Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]2[N:23]=[C:4]([C:3]3[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[NH:24][C:19]=2[CH:18]=1)=[O:25]
Reactant: O=Cc1c(Cl)cccc1C(F)(F)F
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-6-trifluoromethylbenzaldehyde (270 mg, 1.3 mmol) and 3,4-diaminobenzoic acid methyl ester (216 mg, 1.3 mmol) in DMSO (10 mL) was added Yb(OTf)3 (161 mg, 0.26 mmol) and the solution was stirred at ambient temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester as a red oil. This was used directly in the next step.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29])[CH2:23][NH2:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:29])([F:30])[F:31])[CH2:23][NH:24][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 3-fluoro-4-(trifluoromethyl)benzylamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:4]2=[CH:5][C:6]3[CH:11]([C:12]([O:14]CC)=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=3[CH:18]=[C:3]2[O:2]1.[OH-].[Na+].O>C(O)C>[CH2:1]1[CH2:20][O:19][C:4]2=[CH:5][C:6]3[CH:11]([C:12]([OH:14])=[O:13])[S:10][CH2:9][C:8](=[O:17])[C:7]=3[CH:18]=[C:3]2[O:2]1
Reactant: CCOC(=O)C1SCC(=O)c2cc3c(cc21)OCCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CSC(C(=O)O)c2cc3c(cc21)OCCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In ethanol (200 ml) was suspended ethyl 6,7-ethylenedioxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (55 g) followed by addition of 2N-NaOH (200 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-ethylenedioxy-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (32.5 g, yield (65%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [OH:1][C:2]1([CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH2:5]1)C=O.[Br:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[OH:19]>O=P(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[OH:10][C:8]1[CH:7]=[C:6]([OH:11])[CH:5]=[C:2]([OH:1])[C:9]=1[C:21](=[O:22])[CH2:20][C:15]1[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([Br:12])[CH:14]=1
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Reactant: O=CC1(O)C=C(O)C=C(O)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1ccc(O)c(Br)c1)c1c(O)cc(O)cc1O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 18.4 %

Procedure:
1,3.5-Trihydroxybenzaldehyde (1.01 g, 6.95 mmol) and 3-bromo-4-hydroxyphenylacetic acid (1.44 g, 6.25 mmol) were suspended in POCl3 (4 mL). After 1 min, an exothermic reaction occurred. The mixture was allowed to cool to room temperature. Zinc chloride (1M ether solution, 4.7 mmol) was added and the mixture was heated at 75° C. for 1 h. After cooling, the mixture was partitioned in ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine and dried with MgSO4. Purification on silica gel (MeOH/dichloromethane, gradient) afforded 1-(2,4,6-trihydroxyphenyl)-2-(3-bromo-4-hydroxyphenyl)ethanone (390 mg) as a tan solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([I:28])=[CH:26][N:25]=[CH:24][N:23]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[I:28][C:27]1[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: Clc1ncncc1I
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncncc3I)n(-c3ccccc3)c(=O)c12
Yield: 32.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (400 mg, 1.49 mmol) was treated 4-chloro-5-iodopyrimidine (538 mg, 2.24 mmol), cesium fluoride (453 mg, 2.98 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.46 mol) according to Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 230 mg (33% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])[CH:20]=4)[C:15]([S:30][CH3:31])=[CH:14]3)=[N:11][CH:12]=2)[CH:4]=[N:3]1.ClC1C=C(C=CC=1)C(OO)=[O:37].COC1C=CN=C(C2C=NC(N3C4C(=CC=C(C(N5CCOCC5)=O)C=4)C(S(C)=O)=C3)=NC=2)C=1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[O:23])[CH:20]=4)[C:15]([S:30]([CH3:31])=[O:37])=[CH:14]3)=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: CSc1cn(-c2ncc(-c3cnn(C)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Product: Cn1cc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)cn1

Procedure:
The compound obtained in 148a) (380 mg, 0.921 mmol, 1.0 eq) was oxidized with m-chloroperoxybenzoic acid in analogy to the instructions from 141c). White solid. Yield: 150 mg (36% of theory). Melting range: 208-212° C. HPLC (method 6): Rt=7.51 min. Mass spectroscopy: m/z: [M+H]+=451.2.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[CH3:10][C:4]1[CH:3]=[C:8]([CH:7]=[CH:6][CH:5]=1)[O:9][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)c1
Yield: 9.3 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (47.0 mg, 1.176 mmol, Sigma Aldrich) in DMF (1679 μl), m-cresol (123 μl, 1.176 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and heating to 85° C. for 16 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 90%) provided 2-(2-(3-methylphenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (5.8 mg, 9.4%) as the free base following filtration through a Si-carbonate cartridge (Silicyle) with MeOH. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.37-8.41 (1H, m) 8.10-8.14 (1H, m) 7.73-7.76 (1H, m) 7.46-7.56 (1H, m) 7.28-7.37 (2H, m) 7.14-7.22 (1H, m) 7.04 (3H, s) 3.48-3.55 (2H, m) 3.14-3.19 (2H, m) 2.47 (3H, s). m/z (ESI, +ve) 370.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN3CCN(C)CC3)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2cc(Cl)cc3cc(C(=O)O)[nH]c23)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a solution of 30 mg (0.09 mmol) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (2.5 ml) at RT was added 6 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 10 mg (36%) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 306.2 (M−H+).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[CH2:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCCN(Cc2ccccc2)C1
Yield: 63 %

Procedure:
Nipecotic acid (1.31 g, 10.2 mmol), benzaldehyde (1.12 g, 10.6 mmol) and 5% palladium-carbon (0.18 g) in methanol (10 mL) was stirred at room temperature for one day under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (50 mL) was stirred with benzaldehyde (4.40 g, 41.5 mmol) and 5% palladium-carbon (0.118 g) at room temperature for one day. The reaction mixture was filtered, and the filtrated was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1→5/1 (v/v)) to give the title compound as a colorless oil (1.41 g, yield 63%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]C=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[N:22]1C=CC=C2CCC(N)C=12>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3=[N:22][CH:18]=[CH:17][CH:16]=[C:15]3[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCc2cccnc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3cccnc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 8.46, 7.60, 7.17, 5.37, 5.25, 3.11–2.95, 2.75–2.61, 1.94–1.81, 1.36–1.26; (MS/CI) calcd for C16H20N4+H 269.4, found 269.3.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1>CC1CCC(=C(C)C)CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Agent: CC1=CCC(=C(C)C)CC1
Product: Cc1ccc(C(C)C)cc1

Procedure:
When it was sought to isomerize limonene to terpinolene using orthotitanic acid as a catalyst in undiluted limonene, it was found that the reaction was wildly exothermic to 215 degrees C. yielding principally p-cymene. The use of a hydrocarbon solvent, e.g., heptane was found to hold the temperature to 105 degrees C. However, after a few hours, few diene components were found, with mostly dimers and higher polymers being obtained. It was then decided to utilize a material normally regarded as a buffer in effort to moderate the reaction. This proved to be successful in that it allowed control of the reaction easily at 100 degrees C. without exotherm. No solvent was necessary. Sodium acetate as a reaction control agent was found to be especially effective at concentrations of from 0.1% to 1.0% by weight of the limonene charge, and more particularly from 0.2% to 0.5% by weight. Higher amounts of the control agent or buffer appear not to improve the conversion or selectivity and thus, the upper limit of concentration is not critical. The lower limit appears to be about 0.05% by weight of the limonene charge. At levels of 0.2% and 0.5% sodium acetate buffer, excellent results were obtained at 100 degrees C. With 0.5%, after 4 hours, 55% conversion gave 70% selectivity of terpinolene. At 0.2%, after 4 hours 55% conversion gave 69% selectivity. The catalyst was solid orthotitanic acid. The foregoing conversions and selectivities are commercially acceptable.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:27])[CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[O:13][CH2:12]1.C(O)=[O:29]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:27])[CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([OH:13])[CH2:12][OH:29]
Reactant: O=CO
Reactant: COc1cc(C(=O)CSc2ccnc3ccccc23)ccc1OCC1CO1
Solvent: O
Product: COc1cc(C(=O)CSc2ccnc3ccccc23)ccc1OCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4-[2-[3-Methoxy-4-(2,3-epoxypropoxy)phenyl]-2-oxoethylthio]quinoline (Compound 57; 2.0 g, 5.25 mmol) was added at 0° C. to the mixture of formic acid (40 ml) and water (4 ml), and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with an ice-cooled aqueous solution of 40% sodium hydroxide (7.0 ml) and stirred at 0° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was chromatographed by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 1.4 g of the titled compound (67.0%). Melting Point: 177° C. (decomp.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][C:10]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCCCCC.BrC1C=CC=C([OH:34])C=1C>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:11][C:12]([OH:34])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCCC2)CC1=O
Reactant: Cc1c(O)cccc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
3-oxo-2-aza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (253 mg, 1 mmol) was dissolved in THF (5 ml) and an aqueous solution of 1N LiOH (72 mg/3 ml, 3 molequivalents) was added thereto. The mixture was stirred at 25° C. for 6 hours while monitoring the progress of the reaction by TLC, using a 6:4 hexane:ethyl acetate mixture as eluent and bromocresol for developing the TLC plate. Reaction completion was indicated by the appearance of a more polar spot while the starting material gradually disappeared from the middle of the TLC plate. Thereafter, the THF was evaporated under reduced pressure and the basic aqueous residue was acidified by the addition of 15 drops of concentrated HCl (pH 3) and extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate and the combined organic layer was washed with water, dried over NaSO4 and evaporated under reduced pressure to give [1-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid (228 mg, 84% yield) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[C:20]([N:22]([CH2:24]C2C=CC=CC=2OC)C)=[O:21])=[CH:4][CH:3]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:38]CN>>[F:49][C:34]([F:33])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:38][N:22]([CH3:24])[C:20]([C:9]1[N:10]([CH3:19])[C:11](=[O:18])[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:17]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:21]
Reactant: COc1ccccc1CN(C)C(=O)c1c(-c2ccc(F)cc2)c2cccnc2c(=O)n1C
Reactant: NCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2cnccc2c(=O)n1C

Procedure:
Employing 4-(4-fluorophenyl)-1,2-dihydro-2-methyl-1-oxo-3-pyrido[4,3-c]pyridine carboxylic acid (Reference Example 4) and N-[3,5-bis(trifluoromethyl)benzyl]methylamine, reaction was allowed to proceed and the reaction mixture was processed in substantially the same manner as in Example 1 to give the above-titled compound as colorless crystals, m.p.136°-138° C. (recrystallized from ethyl acetate-isopropyl ether).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5])[CH3:2].[CH3:20][O:21]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:20]=[O:21])[CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A stirred, cooled (ice bath) solution of of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treated with titanium tetrachloride (0.4 mL, 3.26 mmol) followed by α,α-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowed to warm to ambient temperature over 2 days, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography to afford the title compound (0.11 g, 20%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>C(#N)C.C(OCC)(=O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[NH:12]1[C:13]2[C:9](=[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:28][CH2:29]3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCCCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-5-(4-indolyloxy)pentane, 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 47% overall yield as a white solid. mp. 178°-180° C. FDMS m/e=412 (M+ of free base).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][C:20](C)([O-])[CH3:21].[K+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1.C(Br)C=C>CCOCC.O>[CH2:21]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH:20]=[CH2:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CCn1ccc2ccccc21
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 ml of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide. The mixture was stirred while 11.72 g (100 mmoles) indole was added. The stirring was continued for 3 hours. All of the solid did not dissolve. Then 14.1 g (116.5 mmoles) of allyl bromide in 100 ml of ether was added during 0.5 hour. The stirring was continued for 67.5 hours. Water (200 ml) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 ml). The combined ether phases were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 16.02 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 10% acetone-Skellysolve B and 2200 ml fractions were collected. The fractions were assayed by silica gel tlc (1×4") (10% acetone-Skellysolve B). Fractions 17-23 were combined giving 11.60 g (74%) of 1-allylindole as a yellow brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[N:5]2.[H-].[Na+].CI.[CH3:31]N(C)C=O>O>[CH3:31][N:12]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)Oc1cccc(N(C)c2cnc3cc(Cl)ccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-{3-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate (10 mmole), sodium hydride (10 mmole), methyl iodide (50 mmole) and dimethylformamide (50 ml) was stirred at room temperature for a period of 3 hours. Water was added to the reaction mixture and the precipitated product was collected by filtration. The product was purified by chromatography over alumina (eluent dichloromethane) to give ethyl 2-{3-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:39]=[C:38]([NH:40][C:41](=[O:53])[C:42]2[CH:47]=[CH:46][C:45]([O:48][C:49]([F:52])([F:51])[F:50])=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]=1[C:54]1[CH:62]=[C:61]2[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]2=[O:63])=[CH:56][CH:55]=1>>[F:33][C:34]1[CH:39]=[C:38]([NH:40][C:41](=[O:53])[C:42]2[CH:43]=[CH:44][C:45]([O:48][C:49]([F:50])([F:51])[F:52])=[CH:46][CH:47]=2)[CH:37]=[CH:36][C:35]=1[C:54]1[CH:62]=[C:61]2[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([OH:67])=[O:66])[C:60]2=[O:63])=[CH:56][CH:55]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3F)cc2C1=O
Yield: 80 %

Procedure:
The compound of example 608 was prepared analogous to compound of example 98 by hydrolysis of compound of example 607.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH3:19]>C(O)C>[NH2:19][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: N
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A mixture of 5 g of 6-(4-chloro-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, 50 ml of 25% aqueous NH3 solution and 50 ml of ethanol is heated at 100° for 16 hours. The mixture is poured into ice water and extracted with methylene dichloride, the phases are separated and the organic phase is dried over sodium sulfate and evaporated to give 6-(4-amino-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 234°-238°.