Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-ethyl-piperazine following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[K+].O1CCO[CH2:18][CH2:17]1>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]3[C:2]=2[N:1]=[CH:18][CH:17]=[CH:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
2.5 g of 6,6′-bis(trifluoromethanesulphonyloxy)-3,3,3′,3′-tetramethyl-1,1′-spirobiindane, 2.2 g of 4-acetylphenylboronic acid, 12 ml of 2M sodium carbonate and 0.40 g of tetrakis(triphenylphosphine)palladium(0) were added to a solvent mixture of 50 ml of toluene and 30 ml of ethanol, and then refluxing carried out for 12 hours under nitrogen so that a Suzuki coupling reaction was conducted and, by treatment in the normal way, 1.5 g of 6,6′-bis(4-acetylphenyl)-3,3,3′,3′-tetramethyl-1,1′-spirobiindane was obtained. 1.50 g of this diacetyl derivative was reacted with 1.26 g of 8-amino-7-quinolinecarbaldehyde and 0.9 g of potassium hydroxide in dioxane at 60° C. and, by treatment in the normal way, Phen-4 (1.40 g) shown below was obtained. 1H-NMR (CDCl3, ppm): 9.21 (d, 2H), 8.35 (d, 4H), 8.25 (t, 4H), 8.09 (d, 2H), 7.80−7.59 (m, 12H), 7.34 (d, 2H), 7.24 (d, 2H), 2.46 (d, 4H), 1.52 (s, 6H), 1.46 (s, 6H)
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1[C:15](=[O:16])[CH2:14][CH2:13]C1=O.C(O)C#C.C(N(CC)CC)C>ClCCl>[C:2]1([C:1]2[CH:13]=[C:14]([CH2:15][OH:16])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1cc(-c2ccccc2)no1
Yield: 76.8 %

Procedure:
10.0 mmol of benzaldehyde oxime and 30 mL of dry dichloromethane were placed in a 250 mL single-necked round-bottom flask. 1.60 g (12.0 mmol) of N-chlorosuccinimide (NCS) was added under stirring. After NCS was completely dissolved by slightly heating, 0.56 g (10.0 mmol) of 2-propyn-1-ol was added dropwise, and then 20 mL solution of 10.1 g (10.0 mmol) of triethylamine in dichloromethane. After the addition was complete, the system was refluxed. After the completion of the reaction monitored by TLC, the mother liquor was washed with water, dried over anhydrous sodium sulfate, and separated by column chromatography (Vpetroleum ether:Vethyl acetate=5:1-2:1) to give 3-phenyl-5-hydroxymethyl-isoxazole in 76.8% yield.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:21]=1[C:22]([O:24]C)=[O:23].[F:32][C:33]([F:50])([F:49])[CH2:34]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:19][C:20]1[CH:29]=[C:28](/[CH:30]=[CH:34]/[C:33]([F:50])([F:49])[F:32])[CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1ccc(C=O)cc1Cl
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
4 Å molecular sieves (powder, 16 g) was added to a 1 M solution of TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of methyl 2-chloro-4-formylbenzoate (210 mg, 0.0010 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (600 mg, 0.0021 mol) in THF (15 mL). After the mixture was stirred for 2 h, the molecular sieves were removed by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt. The organic extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt [1% HOAc]-hexane to give the product as a white solid. LC-MS: t=3.12 min, m/z=248.9 & 250.9 (M−1).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:18])[CH:4]([CH3:6])[CH3:5]>CN(C)C=O>[CH2:3]([N:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[N:2][CH3:1])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:18])[CH:4]([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)Cn1c(N)nc2ccc(C=O)cc21
Solvent: CN(C)C=O
Product: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Add methylamine (3.0 mL, 6 mmol, 2M in tetrahydrofuran) to a solution 1-isobutyl-2-amino-6-formylbenzimidazole (475 mg, 2.19 mmol) in dimethylformamide (5 mL). Stir at room temperature for 18 hours. Concentrate under reduced pressure to provide the title compound (503 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23]OS([O-])=O.[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2(=[O:23])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2(=O)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.9 %

Procedure:
190 mg (0.59 mmole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide [prepared as described in Preparation 4(a)] were dissolved in 30 ml of methanol, and 10 ml of an aqueous solution containing 270 mg (1.77 mmole) of Oxone (trade mark) were added. The reaction mixture was stirred at room temperature for 5 days, after which it was poured into water and then extracted twice with chloroform. The organic extract was separated and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by thin-layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 175 mg (yield 88%) of the title compound as white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](OS(C)(=O)=O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([S:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:32][CH:31]=2)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Yield: 84 %

Procedure:
A mixture of 1-[4-(4-chlorophenyl)-2-methanesulfonyloxy-n-butyl]imidazole hydrochloride (2.0 g), 4-acetylaminothiophenol (1.2 g) and anhydrous potassium carbonate (2.0 g) in 30 ml of acetone and 10 ml of methanol was stirred and refluxed overnight under nitrogen. The solvent was evaporated and the residue treated with water (50 ml) and ether (20 ml) and the mixture stirred until crystallization was complete. Filtration of the product and recrystallization from ethyl acetate gave 1.84 g of 1-[4-(4-chlorophenyl)-2-(4-acetylaminophenylthio)-n-butyl]imidazole as a pale cream solid, m.p. 165.5°-166.5° C. B. Similarly, proceeding as above substituting the appropriate thiophenol for 4-acetylaminothiophenol the following compounds are prepared:
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Br>C(Cl)Cl>[CH3:1][N:2]([O:24][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COCCOCBr
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCON(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (600 mg, 1.65 mmol) in methylene chloride (4 ml) containing diisopropylethylamine (0.43 ml, 1.5 eq.) is added (2-methoxy)ethoxymethyl bromide (310 mg, 1.5 eq.) The mixture is stirred at RT for 16 hours. The reaction mixture is then taken up in methylene chloride, washed, dried, evaporated and purified by prep. TLC to yield N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl](2-methoxy)ethoxymethoxyamine (IXA, R is CH3OCH2CH2OCH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.[C:18]([O-])(O)=[O:19].[Na+].ClC(OC1C=CC=CC=1)=O.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:18](=[O:19])[NH:17][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1cc(Br)ccc1NCCN1CCOCC1
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500-mL round-bottomed flask, mix 4-bromo-N1-(2-morpholin-4-yl-ethyl)-benzene-1,2-diamine 13.25 g, 44.1 mmol), NaHCO3 (5.4 g, 66.2 mmol), water (50 mL) and methanol (250 mL). Slowly add phenyl chloroformate (8.3 mL,66.2 mmol). Stirr the reaction for 1 h at room temperature and then add 5N NaOH (20 mL) and stir overnight at room temperature. Collect the solid by vacuum filtration and wash with methanol. HPLC (ISO60-10M) t=1.42 (97%), MS (ES) 326 (M+1).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1ccc(C(N)CC(=O)O)cc1OCc1ccccc1
Product: COC(=O)CC(N)c1ccc(OC)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-benzyloxy-4-methoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 7.26-7.44 (m, 5H), 6.82-6.93 (m, 3H), 5.13 (s, 2H), 4.31 (t, 1H, J=5 Hz), 3.85 (s, 3H), 3.64 (s, 3H), 2.57 (d, 2H, J=5 Hz), 1.80 (d, 2H, J=5 Hz).
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2.O>C1(C)C=CC=CC=1.[Ti]>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: Cc1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal, 67 mg of 5-amino-2-methylquinoline and 163 μl of titanium tetraethylate are stirred in 8 ml of toluene for 2 hours at 100° C. After cooling, the batch is mixed with 2 ml of water, stirred for 15 minutes at room temperature, and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 111 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Br[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[O:64][N:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:64]1[C:60]([C:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:15]3[C:14](=[O:17])[N:11]4[CH:12]=[N:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[C:9]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:55][CH:56]=2)=[CH:61][CH:62]=[N:63]1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (16.0 mg, 0.05 mmol) in acetone (5 mL) at room temperature under argon was added 5-(4-(bromomethyl)phenyl)isoxazole (23.8 mg, 0.10 mmol), followed by K2CO3 (13.8 mg, 0.10 mmol). The resulting mixture was heated at 60° C. for 17 h. Insoluble material was filtered and rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative HPLC (without TFA). Further purification was performed by silica gel column chromatography eluting with EtOAc-hexanes. Pure product was lyophilized from 1,4-dioxane to obtain the title compound (3.5 mg) as an off-white lyophilate. HPLC/MS: retention time=3.88 min, [M+H]30 =480. 1H NMR (CDCl3): δ 8.71 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.81 (d, J=7.3 Hz, 2H), 7.45 (d, J=7.3 Hz, 2H), 7.26-7.42 (m, 7H), 7.18 (d, J=7.2 Hz, 2H), 6.51(d, J=1.2 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][N:13](C)C=O>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>[NH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)CCCN2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc2c(c1)CCCN2
Temperature: 120 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (10 g, 47.15 mmol) in N,N-dimethylformamide (80 mL) was added Pd(PPh3)4 (2.8 g, 2.42 mmol), and zincdicarbonitrile (6.4 g, 54.49 mmol) and the reaction was stirred for 2 h at 120° C. in an oil bath. The reaction was quenched by the addition of water (400 mL) and extracted with dichloromethane (3×50 mL), and concentrated in vacuo to give a residue, which was purified by a silica gel chromatography with 1%-20% ethyl acetate in petroleum ether to give 1,2,3,4-tetrahydroquinoline-6-carbonitrile as a yellow solid (6 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC.C1CCCCC1.CCOCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(c1ccccc1)c1ccccc1Cl
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Temperature: 15 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a stirred, ice-cooled solution of 2-chlorobenzophenone (21.6 g, 100 mmol) in 150 mL of dry Et2O under N2 was added 60 mL (120 mmol) of 2.0 M phenyllithium solution in cyclohexane-Et2O (7:3), keeping T<15° C. After stirring for a further 1 h at 15° C., the solution was poured onto crushed ice and extracted with Et2O. The organic solution was washed with 0.2 M H2SO4, water (until neutral), brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from hexanes containing a few per cent EtOAc to give 23.1 g (78%) of (2-chlorophenyl)diphenylmethanol as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][C:15]2=[O:23])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc(O)c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Yield: 60 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH:7]=[C:6]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH:7]=[C:6]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1CCC(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCC(C)c2cc(-c3csc(N4CCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 218 mg (0.58 mmol) of 1-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine and 126 μl (0.58 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CN2N=C(C(C)(C)C)CC2=O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)methyl]benzoate (2.00 g, 6.94 mmol), benzyl bromide (0.91 mL, 7.7 mmol), potassium carbonate (0.96 g, 6.9 mmol) and N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (2.14 g, yield 81%) as a yellow oil. 1H NMR (CDCl3) δ: 1.29 (9H, s), 3.90 (3H, s), 5.01 (2H, s), 5.19 (2H, s), 5.49 (1H, s), 7.00-7.37 (7H, m), 7.92-8.00 (2H, m).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:36][CH:37]4[CH2:39][CH2:38]4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: BrCC1CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC3CC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=540.3 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and bromomethyl cyclopropane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](Cl)[C:20]=1[Cl:29].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:20]=1[Cl:29]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3c([N+](=O)[O-])ccc(Cl)c3Cl)cc12
Temperature: 125 °C
Yield: 60 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 1,2,3-trichloronitrobenzene were used. Sodium carbonate was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 125° C. for 3 hours. Column chromatography afforded the title compound (60%) as a red solid: Rf =0.4 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (CDCl3) δ 8.59 (br s, NH), 8.36 (br s, NH), 7.96 (d, J=9.1 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J=9.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.81 (dd, J=8.6 and 2.1 Hz, 1H), 3.15-3.05 (m, 2H), 2.54 (dd, J=13.8 and 9.6 Hz, 1H), 2.46-2.33 (m, 1H), 2.40 (s, 3H), 2.22 (dd, J=17.4 and 9.3 Hz, 1H), 1.84-1.48 (m, 4H); FAB HRMS calculated for [C20H20Cl2N4O2.H] 419.1044, found 419.1046.