Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:32][CH2:33][F:34])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:33][F:34])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCF)C(=O)C1
Reaction time: 0.5 h

Procedure:
1-t-Butoxycarbonyl-3-oxopiperazine (21.6 g) is dissolved in dry DMF (500 ml) and potassium t-butoxide (24.2 g) is added. The mixture is stirred at 20-25° for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (J. Med. Chem., 23(9), 985-90 (1980), 25.9 g) is added and stirring continued at the same temperature for 24 hours. The solvent is removed and the residue partitioned between ethyl acetate and water. The organic phase is washed with water and concentrated. The residue is dissolved in isopropanol and diluted with iso-hexane forming a precipitate which is removed by filtration. The mixture is chromatographed (silica; eluting with a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane) to give 1-t-butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: N#Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N=C(NO)c1cccnc1
Reaction time: 0.21 h

Procedure:
To a solution of 5.012 g (72.1 mmol) of hydroxylamine hydrochloride in 55 mL of isopropyl alcohol, 8.8 g (105.7 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 5.0 g (48 mmol) of 3-cyanopyridine was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue, which was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>>[CH2:23]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
In the same manner as described in Referential Example 15, 4-hydroxy-3-chlorobenzoic acid was reacted with n-dodecyl bromide in an aqueous solution of sodium hydroxide to obtain 4-dodecyloxy-3-chlorobenzoic acid. Then, thionyl chloride was added to 2 g of the so-obtained compound, reaction was carried out under reflux for 3 hours, and unreacted thionyl chloride was removed by distillation, whereby 4-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. The so-obtained compound was diluted with 50 ml of tetrahydrofuran, and 1.7 g of p-benzyloxyphenol and 1.0 g of triethylamine were added to the dilution and reaction was carried out at room temperature with stirring overnight. Precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated and purified by the silica gel column chromatography to obtain 2.1 g of 4-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained compound was catalytically reduced under a hydrogen pressure of 1 kg/cm2 in the pressure of Pd/C as the catalyst according to customary procedures to obtain 1.8 g of (4-hydroxyphenyl) 4 -dodecyloxy-3-chlorobenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].[ClH:17]>CO>[ClH:17].[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1NCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-7-nitro-3,4-dihydroisoquinoline (3.97 g, 20.9 mmol) in methanol (80 ml) was added sodium borohydride (0.87 g, 23.0 mmol) portionwise. The mixture was stirred for 30 min., acidified with 6N HCl, the solvent was evaporated and the solid was stirred in isopropanol, collected and washed with ether: 5.33 g (>100%); MS (M+H)+ 193.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Yield: 92 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (400 mg, 1.5 mmol) in methanol was treated with aqueous sodium hydroxide (2.5 M, 3.75 mmol), heated at reflux temperature for 3 h and concentrated in vacuo. The resultant residue was dispersed in water and acidified with excess formic acid. The resultant precipitate was removed by filtration, washed with water and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (92%) as a white solid, [M+H] 253.2. A solution of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (200 mg, 0.79 mmol) in DMF was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (183 mg, 0.952 mmol) and 1-hydroxybenzotriazole (134 mg, 0.873 mmol), stirred at room temperature for 3 h, treated with a solution of (3′S)-1,3′-bipyrrolidine (166.6 mg, 1.19 mmol) in DMF, stirred at room temperature for 6 h and concenrated in vacuo. This residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate by flash column chromatography (silica, dichloromethane:methanol 20:1 to 10:1) afforded the title compound (73%), identified by mass spectral analysis. [M+H] 253.2.
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[CH:4]=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[F:25][C:21]1[CH:20]=[C:19]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[CH:4]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3cccc(F)c3)sc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc(F)c3)sc21
Yield: 9 %

Procedure:
To a solution of 6-(1-hydroxy-(3-fluorophenyl)methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (Example 51) (957 mg) in trifluoroacetic acid (7 ml) was added then poured onto 10% sodium hydroxide and extracted with ethyl acetate. The organic was then poured onto 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated in vacuo to a viscous oil. The oil was purified by normal phase HPLC to give the title compound (82 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 91.3 %

Procedure:
A solution of 4-chloro-3-nitro-benzene sulfonamide (5.49 g, 23.2 mmol), cyclohexylamine (4.00 mL, 35.0 mmol), and triethylamine (5.0 mL, 35 mmol) in acetonitrile (75 mL) was refluxed overnight under nitrogen atmosphere. The reaction mixture was concentrated almost to dryness. The residue was diluted in ethyl acetate and washed with 1N hydrochloric acid (1×) and saturated NaHCO3 (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was filtered and washed with hexane to give the product as a yellow solid (6.34 g, 91%). ESI-MS m/e 300.1 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1>[Br:21][C:15]1[C:14]([CH3:13])=[CH:19][C:18]([F:20])=[C:17]([CH:16]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(F)c(C=O)cc1Br
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (2.5 mL, 19.1 mmol) was dissolved in THF (24 mL) and the solution was cooled to −70° C., then the solution was added with n-butyllithium (1.57 mol/L hexane solution, 12 mL, 19.1 mmol), followed by stirring for 10 minutes. After warmed to room temperature, the mixture was cooled to −70° C. again and a solution of 2-methyl-4-fluorobromobenzene (3.0 g, 15.9 mmol) in THF (4 mL) was added dropwise thereto. After stirring for 15 minutes, the mixture was added with DMF (1.9 mL, 23.8 mmol) and warmed to 0° C., followed by stirring for 20 minutes. The reaction mixture was added with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-bromo-2-fluoro-4-methylbenzaldehyde as a crude product. In a similar manner to Reference Example 2, 2-amino-6-bromo-7-methylquinazoline (2.0 g, 50%) was obtained using the above-obtained 5-bromo-2-fluoro-4-methylbenzaldehyde. In a similar manner to Reference Example 3 and Reference Example 4, Compound A11 was obtained using the above-obtained 2-amino-6-bromo-7-methylquinazoline.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[CH2:22].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Yield: 91 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004065367) and (2-vinylphenyl)boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 1 h; after cooling, EtOAc was added, and the solution washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The title compound was isolated by chromatography (PE/EtOAc 9:1) in 91% yield; MS (ES+) m/z 360 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (2.79 g, 10 mmol), ethynyltrimethylsilane (1.27 g, 13 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol), CuI (143 mg, 0.75 mmol), and diisopropylethylamine (1.94 g, 15 mmol) in DMF (10 mL) was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20% EtOAc/hexanes) to give a yellow solid (2.55 g, 86%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CCN(CC)CC.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][OH:1])=[O:18]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 0,250 mol) in CH2Cl2 (720 mL) under argon was added Et3N (38.0 mL, 0,273 mol). After cooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 0.251 mol) was added dropwise over 0.75 h maintaining the reaction temperature at -20°±3° C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacuo. An impurity which precipitated during concentration was removed by filtration. The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.37 (dd, J=8,3 Hz, 1H), 4.22 (qd, J=7,3 Hz, 1H), 4.08 (s, 2H), 3.71 (td, J=8, 3 Hz, 1H), 3.68-3.50 (m, 3H), 2.14-1.86 (m, 3H), 1.72-1.62 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetontrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p.=142°-143° C..
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: N#Cc1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: N#Cc1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Yield: 93.1 %

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-aminobenzo[b]thiophene-3-carbonitrile (4.0 g) and 2,5-difluoronitrobenzene (3.7 g), 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (6.7 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
3-Bromo-4-hydroxybenzaldehyde (250 mg) was dissolved in 5 ml of acetic acid. Nitric acid (52 μl) was added and the mixture was stirred for 3 h during which a solid formed. The solid was filtered off, washed with water and dried in vacuo.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+].[I-].[Na+].O>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][C:19]#[N:20])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: [C-]#N
Reactant: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole(6.5g.), sodium cyanide (1.1g) and dry sodium iodide (0.3g) were stirred together in dry dimethylformamide (50ml) for 20 hours at ambient temperature. The mixture was poured into water (500ml.), stirred for one hour and the brown solid filtered off, washed and dried (5.1g). This was recrystallised, with charcoaling, from 50% toluene/60-80 petrol ether (100ml.) To give the title compound as an off-white solid (3.4g) m.p. 118°C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=[O:13].[Na+]>O>[OH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 5 °C
Yield: 59.7 %

Procedure:
In a solution of 10 ml of concentrated sulforic acid in 30 ml of water was dissolved 10 g of 4-amino-2-chlorobenzoic acid, the solution was reacted under reflux for 1 hour, and the thus obtained solution was cooled to 5° C. Then, 4.6 g of sodium nitrite and 20 ml of water were added to the solution and the mixture was refluxed for 5 hours and cooled. The precipitated crystal was recovered by filtration and washed with water to obtain 6.0 g of 4-hydroxy-2-chlorobenzoic acid. Then, 3 g of this 4-hydroxy-2-chlorobenzoic acid was dissolved in an aqueous solution of sodium hydroxide, 10 g of n-dodecyl bromide was added to the solution, and reaction was carried out at 80° C. for 5 hours with stirring. The thus-obtained solution was put in ice-cooled hydrochloric acid. Precipitated 4-dodecyloxy-2-chlorobenzoic acid was recovered by filtration, washed with water, dried and dissolved in dichloromethane. Then, 2.0 g of p-benzyloxyphenol and 2.0 g of dicyclohexylcarbodi-imide were added to the solution, and reaction was carried out at room temperature with stirring overnight. The precipitate was recovered from the thus-obtained solution by filtration, concentrated and purified by the silica gel column chromatography to obtain 2.3 g of 4-benzyloxyphenyl 4-dodecyloxy-2-chlorobenzoate. This product was catalytically reduced in the presence of Pd/C as the catalyst under a hydrogen pressure of 1 kg/cm2 according to customary procedures to obtain 2.0 g of 4-hydroxyphenyl 4-dodecyloxy-2-chlorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[CH3:27]>CS(C)=O>[CH3:27][C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[C:22]([CH3:23])[C:17]=1[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1

Procedure:
A mixture of dimethylsulfoxide (875 ml), p-methoxyphenol (43.3g 0.3 48 mol), powdered potassium carbonate (69.9 g, 0.5 mol) and 4-chloro-3,5-dimethylnitrobenzene (see example 39, 64.6 g; 0.348 mol) is heated at a temperature of 125° for 18 hours. The suspension is cooled to 25° and pumped onto ice water (2620ml) with stirring. The mixture is stirred for 2 hours, the product is filtered, washed with water (4×300 ml) and air dried. A solution of the product in tert-butylmethyl ether (3L) is dried over magnesium sulfate and treated with charcoal (6.4g) for 2.5 hours. The drying agent is filtered off and the filtrate concentrated in vacuo at 50°/3mm Hg to give product which is recrystallized from toluene (212ml) and petroleum ether (600 ml) to give 3,5-dimethyl-4-(4'-methoxyphenoxy)-nitrobenzene, m.p. 120°-123°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH:11]([CH3:13])[CH3:12])([O-:10])=[O:9]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 97.8 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (0.5 mL, 4.7 mmol) in DMSO (10 mL) is added isopropylamine (0.6 mL, 7.1 mmol), followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. 16 h. The reaction is cooled to room temperature and is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (828 mg, 97%) as an orange oil.