Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:17])[C:11](O)=[O:12])=[CH:5][CH:4]=1.[NH2:29][C@@H:30]([CH2:37][C:38]1[CH2:42][CH2:41][CH2:40][CH:39]=1)[C:31]([C@@:33]1([CH3:36])[CH2:35][O:34]1)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:38]1([CH2:37][C@H:30]([NH:29][C:11](=[O:12])[C@@H:10]([NH:14][C:15](=[O:28])[C@@H:16]([NH:18][C:19](=[O:27])[CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH3:17])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:31]([C@@:33]2([CH3:36])[CH2:35][O:34]2)=[O:32])[CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCC2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of (S)-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (850 mg, crude) and (S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 200 mg, 0.680 mmol) in DCM (10 mL) was added HATU (283 mg, 0.750 mmol). The mixture was cooled to 0° C. and basified with DIEA to pH=8. The reaction mixture was stirred at ambient temperature for 30 min and water (30 mL) was added. The resulting mixture was extracted with DCM (30 mL×2) and the extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1 to 1:2, then DCM/methanol=70:1) to afford (S)-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (170 mg, 18%) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ7.29 (br. s, 1H), 7.16 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.74 (d, J=7.2 Hz, 1H), 6.10 (d, J=7.2 Hz, 1H), 5.33 (s, 1H), 4.56-4.44 (m, 2H), 3.80 (s, 3H), 3.75-3.73 (m, 4H), 3.29 (d, J=4.8 Hz, 1H), 3.00-2.91 (m, 5H), 2.53-2.47 (m, 5H), 2.27-2.16 (m, 5H), 1.90-1.81 (m, 1H), 1.73 (s, 3H), 1.37 (d, J=7.2 Hz, 3H). MS (EI) for C30H42N4O7, found 571.4 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:16][C:15]1=[O:23]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:16]1[C:17]2[C:22](=[N:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:15]1=[O:23])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(=O)OC(C)(C)C)[N:16]=[N:17][C:18]=3[C:19](=[O:21])[NH2:20])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:16]=[N:17][C:18]=3[C:19]([NH2:20])=[O:21])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3nccn3)n2)c(C(N)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2nccn2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(5-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (79 mg, 160 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (364 mg, 246 μL, 3.19 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with dichloromethane and 1 N NaOH (2 mL), and then washed with NaHCO3 and brine. The organic layer was dried over MgSO4, then filtered and concentrated in vacuo. The mixture was dissolved in ethanol and concentrated (3×). The residue obtained was triturated with ether and finally filtered to give 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridazine-3-carboxamide (5 mg, 10.8 μmol, 7%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 8.46 (s, 1H), 8.38 (s, 2H), 7.99 (t, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.94 (s., 1H), 1.35-1.85 (m, 8H), 1.46 (m, 2H); MS (EI/CI) m/z: 395.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.CO.O[Li].O.Cl>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (5.0 g, 0.025 mol) in 2:2:1 MeOH:THF:H2O (50 mL) was added LiOH.H2O (5.14 g, 0.128 mol). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo to obtain the crude product. The crude material was acidified with HCl (1N) to pH 2 and then the product was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (4.05 g, 94%) as a solid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:31]=[CH:30][C:23]([CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(Cc2nnn[nH]2)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(Cc3nnn[nH]3)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 5-(4-bromobenzyl)-1H-tetrazole (53.2 mg, 0.223 mmol), Na2CO3 (79 mg, 0.742 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.313 mg, 1.855 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 130° C. for 120 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=348.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.5 Hz, 0.4H), 1.46 (d, J=6.6 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.02-2.11 (m, 2H), 2.22-2.33 (m, 1H), 3.05-3.21 (m, 4H), 3.36-3.48 (m, 1H), 3.52-3.62 (m, 1H), 3.72-3.83 (m, 1H), 4.36 (s, 2H), 7.36-7.44 (m, 4H), 7.61-7.67 (m, 4H).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([CH2:20][O:21][C:22](=[O:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1COC(=O)c1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccc(OC)cc3)cccc2c1=O
Yield: 53.7 %

Procedure:
Ethyl 2-butyryl-3-(2-(4-methoxybenzoyloxymethyl)-phenylamino)acrylate (12.2 g, 28.7 mmol) was added in portions to boiling diphenyl ether (200 ml), then heated at reflux for 30 minutes. Most of the diphenyl ether was distilled off in vacuo, and the residue triturated with ether to give 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone (5.85 g, 54%), m.p. 156°-162°.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:34]O>>[CH3:34][O:2][C:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH:8]([OH:24])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)=[O:3]
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(=O)O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1OCC(O)CN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C

Procedure:
A solution of crude 1-(2-carboxyphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol (43 g.) in 250 ml. of methanol containing 25 ml. of concentrated sulfuric acid was refluxed for 1.5 hours and then allowed to cool to room temperature. Upon completion of this step, the resulting solution was concentrated in vacuo to a volume of approximately 100 ml., then poured into 250 ml. of water and made alkaline with aqueous sodium hydroxide solution. The latter basified solution was next thoroughly extracted with chloroform, and the chloroform extracts subsequently combined and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were ultimately obtained 34 g. of crude product as residual material. Crystallization of a portion of the latter material from methanol then gave pure 1-(2-methoxycarbonylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol, m.p. 127°-128°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]=[CH2:20])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].N#N>CCCC[N+](CCCC)(CCCC)CCCC.[I-].C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:20]=[CH:19]/[CH2:18][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:11])=[CH:24][CH:23]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reactant: Brc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
A solution of cyclopentyl(2S)-2-[(tert-butoxycarbonyl)amino]pent-4-enoate (0.88 g, 3.11 mmol), 1-bromo-4-iodobenzene (0.966 g, 3.42 mmol), TBAI (1.262 g, 3.42 mmol) and NaHCO3 (0.783 g, 9.32 mmol) in acetonitrile (10 ml) was purged with N2 and palladium acetate (0.070 g, 0.311 mmol) was added. The reaction was then heated at 70° C. overnight. LCMS showed incomplete conversion and so the reaction was purged with nitrogen again and a further 0.05 eq (35 mg) of Pd(OAc)2, 0.25 eq (460 mg) of TBAI and 0.25 eq of NaHCO3 (65 mg) was added and stirred for another 24 hr at 70° C. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was absorbed onto silica and purified by column chromatography eluting with 10% EtOAc in iso-hexane. Yield=715 mg, 1.631 mmol, 52.5% yield. LCMS purity>90%: m/z 438 and 440 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:17]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[CH:18]=[CH2:19]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C=CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
2.0 g (12.61 mmol) of 2-chloro-5-nitropyridine were dissolved in 8 ml of dimethylformamide, and 3.49 g (25.23 mmol) of potassium carbonate were added. After that, a solution of 1.75 g (13.88 mmol) of N-allylpiperazine in 2 ml of dimethylformamide was added slowly dropwise to the reaction mixture (exothermic reaction). The reaction mixture was then stirred at room temperature for 2 hours. After the solvent had been concentrated down to dryness, the resulting residue was stirred up in 100 ml of heptane. The precipitate which remained was filtered off with suction. The filtrate was concentrated, resulting in 720 mg of the title compound. The precipitate which had been filtered off with suction was treated with 150 ml of water and extracted three times with diethyl ether. The organic phase was washed with a saturated solution of sodium chloride and dried over sodium sulfate. A further 2.24 g of the title compound were isolated after the solvent had been filtered and concentrated down to dryness. The total yield of 1-allyl-4-(5-nitropyridin-2-yl)piperazine was 2.96 g (95% of theory).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([O:13][C:14](=O)[C:9]=12)=[O:12].O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[OH:12][CH2:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([Cl:7])[C:9]=1[CH2:14][OH:13]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCc1cccc(Cl)c1CO

Procedure:
To a suspension of 5 g of lithium aluminium hydride in 50 ml of dry diethyl ether was added dropwise with stirring a solution of 10 g (54.8 mmole) of 3-chlorophthalic anhydride in 120 ml of dry tetrahydrofuran. After heating under reflux for 6 hours, the mixture was cooled and treated carefully with 5 ml of water, 5 ml of 10% sodium hydroxide solution and 10 ml of water. The solution was filtered, the filtrate was dried over magnesium sulphate, filtered and evaporated to yield the title compound as a colourless waxy solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:47])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[C:23]([F:46])[CH:22]=2)=[CH:14][C:13]=1[C:48]([F:51])([F:50])[F:49])(C(C)(C)C)(C)C.Cl>>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([CH3:52])([CH3:53])[CH2:9][OH:8])=[C:13]([C:48]([F:50])([F:51])[F:49])[CH:14]=3)=[O:47])=[CH:22][C:23]=2[F:46])[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c3)cc2F)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO)c(C(F)(F)F)c3)cc2F)c[nH]c1=O
Yield: 55.3 %

Procedure:
A solution of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoro methyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl) acetamide (100 mg, 0.132 mmol) in HCl (MeOH, 5 mL, 20.00 mmol) was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The crude product was purified by preparative HPLC to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl) acetamide (37.98 mg, 0.073 mmol, 55.1% yield): 1H NMR (400 MHz, CD3OD) 7.94 (d, J=2.2 Hz, 1H), 7.70 (dd, J=2.0, 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 3H), 7.28-7.21 (m, 2H), 4.15 (m, 2H), 3.75 (s, 2H), 3.29 (broad s, 2H), 2.77 (s, 2H), 1.46 (t, J=6.9 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521.2 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].C([O-])(=O)C.[Na+].C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([C:10]1[CH:9]=[C:8](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])[CH:15]=[CH:14][CH:13]=1)#[N:12]
Reactant: N#Cc1cccc(Br)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc(C#N)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
7.31 ml (74.5 mmol) of methyl acrylate, 13.6 g (74.5 mmol) of 3-bromobenzonitrile and 6.6 g (74.5 mmol) of sodium acetate are suspended in 100 ml of DMF and heated at 120° C. for 30 min until a clear solution has formed. Then a solution of 4.0 g of palladium acetate and 21.0 g of tri-p-tolylphosphine in 5 ml of DMF is added dropwise to the reaction solution, and the mixture is stirred at 120° C. for 2 h. The reaction solution is then diluted with 500 ml of water, and the resulting precipitate is filtered off with suction. Drying under high vacuum and recrystallization from ethyl acetate/petroleum ether result in 12.6 g of the title compound. The mass spectrum shows the molecular peak MH+ at 187.7 Da.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:16])=[N:6][CH:7]=1.[F:30][C:31]([F:36])([F:35])C([O-])=O.[K+].C1(C)C=CC=CC=1.O.CCOCC>CN(C)C=O.[Cu](I)I>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[S:20][C:19]([CH3:29])=[N:18][C:17]=2[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[CH2:9][NH:8][C:5]2[N:4]=[CH:3][C:2]([C:31]([F:36])([F:35])[F:30])=[CH:7][N:6]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H]2CNc2ncc(Br)cn2)c(-c2ccc(F)cc2)s1
Reactant: O=C([O-])C(F)(F)F
Agent: I[Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1nc(C(=O)N2CCC[C@H]2CNc2ncc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Yield: 0.3 %

Procedure:
To the compound from Example 194 (0.36 g) in dimethylformamide (5 ml) was added potassium trifluoroacetate (0.23 g), copper iodide (0.3 g) and toluene (5 ml) and the resulting mixture heated at reflux under Dean-Stark conditions for 3 h, before refluxing for a further 20 h. The reaction mixture was cooled, poured into water/ether and filtered through kieselguhr. The aqueous layer from the filtrate was extracted with ether, and the combined ether extracts washed with water, dried and evaporated. The aqueous was re-extracted with dichloromethane and the extract evaporated. The combined extracts were chromatographed on silica gel, eluting with methanol-dichloromethane mixtures, to afford the title product (0.001 g). Mass Spectrum (Electrospray LC/MS): Found 466 (MH+). C21H19F4N5OS requires 465.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][CH:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH:22]([OH:21])[CH3:23])=[CH:25][CH:26]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(O)c1ccc(N)cc1
Product: CC(O)c1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-(1-hydroxyethyl)aniline (53 mg, 0.39 mmol). The title compound was obtained as a solid (50 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.50 (1H, s), 9.00 (2H, s), 8.72 (1H, m), 7.56 (2H, dd), 7.32 (2H, dd), 5.10 (1H, m), 4.68 (1H, m), 1.31 (3H, s). MS m/z: 468.10, 470.10 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[N:17]([CH3:18])[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Product: CN1CC(CCN2CCOCC2)N(C)c2nc3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 3.0 g (0.0103 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one was added 20 mL of morpholine. The mixture was stirred at 60° C. for 4 hr. The morpholine was removed at 60° C. and approximately 1 mm Hg. The residue was partitioned between 100 mL of CH2Cl2 and 100 mL of 1N NaOH. The basic layer was reextracted with 50 mL of CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to afford 2.1 g (59%) of white analytically pure crystals, mp 149°-151.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]/[N:7]=[C:8](/[CH3:14])\[CH:9](OC)OC)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:7][C:8]([CH3:14])=[CH:9]2
Reactant: COC(OC)/C(C)=N\Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2cc(Cl)ccc2cn1
Temperature: 140 °C

Procedure:
During 10 min. (4-chloro-benzyl)-[2,2-dimethoxy-1-methyl-eth-(Z)-ylidene]-amine (120 g, 0.496 mol) was added dropwise to polyphosphoric acid (1000 g) at 130° C. The resulting reaction mixture was heated for 3 h at 140° C. After cooling below 100° C. the reaction mixture was poured onto ice (1 kg) and neutralized (pH=7) with a 33% aqueous NaOH solution. Care was taken that the temperature did not rise above 35° C. by adding additional ice. The reaction mixture was extracted with dichloromethane (3×1 L) and the combined organic layers were dried over Na2SO4, filtered and concentrated at reduced pressure to afford a black oil. The crude product was purified bulb-to-bulb distillation (105-110° C., 2 mbar) to afford the title compound as colorless oil which crystallized upon standing (66.7 g, 0.375 mol, 76%). MS (ES+): 178 (M(C10H835ClN)+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+:26]>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:23][CH:24]=1)([CH3:3])[CH3:2].[Na+:26]
Reactant: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)[O-])cc2)cc1
Yield: 70.5 %

Procedure:
4-[2-(4-Isopropylbenzamido)ethoxy]benzoic acid (3.27 g) was dissolved in 50 ml of methanol, a solution of 0.40 g of sodium hydroxide in 5 ml of water was added thereto, the mixture was concentrated in vacuo, and crystallized residue was recrystallised from methanol to give 2.46 g of crystalline product, m.p. not lower than 300° C. IR γmaxKBr (cm-1): 1640, 1605.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([NH2:7])=[O:6].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([N:7]=[C:13]=[O:14])=[O:6]
Reactant: NC(=O)c1ccc(I)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(I)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-fluoro-4-iodobenzamide (2.0 g), oxalyl chloride (0.120 mL) and EDC (25 mL) to afford 1.0 g of the desired product.