Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20](OC)=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH3:27]>CO>[O:26]=[S:2]1(=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[C:9]([F:25])=[CH:10][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([NH2:27])=[O:21])[O:17][C:16]3=[O:24])=[CH:12][C:13]=2[F:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A solution of methyl(5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (Step 3, 0.090 g, 0.23 mmol) in methanol (2 mL) is treated with a solution of ammonia in methanol (2 mL of a 2.0M solution). The mixture is stirred for 1.5 h and concentrated. The residual solids are washed with methanol to provide 75 mg (86%) of the title compound as a white solid, MS (m/z) for C14H13F2N3O5S: [M+H]+=374; 1H NMR (300 MHz, d6-DMSO): δ 3.33-3.39 (m, 2H), 3.99-4.06 (m, 3H), 4.26 (t, 1H), 5.04-5.09 (m, 1H), 5.48 (d, 1H), 6.93 (d, 1H), 7.50 (d, 2H), 7.65 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1Cl)(=[O:4])=[O:3].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:16]([C:20]1[O:24][N:23]([C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(S(C)(=O)=O)cc2S(C)(=O)=O)o1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
After mixing 1 g of 2,4-bismethanesulfonylchlorobenzene, 1 g of 5-t-butyl-3-hydroxyisoxazole, 1 g of potassium carbonate, and 8 ml of dimethyl sulfoxide, the reaction was performed for 4 hours at 80° C. After the reaction was over, the reaction mixture obtained was poured into water and extracted with ethyl acetate. Then, the ethyl acetate was distilled off from the extract under reduced pressure and the residue thus formed was recrystallized from a mixture of water and methanol to provide 0.85 g of the desired compound with a yield of 61.2%. The melting point thereof was 166° C. to 168° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
A solution of 6-bromo-2-pyridinecarboxaldehyde (512 mg, 2.75 mmol) and 4-(triflouromethyl)benzeneboronic acid (522 mg, 2.75 mmol) in DME (46 mL) was treated a slurry of Na2CO3 (875 mg, 8.26 mmol) in water (23 mL) followed by Pd(PPh3)4 (64 mg, 0.06 mmol). The resulting mixture was then heated to reflux, under nitrogen over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt, was reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (100 mL), dried (MgSO4), filtered and reduced to give a yellow solid residue. Purification by SPE (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a yellow foam (565 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(F)cccc23)cc1
Yield: 61.9 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.088 g) as a white solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])[CH3:10])[CH3:7].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=1)[O:34][Si](C)(C)C(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.C1COCC1>[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH2:28][CH2:30][C:31]1[CH:32]=[C:33]([OH:34])[CH:42]=[CH:43][CH:44]=1)[CH3:10])[CH3:7]
Reactant: CCOC(C)n1c(C)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C)n1c(CCc2cccc(O)c2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
n-Butyllithium (3.89 g, 61mmol) in hexane (24.31 mL) was added dropwise to a stirred solution of 1-(1-ethoxyethyl)-2-methyl-4,5-diphenyl-1H-imidazole (l5.50 g, 51 mmol) in dry THF (300 mL) maintained at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 45 minutes and [3-(bromomethyl)-phenoxy]dimethyl(1,1-dimethylethyl)silane (l6.77 g, 50 mmol) added dropwise. After 10 minutes, the mixture was poured onto water, extracted with CH2Cl2, the extracts combined and dried over sodium sulfate. Evaporation of the solvent left an oil which was dissolved in THF (75 mL) and a solution of tetra-n-butylammonium fluoride (l7.22 g, 66mol) in THF (65 mL) added. The solution was stirred at room temperature for 30 minutes, the solvent evaporated and the residue diluted with water. After addition of 2N HCl solution (about 20 mL) to pH=5, the mixture was extracted with CH2Cl 2 The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual material chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexanes (1.0 gave 3-[2-[1-(1-ethoxyethyl)-4,5-diphenyl-1H-imidazol-2-yl]ethyl]-phenol (8.l8 g, 39%), mp 165.5°-167° C. after recrystallization from a mixture of CH2Cl2 and hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=2)[CH2:16][CH2:15]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:19]2[CH:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[NH:21][N:20]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (3.6 g, 16.3 mmol, 1.0 equiv.) and 5-cyclopropyl-1H-pyrazol-3-amine (3.0 g, 24.45 mmol, 1.5 equiv.) in EtOH (6 mL) was stirred at 20° C. under a nitrogen atmosphere for 10 min. The reaction mixture was filtered and the solid was washed by EtOH (10 mL) and MeOH (3 mL) to afford ethyl 2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (3.5 g, 70%) as a white solid. LC-MS (m/z)=308.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:26])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:26])[N:17]=2)[C:3]=1[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C(C)(C)c1c(O)cccc1F
Reactant: Fc1cccc2nc(Cl)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C(C)(C)c1c(F)cccc1Oc1cnc2c(F)cccc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
0.32 g of 3-(2-fluoro-6-hydroxy-phenyl)-3-methyl-butan-2-one and 0.28 g of 2-chloro-5-fluoro-quinoxaline were dissolved in 3 ml of dimethylformamide. 0.25 g of potassium carbonate were added thereto followed by stirring for 2 hours at 100° C. Subsequently, the reaction mixture was purified by silica gel column chromatography to obtain 0.14 g of 3-[2-fluoro-6-(5-fluoro-quinoxalin-2-yloxy)-phenyl]-3-methyl-butan-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=1)[C:12]#[N:13])=[O:6]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C=O)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc(C=O)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
step 3—A solution of 3-bromo-5-methoxy-benzaldehyde (1 mmol) in DMF (2 mL) is added to a round bottomed flask containing Zn(CN)2 (0.7 equivalents), Pd(PPh3)4(0) (0.2 equivalents) in DMF (15 mL). The reaction is stirred at 90° C. under an atmosphere of argon for 48 h. The reaction mixture is cooled and evaporated to dryness. The crude residue is dissolved in EtOAc, washed with brine solution, dried (MgSO4) and evaporated. The crude product is purified by SiO2 chromatography to afford 3-formyl-5-methoxy-benzonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])[O:20][N:19]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[C:21]1[O:20][N:19]=[C:18]([CH3:17])[N:22]=1)=[O:26]
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Product: Cc1noc(-c2ccccc2C(=O)N2CCCCC2Cc2nc3ccccc3s2)n1

Procedure:
The title compound (0.170 g) was prepared from 2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g), and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)benzoic acid (0.126 g) using the procedure described in Example 60.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][NH:6][C:7]#[N:8])[CH3:2].C(N(CC)CC)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][N:6]=[C:7]=[N:8][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH3:2]
Reactant: CCOC(CNC#N)OCC
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(CN=C=N[Si](C)(C)C)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-diethoxyethylcyanamide (5.5 g.) in anhydrous THF (100 ml.) at 0° was added triethylamine (6.29 ml.) and trimethylsilyl chloride (5.73 ml.). The reaction mixture was stirred at room temperature for 3 hours, the precipitated triethylamine hydrochloride removed by filtration under nitrogen and the filtrate concentrated. The residue was taken up in CCl4, the solvent evaporated and the residue was distilled at 80°/0.2 mm to give 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (6.5 g.) having the following n.m.r. in CDCl3 : 0.219 (s, 9H); 1.244 (t, 6H); 3.256 (d, 2H); 3.486-3.798 (m, 4H); 4.55 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1N.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(ON=O)(C)(C)C>[Cu]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: c1ccsc1
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cccs1
Temperature: 55 °C
Yield: 53.6 %

Procedure:
A stirred mixture of 38.1 g (0.23 mole) of 2-methoxy-4-nitroaniline and 38.1 g (0.6 mole) of copper powder in 953.0 g (11.33 mole) of thiophene was heated at 55° C. During a 1.1 hour period 40.5 ml (0.34 mole) of t-butylnitrite was added to the warm reaction mixture. After complete addition the mixture was heated at 70° C. for approximately 18 hours then cooled to room temperature. The solvent was removed from the reaction mixture by distillation under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with heptane:toluene (25:75), to yield 29.0 g of 2-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2NN=C(N)N=2)C[CH2:26]1>>[CH:1]1([C:2]2[N:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:26][CH2:25]1
Reactant: Nc1n[nH]c(C2CC2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Product: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-cyclopropyl-1,2,4-triazol-3-amine in the first step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(O)C>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(CCOc2ccc(N)cc2)CC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Into a Round bottom flask, 1-Methyl-4-[2-(4-nitro-phenoxy)-ethyl]-piperazine (3.89 g, 0.0147 mol), 10% Pd/C (10:90, Palladium:carbon black, 1.6 g, 0.0015 mol), and Ethanol (100 mL, 2 mol) were added. The mixture was evacuated under house vacuum and charged with a hydrogen balloon (3×). The reaction was stirred at room temperature under an atmosphere of Hydrogen via a balloon. The solid was filtered. The solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10%). The collected fractions afforded 4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenylamine as a red solid (2.35 g, 68%). NMR 1H (DSMO-d6-6.63 (dd, 2H, JJ=1.92, 4.72 Hz), 6.48 (dd, 2H, JJ=1.96, 4.72 Hz), 4.52 (bs, 2H), 3.89 (t, 2H, J=5.92 Hz), 2.59 (t, 2H, J=5.92 Hz), 2.44 (bs, 4H), 2.29 (bs, 4H), 2.13 (s, 3H)
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[C:29](Cl)(=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[F:6][C:7]1[CH:8]=[C:9]([CH2:10][CH:11]([NH:12][C:29](=[O:36])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CCCC/C=C/C(=O)Cl
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC/C=C/C(=O)NC(Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are added slowly and then, dropwise, 3.64 g (24.9 mmol) of trans-2-heptenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for 2 days. For working up, it is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aqueous sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with ether, and the combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue is washed by stirring with diethyl ether and filtered. The filter residue is isolated, the filtrate is concentrated and again treated with diethyl ether. After repetition twice, a total of 6.12 g (79% of th.) of product are obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]([NH2:26])=[N:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([O:15]CC2C=CC=CC=2)=[CH:7][C:6]=1[CH2:23][CH3:24].[H][H]>C1(C)C=CC=CC=1.[Pd].[C]>[NH2:26][C:2]([NH2:1])=[N:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([OH:15])=[CH:7][C:6]=1[CH2:23][CH3:24]
Reactant: CCc1cc(OCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCc1cc(O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
1.1 g of N-diaminomethylene-2-ethyl-4-benzyloxy-5-methylsulfonylbenzamide (obtainable according to Ex. 6) are dissolved in 30 ml of toluene and treated at room temperature for one hour with hydrogen gas (p=1 atm) under the catalytic action of 150 mg of Pd-carbon (Pd content 1%). The reaction mixture is then filtered, and customary working up gives N-diaminomethylene-2-ethyl-4-hyrdoxy-5-methylsulfonylbenzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (313 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C[O:24]B(OC)OC.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[OH:24]
Reactant: COB(OC)OC
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(O)c(F)c2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
In a nitrogen atmosphere, 10.00 g of 3,5-difluoro-1-(4-propylphenyl)benzene was dissolved in 50 mL of THF, and the resultant solution was cooled to −40° C. Then, 30 mL of butyl lithium (1.6 mol/L, hexane solution) was added at such a rate that the inside temperature did not exceed −35° C. After stirring at −40° C. for 1 hour, 5.37 g of trimethoxyborane was added at such a rate that the inside temperature did not exceed −35° C. After stirring at −40° C. for 1 hour, the inside temperature was increased to room temperature, and 10% hydrochloric acid was added until the reaction system became acidic. Then, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and cooled with ice, and 11.71 g of a 15% aqueous hydrogen peroxide solution was added to the mixture, followed by stirring at room temperature for 15 hours. Further, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and washed with a 10% aqueous sodium sulfite solution and saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to yield 10.24 g of 2,6-difluoro-4-(4-propylphenyl)phenol.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([C:41]([F:44])([F:43])[F:42])([O:10][C:11]([F:40])([F:39])[C:12]([F:38])([C:34]([F:37])([F:36])[F:35])[O:13][C:14]([F:33])([F:32])[C:15]([F:31])([C:27]([F:30])([F:29])[F:28])[O:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:7](F)=[O:8].Cl>>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:5])([C:41]([F:42])([F:43])[F:44])[O:10][C:11]([F:39])([F:40])[C:12]([F:38])([C:34]([F:35])([F:36])[F:37])[O:13][C:14]([F:32])([F:33])[C:15]([F:31])([C:27]([F:30])([F:29])[F:28])[O:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: Cl
Product: C=CCNC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Yield: 51.7 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 9.0 g of allyl amine (160 mmoles). The liquid was stirred and 40 g of 97% perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoyl fluoride (60 mmoles) was added dropwise. Dilute hydrochloric acid was added to the flask and the two phase mixture was transferred into a separatory funnel and the aqueous layer separated from the amide layer. The amide layer was washed again with dilute hydrochloric acid and twice with water. The amide layer was transferred into a round bottom flask and distilled at 101° C. and 3 mmHg to yield a fraction of 21.6 (52% yield) of >99% N-allylperfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanamide (31 mmoles).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]([O:27][CH3:37])=[O:26])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(NCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(NCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylamino]acetic acid (85.49, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.