Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-:36]=[N+:37]=[N-:38].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:31]([CH:33]3[CH2:35][CH2:34]3)=[N:38][N:37]=[N:36]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2ccc(-n3nnnc3C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
Trifluoromethane sulfonic anhydride (9.42 ml) was added dropwise over 10 min to a solution of cyclopropanecarboxylic acid(4-benzyloxy-phenyl)-amide (15 g) and sodium azide (3.64 g) in acetonitrile (250 ml) at 0°. The reaction mixture was stirred at room temperature under nitrogen for 16 h. 10% Aqueous sodium hydrogen carbonate (80 ml) was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×100 ml). The combined organic pads were dried over anhydrous sodium sulphate and concentrated in vacuo to give a brown oil. Purification by chromatography with ethyl acetate:isohexane (1:1) as eluant afforded the title compound (2.4 g) as a yellow solid, m.p. 118°.
Reaction SMILES: C(O[C:4](=[N:15][OH:16])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)C.[NH3:17]>C(O)C>[O:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:6]([CH2:5][C:4](=[N:15][OH:16])[NH2:17])=[N:7]1
Reactant: N
Reactant: CCOC(Cc1noc2ccccc12)=NO
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Temperature: 150 °C

Procedure:
In ethanol (35 ml) was dissolved 1,2-benzisoxazole-3-acetohydroximic acid ethyl ester (0.5 g) and the mixture was saturated with ammonia gas and then heated in a sealed tube at 150°C for 7 hours. The reaction mixture was distilled under a reduced pressure and the oily residue was subjected to silica gel column chromatography and eluted with 5 % methanol-chloroform. The eluates were collected and resulting crystallines were recrystallized from ethanol to give the desired compound (0.05 g). m.p. 160° to 162°C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:21]2[N:26]=[C:25](Cl)[N:24]=[C:23]([Cl:28])[C:22]=2[CH:29]=[O:30])[CH2:19][CH3:20])=[CH:16][CH:15]=1>O1CCCC1>[Cl:28][C:23]1[C:22]([CH:29]=[O:30])=[C:21]([N:18]([CH2:19][CH3:20])[C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:26]=[C:25]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:24]=1
Reactant: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1nc(Cl)c(C=O)c(N(CC)c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
Over five hours, at a temperature of -30° C., a solution of 9.28 g (0.127 mole) of diethylamine and 12.84 g (0.127 mole) of triethylamine in 80 ml of tetrahydrofuran was added dropwise to a solution of 40.0 g (0.121 mole) of 6-(4-chloro-N-ethylanilino)-2,4-dichloro-pyrimidine-5-carbaldehyde in 400 ml of tetrahydrofuran. The solution was then stirred for four hours at -30° C. and for two hours at 20° C., the triethylammoniumchloride was filtered off, and the filtrate evaporated in vacuo. After the filtrate was mixed by stirring with 120 ml of diethylether, 27.3 g of colorless crystals were obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:23][NH:24][CH3:25].O>C(O)CCC>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([N:24]([CH3:25])[CH3:23])[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: CNC
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCNc1nc(N(C)C)c2ccn(C)c2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (1.0 g, 4.5 mmol) (CXXIV) in n-butanol (20 mL) was added potassium carbonate (3.7 g, 27 mmol) and dimethylamine hydrochloride (1.0 g (22 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 120° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=6/1) to yield 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXVII, 800 mg, 76%) as a yellow solid. LCMS (ESI) m/z=234 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[C:18]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1.ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[C:18]([C:19]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Reactant: CCCCCC
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cccnc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.66 ml, 1.03 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (156 mg, 0.516 mmol) obtained in Example 98. At −78° C., the resulting mixture was stirred for 20 minutes, followed by the addition of 1,5-diiodopentane (0.092 ml, 0.619 mmol). The temperature of the reaction mixture was gradually elevated to room temperature, at which stirring was performed for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (72 mg, 38%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:19]=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[OH-:22].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([C:19]([OH:22])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carbaldehyde (1.00 g, 3.22 mmol) in methanol (40 mL) was added 1.0 M sodium hydroxide in water (16 mL, 16 mmol), followed by 1.0 M sodium hydroxide in water. After stirred at rt overnight, the mixture was slowly acidified to pH 5 with 1 N HCl, then extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dry under reduced pressure. The crude residue was used directly in next step (1.05 g, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[CH2:14][CH:15]=[O:16])([CH3:3])[CH3:2].[CH2:17]1C(=O)N(Br)C(=O)C1.C1(S(O)(=O)=O)C=CC=CC=1>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH:11]([CH3:12])[CH3:13])[C:5]=1[CH:14]([CH3:17])[CH:15]=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1CC=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)cc(C(C)C)c1C(C)C=O
Yield: 70.4 %

Procedure:
To a dry DMF solution of 2,6-diisopropyl-4-bromophenylacetaldehyde (7.3 g, 25.8 mmol) at 0° C. was added 2,6-ditert-butyl-4-methylphenol (0.056 g, 0.26 mmol), followed by NBS (4.59 g, 25.8 mmol). After stirring for few minutes, benzenesulfonic acid (8.16 g, 51.6 mmol) was added. The resulting mixture was stirred at 35° C. for 12 h under nitrogen. After regular work up, the crude product was purified by column chromatography to afford 2-(2,6-diisopropyl-4-bromophenyl)propionaldehyde (5.4 g).
Reaction SMILES: ON=[C:3]([CH3:18])[C:4](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:19](=O)([O-])[O-].[K+].[K+].C.CI>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]2[N:13]=[N:14][C:15]([S:16][CH3:19])=[N:17][C:3]=2[CH3:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nnc(SC)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of 2-hydroxyimino-4'-methoxypropiophenone thiosemicarbazone (5.32 g), potassium carbonate (6.35 g) and water (50 ml) was treated in a similar manner to that of Example 25-(2), and then treated with activated charcoal. To the filtrate was added methyl iodide (6 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, treated with silica gel, and filtered. The filtrate was concentrated to dryness to give a residue, which was crystallized from diisopropyl ether. The resultant crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-(4-methoxyphenyl)-5-methyl-3-methylthio-1,2,4,-triazine (2.42 g).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C([O-])(O)=O.[Na+]>O1CCCC1>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CO
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
30 ul of boron trifluoride etherate were added to a suspension of 216 mg (1.15 mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 400 mg (2.3 mmols) of freshly prepared tert.-butyl 4-hydroxyacetoacetate in 4 ml of anhydrous tetrahydrofuran at room temperature. After a short time a clear, light yellow solution formed, which was stirred for 0.5 hour at room temperature. It was then poured into dilute NaHCO3 solution. The mixture was extracted with methylene chloride, washed with water and dried over magnesium sulphate. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 1:3), 128 mg (31%) of tert.-butyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]acetoacetate were obtained as colorless crystals, melting point: 142° C., RF : 0.36 (toluene:ethyl acetate 1:4), [α]D20 =32.24° (0.955 percent in CHCl3).
Reaction SMILES: Cl.O[C:3]1[N:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][N:7]=1.C[O-:22].[Na+]>CO>[OH:22][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)[CH2:8][N:4]1[CH:5]=[CH:6][N:7]=[CH:3]1
Reactant: CS(=O)(=O)Nc1ccc(CCn2ccnc2O)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(O)Cn2ccnc2)cc1

Procedure:
Heat a mixture of 30.83 g (0.097 mole) of (±)-1-[2- hydroxy-2-[4-((methylsulfonyl)amino)phenyl]ethyl-1H-imidazole hydrochloride and 5.24 g (0.097 mole) of sodium methylate in 100 mL of methanol and filter hot through 300 g of alumina (Fisher, neutral, activity III). Wash the alumina with 20% methanol in methylene chloride (200 mL). Concentrate the filtrate in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[C@H:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)[NH2:8]
Reactant: CO
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(F)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.8 g (10 mmole) of 4-fluorophenylalanine is suspended in 3.0 ml of methanol and cooled to -10° C. under nitrogen and 0.81 ml of thionylchloride added dropwise, keeping the temperature at or below -2° C., and stirred for 1 hour at -5° C. to -10° C. About 10 ml of methanol was added and the solution stirred at room temperature overnight. The solution was concentrated in vacuo and the residue triturated with dry ether and filtered to give the hydrochloride salt of 4-fluorophenylalanine methyl ester, m.p. 177.5° to 178° C. The ester hydrochloride is substituted for L-phenylalanine methyl ester hydrochloride in the procedure of Example 6a to yield 6b.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@@H:4]([CH3:25])[O:3]1.[NH:26]1[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]1=[O:34]>CS(C)=O>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:25])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:30]1([C:29](=[O:33])[NH:28][C:27](=[O:34])[NH:26][C:31]1=[O:32])[CH2:22]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@@H](C)O1
Solvent: CS(C)=O
Product: C[C@@H]1CN2c3c(cc4c(-n5cncn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 150 °C
Yield: 43.9 %

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1H-1,2,4-triazol-1-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 574, 500 mg, 1.45 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (185 mg, 1.45 mmol) in DMSO (6 ml) was heated at 150° C. for 2 hours in a microwave reactor. The reaction mixture was purified by Super Critical Fluid chromatography on a Chiralpac IC column with a 35% MeOH, 65% CO2 mobile phase to give 290 mg of product as a solid as the first eluting compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:20][CH:19]=3)[CH2:25]2)=[O:33])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CC3)C2)cn1
Yield: 63 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using cyclopropylamine instead of methylamine, to the title compound (52 mg, 63%) which was obtained as a white solid. MS: m/e=490.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([C:12]([F:13])([F:14])[F:15])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.80 g (39.7 mmol) N-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide were added to 60 mL 97% sulphuric acid while cooling with ice. 6.60 mL (95.3 mmol) nitric acid were slowly added dropwise to this mixture at 0° C. and with constant stirring. After the addition had ended the mixture was stirred for 30 min at 0° C. Then the cooling was removed and the reaction mixture was stirred for a further 1.5 h to complete the reaction. The reaction mixture was carefully poured onto 500 g ice and stirred for 30 min. The precipitate formed was filtered off, washed with 150 mL water and dried i. vac.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:33])=[CH:11][C:12]([F:32])=[C:13]([CH:31]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][OH:30])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[F:32][C:12]1[CH:11]=[C:10]([CH3:33])[C:9]([OH:8])=[CH:31][C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][OH:30])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: [H][H]
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCO
Yield: 42.2 %

Procedure:
A mixture of 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (150 mg, 0.33 mmol), (prepared as described for the starting material in Example 13), and 10% palladium-on-charcoal catalyst (20 mg) in ethyl acetate (8 ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and most of the solvent removed by evaporation and hexane added to the residue. The resulting precipitate was collected by filtration and dried to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (50 mg, 41%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[C:15]([NH:17][C:18](SC)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]>>[C:15]([NH:17][C:18]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COCCN=C(NC#N)SC
Product: COCCN=C(NC#N)NCCSCc1ccc(CN(C)C)o1
Yield: 41.3 %

Procedure:
A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and N-cyano-N'-(2-methoxyethyl)-carbamimidothioic acid, methyl ester (1.73 g) was heated on a steam bath for 6.5 hr. Vacuum was applied occasionally to remove methanethiol. The crude product was purified by chromatography (silica gel/methanol) to give N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-methoxyethyl)guanidine (1.4 g). Analysis Found: C, 50.51; H, 7.20; N, 19.41, C15H25N5O2S.H2O requires: C, 50.42; H, 7.50; N, 19.60%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]>C(O)(=O)C.ClCCl.[Zn]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:22](=[O:24])[CH3:23])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(OCc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reaction time: 3 h
Yield: 536.6 %

Procedure:
Add zinc (21.6 g, 331 mmol) slowly to a solution of 1-[2-hydroxy-4-(3-nitro-benzyloxy)-3-propyl-phenyl]-ethanone (10.9 g, 6.07 mmol) in glacial acetic acid (120 mL). Stir the mixture for 3 hours. Dilute with dichloromethane (600 mL). Filter the reaction mixture through celite. Wash the celite pad several times with dichloromethane. Concentrate the combined filtrates. Partition the residue between ethyl acetate and saturated sodium bicarbonate. Wash the organic layer with brine, dry and concentrate to afford the title compound as a yellow solid (9.75 g, 98%): 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.58 (sextet, 2H), 2.54 (s, 3H), 2.71 (t, 2H), 5.07 (s, 2H), 6.46 (d, 1H), 6.62 (d, 1H), 6.71 (s, 1H), 6.78 (d, 1H), 7.16 (t, 1H), 7.54 (d, 1H), 12.75 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=3)[CH:29]=1)=[CH:17]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.47 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 7 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from methanol gave the product (300 mg), mp 195-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[C:41](N(C)C)=[N+:42](C)[CH3:43])C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:41][N:42]([CH3:43])[C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 12 h
Yield: 99.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), dimethylamine hydrochloride (156 mg, 2 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 50 mL of ethyl acetate, and washed successively with saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 22a (362 mg) as a light yellow solid. The product was used directly in the next reaction without purification.