Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]3[S:30][CH:31]=[C:32]([CH:34]([CH3:36])[CH3:35])[N:33]=3)[CH:24]=[CH:23][N:5]2[C:6](=[O:22])[C:7]=1[C:8]1[N:9]=[N:10][N:11](CC2C=CC(OC)=CC=2)[N:12]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:1][C:2]1[N:3]=[C:4]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]3[S:30][CH:31]=[C:32]([CH:34]([CH3:36])[CH3:35])[N:33]=3)[CH:24]=[CH:23][N:5]2[C:6](=[O:22])[C:7]=1[C:8]1[NH:9][N:10]=[N:11][N:12]=1
Reactant: COc1ccc(Cn2nnc(-c3c(O)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2ccn3c(=O)c(-c4nnn[nH]4)c(O)nc3c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
2-Hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (30 mg) was added with anisole (0.15 ml) and trifluoroacetic acid (1 ml) and stirred at room temperature for 20 hours. After the solvent was evaporated under reduced pressure, the residue was added with methanol and toluene and the solvents were evaporated again under reduced pressure. The residue was added with methanol and methylene chloride, and the deposited crystals were collected by filtration to obtain the title compound (15 mg).
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CCCCCC.C(OCC)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]([NH2:6])=[NH:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
380 mL 1N LiHMDS-solution in n-hexane was added to 20 g 4-fluoro-benzonitrile in 1 L diethylether. The reaction was stirred for 2 h at RT and decomposed with 1 L 4 NHCL-solution at 0° C. 4 N sodium hydroxide was added until pH 12 was reached and the water layer was extracted with chloroform. The organic layer was dried and evaporated to give 6.6 g of the desired product. Rt: 0.30 min (method B), (M+H)+: 139
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2NN=[N:24][N:23]=2)=[CH:18][CH:17]=1.N1C=CC=CC=1>O>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Yield: 3487.1 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.39 g), 5-(4-trifluoromethylphenyl)-1H-tetrazol (1.50 g) and pyridine (30 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and purified by silica gel column chromatography (hexane:tetrahydrofuran=1:9, volume ratio) to give methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1. 85 g, yield 76%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 216–217° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.[NH:17]1[CH:21]=[N:20][C:19]([S:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[CH:30][CH:31]=2)=[N:18]1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:33][CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:24][CH2:23][S:22][C:19]3[N:20]=[CH:21][NH:17][N:18]=3)[CH:27]=2)=[O:14])[NH:3]1
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(OCCSc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 8 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (200 mg, 0.917 mmol), 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (298 mg, 1.19 mmol) and diisopropylethylamine (237 mg, 1.83 mmol) in ethanol (10 mL) was stirred at 90° C. for 15 hr. The reaction solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile-90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and the obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (29.2 mg, 8%).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([C:23]([C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]4)=[CH2:24])=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1>[Pd].C1COCC1>[F:35][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH:23]([C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]4)[CH3:24])=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: C=C(c1ncc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}cyclohexanecarboxylate (5 mg, 10.43 μmol) and palladium on carbon (5 mg, 10 wt %) in THF (10 mL) was stirred at 25° C. under a hydrogen atmosphere (45 psi) for 16 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure to afford methyl trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylate. MS ESI calc'd for C26H30F2N5O2 [M+H]+ 482. found 482.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1

Procedure:
Starting materials: (2-{(E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}phenyl)-carbamic acid tert-butyl ester (compound A8) (0.141 g), CH2Cl2 (10 ml), TFA (1 ml). Reaction conditions: room temperature, 20 hours.
Reaction SMILES: N([O-])=O.[Na+].C(O)(=O)C.N[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17]2)=[CH:12][CH:11]=1.[BrH:23]>S(=O)(=O)(O)O>[Br:23][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH:19]=1
Reactant: Br
Reactant: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ccc(Br)cc2c1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of NaNO2 (1.1 g, 24 mmol) in sulfuric acid (8.4 ml) was added at 0° C. acetic acid (8.9 ml) and 7-amino-2-nitro-naphthalene (2.1 g, 1mmol). This solution was added to a suspension of CuBr (2.5 g, 39 mmol) in conc. HBr (16 ml) at 0° C. and the mixture was stirred for 1 hour. The mixture was poured on ice and the aqueous phase was extracted with methylene chloride. The crude product was purified by chromatography to give 1.9 g (7.4 mmol, 51%) of the title compound, MS: m/e=251.2 (M+).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32]>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:33][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCC(C)C

Procedure:
In 35 ml of acetone is dissolved 1.0 ml of 4-methylvaleric acid, and 4.6 ml of 2N-NaOH and then 1.9 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added to the above solution. The mixture is refluxed for 6 hours. The acetone is distilled off under reduced pressure and 10 ml of water is added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is subjected to column chromatography, elution being carried out with 600 ml of diisopropyl ether-n-hexane (1:1). The eluate is evaporated under reduced pressure to remove the solvent, giving 1.3 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH:18]1([CH2:23][C:24](OC)=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+].Cl.[Cl-].[Na+]>C(O)C>[CH:18]1([CH2:23][C:24]2[NH:17][C:15](=[O:16])[C:3]3[CH:4]=[N:5][N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=4[CH3:14])[C:2]=3[N:1]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)CC1CCCC1
Reactant: Cc1cccc(-n2ncc(C(N)=O)c2N)c1C
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Product: Cc1cccc(-n2ncc3c(=O)[nH]c(CC4CCCC4)nc32)c1C
Temperature: 25 °C

Procedure:
0.1 g (0.43 mmol) of 5-amino-1-(2,3-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 16A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.7 mmol) of methyl cyclopentylacetate and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The mixture of sodium chloride and the product precipitated thereby is filtered off and washed several times with water and diethyl ether. Drying under high vacuum results in 69 mg (49% of theory) of the product as colourless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1.[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:27]\[S@@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])/[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(=N\[S@](=O)C(C)(C)C)C(F)F)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A mixture of 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone (0.666 g, 1.808 mmol), (R)-2-methylpropane-2-sulfinamide (0.219 g, 1.808 mmol) and tetraethoxytitanium (0.758 ml, 3.62 mmol) in THF (4.52 ml) in a sealed microwave vial was stirred at 80° C. for 3 h. After cooling to RT, the reaction mixture was poured into an ice-cold saturated NaCl solution, stirred for 10 min, and the precipitate was filtered through a pad of celite and washed with EtOAc. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were dried (MgSO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (0.481 g, 1.020 mmol, 56.4% yield) as dark-brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.[CH3:18][NH2:19]>>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([NH:19][CH3:18])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: O=C1CCCCN1c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc(N2CCCCC2=O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7b from 4-(2-oxo-piperidin-1-yl)-2-nitro-fluorobenzene and aqueous methylamine solution.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][Si](C(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:39][CH:38]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.CO>[OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[O:19])[CH2:16][CH2:17]2)=[CH:33][CH:34]=1
Reactant: COC(=O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)C)cc4)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 56.3 %

Procedure:
Methyl 2-{4-[({4-[4-(2-{[(2S)-2-hydroxy-3-(4-{[isopropyl(diphenyl)silyl]oxy}phenoxy)propyl]amino}ethyl)anilino]piperidinyl}carbonyl)amino]phenoxy}acetate (0.16 g, 0.192 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.64 g, 0.108 mmol)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[CH:11]=[CH2:12].CC(N)(C)CC(C)(C)C.C(O)(=O)C>[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)CC(C)(C)N
Solvent: CC(=O)O
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 4.68 g (20 mmol) of p-iodoanisole, 4.05 g (22 mmol) of 2-ethylhexyl acrylate, 2.84 g (22 mmol) of 1,1,3,3-tetramethylbutylamine, 1.32 g (22 mmol) of acetic acid and 32 mg of palladium on charcoal (5%) is stirred at 150° C. for 3 hours. After working up as in Example 1 there is obtained 2-ethylhexyl p-methoxycinnamate in 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C)CC2)c1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1(10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 94.0%).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]1[C:9](=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:23])[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=31)[O:8]2)(=O)C>S(=O)(=O)(O)O.C(O)C.O>[NH2:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]1[C:9](=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:23])[C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=31)[O:8]2
Reactant: CCOC(=O)c1c2oc3cc(NC(C)=O)ccc3nc-2c2ccccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c2oc3cc(N)ccc3nc-2c2ccccc2c1=O

Procedure:
The 9-acetamido-6-carbethoxybenzo[a]phenoxazin-5-one obtained in point 3.2 was dissolved in a mixture of sulfuric acid (3 ml) and ethanol (3 ml). The mixture was heated to 80° C. while at the same time gradually adding water (1 ml). The purple color characteristic of the amine rapidly appeared. The hydrolysis was continued until the sample, diluted with water, and then extracted in ethyl acetate, no longer showed any 9-acetamido-6-carbethoxybenzo[a]phenoxazin-5-one by thin layer chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:26]=[C:25](F)[CH:24]=[C:23]2[C:18]=1[C:19]([NH2:28])=[N:20][CH:21]=[N:22]2>CN(C=O)C>[NH2:28][C:19]1[C:18]2[C:23](=[CH:24][C:25]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:26][C:17]=2[F:16])[N:22]=[CH:21][N:20]=1
Reactant: Nc1ncnc2cc(F)cc(F)c12
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(F)c3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.61 mmol, 107.6 mg) is dissolved in 5 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil) (0.77 mmol, 30.8 mg) and the mixture is stirred at rt for 5 min. and then 5,7-Difluoro-quinazolin-4-ylamine (0.55 mmol, 100 mg) is added. The reaction is stirred at 50° C. for 22 h. The reaction is cooled and quenched by pouring into 100 ml sat. NH4Cl aq. and extracted 3 times with 20 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in CH2Cl2. 1-(4-Amino-5-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (35 mg, LC/MS m/z=339 [M+H]+) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1C=C(C=C(C)C=1O)C=O)[CH3:2].C(C1C=CC=C(C)C=1O)C.[CH2:23]([C:25]1[CH:26]=[C:27]([CH:32]=[C:33]([CH3:36])[C:34]=1[OH:35])[C:28]([NH:30][OH:31])=[NH:29])[CH3:24]>>[CH2:3]([O:35][C:34]1[C:33]([CH3:36])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=1[CH2:23][CH3:24])[CH:1]=[CH2:2]
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Agent: CCc1cccc(C)c1O
Product: C=CCOc1c(C)cc(C(=N)NO)cc1CC

Procedure:
The title compound is prepared by allylating 3-ethyl-4-hydroxy-5-methyl-benzaldehyde which is prepared from 2-ethyl-6-methyl-phenol following literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). The aldehyde is then transformed into the corresponding hydroxyamidine according to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.72 min; [M+1]+=235.09; 1H NMR (CD3OD): δ 7.31 (s, 1 H), 7.29 (s, 1 H), 6.10 (m, 1 H), 5.43 (dd, J=17.0, 1.5 Hz, 1 H), 5.27 (dd, J=10.3, 1.2 Hz, 1 H), 4.81 (s br, 3 H), 4.31 (d, J=5.6 Hz, 2H), 2.67 (q, J=7.6 Hz, 2 H), 2.30 (s, 3 H), 1.23 (t, J=7.6 Hz, 4 H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Br[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[N:22]=[C:18]([CH2:17][O:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=3)[S:19][C:20]=2[CH:26]=1
Reactant: COC(=O)Nc1ccc(O)cc1C
Reactant: COc1ccc2nc(CBr)sc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3ccc(OC)cc3s2)cc1C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
23 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 82 mg of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 5 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 15 minutes, and then 150 mg of 2-bromomethyl-6-methoxybenzothiazole [prepared as described in Example 6(a) above] were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 6 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 110 mg (yield 68%) of the title compound as a solid having a melting point of 123° to 125° C.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:10]=1/[N:11]=[CH:12]/[CH:13]([CH3:15])[CH3:14])[CH3:8].C([N-]C(C)C)(C)C.[Li+:29]>CCCCC>[CH2:7]([C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:10]=1[N-:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:8].[Li+:29]
Reactant: CCc1cccc(CC)c1/N=C/C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: CCCCC
Product: CCc1cccc(CC)c1[N-]C=C(C)C
Temperature: 50 °C

Procedure:
Benzene (70 mL) and compound 1 (6.63 g, 32.6 mmol) were combined. Then solid lithium diisopropylamide (4.01 g, 37.4 mmol) was added. The mixture was heated to 50° C. to form a cloudy red-orange solution. After a few hours the solution was filtered through diatomaceous earth to afford a clear yellow solution. The volatiles were evaporated to give a yellow solid. Pentane (15 mL) was added and the mixture was stirred briefly and then cooled to −10° C. overnight. The product was then collected on a glass frit and washed with pentane (2×20 mL) to give a white solid that was dried under reduced pressure. Yield: 5.50 g, 80.6%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: [H][H]
Reactant: OC/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCCc1ccc(Cc2cccnc2)cc1
Yield: 99.1 %

Procedure:
In 10 ml of ethanol was dissolved 500 mg of (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol, and to the resulting solution was added 100 mg of 5% palladium-carbon, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 2.5 hours. The reaction mixture thus obtained was filtered and the filtrate thus obtained was concentrated under reduced pressure to obtain 500 mg (yield 99.1%) of colorless, oily 3-[4-(pyridin-3-ylmethyl)phenyl]propanol.