Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].[OH:3][C:4]([C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:8]=1)([CH3:6])[CH3:5].[N:23]1[N:24]=[C:25]([C@@H:28]([NH2:30])[CH3:29])[NH:26][CH:27]=1.C(N(CC)CC)C.C(Cl)C[Cl:40]>CN(C=O)C.O>[ClH:40].[OH:3][C:4]([C:7]1[CH:12]=[C:11]([C:13]([NH:30][C@H:28]([C:25]2[NH:26][CH:27]=[N:23][N:24]=2)[CH3:29])=[O:15])[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:8]=1)([CH3:5])[CH3:6]
Reactant: C[C@H](N)c1nnc[nH]1
Reactant: ClCCCl
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(C)(C)O)n2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)c3nnc[nH]3)cc(C(C)(C)O)n2)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of the sodium chloride salt of 2-(2-hydroxypropan-2-yl)-6-(4-methylphenyl)pyridine-4-carboxylic acid (224 mg, 0.58 mmol) in DMF (2.3 mL) was added the hydrochloride salt of (1S)-1-(4H-1,2,4-triazol-3-yl)ethanamine (160 mg, 0.87 mmol), HOST (89 mg, 0.58 mmol), triethylamine (322 pt, 2.31 mmol), and EDC (139 mg, 0.72 mmol). The resulting mixture was heated to 60° C. After 30 min, the mixture was cooled to ambient temperature. A small amount of water was added and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid). Treatment with 2 M hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt. (230 mg). HRMS 366.1920 (M+1). 1H NMR (399 MHz, DMSO): δ 9.28 (d, J=7.9 Hz, 1H); 8.38 (s, 1H); 8.18 (s, 1H); 8.07 (d, J=8.0 Hz, 2H); 8.02 (d, J=1.3 Hz, 1H); 7.33 (d, J=7.9 Hz, 2H); 5.37 (t, J=7.3 Hz, 1H); 2.38 (s, 3H); 1.59 (d, J=7.0 Hz, 3H); 1.52 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1
Reactant: Oc1cc2nc(-c3ccccc3)nn2c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccccc3)nn2c2ccccc12
Reaction time: 1 h

Procedure:
One gram (0.00383 mole) of the compound of Example 1 is dissolved at 60° C. in 30 ml. of dimethylformamide, the resulting solution is brought to room temperature, then 0.2 g. of a 50% oily suspension of sodium hydride is added. After 1 hour, 0.25 ml. (0.004 mole) of methyl iodide is added and the obtained mixture is stirred for 5 hours and concentrated to dryness. The obtained residue is taken up with water and recrystallized from ethanol. Yield, 0.55 g., m.p., 144°-145° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CCOCC.O>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc(Oc2ccc(OCCN3CCCC3)cc2)cc1
Reaction time: 15 h
Yield: 92.9 %

Procedure:
A solution of 4-phenoxyphenol (0.56 g, 3.0 mmol), 1-(2-chloroethyl)-pyrrolidine HCl (0.51 g, 3.0 mmol) and powdered K2 CO3 (1.2 g, 8.7 mmol) in 30 mL DMF was stirred at 80°-90° C. for 15 hours. The solution was cooled, poured into Et2O and water and the ether layer washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 0.79 g of a brown oil. The crude product was flashed chromatographed on silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc to provide the title compound (0.65 g, 76.5%) as a light yellow oil:
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OC(=O)C)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][CH:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)Nc1nc2ccc(CCBr)cc2s1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1nc2ccc(CCN3CCC(Cc4ccccc4)CC3)cc2s1
Yield: 67 %

Procedure:
A solution of 3 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethane and 1.95 g of 4- benzylpiperidin and 3.5 g of K2CO3 in 20 ml of DME was heated at 75° C. for 2 hours. The solution was diluted with ethylacetate and washed with brine, after removal of the solvent the residue was heated at reflux in 50 ml of ethanol containing 5 ml of 5 M NaOH for 1 hour. The solvent was evaporated and the residue taken up in ethylacetate was washed with brine and dried. After removal of the solvent, the reaction produce was chromatographed on silica gel eluting with ethylacetate/cyclohexane ⅓ affording the title compound in 67% yield, m.p. 152-153° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CS(C)=O>[OH:1][CH2:2][CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[S:24]
Reactant: S=C=S
Reactant: OCC1Cc2c([nH]c3ccccc23)CN1
Reactant: COc1ccc(CCl)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3CC2CO)cc1
Yield: 71 %

Procedure:
In the same manner as described in Example 29 by using (3RS)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.01 g), triethylamine (0.7 ml), CS2 (0.3 ml), 4-methoxybenzyl chloride (1.0 g) and dimethylsulfoxide (5 ml), there is prepared the title compound (1.41 g, 71%) as white powder, NMR (CDCl3 +DMSO-d6, δ): 4.52 (s, 2H, ##STR16## Mass m/e: 398 (M+), 244 (M+ -- ##STR17##
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Cl[C:16]1[C:17](=[O:35])[N:18]([CH2:33][CH3:34])[C:19]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:23]=[CH:22][C:20]=2[N:21]=1.CCOC(C)=O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[C:19]2[N:18]([CH2:33][CH3:34])[C:17](=[O:35])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[N:21][C:20]=2[CH:22]=[N:23]1
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
Reactant: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(C(=O)O)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 130 °C

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (175 mg, 0.88 mmol) and 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (250 mg, 0.80 mmol) in 4.0 mL dioxane and 2.0 mL of 1 N sodium carbonate was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (15 mL) and extracted with 1N NaOH (3×10 mL). The aqueous extracts were treated with 5 N HCl to pH 2 and extracted with DCM (3×15 mL). The combined DCM layers were dried over MgSO4, filtered and concentrated affording 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid as a light orange-brown viscous oil. This material was used without purification. MS (ES+): 429.1 (M+H)+.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:19])([F:20])[F:21])[O:16][CH2:17]1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (19.0 mL) was added to a solution containing ((2S,3R,45)-4-amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (28.72 g) in DCM (150 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 200 mL) was then added, the mixture extracted with EtOAc (3×300 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 30% EtOAc in hexanes) to obtain the title compound (37.07 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.22 (dd, J=8.1, 4.5 Hz, 1H), 3.31 (td, J=8.0, 3.0 Hz, 1H), 3.94-4.07 (m, 1H), 4.31-4.46 (m, 1H), 4.53 (d, J=9.9 Hz, 1H), 4.83 (d, J=9.9 Hz, 1H), 6.97-7.14 (m, 1H), 7.22 (td, J=7.7, 1.3 Hz, 1H), 7.31-7.45 (m, 1H), 7.49-7.61 (m, 2H), 7.61-7.70 (m, 1H), 7.75 (td, J=8.1, 1.5 Hz, 1H), 7.79-7.93 (m, 2H), 8.90 (s, 1H), 11.85 (s, 1H)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[CH3:27][N:28]([CH3:35])[CH2:29][CH2:30][CH2:31]C(Cl)=O.[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40][NH2:41])[CH3:37]>>[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40][NH:41][C:24]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:12][N:8]1[C:6](=[O:7])[CH2:31][CH2:30][CH2:29][N:28]([CH3:35])[CH3:27])=[O:26])[CH3:37]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CN(C)CCCC(=O)Cl
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1C(=O)CCCN(C)C

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=476.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[N:35]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]4[CH2:44][CH2:45][CH:40]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:41][CH2:42]4)=[C:8]([O:33][CH3:34])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:20]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-(1-pyrrolidinyl)piperidine (60 mg), and potassium carbonate (90 mg) was suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then 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 methanol-chloroform to give the title compound (69 mg, yield 90%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][CH3:16])[CH2:8][C:7]1=[O:17])(=O)[CH2:2][CH2:3][CH3:4].[CH2:18]([O:21][NH2:22])[CH:19]=[CH2:20]>C(O)C>[CH2:18]([O:21][NH:22][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][CH3:16])[CH2:8][C:7]1=[O:17])[CH2:2][CH2:3][CH3:4])[CH:19]=[CH2:20]
Reactant: C=CCON
Reactant: CCCC(=O)C1C(=O)CC(CCSC)CC1=O
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCSC)CC1=O
Yield: 95 %

Procedure:
2.6 g of 2- butyryl-5-(2-methylthioethyl)-cyclohexane-1,3-dione was allowed to react with 0.8 g of allyloxyamine at room temperature for 10 hours in 20 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 3 g of the desired compound as colorless oily material. nD27 1.5402
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(OCC)C.O.[Cl-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(C(=O)O)cccc1-c1cccs1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(CO)cccc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, a stirred solution of 5.7 g (0.026 mol) of 2-methyl-3-(2-thienyl)benzoic acid in 50 mL of tetrahydrofuran was cooled to 0° C.±2° C. To this solution was added dropwise 4.4 g (0.051 mol, 51.3 mL of a 1.0 M solution) of borane tetrahydrofuran complex. The addition was made over 35 minutes. The reaction mixture was stirred for 0.5 hour at ambient temperature, then for two hours at reflux temperature. The reaction mixture was cooled, and 100 mL of diethyl ether saturated with water, then 20 mL of water, were cautiously added. The mixture was transferred to a separatory funnel containing 50 mL of ice, and was saturated with solid sodium chloride, and extracted with three portions of 200 mL each of diethyl ether. The combined extracts were dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 5.3 g of 2-methyl-3-(2-thienyl)phenylmethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:23]([CH:24]=[CH2:25])=[CH:22][N:21]=[C:20]([CH3:26])[CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([CH3:26])=[CH:19][C:18]=3[C:17]([F:28])([F:16])[F:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(F)(F)F)c(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:23][S:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:25]([S:24][CH3:23])[C:26]([NH:28][CH3:29])=[O:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CNC(=O)CSC
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C(SC)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 38.3 g (0.166 mole) of 2-amino-5-chlorobenzophenone in 1 liter of methylene chloride cooled to -70° C. under an atmosphere of nitrogen was added 18.05 g (0.167 mole) of t-butylhypochlorite. The solution was stirred for 15 min and then a solution of 20.3 g (0.171 mole) of 2-methylthio-N-methylacetamide in 100 ml of methylene chloride was added. The solution was stirred at -70° C. for 2 hrs and 25 ml of triethylamine was added. While stirring, the solution was allowed to warm to room temperature followed by extraction with water and drying of the organic layer with magnesium sulfate. The volume of the solution was reduced to about 400 ml, ether was added and the solution placed in a refrigerator at about 0° C. overnight. The solid which crystallized was dried under high vacuum for about 4 hr at 50° C. Weight of the product was 31.56 g (54.6%) which melted at 170°-171° C.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)[CH3:7]
Reactant: CCC(=O)CC#N
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCc1cc(N)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+.
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[N:20]1[CH:21]=[C:22]([C:29](O)=[O:30])[N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=12.C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:29]([C:22]3[N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[N:20][CH:21]=3)=[O:30])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Reactant: O=C(O)c1cnc2ccccn12
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2ccccn12

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=368 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1cccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)n1
Solvent: CS(C)=O
Product: Cc1cccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)n1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:4]1=[O:20].[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[C:21]1([CH2:27][CH2:28][NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[C:4]2=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(CN1CCC[C@H](NCCc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a mixture of 41 (1.50 g, 5.02 mmol) and phenylacetaldehyde (0.724 g, 6.03 mmol) in 35 mL of 1, 2-dichloroethane was added triethylamine (2.03 g, 21.1 mmol, 2.80 mL). After stirring at ambient temperature for 10 min, sodium triacetoxyborohydride (1.49 g, 7.03 mmol) was added rapidly over a 5 min period. The reaction mixture was stirred at room temperature for 15 hrs and quenched with 30 mL of water. The mixture was diluted with 50 mL of CH2Cl2 and the organic phase was separated, washed with 30 mL portions of saturated NaHCO3, water, brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with CH2C12, ethanol: 95, 5 to afford 1.21 g (66% yield) of product 42 as a pale yellow oil; TLC (silica gel; CH2Cl2, ethanol: 9, 1): Rf=0.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:37]=1[NH:38][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(F)c4F)cc3)c2cc1OC
Yield: 78.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,3-Difluoroaniline (51 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 60 mg of the title compound (yield: 79%).