Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH3:14])[CH:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][CH:6]3[C:5]=2[CH:4]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:12]=[C:13](/[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)\[CH3:14])[C:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1CN(C)CCC1N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)c1c(n2/C=C(\C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(8-Methoxy-2-methyl-2,3,4,4a-tetrahydro-1H-pyrido[4,3-b]indol-5(9bH)-yl)-2-(pyridin-4-yl)propan-2-ol (500 mg, 1.4 mmol) in thionylchloride (5 mL) and stirred at RT for 2 h. The reaction mixture was concentrated followed under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (4 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (798 mg, 14.2 mmol) was added, the reaction mixture was stirred at RT for 5 min. and then at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. Upon completion the reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.70 (d, 2H), 7.30 (s, 1H), 7.10 (d, 1H), 6.95 (s, 1H), 6.80 (d, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 3.10 (t, 2H), 2.90 (t, 2H), 2.70 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH2:10]([O:17][C:18](=[O:44])[C:19]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][CH2:21][C:22](=[O:27])N(OC)C)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC>[CH2:10]([O:17][C:18](=[O:44])[C:19]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:20][CH2:21][CH:22]=[O:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)CCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC(CCC=O)(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
A solution of DIBAL (1.0 M, 14.7 mL, 14.7 mmol) in hexane was added dropwise to a solution of 2,2-bis(tert-butoxycarbonylamino)-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (4 g, 10.5 mmol) under an atmosphere of nitrogen at −78° C. After 2 hours the mixture was quenched with saturated ammonium chloride (30 mL) and allowed to warm to room temperature. Water (20 mL) was added, and the mixture was extracted with diethyl ether (3×50 mL). The combined organic phases were left to stand at room temperature for 15 minutes. The resulting thick gel was filtered through a pad of CELITE. The filtrate was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to provide 2,2-bis(tert-butoxycarbonylamino)-5-oxo-pentanoic acid benzyl ester (3.34 g, 7.9 mmol, 75%). This was used immediately in the next step.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][O:4][CH2:3]1>C1COCC1>[C:9]1([CH2:8][N:7]2[CH2:2][CH2:3][O:4][CH2:5][C@@H:6]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H]1COCC(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1COCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title Compound was prepared according to the procedure used by G. R. Brown, J. Chem. Soc. Perkin Trans 1, 1985, 2577, using ethyl (3R)-5-oxo-4-(phenylmethyl) -3-morpholinecarboxylate (D45, 3.64 g, 13.84 mmol) in dry THF (70 mL), cooled in an ice bath before adding borane-dimethylsulphide complex (1.84 mL, 10M), slowly. The reaction mixture was allowed to warm up to room temperature overnight. Stirred for further six hours, added more borane-dimethylsulphide complex and stirred at R.T. over the weekend. Reaction quenched carefully with water, dropwise till the effervescence had finished. Solvent evaporated. Residue dissolved in water, basified to pH ˜10 using 2N NaOH solution before extracting with Et2O. Organic layer was then extracted with 2N HCl solution. Acid layer was then basified using 2N NaOH solution before extracting with Et2O ×3. Combined extracts were dried (MgSO4). Filtered. Evaporated under reduced pressure to afford the title compound as a colurless oil in a 68% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([F:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: Oc1cc(F)ccc1F
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 100 mL of CHCl3. To the stirred solvent were added 2,5-difluorophenol (5.0 g, 38.4 mmol), bromine (6.14 g, 38.4 mmol), at 0° C. and stirred at room temperature for 3 h. The reaction mixture was quenched with sodium thio sulphate solution (20 mL) and extracted with ethyl acetate (15 mL×2). The organic layer was washed with water (50 mL), followed by brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain product (6.5 g, yield: 81.05%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)C(=O)CCl
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [N:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O>ClCCCl>[Br:13][CH:8]([C:9](=[O:11])[CH3:10])[C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)CC(=O)N1CCOCC1
Solvent: ClCCCl
Product: CC(=O)C(Br)C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 1-morpholin-4-yl-butane-1,3-dione (0.53 g, 3.1 mmol) in 1,2-dichloroethane (30 mL) stirred at 0° C., N-bromosuccinimide (0.55 mg, 3.1 mmol) was added in small portions and the mixture was stirred for 1 h. The solution was washed with brine (3×5 mL), dried over MgSO4 and concentrated below 30° C. 2-Bromo-1-morpholin-4-yl-butane-1,3-dione 0.76 g, 3.04 mmol, 98.1%, LCMS/BB_LCMS01(+)/: M+1=250, 252, Rt: 1.831 min] was obtained as a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[CH:15]([CH2:32]C([O-])=O)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1>CS(C)=O.[Na+].[Cl-]>[C:1]([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([CH2:32][CH:15]([O:7][C:6](=[O:5])[CH3:8])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCc1ccc(OCC(CBr)CC(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(Cn2ccc(C(=O)OC(C)(C)C)c2)OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
0.145 g (0.867 mmol) tert-butylpyrrole-3-carboxylate is dissolved in 10 ml absolute DMSO, mixed with 0.107 g (0.952 mmol) potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of 0.333 g (0.864 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO is added drop-wise. Following 30 minutes of heating at 110° C. and subsequent cooling, hydrolysis is carried out in saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps using saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 93:7) and yields the product as a colorless oil.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11](Cl)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][C:4]=2[O:5]1
Reactant: ClCC=Cc1ccccc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=Cc1ccccc1)COc1ccc2c(c1)OCO2

Procedure:
A mixture of sesamol (27.6 g.), cinnamyl chloride (30.4 g.), anhydrous potassium carbonate (50.0 g.), potassium iodide (2.0 g.) in anhydrous acetone (100 ml.) was heated under reflux for 1.5 hrs. The acetone was removed by evaporation, and the residue was treated with excess water and cooled to give an oil, which subsequently solidified. The crude product was collected by filtration and recrystallized from methanol to give MDCB as colorless prisms, m.p. 83° C., yield 15.0 g. (Found: C, 75.4; H, 5.67. Calculated for C16H14O3 : C, 75.6; H, 5.55.) The nuclear magnetic resonance (NMR) spectrum of MDCB at 100 MHz in deuterated chloroform (CDCl3) exhibited absorbances as follows: a doublet (2 protons) at δ 4.59 (coupling constant J = 6.0 Hz), singlet (2 protons at δ 5.89, a multiplet (5 protons) at δ 6.22-6.80, and a multiplet (5 protons) at δ 7.18-8.48.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N.[Na].Br[CH2:18][CH2:19][C:20]([OH:22])=[O:21].Cl>CCOCC.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: Fc1ccccc1Cc1ccccc1
Reactant: O=C(O)CCBr
Agent: [Fe+3]
Agent: Cl
Agent: N
Solvent: CCOCC
Product: O=C(O)CCC(c1ccccc1)c1ccccc1F
Reaction time: 0.17 h

Procedure:
100 g of 2-fluorodiphenylmethane are slowly added dropwise to a solution of sodiuum amide which has been prepared from 500 ml of liquid ammonia, 0.22 g of iron (III) nitrate and 13.2 g of sodium. After 10 minutes, a solution of 40.75 g of 3-bromopropionic acid in 500 ml of ether is added dropwise. After a further 15 minutes, the ammonia is allowed to distill off. The crystallized-out sodium salt of 4-(2-fluorophenyl)-4-phenylbutyric acid is filtered off and washed with ether. The free acid is obtained by treating the sodium salt with dilute hydrochloric acid, extracting the mixture with ether and evaporating the ethereal solution. There is obtained 4-(2-fluorophenyl)-4-phenylbutyric acid of melting point 105°.
Reaction SMILES: N1[C:9]2[C:4](=[C:5](C3N=C(N4CCOCC4)C4SC(COC)=CC=4N=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with benzyl bromide to give 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Suzuki coupling of 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine and 7 was carried out via General Procedure A. Purification using column chromatography gave 315. NMR: CDCl3: 3.88-3.94 (4 H, m, CH2), 4.09-4.14 (4 H, m, CH2), 4.69 (2 H, s, CH2), 4.86 (2 H, s, CH2), 7.31-7.46 (6 H, m, Ar), 7.53 (1 H, t, J 8.22, Ar), 7.56 (1 H, t, J 8.24, Ar), 8.30 (1 H, d, J 6.94, Ar), 9.03 (1 H, s, Ar) and 10.1 (1 H, s, NH). MS: (ESI+): MH+ 458.16
Reaction SMILES: Cl.[I:2][C:3]1[C:8]([O:9]C2CCCCO2)=[CH:7][N:6]=[C:5]([O:16][CH3:17])[CH:4]=1>O1CCOCC1.O>[I:2][C:3]1[CH:4]=[C:5]([O:16][CH3:17])[N:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(I)c(OC2CCCCO2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(I)c(O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 ml (3 molar, 150 mmol) of hydrochloric acid were added to a solution of 25.1 g (purity 82%, 61.3 mmol) of 4-iodo-2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 50 ml of dioxane and 50 ml of water, and the mixture was stirred at RT for 2 h. The reaction mixture was then filtered and the precipitate was rinsed with water and dried under high vacuum. Yield: 13.5 g (purity 93%, 81% of theory)
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Nc1ccccc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(Nc2ccccc2Cl)n1
Temperature: 20 °C
Yield: 97.6 %

Procedure:
272.0 g of cyanuric chloride (content >99%), 1,000 ml of water and 275 ml of toluene are mixed at 5° C. The aqueous phase thereby assumes a pH value of 3.5. 188.2 g of o-chloroaniline are added in the course of 30 minutes without cooling or heating the mixture, whereupon the temperature rises to 30° C. A pH value of 7 is then established in the course of 1 hour by addition of 45% strength sodium hydroxide solution, whereupon the temperature rises up to 55° C. The mixture is then cooled to 20° C. in the course of 15 minutes. The product is filtered off, washed salt-free with water and dried at 60° C. in a waterpump vacuum. 396.5 g of 2-(2-chlorophenylamino)-4,6-dichloro-s-triazine are obtained with a melting point of 159° C. and a content of 98.9%, which corresponds to a yield of 97.5% (based on 99 % pure cyanuric chloride).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35]C)[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[O:31])[O:13][C:14]2[CH:27]=[C:26]3[CH2:28][CH2:29][CH2:30][C:25]3=[CH:24][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9].[B].C(O)C>ClCCl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[OH:35])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[O:31])[O:13][C:14]2[CH:27]=[C:26]3[CH2:28][CH2:29][CH2:30][C:25]3=[CH:24][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9]
Reactant: COc1ccc(C=CC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc1OC
Agent: [B]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1-c1c(NC(=O)C=Cc2ccc(O)c(O)c2)c(=O)oc2cc3c(cc12)CCC3
Yield: 95.8 %

Procedure:
To a solution of 3-(3,4-dimethoxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocylopenta[g][1]benzopyran-2(6H)-one (400 mg) in dichloromethane (6 ml) was added boron tribromidedichloromethane (1:2, 1 ml) dropwise with ice-cooling and stirring. The mixture was further stirred under ice-cooling for 1 hour and, then, added gradually to ethanol (5 ml) with ice-cooling. The mixture was diluted with water and extracted with ethyl acetate, the extract was washed with water and dried (MgSO4), and the solvent was distilled off to give crystals of 3-(3,4-dihydroxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g][1]benzopyran-2(6H)-one (361 mg, 95.8%). Recrystallization from ethanol gave light brown prisms, m.p. 295°-297° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[C:33]([S:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][N:28]=1>C(#N)C>[CH3:39][S:38][C:33]1[C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:31]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CSc1ncccc1-c1nc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccnc2SC)n1
Yield: 83.9 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.100 g, 0.396 mmol) in anhydrous acetonitrile (20 mL) was added Cs2CO3 (1.30 g, 4.00 mmol) and 3-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2-(methylthio)pyridine (0.170 g, 0.594 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.152 g, 84% yield): MS (ES) m/z 458 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2c(Br)c(Cl)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ccn12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (515 mg, 2.258 mmol) in anhydrous DMF (10 mL) was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (883 mg, 4.518 mmol), followed by solid potassium carbonate (624 mg, 4.518 mmol). The resulting suspension was stirred under argon at 80° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc twice. The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure to provide crude product as a brown solid. The crude product was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexanes to obtain the title compound as a beige solid (742 mg, 81%). HPLC/MS: retention time=3.17 min, [M+H]+=407. See 7,8-bis(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one for data addressing the question of N vs. O-alkylation.
Reaction SMILES: [CH:1]1([N:7]2[CH2:43][CH2:42][C:10]3([CH2:14][N:13]([CH2:15][C:16]4[CH:41]=[CH:40][C:19]([CH2:20][N:21]([CH2:28][C:29]5[N:30]([CH2:34][C:35]([O:37]CC)=[O:36])[CH:31]=[CH:32][N:33]=5)[CH2:22][C:23]5[NH:24][CH:25]=[CH:26][N:27]=5)=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([N:7]2[CH2:43][CH2:42][C:10]3([CH2:14][N:13]([CH2:15][C:16]4[CH:41]=[CH:40][C:19]([CH2:20][N:21]([CH2:28][C:29]5[N:30]([CH2:34][C:35]([OH:37])=[O:36])[CH:31]=[CH:32][N:33]=5)[CH2:22][C:23]5[NH:24][CH:25]=[CH:26][N:27]=5)=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cn1ccnc1CN(Cc1ccc(CN2CCC3(CCN(C4CCCCC4)CC3)C2)cc1)Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1ccnc1CN(Cc1ccc(CN2CCC3(CCN(C4CCCCC4)CC3)C2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ethanol (7.6 mL) solution of the compound (50 mg) obtained in Example 8, an aqueous 2N-sodium hydroxide solution (1.0 mL) was added. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was neutralized with 2N-hydrochloric acid (1.0 mL) added thereto and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=7:3) to obtain the title compound having the following physical properties (38 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][O:50]1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:55][CH:52]([CH2:53][OH:54])[CH2:51][OH:50])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 332) (85 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (120 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (40 mg), and diethylazodicarboxylic acid (0.083 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (80 mg, yield 76%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1([CH3:25])[CH2:22][C:21](=O)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=2)[S:14]1>C1COCC1.CCCCCC.CCOCC>[CH3:12][C:13]1([CH3:25])[CH:22]=[C:21]([C:4]2[S:3][C:2]([CH3:1])=[CH:6][CH:5]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=2)[S:14]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2S1
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)s1
Temperature: 25 °C

Procedure:
To a cold (-78° C.) solution of 2-methylthiophene (1.2 g, 12.2 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6M, 8.5 mL). The mixture was warmed to ambient temperature over 30 minutes. with stirring. The mixture was recooled to -78° C. and a solution of 2,2-dimethyl-6-bromo-thiochroman-4-one (Compound M, 1.4 g, 5.2 mmol) in THF (10 mL) was added. The mixture was stirred for 16 hours at ambient temperature. Then the reaction mixture was diluted with ether (125 mL), washed with water (10 mL), brine (10 mL) dried and the solvent was removed by evaporation. The product was seperated by column chromatography and was dissolved in dichloromethane (5 mL). To this solution p-TSA (5 mg) was added and the mixture was stirred at ambient temperature for 5 min. The reaction was quenched with 10% NaHCO3 (3 mL), washed with brine (5 mL), dried and the solvent was removed by distillation. The residual crude material was purified by column chromatography to obtain the title compound as a pale yellow oil.