Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([NH2:8])[N:4]=1.[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][C:16]1[N:6]2[N:7]=[C:3]([S:2][CH3:1])[N:4]=[C:5]2[N:8]=[C:12]([C:11]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=2[Cl:9])[C:13]=1[C:14]#[N:15]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: CSc1nc(N)n[nH]1
Product: CSc1nc2nc(-c3ccc(Cl)cc3Cl)c(C#N)c(N)n2n1

Procedure:
According to the procedure of Example 1, Step A, commercial 5-(methylthio)-1H-1,2,4-triazol-3-amine and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted to give the title compound as a dark brown solid. LC-MS 351 (M+1).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>O.Cl>[C:26]([C:25]1[CH:24]=[N:23][N:22]2[CH:3]=[CH:4][C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[N:20][C:21]=12)#[N:27]
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: Cl
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccn3ncc(C#N)c3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (5.2 g, 0.02 mol) and 3-amino-4-cyanopyrazole (2.16 g, 0.02 mol) were dissolved in the mixture of water (50 ml) and concentrated hydrochloric acid (40 ml) and the mixture was stirred at room temperature for 8 h. The reaction mixture was then cooled to 5° C. and the precipitate was removed by filtration. The filtrate was neutralized by concentrated aqueous ammonia solution to precipitate 380 mg of the mixture of zaleplon and its regioisomer 4 which was collected by filtration. The filtrate was extracted with 100 ml of ethylacetate to give 100 mg of the mixture of the above two compounds upon evaporation. The two crops combined were put to a silica gel column (100 g) and the elution was performed by the solvent mixture of chloroform and acetone 3:1 (v/v) to yield as a second crop 240 mg (4%) of 4; mp 194-196° C.; 1H-NMR (CDCl3) δ (ppm) 1.143 (t, 3H), 1.876 (s, 3H), 3.804 (q, 2H), 7.361 (d, 1H), 7.532 (d, 1H), 7.613 (t, 1H), 8.018 (s, 1H), 8.159 ( d, 1H), 8.375 (s, 1H), 8.805 ((d, 1H); 13C-NMR (CDCl3) δ (ppm) 12.89, 22.68, 43.84, 83.17, 107.71, 112.84, 127.17, 127.48, 130.62, 131.63, 136.67, 137.46, 144.10, 148.31, 149.99, 158.60, 169.90; MS (EI, 70 EV) m/z (%) 305 (M+, 18), 248 (59).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)cc1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 15.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.17 g, 0.36 mmol) obtained in step 2 and ethanesulfonamide (0.20 g, 1.89 mmol), the title compound (0.03 g, 14%) was obtained.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22](O)[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[C:24]([O:26][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])[CH:23]=[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:21]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (7.05 g, 25.0 mmol) was added dropwise to a solution of 3,5-dihydroxyphenyl acetic acid methyl ester (1.80 g, 10.0 mmol) and pyridine (4.9 mL, 60.0 mmol) in DCM (20 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 4.0 g (89%), 1H NMR (CDCl3) δ 7.31 (d, 2H), 7.17 (t, 1H), 3.74 (s, 3H), 7.73 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:23][C:24]4([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:23][C:24]4([CH3:36])[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCN(C(=O)OC(C)(C)C)C5)c4n3)nn(C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCNC5)c4n3)nn(C)c2c1
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a stirred mixture of tert-butyl 3-(2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamido)-3-methylpyrrolidine-1-carboxylate (130 mg, 0.266 mmol) in dichloromethane (2.5 mL) was added drop-wise trifluoroacetic acid (2 mL) at room temperature and the reaction mixture stirred for 2 hours. The mixture was diluted with aqueous NaHCO3, filtered, washed with water and dried to give 2-(1,6-dimethyl-1H-indazol-3-yl)-N-(3-methylpyrrolidin-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 34%) as a pale solid.
Reaction SMILES: CC1C(C)CCC(C)C1=[O:10].[CH3:11][C:12](=[CH:14][CH2:15][CH:16]=[C:17]([CH3:20])[C:18]#[CH:19])[CH3:13].CC(=CCCC(=C)C#C)C>O>[CH3:11][C:12]([CH3:13])=[CH:14][CH2:15][CH2:16][C:17]([OH:10])([C:18]#[CH:19])[CH3:20]
Reactant: CC1CCC(C)C(C)C1=O
Reactant: C#CC(C)=CCC=C(C)C
Agent: C#CC(=C)CCC=C(C)C
Solvent: O
Product: C#CC(C)(O)CCC=C(C)C

Procedure:
A mixture of 28 g of 2,3,6-trimethyl-cyclohexanone and 27 g of the isomer mixture consisting of 2,6-dimethyl-oct-2,5-dien-7-yne and 2-methyl-6-methylene-oct-2-en-7-yne, obtained by elimination of water from 2-dehydrolinalool, is added dropwise to a suspension of 35 g of KOH in 200 ml of toluene at 0° C. The reaction mixture is then kept for 6 hours at 0° C, whilst being stirred, after which water is added and the organic phase formed is dried and concentrated. Subsequent fractional distillation gives 12.3 g of unconverted trimethylcyclohexanone and 12 g of a mixture of 2,3,6-trimethyl-1-(3',7'-dimethyl-oct-1'-yn-3',6'-dien-1'-yl)-cyclohexanol and 2,3,6-trimethyl-1-(7'-methyl-3'-methylene-oct-1'-yn-6'-en-1'-yl)-cyclohexanol of boiling point 125°-127° C/0.4 mm Hg as a viscous oil. This corresponds to a yield of 39%, based on ketone converted. Fragrance note: faintly floral, spicy, minty.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9](=[O:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCN(CC)CC.CO.CS(C)=O>[C:9]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9](=[O:25])[O:10]2)=[CH:15][CH:14]=1)([O:10][CH3:11])=[O:25]
Reactant: O=c1cc(-c2ccccc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1

Procedure:
A solution of 4-phenyl-7-trifluoromethanesulfonyloxycoumarin (1.75 g) and tetrakis (triphenylphosphine)palladium (0) (600 mg) in Et3N (1.3 mL), MeOH (15 mL) and DMSO (25 mL) was stirred under an atmosphere of carbon monoxide for 1 hr at 70° C. The mixture was then poured onto sat'd. NH4Cl solution, extracted with EtOAc, dried and evaporated. Chromatography on silica gel (30% EtOAc/hexane) yielded the title compound as a solid, m.p. 133°-135° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([C@H:28]([CH3:29])[CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:35][CH:34]=1
Reactant: C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 48.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.6 g, 8.2 mmol) was reacted with (S)-tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate (4.6 g, 12 mmol) to afford the desired product (1.9 g, 50%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:25]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[N:27]=[C:26]([NH:25][C@@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:28]=[CH:20][C:11]=3[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=N)N)C1
Reactant: CN(C)C=C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)C1
Yield: 89.2 %

Procedure:
This product was prepared from (S)-4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one (1.45 mmol) and (R)-tert-butyl 3-guanidinopiperidine-1-carboxylate hydrochloride salt (3.62 mmol) under the condition described in the general procedure 1 to afford (R)-tert-butyl 3-((S)-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)piperidine-1-carboxylate (0.68 g) as a light yellow solid. M.p.=85-87° C. 1H NMR 400 MHz (DMSO-d6) δ 8.29 (bs, 1 H), 8.12 (s, 1 H), 7.50-7.35 (m, 4 H), 7.08 (s, 1 H), 7.02-6.98 (m, 2 H), 4.39 (t, J=5.2 Hz, 1 H), 3.74 (bs, 2 H), 3.12-3.04 (m, 2 H), 2.90-2.84 (m, 2 H), 1.89-1.51 (m, 3 H), 1.38-1.24 (m, 11 H). LCMS m/e 525 (M+H).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([F:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([F:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2F)CC1
Yield: 91.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetic acid (0.15 g, 0.49 mmol), prepared from the step 4, and 1-methylpiperazine (0.049 g, 0.49 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-fluorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.173 g, 91.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(CO)cs2)cc1

Procedure:
The reaction described in Preparation 15 was repeated, but using 5.0 g of ethyl 2-p-anisidinothiazole-4-carboxylate, 1 5 g of lithium aluminum hydride and 100 ml of anhydrous tetrahydrofuran, giving the title compound as a pale red powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1C=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 2-nitrobenzaldehyde (50 g, 0.33 mol) in tetrahydrofuran (0.33 liter) was added dropwise to an aqueous solution (1.2 liters) of sodium dithionite (230 g, 1.32 mols) and sodium carbonate (1.68 g, 1.59 mols) under ice-cooling over a period of 2 hours while maintaining the internal temperature at 10° C. or lower. After 30 minutes, the reaction solution was extracted with ethyl acetate and the extract solution was washed with water and then dried over anhydrous sodium sulfate. The organic solvent was removed by concentration under reduced pressure to obtain the desired compound (26 g, 64%) as an yellow oil.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=3)[C:4]=2[CH2:3][O:2]1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:18](=[O:22])[C@@H:19]([CH3:21])[NH:20][C:24]4=[O:26])=[CH:15][CH:16]=3)[C:4]=2[CH2:3][O:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3COC4)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 134.6 %

Procedure:
A solution of N1-[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]-D-alaninamide (Intermediate 7, 80 mg) and TEA (0.187 ml, 1.341 mmol) in dichloromethane (10 ml) was stirred under argon at 0° C. Triphosgene (39.8 mg, 0.134 mmol) in dichloromethane (4 ml) was added and the mixture was left under stirring at 0° C. for 45 minutes. An aqueous saturated solution of NaHCO3 was then added. The phases were separated and the aqueous one was extracted 3 times with dichloromethane. The gathered organic phases were dried over sodium sulphate and concentrated under vacuum. The crude was purified by flash chromatography (FlashMasterPersonal), using as eluents a gradient Cyclohexane/Ethyl acetate from 100:0 to 40:60. This afforded the title compound as a white solid (58.5 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:21]([O:22][CH3:23])[CH3:20])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1.0 g, 4.0 mmol) in dichloromethane (10 mL) were added N,O-dimethyl hydroxylamine hydrochloride (0.77 g, 8.0 mmol), EDCl (1.2 g, 6.0 mmol), HOBt (0.05 g, 0.4 mmol), Et3N (0.8 g, 8.0 mmol) and the contents were stirred at ambient temperature. After 2 hr, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-tert-butyl(2-(methoxy(methyl)amino)-2-oxo-1-phenylethyl)carbamate. 1H NMR (300 MHz, CDCl3) δ 7.39-7.29 (m, 5H), 5.77 (bs, 1H), 5.73 (bs, 1H), 3.47 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1.[S:45]1[CH2:49][C:48](=[O:50])[NH:47][C:46]1=[O:51]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO.O>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[C:49]3[S:45][C:46](=[O:51])[NH:47][C:48]3=[O:50])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Dissolve (S)-2-tert-butoxycarbonylamino-3-(4-(4-formylphenoxy)phenyl)-propanoic acid methyl ester (3.05 Kg, 7.64 moles) in toluene (18 L). Add benzoic acid (144.9 g), piperidine (87.6 g) and 2,4-thiazolidinedione (1.11 Kg, 20.5) sequentially. Remove water azeotropically for 6 h. Check completion of the reaction by TLC (SiO2 gel, CHCl3-MeOH, 19:1). Distil off half of the solvent and cool down to room temperature, washed with 5% sodium bicarbonate solution, water, brine and dried over anhydrous sodium sulfate. Yield 3.80 Kg, 99.9%, chiral purity 100% ee. 1HNMR (300 MHz, CD3OD): 7.75 (s, 1H), 7.52 (d, J=9.0 Hz, 2H) 7.26 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.38 (m, 1H), 3.71 (S, 3H), 3.12 (dd, J=5.4 and 13.5 Hz, 1H), 2.85 (dd, J=9.3 and 13.5 Hz, 1H), 1.30 (s, 9H).
Reaction SMILES: O[C@@H]1CCCC[C@H]1NC(C1C(C(F)(F)F)=N[C:14]([O:21]CC2CC2)=[C:13]([C:26]2[CH:31]=[CH:30][C:29](Cl)=CC=2)[N:12]=1)=O.[OH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH:40][C:41]([C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][C:46](Br)=[C:45]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)[N:44]=1)=[O:42].C1(CO)CC1.N1C=CC=CC=1CO>>[OH:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH:40][C:41]([C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[N:47][C:46]([O:21][CH2:14][C:13]2[CH:26]=[CH:31][CH:30]=[CH:29][N:12]=2)=[C:45]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)[N:44]=1)=[O:42]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Agent: OCC1CC1
Agent: OCc1ccccn1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
In analogy to example 1 (6-(4-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) this compound was prepared by substituting 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide with 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide and cyclopropylmethanol with pyridin-2-yl-methanol.
Reaction SMILES: [F:1][C:2]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=[C:28]([F:43])[C:5]2=[N:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.C(O)(=O)C>C(O)C.[OH-].[K+]>[F:1][C:2]1[C:29]([N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:34][CH2:35]2)=[C:28]([F:43])[C:5]2=[N:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A suspension of 1.2 g of ethyl 7,9-difluoro-1-(2,4-difluorophenyl)-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate in 15 cm3 of ethanol and 16 cm3 of 1N aqueous potassium hydroxide solution was heated with stirring at a temperature around 80° C. for 2 hours. 10 cm3 of a 10% aqueous acetic acid solution were added, at approximately 80° C., to the solution obtained. The insoluble material was filtered off at this temperature, washed 2 times with 30 cm3 of water and recrystallized from a mixture of 12.5 cm3 of ethanol and 12.5 cm3 of dimethylformamide. 0.75 g of 7,9-difluoro-1-(2,4-difluorophenyl)-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 284-286° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[N:9]=2)[NH:4][C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[CH3:36][Zn]C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[N:9]=[C:10]3[C:2]([CH3:36])=[C:3]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[NH:4][C:5]3=[N:6][CH:7]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: C[Zn]C
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(Br)c3n2)cc(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(C)c3n2)cc(OC)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of 7-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 46, 20.0 mg, 37.3 μmol) and Pd(dppf)Cl2 (2.7 mg, 3.7 μmol) in 1,4-dioxane (0.8 mL), dimethylzinc (2.0 M in toluene, 47 μL, 94.0 μmol) was added at ambient temperature. The reaction mixture was then warmed up to 90° C. After 4 hours, the volatiles were removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (4.2 mg) as its TFA salt. LCMS calculated for C28H34N5O2 (M+H)+: m/z=472.2. Found: 472.2.