled off under reduced pressure. 110 parts of N-ethylaniline, corresponding to a yield of 83% of theory, distil at a boiling point of 205° C/760 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Reactant: BrC1CCCC1
Product: CCc1cc(OCCCCCC(C)(C)C#N)c(OCc2ccccc2)c(OC2CCCC2)c1
Yield: 92 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-cyclopentyloxy benzene was prepared in 92% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and bromo-cyclopentane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:9][OH:10])N)=[N:4][O:5][N:6]=1.[ClH:11].[Cl-].[Na+].N([O-])=O.[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:7]([Cl:11])=[N:9][OH:10])=[N:4][O:5][N:6]=1
Reactant: NC(=NO)c1nonc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nonc1C(Cl)=NO
Temperature: 43.5 °C
Yield: 53.4 %

Procedure:
4-Amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (422 g, 2.95 mol) was added to a mixture of water (5.9 L), acetic acid (3 L) and 6 N hydrochloric acid (1.475 L, 3 eq.) and this suspension was stirred at 42-45° C. until complete solution was achieved. Sodium chloride (518 g, 3 eq.) was added and this solution was stirred in an ice/water/methanol bath. A solution of sodium nitrite (199.5 g, 0.98 eq.) in water (700 mL) was added over 3.5 hrs while maintaining the temperature below 0° C. After complete addition stirring was continued in the ice bath for 1.5 hrs and then the reaction mixture was allowed to warm to 15° C. The precipitate was collected by filtration, washed well with water, taken in ethyl acetate (3.4 L), treated with anhydrous sodium sulfate (500 g) and stirred for 1 hr. This suspension was filtered through sodium sulfate (200 g) and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in methyl t-butyl ether (5.5 L), treated with charcoal (40 g), stirred for 40 min and filtered through Celite. The solvent was removed in a rotary evaporator and the resulting product was dried in a vacuum oven (45° C.) to give the desired product (256 g, 53.4%). LCMS for C3H4ClN4O2 (M+H)+: m/z=162.9. 13C NMR (100 MHz, CD3OD): δ 155.8, 143.4, 129.7.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([NH:14][NH2:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)/[CH:20]=[N:21]/[C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])=[N:21][CH:20]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Solvent: CC(=O)O
Product: Fc1ccc(-c2ncnn2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A suspension of (8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-hydrazine (312 mg, 1 mmol) and N-[1-dimethylamino-meth-(E)-ylidene]-2,4-difluorobenzamide (232 mg, 1.1 mmol) in acetic acid (6 mL) was heated at 90° C. for 3 h, allowed to cool down to RT and filtered. The precipitate was washed with diethyl ether and dried to afford the title compound as a beige solid (300 mg, 65%). LCMS (Method B): RT=4.51 min, [M+H]+=461 and 463. 1H NMR (DMSO-d6): 8.50 (1H, s), 7.82 (1H, td, J=8.4, 6.4 Hz), 7.57 (1H, ddd, J=10.4, 9.4, 2.5 Hz), 7.39-7.30 (2H, m), 7.23 (1H, d, J=2.0 Hz), 7.13 (1H, dd, J=8.6, 2.0 Hz), 4.33 (2H, t, J=5.0 Hz), 3.34 (2H, t, J=5.0 Hz).
Reaction SMILES: COCC1C=C([NH2:10])C=CC=1N.N.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][C:17]=1[CH2:23][O:24][CH3:25])([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:10])=[CH:18][C:17]=1[CH2:23][O:24][CH3:25])([O-:15])=[O:14]
Reactant: COCc1cc(N)ccc1N
Reactant: COCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: N
Product: COCc1cc(N)ccc1[N+](=O)[O-]

Procedure:
Another embodiment of the present application relates to a method of making 2-methoxymethyl-1,4-benzenediamine comprising the steps: (a) introducing ammonia to a 4-nitro-3-methoxymethyl-chlorobenzene to obtain 4-nitro-3-methoxymethyl-aminobenzene; and (b) hydrogenating the 4-nitro-3-methoxymethyl-aminobenzene in the presence of a hydrogenation catalyst to obtain the 2-methoxymethyl-1,4-benzenediamine.