Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)c(F)cc1F
Yield: 94.4 %

Procedure:
A mixture of 2,4-difluoro-5-methoxycarbonyloxy-1-nitrobenzene (2.7 g, 0.012 mol) and 10% palladium-on-charcoal catalyst (500 mg) in ethanol (20 ml) and ethyl acetate (10 ml) was stirred under 1 atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation to give 2,4-difluoro-5-methoxycarbonyloxyaniline (2.3 g, 97%).
Reaction SMILES: ClC1C=CC(C(=C)CCCO)=CC=1.[CH2:14]([CH:16]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[CH2:23])[CH2:17][C:18](OC)=[O:19])[CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:14]([CH:16]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[CH2:23])[CH2:17][CH2:18][OH:19])[CH3:15]
Reactant: C=C(c1ccc(Cl)cc1)C(CC)CC(=O)OC
Agent: C=C(CCCO)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C(c1ccc(Cl)cc1)C(CC)CCO
Yield: 105 %

Procedure:
By the procedure described for the preparation of 4-(4-chlorophenyl)pent-4-en-1-ol (see Example 1), methyl 3-ethyl-4-(4-chlorophenyl)pent-4-enoate (1.50 g) and lithium aluminium hydride (0.57 g) in dry diethyl ether (50 ml) gave 3-ethyl-4-(4-chlorophenyl)pent-4-en-1-ol (1.40 g, quantitative) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)=[CH:14][C:13]1=[O:29])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=3)=[CH:14][C:13]2=[O:29])[C:3]([OH:30])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC(F)(F)F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0.520 g, 0.001 mol) in tetrahydrofuran-water (3:1, 20 mL) was added lithium hydroxide (153 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (380 mg, 76%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 90 °C
Yield: 62.7 %

Procedure:
A mixture of 10 g (42.4 mmol) 1,4-dibromobenzene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)Palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 9.5 g (63%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.O(Br)[Br:11].[Na].BrBr.[OH-].[Na+].[Cl-].[NH4+]>O>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: BrOBr
Reactant: c1cc2cn[nH]c2cn1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Brc1n[nH]c2cnccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 1H-pyrazolo[3,4-c]pyridine (0.50 g, 3.5 mmol) in water (10 mL) was added a solution of sodium oxybromide (prepared by dropwise addition of bromine (0.25 mL) to sodium hydroxide solution (0.40 mg in 5 mL) at 0° C. over 5 min). The reaction mixture stirred for 1 h at 10° C. The mixture was then acidified to pH ˜5.5 with ammonium chloride, and extracted with ethyl acetate (3×20 mL). The combined organic fractions were dried over sodium sulfate and concentrated to afford 0.43 g (62%) of the title compound. 1H NMR (300 MHz, CD3OD): δ 7.79 (dd, J=1.5, 4.2 Hz, 1H), 8.32-8.33 (d, J=5.7 Hz, 1H), 9.07 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:36]2[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])(=[O:24])=[O:23])[C:13]1=[O:35]>ClCCl.N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])(=[O:23])=[O:24])[C:13](=[O:35])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:36]1[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
0.83 ml (6.6 mmol) of phenyl chloroformate was slowly added dropwise to a solution, cooled to 0° C., of 2.57 g (5.1 mmol) of 3-amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 10 ml of dichloromethane and 4.1 ml of pyridine. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in a little dichloromethane, and six times the volume of diisopropyl ether were added. The resulting precipitate was filtered off, washed with diisopropyl ether and dried in vacuo. 3.01 g of the title compound were obtained as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:19]1[NH:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([CH:19]1[N:23]([C:22]2[CH2:21][CH2:20][CH:19]([CH2:15][CH2:16][CH2:17][CH3:18])[N:23]=2)[C:22]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1CCC(=O)N1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Product: CCCCC1CCC(N2C(N3c4ccccc4Sc4ccccc43)=CCC2CCCC)=N1

Procedure:
reaction of phenothiazine with 5-n-butyl-2-pyrrolidinone according to the procedure of Example 4 provides 10-[5-n-BUTYL-1-(5-n-BUTYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]3[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=3[C:17]=2[CH2:29][CH2:30][CH3:31])=[C:9]([CH2:34][CH2:35][CH3:36])[C:8]=1[O:37][CH3:38])=O.O.[NH2:41]N.Cl.C(OCC)(=O)C>CO>[CH3:38][O:37][C:8]1[C:9]([CH2:34][CH2:35][CH3:36])=[C:10]([CH:32]=[CH:33][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:41]=1)[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:19]2[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=2[C:17]=1[CH2:29][CH2:30][CH3:31]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)/C=C\N(C)C)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(-c3cc[nH]n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2

Procedure:
The crude compound from Example 5 was stirred in 4.0 ml of methanol/1.0 ml water with 0.1 ml hydrazine hydrate at reflux for 2.0 hours. The reaction mixture was poured into 1N hydrochloric acid/ethyl acetate, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. Flash chromatography of the concentrate on silica gel using 5:1 to 2:1 hexane/ethyl acetate (1% acetic acid) as eluant gave the product, melting point 156°-158° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[O:24]=[C:25]1[CH:30]=[CH:29][O:28][C:27]([C:31](O)=[O:32])=[CH:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:23])[CH:10]([NH:22][C:31]([C:27]2[O:28][CH:29]=[CH:30][C:25](=[O:24])[CH:26]=2)=[O:32])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc(=O)cco1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1)c1cc(=O)cco1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4-oxo-4H-pyran-2-carboxylic acid (266 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide (570 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][CH:27]3[C:29]([OH:32])([CH3:31])[CH3:30])[N:23]([CH3:33])[C:22]=2[CH:34]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][CH:27]5[C:29]([OH:32])([CH3:30])[CH3:31])[N:23]([CH3:33])[C:22]=4[CH:34]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(Br)cc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 150 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (27 mg), 2-((1RS,2SR)-2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)propan-2-ol (35 mg), copper iodide (21.8 mg), N,N′-dimethylethylenediamine (10.1 mg), potassium carbonate (31.7 mg) and DMSO (1 ml) was stirred at 150° C. overnight. The mixture was quenched with 28% NH3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (10 mg) as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12](O)(=O)[CH2:13][C:14]([CH2:19][C:20](O)=O)([C:16]([OH:18])=O)O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:10])[CH:1]([CH2:2][CH3:3])[C:16]([C:14]2[CH:13]=[CH:12][C:5]([O:8][CH3:9])=[CH:20][CH:19]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(OC)cc1)C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-methoxybutyryl phenone (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-ethylpropane-1,3-dione.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:21](/[C:20]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH3:16])[CH:19]=2)\[C:22]#[N:23])=[CH:7][CH:6]=1)[CH3:2]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Product: CCOC(OCC)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 89.1 %

Procedure:
4-Diethoxymethyl-benzaldehyde (4.16 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (6.54 g, yield: 89%). The thus-produced (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (1.84 g) was dissolved in methanol, and water and 2N sulfuric acid were added to the resultant solution, followed by stirring, to thereby produce the target product (1.20 g, yield: 82%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:19]1C=CC2OCCC=2C=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[CH:4][C:3]=2[CH2:19][CH2:10]1
Reactant: Brc1ccc2c(c1)CCO2
Reactant: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Product: C[C@@H]1CN(c2ccc3c(c2)CCO3)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 25, but starting from 5-bromo-2,3-dihydrobenzo[b]furan. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a brown oil. M+(ESI): 219.2. HPLC (Condition A), Rt: 1.3 min (HPLC purity: 99.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([C:15]#[CH:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>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.[Cu](I)I.C1COCC1.C(N(CC)CC)C>[CH:10]1([C:15]#[C:16][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C#CC1CCCC1
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(Cl)nc(C#CC2CCCC2)n1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
2,6-Dichloropyrimidin-4-amine (0.2 g, 1.22 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.043 mmol) and copper iodide (14 mg, 0.07 mmol) were introduced in a flask. A mixture of THF-triethylamine 2:3 (5 mL) was added and the system was inertized 3 times with vacuum/argon cycles. Finally, cyclopentyl acetylene (0.16 mL, 1.34 mmol) was added and the resulting mixture was heated at 100° C. overnight. The reaction crude was cooled at room temperature and filtered over Celite®. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.15 g of the title compound, impurified with its regioisomer.
Reaction SMILES: [C-]1CCCCC=CC=1.[K+].CC1C(C)=C(C)C([Si](Cl)(C)C)(C)C=1.[CH3:23][C:24]1[C:25]([CH3:42])=[C:26]([CH3:41])[C:27]([Si:30]([CH:33]2[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34]2)([CH3:32])[CH3:31])([CH3:29])[CH:28]=1.CC1C(C)=C(C)C([Si](C2CCCC=CC=C2)(C)C)(C)C=1>C1COCC1>[CH3:23][C:24]1[C:25]([CH3:42])=[C:26]([CH3:41])[C:27]([Si:30]([C:33]2[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][CH:34]=2)([CH3:32])[CH3:31])([CH3:29])[CH:28]=1
Reactant: CC1=CC(C)([Si](C)(C)C2C=CCCCC=C2)C(C)=C1C
Agent: CC1=CC(C)([Si](C)(C)C2C=CC=CCCC2)C(C)=C1C
Agent: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Agent: [C-]1=CC=CCCCC1
Solvent: C1CCOC1
Product: CC1=CC(C)([Si](C)(C)C2=CC=CCCCC2)C(C)=C1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium cyclooctadienide (3.42 g, 23.4 mmols) dissolved in about 50 mL of THF was added to a solution of (tetramethylcyclopentadienyl)chloro-dimethylsilane (5.02 g, 23.4 mmols) in about 80 mL of THF at about 25° C. A precipitate formed and the reaction mixture was stirred for about 16 hours at about 25° C., after which time the reaction mixture was filtered and the solvents removed under reduced pressure. The residue was extracted with hexane and filtered. The solvents were again removed under reduced pressure leaving the desired isomeric product comprising (tetramethylcyclopentadienyl)(cylcoocta-2,7-dien-1-yl)dimethylsilane and (tetramethylcyclopentadienyl)(cylcoocta-2,4-dien-1-yl)dimethylsilane.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:13][C:12]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:11]=3[NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.FC(F)(F)C(O)=O.ClC(Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH:29]1[CH:33]=[C:32]([CH2:34][N:10]2[C:11]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:12]=3[CH2:13][N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[C@H:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[N:31]=[CH:30]1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
In a 500 mL flask was charged (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (25.0 g, 1 eq.), imidazole-4-carboxaldehyde (6.45 g, 1.1 eq.), and CH2Cl2 (150 mL) at room temperature. Cool to 0-5° C. Add trifluoroacetic acid (18.8 mL, 4 eq.) in a period of 10 min. A solution was obtained after addition. Stir the mixture for 10 min at 2° C. Add trichloroacetic acid anhydride (11.7 mL, 1.05 eq.) in a period of 20 min at 2° C. Stir the mixture for 30 min at 0-5° C. Add Na(OAc)3BH (15.51 g, 1.2 eq.) in two portions at 0-5° C. Agitate the mixture at 0° C. for 1.5 h, then room temperature for 1 hour. Add CH2Cl2 (100 mL), then cool to 0° C. Adjust the pH to 8-9 with 10% NaOH (about 125 mL used). Stir for 30 min. Separate the two phases. Wash the organic phase with H2O (2×100 mL), then separate the two phases. Remove most of the solvents, and add EtOH (200 mL); and heat up to 74° C. Stir for 10 min at 74° C. Cool to room temperature in a period of 60 min. Crystals appeared at 65° C. Filter and wash the crystals with EtOH (40 mL). Dry at 40° C. in vacuum oven over night to give the product (13.55 g, 90.7% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].[H-].[Na+].Br[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:17].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:17])[C:7]2=[O:12]
Reactant: O=C1NCCc2c(Br)cccc21
Reactant: CC(Br)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(F)cc1)N1CCc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 140.7 %

Procedure:
A solution of 0.15 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one in 5 cm3 of dimethylformamide is poured into a mixture containing 31 mg of sodium hydride (60% in oil) and 10 cm3 of dimethylformamide at a temperature close to 20° C. under an inert atmosphere. Then a solution of 0.2 g of 1-(1-bromoethyl)-4-fluorobenzene in 5 cm3 of dimethylformamide is poured into the reaction mixture. The latter is stirred for 20 h at a temperature close to 20° C. Water and ethyl acetate are added to the reaction mixture. After decanting, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 325 mg of crude product obtained are purified by filtration through a silica pellet (eluent: 20% ethyl acetate/80% cyclohexane). After concentrating the fractions under reduced pressure, 146 mg of 5-bromo-2-[1-(4-fluorophenyl)ethyl]-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a thick pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccco2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1coc(CCCN2CCNCC2)c1
Yield: 131.3 %

Procedure:
To 1.5 g of 1-t-butoxycarbonyl-4-[3-(2-furyl)propyl]-piperazine was added 5 ml of trifluoroacetic acid under ice-cooling, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate 10 ml. To the solution was added 4N hydrochloric acid-dioxane solution under ice-cooling to yield 1.3 g of 1-[3-(2-furyl)propyl]piperazine. 2 hydrochloride.