Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]=1[CH3:30])=[O:15].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:10])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[CH3:30])=[O:15]
Reactant: Cc1c(COC(=O)C2C(C(O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(COC(=O)C2C(C(OC(=O)c3ccccc3)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.8 %

Procedure:
To a solution of 390 mg (0.821 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 3, in 2 ml of diethyl ether, 0.114 ml (0.98 mmol) of benzoyl chloride and 0.137 ml of triethylamine, were added, and the mixture was stirred at room temperature for 12 hours. Then, 0.23 ml of benzoyl chloride and 0.28 ml of triethylamine were further added, and the mixture was stirred overnight at room temperature. After an addition of 5 ml of hexane, the inorganic salts are filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 175 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-benzoyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42].N1C=CN=C1>C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:45]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 42 ml of DMP are silylated, under a protective gas, with 3.15 g (20.9 mmol) of tert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RT for 20 h. The reaction mixture is diluted with ethyl acetate, and this mixture is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ethyl acetate, and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1 h. Subsequently, the reaction mixture is partially evaporated and the residue is diluted with ice-cold 10% citric acid solution; this mixture is then extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1) results in the pure title compound: TLC Rf (C)=0.13; tRet (II)=21.7 min. 7d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(N)([NH2:20])(=O)=O.O>N1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:20])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Temperature: 117.5 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of 4-methyl-3,5-dinitrobenzoic acid (48.2 kg) (3) and sulfamide (50.1 kg) in pyridine (197 kg) is heated to reflux (about 115-120° C.) for about 1.5 hours. The solution is then cooled to ambient temperature and water is added (178 kg) over about 1 hour. The mixture is then cooled to about ˜5° C. and held at this temperature for about 1 hour. The product slurry is centrifuged and the solids obtained are washed with water (621 L). The product is dried in a vacuum tray dryer at a temperature of about 65° C. and a vacuum of about 10 torr to provide 4-methyl-3,5-dinitrobenzamide (6) (43.8 kg, 91.3% yield).
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: OBO
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
6-(4-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (4-(trifluoromethyl)phenyl)boronic acid (79 mg, 135.1 mg theoretical, 58.5%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M+H)+.
Reaction SMILES: C(C(CCCC)CO[C:6](=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[N:20]=[CH:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[N:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][CH:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:6][CH:7]=1)=[CH:19][CH:18]=3
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3ncnn32)c1
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5ncnn54)c3)n2)CCOCC1
Temperature: 90 °C

Procedure:
8e (201 mg, 0.50 mmol) and 4-(6-Fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (8f, 105 mg, 0.51 mmol) were dissolved in DMF at room temperature and degassed for 10 minutes with N2. Potassium tert-butoxide (67 mg, 0.60 mmol) was added, and the mixture was degassed with N2 for another 10 minutes. The reaction was heated to 90° C. for 12 hours, and then concentrated and purified by silica gel chromatography (25-50% EtOAc in hexanes) to give the desired product, 8g.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)([O-])O.[Na+].Cl.Cl[CH2:28][CH2:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[CH:38]=1.[I-].[K+]>CN(C)C=O>[N:31]1[C:30]([CH2:29][CH2:28][N:16]2[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:38][N:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=12
Reactant: ClCCc1cn2ccccc2n1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCc3cn4ccccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A mixture of 1.02 g (3.2 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 1.34 g of sodium hydrogencarbonate and 10 ml of dimethylformamide was stirred at 80° C. for 1 h. 0.48 g of 2-(2-chloroethyl)imidazo[1,2-a]pyridine hydrochloride and 0.53 g of potassium iodide were added thereto and the mixture was stirred at 80° C. for 2 h. The mixture was filtered and the filtrate was concentrated to obtain a solid residue, which was then purified according to silica gel column chromatography (chloroform:methanol:aqueous ammonia=190:9:1). The fraction of the intended compound was concentrated to obtain a solid residue, which was then recrystallized from ethyl acetate to obtain 0.25 g (yield: 18%) of the intended compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)CCl.[Pd]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NNC(c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: ClCCCl
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Yield: 79.3 %

Procedure:
3,5-Diphenyl-2-pyrazoline (21.9 parts) is dissolved in ethylene dichloride (75 parts by volume). There is next added 5% palladium on carbon catalyst (4 parts containing 40% water) is added and the mixture is heated at reflux for 8 hours. There is obtained 3,5-diphenylpyrazole in a 79.3% yield whose melting point ranges from 196° to 200° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11](=[O:27])[CH:12]([O:24][CH2:25][CH3:26])[CH2:13][C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[C:17]([OH:23])=[CH:16][CH:15]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35]>CN(C)C=O>[CH3:9][O:10][C:11](=[O:27])[CH:12]([O:24][CH2:25][CH3:26])[CH2:13][C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[C:17]([O:23][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:16][CH:15]=1
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)OC
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (37 mg, 300 μmol, 1.4 eq.) and potassium iodide (4 mg, 30 μmol, 0.1 eq.) were added to a solution of [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (50 mg, 189 μmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole (39 mg, 189 μmol, 1 eq.) in N,N-dimethylformamide (0.5 ml). The mixture was shaken at 80° C. for 12 h, filtered off and the filtrate evaporated in vacuo to give [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester. Crude [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester was dissolved in a 2:1:1 mixture of THF/ethanol/water. Lithium hydroxide (40 mg, 945 μmol, 5 eq.) was added and the solution was shaken at ambient temperature for 12 h. Acidification with 25% aqueous hydrochloric acid and evaporation of the solvent in vacuo were followed by purification through a preparative HPLC column to give the title compound (28 mg, 66 μmol, 35%) as white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[F:15][C:14]([F:16])([F:17])[CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[C:10]#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(OCC(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1OCC(F)(F)F
Temperature: 70 °C

Procedure:
4-Cyano-3-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester from step 1 (1.6 g, 6.2 mmol ) was dissolved in THF (62 ml). LiBH4 in THF (2 M, 6.2 ml, 12.4 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4) filtered and concentrated to yield the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[O:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])(=O)=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[Si:55]([O:1][CH:2]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[O:4][CH2:3]1)([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(O)CO3)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(O[Si](C)(C)C(C)(C)C)CO3)c2ncnn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
4′-{[4-(3-Hydroxy-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g) and 2,6-lutidine (0.50 mL) were dissolved in tetrahydrofuran (5 mL), and tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.98 mL) was added at 0° C. The mixture was stirred at room temperature for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, the mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (1.9 g, 100%).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C(C)(C)C)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (compound 4) (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added thereto, and the mixture was stirred at −78° C. for 20 min. Pivaloyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (21 mg, yield 21%).
Reaction SMILES: [F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(F)=Cc1ccccc1
Product: O=C(Cl)C(F)=Cc1ccccc1
Temperature: 80 °C

Procedure:
To α-fluorocinnamic acid (5.48 g, 33 mM), thionyl chloride (40 ml) was added, and the thus obtained mixture was stirred at 80° C. under refluxing for 2 hours. After cooling it to a room temperature, the unreacted thionyl chloride was distilled off under reduced pressure to give a syrup-like α-fluorocinnamoyl chloride.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl.CC(=C)C>[CH:1]1([C:7]([O:9][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:8])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)C1C=CCC=C1
Agent: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1C=CCC=C1

Procedure:
A solution of 16 g of 2,5-cyclohexadiene carboxylic acid in 20 ml of dichloromethane containing 10 drops of sulfuric acid is treated with 40 ml of isobutylene in an autoclave overnight after which the contents were poured into a sodium bicarbonate solution. The organic phase is isolated and passed through alumina to afford tert-butyl 2,5-cyclohexadienecarboxylate.
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH:31]1([CH2:37][CH2:38][O:39][CH:40]([C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=4[O:58][CH3:59])[CH:50]=3)[NH:45][C:44]([CH3:61])([CH3:60])[CH:43]=2)[CH3:41])CCCC[CH2:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(CCBr)CCCCC1>C1COCC1>[CH2:38]([O:39][CH:40]([C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH3:59])[CH:50]=2)[NH:45][C:44]([CH3:61])([CH3:60])[CH:43]=1)[CH3:41])/[CH:37]=[CH:31]/[CH3:32]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCC1CCCCC1)=CC(C)(C)N2
Agent: BrCCC1CCCCC1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 101 %

Procedure:
4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 49 mg of 2-cyclohexylethyl bromide to give the alkylated product, which was deprotected to yield 31 mg of title compound as an oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:37])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:35])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][C@H:25]([CH2:33][OH:34])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:15][C:14]=3[CH:36]=2)[CH2:6][CH2:5]1)(=O)C.O>Cl.O1CCOCC1>[OH:34][CH2:33][C@@H:25]([NH:24][C:23]1[CH:22]=[CH:21][NH:20][C:19](=[O:35])[C:18]=1[C:16]1[NH:15][C:14]2[CH:36]=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[CH:11]=[C:12]([CH3:37])[C:13]=2[N:17]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 10.1 %

Procedure:
To a solution of (S)-3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-(1-hydroxymethyl-2-phenyl-ethylamino)-1H-pyridin-2-one (900 mg, 18 mmol) in 4 M HCl in dioxane (10 mL) was added water (1 mL). The reaction mixture was heated to 80° C. for 14 h and cooled to room temperature. Concentration with high vacuum gave the title compound (0.83 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 459 (t=1.13 min.).
Reaction SMILES: CO.C(OC([NH:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[NH2:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](N)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.5 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 35 ml of methylene chloride is cooled to 0° C. Then, there is added a solution of 7.7 ml of trifluoroacetic acid in 40 ml of methylene chloride and the mixture is left to stand under stirring at first 30 minutes at a temperature of 0°-5° C., then 4 hours at room temperature. After neutralization with a solution of sodium bicarbonate, the organic phase is separated, washed with water, dried and evaporated to dryness. The residue is taken up with 15 ml of ethyl acetate and made acid with a solution of hydrochloric acid in ethanol. The precipitated so obtained is filtered and washed with ether. Thus, 1.1 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride is obtained; m.p. 168°-171° C., /alpha/=+51.14° (methanol, c=1%). (b) To a solution of 5.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 135 ml of absolute ethanol there is added at room temperature 82 ml of a 7.2N solution of hydrogen chloride in ethanol. The mixture is left under stirring at room temperature for 150 minutes, then it is evaporated to dryness under reduced pressure. The residue is taken up with ethyl ether and filtered. Thus, 4.6 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride are obtained; m.p. 170°-171° C., /alpha/=+51° (methanol, c=1%). By crystallization from methanol, the melting point remains unchanged (170°-172° C.) and the /alpha/ rises to +51.6° (methanol, c=1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:33])=[CH:17][N:16]=1>>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow solid (67 mg, 32%). m.p.=180-190° C.; LCMS (m/e) 455 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.35-9.22 (m, 3H), 8.56-8.47 (m, 1H), 8.17 (s, 1H), 7.50-7.42 (m, 2H), 7.40-7.31 (m, 1H), 7.23 (d, 1H, J=8.3 Hz) 7.09 (s, 1H), 6.93 (d, 1H, J=8.3 Hz), 2.72 (d, 3H, J=4.4 Hz), 2.56 (t, 2H, J=6.2 Hz), 2.12-1.97 (m, 4H).