Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3]1=[O:23].S(Cl)([Cl:27])(=O)=O.ClCCCl>C(Cl)Cl>[Cl:27][C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3](=[O:23])[N:2]([CH3:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nsc2ccc(-n3c(=O)c(Cl)c(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A mixture of 1-methyl-3-(3-methyl-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00293 mol), sulfuryl chloride (2.00 g 0.0148 mol) and 1,2-dichloroethane is stirred for five hours at reflux, cooled to room temperature, and diluted with methylene chloride. The resultant mixture is washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel with ethyl acetate/hexanes to afford the title product as a white solid (0.350 g, 31.8%, mp 252-254° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH:5]C(OC(C)(C)C)=O.C(O)CC.[BrH:32]>C(OCC)(=O)C>[BrH:32].[CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH2:5]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1Cl

Procedure:
1-[N-Methyl-(t-butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)pyrrole (24 g, 61.2 mmol) was dissolved in 100 ml of ethyl acetate, and 60 ml of n-propanol solution containing 12 ml of 48% HBr was added thereto with stirring. After 1 hour at 35° the solution was evaporated and the residue triturated with ether to give 23.2 g of powder. This powder was recrystallized from isopropanol-ether to give 22 g (96%) of flocculent crystals, m.p. 193°-195°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
To 2.5 mL (0.033 mol) of diisopropylamine dissolved in 50 mL of anhydrous tetrahydrofuran at 0° C. under argon was added dropwise 11.1 mL (0.028 mol) of a 2.5 M solution of n-butyllithium in hexanes over 30 min. After the mixture was stirred at 0° C. for 20 min and cooled to −78° C., 2 mL (0.0126 mol) of ethyl phenylacetate was added followed by stirring for 30 min. The resulting solution was treated with 1.61 mL (0.014 mol) of benzoyl chloride at −78° C. After being stirred at −78° C. for 1 h, the reaction mixture was added to 10 mL of saturated NH4Cl solution. The mixture was then diluted with ethyl acetate and washed with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water (1×) and then with saturated aqueous sodium chloride solution (1×). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 5-10% ethyl acetate/hexanes to give 1.2 g (36%) of 3-oxo-2,3-diphenylpropionic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][N:14](C(=O)[C@H](C3C=CC4C(=CC=C(OC)C=4)C=3)C)[CH2:13]1)[CH2:11][C:10]2=[O:37].O>CC(O)=O>[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:37]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)[C@@H](C)c3ccc4cc(OC)ccc4c3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
HCl 20% aq. (5 ml, 30 mmol) was added to a suspension of (+)-(E)-3-[1′-[(S)-2-(6-methoxynaphthalen-2-yl)propanoyl]-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (926 mg, 1.85 mmol) in glacial AcOH (5 ml). The mixture was stirred in the microwave oven at 120° C. for 3 h. Water (5 ml) was added and the reaction mixture was extracted three times with DCM. The aqueous phase was evaporated under vacuum. MeOH (25 ml) and a catalytic amount of H2SO4 were added and the mixture was heated to 70° C. overnight. The solution was poured into water and NH3 was added to adjust the pH value to 9-10. The aqueous phase was extracted with DCM, dried over Na2SO4 and filtered. The solvent was evaporated to give (+)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (210 mg) as a yellow oil (free base).
Reaction SMILES: C([O:3][CH:4]1[CH2:13][C:12]2[CH:11]=[CH:10][C:9]3[C:14]4[C:19]([CH:20]=[CH:21][C:8]=3[C:7]=2[O:6][CH2:5]1)=[CH:18][CH:17]=[CH:16][CH:15]=4)C.[OH-].[Na+].Cl(O)(=O)(=O)=O>>[OH:3][CH:4]1[CH2:13][C:12]2[CH:11]=[CH:10][C:9]3[C:14]4[C:19]([CH:20]=[CH:21][C:8]=3[C:7]=2[O:6][CH2:5]1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: CCOC1COc2c(ccc3c2ccc2ccccc23)C1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Product: OC1COc2c(ccc3c2ccc2ccccc23)C1

Procedure:
On other hand, 2-ethoxynaphthochroman 5a is photochemically stable and shows no decomposition even after prolonged irradiation at 254, 300 nm or 350 nm. The stability of 5a was measured in aqueous solution at pH˜7, 0.1N aqueous sodium hydroxide solution, and 0.1N aqueous perchioric acid for the 24 h period. HPLC analysis indicates that there are no changes in the concentration of 5a in aqueous solution of neutral pH and 0.1N aqueous sodium hydroxide solution. This observation clearly demonstrates that 5a is stable under neutral or basic conditions. 5a undergoes slow hydrolysis (life time τ˜9.5 h) in aqueous solution of perchloric acid of pH 1 to produce 2-hydroxynapthochroman (5e, FIG. 5). Besides, vinyl ethers are stable at ambient conditions and do not react in the dark.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][N:39]=[N+]=[N-])[CH3:11])=[CH:6][CH:5]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3](=[O:42])[C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 78 %

Procedure:
A solution of 4-({2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester (410 mg, 0.709 mmol) and 10% Pd/C (155 mg) in MeOH:CH2Cl2 (=7 mL:1 mL) was stirred under H2 atmosphere (1 atm) for 2 h 15 min. The reaction mixture was filtered through celite and rinsed with MeOH and CH2Cl2. Flash column chromatography (CH2Cl2 to 8% MeOH/CH2Cl2) of the residue gave the desired 4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester in 78% yield (305 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[OH:11][CH2:12][CH:13]([CH2:15]O)[OH:14]>COCCOC>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:14][CH:13]([CH2:12][OH:11])[CH2:15][O:4]1
Reactant: OCC(O)CO
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1

Procedure:
In a 4 L round bottom flask, hexafluoroacetone (99.7 g; 0.6 moles) was condensed at 0° C. into a well stirred solution of glycerol (55.3 g; 0.6 moles) in 500 mL of anhydrous ethylene glycol dimethyl ether. After the addition of hexafluoroacetone was complete, the solution was allowed to warmn to ambient temperature. Next, a solution of 1,3-dieyclohexylcarbodiimide (136.2 g; 0.66 moles) in 2 L of anhydrous ethylene glycol dimethyl ether was added slowly to the resulting hemiketal solution over a period of about one and a half hours. The combined solution was stirred for an additional hour and then the low boiling solvent was removed using a rotary evaporator. The remaining liquid was transferred to a 250 mL round bottom flask and the liquid heated with stirring at 100° C. for 1 hour. While continuing to heat the liquid, the product was isolated by vacuum distillation at 76° C. and 18 mm of Hg. The yield of product was 117 g which is 81% of the theoretical value.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][C@H:10]1[OH:25])=[O:7])([CH3:4])[CH3:3].[OH-].[Na+].S(OC)(O[CH3:32])(=O)=O.O>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][C@H:10]1[O:25][CH3:32])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Phenylmethyl (3R,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-1-piperidinecarboxylate (for a synthesis, see WO2004058144, Example 5 (b) cis-4-tertbutoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid benzyl ester, Enantiomer 1) (2.2 g, 6.28 mmol) in THF (12 ml) was treated with 50% sodium hydroxide solution (12 ml), benzyltriethylammonium chloride (0.04 g) and dimethyl sulphate (1.31 g, 10.43 mmol) and stirred at RT for 60 hours. Water (100 ml) was added and the product was extracted with ethyl acetate (150 ml). The organic phase was separated and dried. Filtration and evaporation to dryness gave the title compound (2.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[OH:12].[CH2:14]([Mg]Cl)[CH2:15][CH3:16]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:14][CH2:15][CH3:16])=[CH:6][C:5]=1[OH:12]
Reactant: COC(=O)c1ccc(C=O)cc1O
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OC)c(O)c1
Temperature: -78 °C

Procedure:
4-Formyl-2-hydroxy-benzoic acid methyl ester (360 mg, 2 mmol) is dissolved in THF (anhydrous, 10 mL). The solution is cooled to −78° C. and stirred under nitrogen. To this solution is added n-propyl-magnesium chloride (2M in THF, 2 mL, 2 mmol) dropwise via syringe. The reaction mixture is stirred at −78° C. for 1 hour, then gradually warmed to room temperature over 1 hour after which point, the reaction is quenched by adding saturated aqueous ammonium chloride. The resulting mixture is extracted with EtOAc (3×15 mL). The combined organic phase is washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the crude product is purified with silica gel flash column chromatography (10-20% ethyl acetate in hexanes gradient) to afford 2-hydroxy-4-(1-hydroxy-butyl)-benzoic acid methyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 6.95 (d, 1H, J=1.2 Hz), 6.86 (dd, 1H, J=1.6, 8 Hz), 4.67 (t, 1H, J=6.8 Hz), 3.94 (s, 3H), 1.82 (br, 1H), 1.80-1.62 (m, 1H), 1.46-1.28 (m, 2H), 0.93 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:6]([NH2:7])=[C:5]([F:13])[CH:4]=1.[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:6]([N:7]=[C:14]=[O:15])=[C:5]([F:13])[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 85 °C
Yield: 37.7 %

Procedure:
Dry HCl gas is passed into a solution of 66.7 g (0.35 mol) of 4-chloro-2-fluoro-5-nitroaniline in 1180 ml of toluene at 0° to 5° C. until the solution is saturated. 34.7 g (0.35 ml) of phosgene are subsequently metered in, and the mixture is heated slowly at 85° C. After a further 17.3 g (0.175 mol) of phosgene have been added and the mixture has been heated at 85° C. (1 h), the batch is flushed with nitrogen until free from phosgene and cooled. Removal of the precipitate by filtration and concentration gives 28.6 g (37.7% of theory) of 4-chloro-2-fluoro-5-nitrophenyl isocyanate of melting point 43°-46° C.; boiling point 125° C. at 0.3 torr (bulb-tube distillation).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[CH:14][N:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2ccnn2)nc1
Product: Ic1ccc2nc(-c3ccc(-n4ccnn4)nc3)cn2c1

Procedure:
The obtained 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine is allowed to react with 2-amino-5-iodopyridine in accordance with known methods (for example, the method described in a literature, Zhi-Ping Zhuang et al., J. Med. Chem., 2003, 46, p. 237-243), to obtain 6-iodo-2-[2-(1H-1,2,3-triazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 1, step 3).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23]([NH2:26])[CH:24]=[CH2:25]>ClCCl>[CH2:23]([NH:26][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:8])[C:18]=1[N+:19]([O-:21])=[O:20])[CH:24]=[CH2:25]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 105.2 %

Procedure:
Triethylamine (17.0 mL, 123 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (20.0 g, 82.3 mmol) in dichloromethane (350 mL) followed by the dropwise addition of allylamine (5.90 mL, 78.2 mmol). The solution was allowed to stir and warm to room temperature overnight. The solvent was evaporated under reduced pressure and the resulting orange solid was suspended in water (300 mL). Solid sodium carbonate was added to adjust the pH to 10-11 and the suspension was stirred for 2 hours at 0° C. A yellow solid was isolated by filtration and dried under vacuum overnight to yield N-allyl-2-chloro-3-nitroquinolin-4-amine (21.7 g) that contained small amounts of an impurity and water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[S:10][C:9]=2[C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.B1([O-])OO1.[OH2:26].[OH2:27].O.O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[N:13]=[C:14]([S:17]([CH3:18])(=[O:27])=[O:26])[N:15]=[CH:16][C:11]=3[S:10][C:9]=2[C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O
Reactant: CSc1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Temperature: 70 °C
Yield: 60.6 %

Procedure:
A mixture of 135 mg of 7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxamide and 293 mg of sodium perborate tetrahydrate in 5 ml of acetic acid is microwave-heated at 70° C. in a sealed tube for 1 h 30. The mixture is taken up with dichloromethane and 100 ml of a sodium thiosulfate solution. The pH is adjusted to pH 8-9 by adding solid potassium carbonate and the aqueous phase is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain a beige solid. This crude is purified on 40 g of silica, elution being carried out with dichloromethane, so as to obtain 90 mg of 7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>[Ni]>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: NNC(N)=S
Agent: [Ni]
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1I

Procedure:
Iodination of 4-aminobenzonitrile 30 with ICI produces 4-amino-3-iodobenzonitrile 31. Acetylatation of 4-amino-3-iodobenzonitrile 31 results in compound 32, which can be reduced with Raney nickel to form 4-acetamido-3-iodobenzaldehyde 33. Reaction of compound 33 with thiosemicarbazide yields 4-acetamido-3-iodobenzaldehyde thiosemicarbazone 34, as illustrated below.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)CC(C)C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 14, making variations only as required to use 4,4,4-trifluoro-3-methylbutyric acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white flaky solid (63% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.85, 7.00, 3.69-3.98, 3.67, 3.50, 3.00, 2.71, 2.35, 1.70, 1.50, 1.20, 0.95. MS (ES+) m/z 415 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH3:12]>>[NH2:12][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Product: Nc1ccnc(Cl)c1[N+](=O)[O-]
Yield: 71 %

Procedure:
A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of ammonia-saturated ethanol was stirred for four days at ambient temperature, then evaporated to dryness and the crude product thus obtained was purified by column chromatography (silica gel, eluant:dichloromethane with 0–5% ethanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:8]=[C:9]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])[CH:10]=1)[C:5](O)=[O:6].[Cl-].[NH4+].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[C:4]([CH:8]=[C:9]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH:17]([CH2:22][CH2:23][CH3:24])[CH2:16][C:15]=3[NH:14][C:13]([CH3:25])=[C:12]2[C:26]#[N:27])[CH:10]=1)[C:5]([NH2:41])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(N)=O)c1
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-benzyloxy)-benzoic acid (57 mg), ammonium chloride (18 mg), HATU (57 mg) and N,N-diisopropylethylamine (34 μl) in DMF (0.8 ml) was stirred for 17 h. The mixture was diluted with water and extracted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2.O.[NH2:18][NH2:19]>C(O)C>[NH:18]([C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2)[NH2:19]
Reactant: COc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1nc2ccc([N+](=O)[O-])cc2nc1NN
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 3.4 g (14.2 mmol) of 3-chloro-2-methoxy-6-nitroquinoxaline and 1.65 g (33 mmol) of hydrazine hydrate in 150 ml of ethanol was stirred at room temperature over night. The precipitate was collected and washed with water and cold ethanol to give 3.13 g (94%) of crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:7])([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([C:16]([F:19])([F:17])[F:18])[CH:10]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Br)c(C(F)(F)F)c1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1

Procedure:
A solution of 2-nitro-N-(4-bromo-3-trifluoromethylphenyl)benzamide (intermediate 1a; 32 g, 82 mmol) in methanol (1000 mL) is hydrogenated at atmospheric pressure over Raney nickel (6 g) at 21° C. The calculated amount of hydrogen is taken up after 7 hours. The mixture is filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by recrystallisation from diethylether-hexane to give the title compound as a colourless crystalline solid, m.p. 142–144° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[CH2:11]1[O:14][CH:12]1[CH3:13]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]([OH:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CC1CO1
Product: CC(O)COc1ccccc1C(C)C
Yield: 100 %

Procedure:
The title compound is prepared as described in Example 33, except that 2-isopropylphenol and propylene oxide are used as starting materials to give the crude product in a yield of 100%; Rf=0.1 (toluene).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(OCC)=O.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:29]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Reaction time: 0.08 h

Procedure:
2-Chloronicotinic acid (0.78 g, 5.0 mmol) and TEA (1.6 ml, 10.0 mmol) were added to anhydrous THF (50 ml) under a N2 atmosphere at 0° C. After stirring for 5 min, ethyl chloroformate (0.54 g, 5.0 mmol) was added dropwise and the mixture gradually came to RT over a period of 1 h. 4-Phenoxyaniline (0.83 g, 5.0 mmol) was added and the mixture was stirred for 14 h. The mixture was partitioned between H2O and EtOAc. The aqueous layer was extracted two additional times with EtOAc (50 ml). The combined organic layers were then washed with brine, dried over Na2SO4, and evaporated. The resulting brown oil was used directly in the subsequent reaction without further purification. MS m/z: 325 (M+1). Calc'd for C18H13ClN2O2: 324.07.