Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.Cl[CH2:23][C:24]([CH3:26])=[CH2:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:25][C:24](=[CH2:23])[CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Temperature: 25 °C

Procedure:
To a solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (1.5 g, 5.34 mmol) in acetone (80 ml) is added 3-chloro-2-methylpropene (8 ml, 8.01 mmol), Cs2CO3 and a catalytic amount of Kl. The reaction is then refluxed for 24 hours. After this time the reaction mixture is cooled to ambient temperature and filtered. The filter cake is washed with acetone (3×50 ml) and the combined organics concentrated in vacuo. The residue is chromatographed (silica gel, 1:4 EtOAc/hexane) to give 6-(2-methyl-2-propenyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N+:17]([O-])=O>CO.[C].[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl (4-fluoro-3-nitrophenyl)methylcarbamate (1.0 g, 3.70 mmol) in methanol (4 mL) was added 10% palladium-carbon (150 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 18 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (0.88 g, 99%) as a brown oil.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[C:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 78.9 %

Procedure:
In a manner similar to that described in Example 3, octanoyl chloride (0.063 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.063 g of 4-[4-(octanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+320.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[C:10]([NH:14][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)ncc1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To 20 ml of acetonitrile were added 6.4 g of 2,4-dichloro-5-fluoropyrimidine and 7.0 g of t-butylamine, then the mixture was stirred at 50° C. for 20 minutes. The solution was concentrated under reduced pressure, and separated by adding 40 ml of distilled water and 70 ml of chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated pale yellow crystals were dispersed in diisopropylether and collected by filtration to obtain 4.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[N:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C@@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:17][CH:18]=1
Reactant: C[C@H](N=Cc1ccc(OCc2ccccc2F)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Temperature: 3.5 °C
Yield: 95 %

Procedure:
A mixture of (S)-2-[4-(2-fluorobenzyloxy)benzylideneamino]propanamide (IIIb) prepared as described above (30 g) and methanol (180 mL) is cooled under stirring to 2-5° C. Sodium borohydride (3.8 g) is added in eighteen small portions in 90 min to the previously prepared cold mixture keeping the temperature below 5° C. The mixture is then stirred for additional 10 min at 5° C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to provide 28.75 g (95% yield) of (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide, Ib) with a HPLC purity of 99.5 (area %) determined according to the method of Example 25A and a C,O-dialkylated (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide content less than 0.005% by weight determined by HPLC, according to the method of Example 25B.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH3:32])[C:14]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:30])[C:7]([O:9]CC)=[O:8].CO>C1COCC1>[CH3:32][C:13]1[CH:12]=[C:6]([CH:5]=[C:4]([CH3:3])[C:14]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][C:26](=[O:29])[CH2:27][CH2:28]2)[CH:20]=[CH:19][C:18]=1[CH3:30])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of ethyl 3,5-dimethyl-4-[[2-methyl-5-(4-oxo-1-piperidyl)benzoyl]amino]benzoate (0.11 g, 269.28 μmol) in THF:MeOH (2.4 ml:1.2 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 7 with 1N HCl, and extracted twice with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The resulting solids are triturated with 1:1 mixture of acetonitrile and ethanol to give white slurry that is filtered through Celite™ bed. The filtrate is concentrated under reduced pressure and the precipitate is triturated with acetone and filtered to afford the title compound as an off-white solid (99 mg, 99%). Mass spectrum (m/z): 381.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccc(F)c1F
Product: COc1ccc(/C(C#N)=C/c2cccc(F)c2F)cc1OC
Yield: 90 %

Procedure:
2,3-Difluorobenzaldehyde (426 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (813 mg, yield: 90%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[C:10]([OH:13])=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.N1CCCC1>C1COCC1>[CH3:14][C:15]([CH3:20])([CH3:19])[CH:16]=[CH:17][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[OH:13])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)(C)CC=O
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)C=CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
Lawsone (2-hydroxynaphthalene-1,4-dione) (1.4 g) and 3,3-dimethyl-butanal (1.0 g) were dissolved in 20 ml THF at room temperature and 795 μl pyrrolidine added before stirring the reaction for a further 20 minutes. The solvent was removed under vacuum and the residue dissolved in benzene (40 ml) before addition of p-toluenesulphonic acid (2.3 g). The mixture was refluxed for 1 hour, cooled then diluted with ether before the organic phase was washed with sodium bicarbonate solution, followed by one wash with dilute HCl and one wash with water followed by drying under vacuum. The product was purified by chromatograpy using 10% EtOAc/petroleum ether eluant and then crystallised from methanol to yield 260 mg; m.p. 126-128° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)([CH3:6])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[CH2:40]([NH:44][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:6])[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CN
Reactant: CC(C)(C(=O)O)c1nc(-c2ccccc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)CNC(=O)C(C)(C)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a solution of 2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanoic acid (example 41a) (307 mg, 1.32 mmol) in CH2Cl2 (10 mL) were added HOBt (196 mg, 1.45 mmol), EDCI.HCl (278 mg, 1.45 mmol) and isobutylamine (146 μL, 1.45 mmol). The reaction was stirred at room temperature under N2 for 18 h. Upon completion, the reaction was concentrated and purified by flash-chromatography (0-75% EtOAc in Hexane) to yield N-isobutyl-2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanamide (198 mg, 52%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 0.81-0.83 (d, 6H, J=6.7 Hz), 1.66 (s, 6H), 1.70-1.80 (sept, 1H, J=6.7 Hz), 2.89-2.92 (t, 2H, J=6.4 Hz), 7.56-7.61 (m, 3H), 7.92-7.95 (t, 1H, J=5.6 Hz), 8.01-8.03 (m, 2H). MS(M+H, 288).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15]CC1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(O)c1

Procedure:
To a solution of [4-methyl-2-(phenylmethoxy)phenyl]acetic acid tert-butyl ester (10.67 g, 34.2 mmol) in 125 ml of ethanol was added palladium block (200 mg), the mixture was hydrogenated (using a hydrogen balloon) at 30° C. for 10 hr. After the starting material disappeared completely (detected by TLC), the solid was filtered off, and the solvent was evaporated to give a crude product of (2-hydroxy-4-methylphenyl)acetic acid tert-butyl ester, 7.32 g, (96%) as white solid. 1H NMR (CDCl3) δ: 7.931 (1H, s, br), 6.955 (1H, d, J=7.56 Hz), 6.799 (1H, s), 6.688 (1H, d, J=7.81 Hz), 3.551 (2H, S), 2.299 (3H, s), 1.472 (9H, s) ppm.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 2H), 7.61 (s, 1H), 7.33 (dd, J=8.2, 1.4 Hz, 1H), 5.79 (d, J=7.8 hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.40 (d, J=16 Hz, 1H), 4.16-4.06 (m, 1H), 0.83 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][N:18]([CH:20]=[O:21])C>>[CH2:5]([C:17]1[N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[C:20](=[O:21])[CH:2]=[CH:3][CH:4]=1)[CH2:6][CH2:7][CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CN(C)C=O
Product: CCCCc1cccc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.17 h

Procedure:
1.12 g of potassium tert-butylate are added to a solution of 1.5 g of 6-butyl-1,2-dihydro-2-oxopyridine ["IIIa"; m.p. 69°; obtainable by condensation of hexan-2-one with ethyl formate in toluene, in the presence of NaOCH3, to give 1-hydroxyhept-1-en-3-one, condensation with cyanoacetamide in water, in the presence of piperidine and acetic acid, at 90°, to give 6-butyl-3-cyano-1,2-dihydro-2-oxopyridine ("IIIb"; m.p. 110°), hydrolysis with 37% hydrochloric acid (boiling for 5 hours) to give 6-butyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid (m.p. 149°) and decarboxylation at 180°-200°] in 25 ml of DMF. The mixture is stirred for 10 minutes, a solution of 2.72 g of 4'-bromomethyl-2-cyanobiphenyl ("IIa") in 15 ml of DMF is added dropwise over 30 minutes and the resulting mixture is stirred for 16 hours at 20°. It is evaporated, worked up in a conventional manner (pH 7; ethyl acetate) and purified by chromatography (silica gel; methylene chloride/methanol 98:2) to give 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine; Rf 0.4; (M+H)+ 343. 6-Butyl-2-(2'-cyanobiphenyl-4-yl-methoxy)pyridine is obtained as a by-product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[H-].[Na+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[N:13]=1>C(O)C>[OH:1][CH2:2][CH2:3][S:4][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[N:13]=1
Reactant: Clc1ccc2nccn2n1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: OCCSc1ccc2nccn2n1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
In 30 ml of ethanol is suspended 1.46 g of 2-hydroxyethylmercaptan. With ice-cooling, 897 mg of sodium hydride (oily, 60 wt.%) is added and the mixture is stirred for 10 minutes. Then, 1.91 g of 6-chloroimidazo[1,2-b]pyridazine is added and the mixture is stirred at room temperature for 6 hours. The solvent is distilled off under reduced pressure and the residue is shaken well with dichloromethane and water. The dichloromethane layer is separated and dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel (200 g) column chromatography and after the column is washed with ethyl acetate, elution is carried out with acetone. The fractions rich in the desired compound are pooled and the solvent is distilled off under reduced pressure. To the residue are added dichloromethane and isopropyl ether and the resulting pale-brown powder is collected by filtration. This procedure gives 500 mg of 6-(2-hydroxyethylthio)imidazo[1,2-b]pyridazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cc(N)ccc1OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OCc2ccccc2)c(OC)c1)C(=O)OCC
Temperature: 120 °C
Yield: 100.1 %

Procedure:
A mixture of 4-(Benzyloxy)-3-methoxyaniline (9.3 g, 40 mmol) and diethyl ethoxymethylenemalonate (9.65 g, 45 mmol) were heated at 120° C. for 1–1.5 h, the ethanol produced was removed under reduced pressure, affording 16 g (100% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)=[O:5])[CH3:2].Cl.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:22]3[C:21](=[C:20]([F:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:14]=2[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)c1cccc(SCC(C)=O)n1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 6-(2-oxo-propylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][C:13]=1[CH3:18])[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
18.31 g (100.0 mmol) of 2,5-dichloro-2,5-dimethylhexane, 17.10 g (100.0 mmol) of 2-bromotoluene and 200 ml of 1,2-dichloroethane are introduced into a three-necked flask under an argon atmosphere. 1.33 g (10.0 mmol) of aluminium chloride are added rapidly in a single portion and the reaction medium is stirred for thirty minutes at room temperature. The reaction medium is poured into water, extracted with dichloromethane and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. After recrystallization of the residue from methanol, 17.78 g (63%) of the expected compound are collected in the form of fine white crystals with a melting point of 73° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[CH2:29]1[C:37]2[C:32](=[CH:33][C:34](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:40](=[O:41])/[CH:39]=[CH:38]/[C:34]4[CH:33]=[C:32]5[C:37](=[CH:36][CH:35]=4)[CH2:29][CH2:30][CH2:31]5)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCC2
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCC3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-indan-5-ylprop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O2: 525 (M+H). Found: 525
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCOCC1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)CCC>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.C(OCC)(=O)C>[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(-c3cnccn3)cc2cn1)C1CC1
Yield: 54.8 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide 1 (42.8 mg, 0.147 mmol) and 1,4-Dioxane (1.5 mL, 19 mmol) was added 2-(tributylstannyl)pyrazine (51.0 uL, 0.162 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.0121 mmol). The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture is poured into ethyl acetate and washed with dilute NH4OH. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.4 mg (55%) of N-(7-(pyrazin-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.106, M+H=291.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.42 (s, 1H), 9.27 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 2.10 (s, 1H), 0.94-0.74 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: C[C@@H](N)CC(=O)OC(C)(C)C
Product: C[C@H](CC(=O)OC(C)(C)C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1,1-dimethylethyl (3R)-3-aminobutanoate using methods similar to Example 563 to provide an orange solid: ES+ MS: 581 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)#[N:2].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:26])=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[CH:5]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)no1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C(N)=O)no1
Reaction time: 0.08 h
Yield: 38.6 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(5-methylisoxazol-3-ylamino)phenylamino)-4-methylpentanamide (15 mg, 0.045 mmol) in DMSO (1 mL), K2CO3 (150 mg, 1.08 mmol) and H2O2 (50% aq., 0.800 mL) were added. After being stirred at 90 C for 5 min, the mixture was purified by HPLC to give the titled compound (6 mg). MS 346.3 (M+H); UV 203.5, 270.0, 293.4 nm
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=2)([OH:32])[CH2:27][CH2:28]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCOc1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Product: Cc1ccc(CC2(O)CCN(CCCOc3cccc(OCc4ccccc4)c3)CC2)cc1

Procedure:
The title compound, MS: m/e=446.5(M+H+), was prepared from 1-(3-bromopropoxy)-3-(phenylmethoxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.