Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][S:13][CH3:14]>CN(C)C=O>[CH3:12][S:13][CH2:14][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CSCCl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc([N+](=O)[O-])n1
Yield: 67.1 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 50 mg, 4.42 mmol) in anhydrous N,N-dimethylformamide (5 mL), a 60% dispersion of sodium hydride in mineral oil (230 mg, 5.75 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, chloro-methylsulfanyl-methane (555 mg, 5.75 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-methylsulfanylmethyl-3-nitro-1H-pyrazole (514 mg, 67%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1>[Pd].C(O)C>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][CH:2]=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1)[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1ccccc1O2
Reaction time: 8 h

Procedure:
A mixture of (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.0500 g, 0.120 mmol), ethanol (2 mL), and palladium 10% on activated carbon (0.013 g, 0.012 mmol) was stirred under 1 atm of H2 gas overnight. The catalyst was filtered through celite and the filtrate was concentrated in vacuo to provide (S)-2′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.F[C:19](F)(F)S(OC)(=O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Li+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]1[CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH:17]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: FC(F)(F)c1ccc(Br)c(-c2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Product: CN1CCC=C(c2cc(C(F)(F)F)ccc2Br)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
A solution of 3-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (2.000 g, 6.62 mmol) in 13 mL DCM was treated with methyl trifluoromethanesulfonate (0.802 ml, 7.28 mmol) and was allowed to stir at room temperature for one hour. LC/MS showed mostly product so the reaction mixture was treated with sodium triacetoxyborohydride (4.21 g, 19.86 mmol) and was allowed to stir at room temperature overnight. LC/MS showed only a small amount of product, so the reaction mixture was concentrated then taken back up in 12 mL THF and cooled to 0° C. lithium borohydride (3.31 ml, 6.62 mmol) was added, and the reaction mixture was allowed to stir for one hour. LC/MS showed mostly product, so the reaction mixture was quenched with 7N ammonia in MeOH and was allowed to stir over the weekend. The reaction mixture was poured into water and was extracted with DCM. The organics were concentrated the purified directly by reverse phase column chromatography yielding 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine (0.860 g, 2.69 mmol, 40.6% yield) with impurities. m/z (ESI) 321.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([O:28]C)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([OH:28])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Temperature: 50 °C
Reaction time: 10 h

Procedure:
Methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (0.9 g, 2 mmol, 1 eq) and sodium hydroxide (0.4 g, 10 mmol, 5 eq) were dissolved in methanol/water (20/5 ml) and the reaction was stirred at 50° C. for 10 h. Then the reaction mixture was concentrated and diluted with water and the pH of the solution was brought to 3 by using Conc HCl. The solid obtained was filtered and dried overnight. Yield: 0.72 g (82%). 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 2.87 (d, 3H), 3.87 (s, 3H), 7.09 (s, 1H), 7.40-7.60 (m, 3H), 7.57 (m, 2H), 7.65 (d, 1H, J=8.74 Hz), 7.98-8.01 (m, 2H), 8.46 (q, 1H, J=4.40 Hz), 12.5 (br s, 1H). LCMS: (ES+) m/z=434 (M+H) Method: Mphase A: water Mphase B: 0.1% acetone in water Flow-2 mL/Min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17]C(C)C)=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1.[Li+].[OH-].C(OCC)(=O)C>C1COCC1.O.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(Cl)nc(OC(C)C)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-c2ncn(/C=C\C(=O)O)n2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
In a 250-mL, 2-neck round-bottomed flask equipped with rubber septum, (Z)-isopropyl 3-(3-(2-chloro-6-isopropoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate (2.0 g, 1.0 eq.) was dissolved in THF:Water (1:1) (20 mL: 20 mL). To this reaction mixture LiOH (0.478 g, 2 eq.) was added and reaction mixture was stirred at room temperature to 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 20% ethyl acetate in hexane as mobile phase. Reaction mixture was quenched in water (500 mL) and acidified using dilute HCl. The aqueous layer was extracted multiple times with ethyl acetate (100 mL×3). The organic layer were washed with saturated brine solution and dried over anhydrous NaSO4. The organic layer was concentrated under reduced pressure to obtain 1.61 g (91.7%) of desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([O:23][CH3:24])=[CH:15][C:10]=2[C:11](OC)=[O:12])=O)=[CH:4][CH:3]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[N:27]=[C:11]([OH:12])[C:10]3[C:9](=[C:18]([O:19][CH3:20])[C:17]([O:21][CH3:22])=[C:16]([O:23][CH3:24])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1NC(=O)c1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: COc1cc2c(O)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Temperature: 100 °C

Procedure:
A suspension of 28.5 g of methyl 2-(4-chlorobenzoylamino)-3,4,5-trimethoxybenzoate in 200 ml of methanol was treated with 150 ml of liquid ammonia and heated at 100° C. for 5 h in an autoclave. On cooling, a precipitate deposited, which was filtered off with suction and dried under reduced pressure. Yield: 25 g. M.p.: 289° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[CH3:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C)c(C)c1N
Reaction time: 48 h
Yield: 101.5 %

Procedure:
A suspension of methyl 3,4-dimethyl-2-nitrobenzoate (23 g) and Pd/C (2.3 g) in methanol (400 ml) was stirred under hydrogen (1 bar) for 48 h and filtered through Celite under nitrogen atmosphere. Evaporation of methanol gave methyl 3,4-dimethyl-2-aminobenzoate (20 g). 1H-NMR (400 MHz, CDCl3): 7.67 (d, 1H), 6.6 (d, 1H), 3.86 (s, 3H), 2.27 (s, 3H), 2.1 (s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: COc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 260A (0.045 g, 0.095 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.19 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methanol/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.77 (s, 3 H) 3.82 (s, 2 H) 5.98 (s, 1 H) 6.95 (d, J=8.46 Hz, 2 H) 7.10 (t, J=7.54 Hz, 1 H) 7.30 (m, 2 H) 7.45 (d, J=8.46 Hz, 2 H) 7.56 (s, 2 H) 7.70 (t, J=9.38 Hz, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.29 (m, 1 H). MS (ESI−) m/z 475 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[N+:15]=[N-:16])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C)cc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C)cc(N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 9.68g. (0.08 mole) of 3,5-dimethylaniline in 100 ml. of water and 10 ml. of concentrated HCl was cooled to 0° C. Then a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water was added dropwise to the solution of 3,5-dimethylaniline, and the reaction mixture was aged for one-half hour. There was then added to the reaction mixture 70 ml. of n-hexane followed by a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water which was added dropwise and accompanied by vigorous evolution of gas from the reaction mixture. The reaction mixture was then stirred for 15 minutes at room temperature. Separate layers were observed to form and the hexane layer was noted to have a deep yellow color. The reaction mixture was extracted again with 50 ml. of hexane, and the combined hexane extracts were dried over MgSO4 and concentrated to a volume of 95 ml. Structure of the final product was confirmed by IR. The 95 ml. solution of product was used as a starting material for Step B below.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: BrCC1CO1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCC2CO2)c1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
In 10 ml of acetonitrile were dissolved 390 mg (1.09 mmol) of 5-[2-(4-dibutylamino-2-hydroxyphenyl) vinyl]thiophene-2-carboaldehyde and 0.22 g (1.61 mmol) of epibromohydrin. To this mixture were added 0.3 g (2.17 mmol) of anhydrous potassium carbonate and 40 mg of tetrabutylammonium iodide, and the mixture was stirred with heating at 60° C. for 4 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography. The oily matter was dissolved in 50 ml of ether and 10 mg of iodine was added thereto. The mixture was stirred for 1 hour. The mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous magnesium sulfate and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 264 mg of a dark reddish brown oily matter (yield: 58.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13](Cl)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:32])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:32][C:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[O:2][CH3:1])=[O:14])[CH3:30]
Reactant: CCN(N)c1ccccc1
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(NC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The 3-methyloxy-2-phenyl-4-quinolinecarbonyl chloride obtained in Step 1 was dissolved in CH2Cl2 (2 mL) and added dropwise to a solution of Et3N (104 μL, 0.76 mmol) and 1-ethyl-1-phenylhydrazine (102 mg, 0.76 mmol) [Synthesis 1983, 157-158] in CH2Cl2 (3 mL) at 0° C. After stirring at 0° C. for 2 h the cooling bath was removed and the solution stirred at room temperature for 18 h. The solvent was evaporated and the residue taken up in ethyl acetate (20 mL). The organic phase was washed with H2O (2×10 mL), 1N NaOH (20 mL) and brine (20 mL). The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with isohexane:ethyl acetate (2:1). The fractions containing the desired product were combined, evaporated and triturated with diethyl ether. The title compound (159 mg, 53%) was isolated as a colourless solid. 1H NMR (CDCl3, 400 MHz), δ 8.09 (1H, d, J=7.6 Hz), 7.96-7.93 (2H, m), 7.70 (1H, d, J=7.6 Hz), 7.63 (1H, dt, J=7.0 and 1.4 Hz), 7.51-7.45 (6H, m), 7.42-7.28 (4H, m), 5.36-5.35 (1H, broad s), 4.21-4.19 (1H, m), 3.48 (3H, s). MS (ES+) C26H25N3O2 requires: 411, found: 412 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>CN(C=O)C>[CH3:11][N:12]([CH3:14])/[CH:13]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:8](=[O:10])[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)/C(=C/N(C)C)c1ccccc1
Yield: 18.5 %

Procedure:
A solution of 1-phenylpropan-2-one (2.3 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by silica gel column (PE/EtOAc=4:1-2:1) to give the title compound (0.7 g, 18%) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1([CH3:25])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12]([CH3:24])=[N:13][N:14]3[CH3:23])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[CH:1]([C:4]1([CH3:25])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12]([CH3:24])=[N:13][N:14]3[CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c(C)nn2C)c1C1=NC(C)(C(C)C)C(=O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)c2ccc(C(=O)O)c(C3=NC(C)(C(C)C)C(=O)N3)c12
Reaction time: 1.5 h
Yield: 53.8 %

Procedure:
A mixture of methyl 4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-1,3-dimethyl-1H-indazole-5-carboxylate (0.310 g, 0.905 mmol), 2N sodium hydroxide (0.91 mL, 1.82 mmol) and tetrahydrofuran (11 mL) is stirred for 1.5 hours at 42°-52° C., cooled in an ice bath, acidified to pH 3-3.5 with 5N sulfuric acid and extracted with chloroform. The organic extract is dried (Na2SO4) and concentrated in vacuo to give a residue which is recrystallized from acetonitrile to afford the title product as a white solid (0.160 g, 53.2%), mp 156.5°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:9][CH2:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: OCc1cc(Cl)ccn1
Reactant: CC(=O)c1ccc(O)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cc(Cl)ccn2)c(Br)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (4-chloro-2-pyridinyl)methanol (Commercial eg Aldrich) (0.2 g) in THF (5 ml) were added 1-(3-bromo-4-hydroxyphenyl)ethanone (0.3 g) and triphenylphosphine (0.547 g). This was stirred for 10 min before cooling and adding slowly DEAD (0.363 g). This was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous was reextracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was purified through silica eluting with 0-35% ethyl acetate in hexane to give the title compound, 0.30 g
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>O.CO>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Yield: 78.7 %

Procedure:
A solution of 4.4 g of NaOH in 20 ml of distilled water was added to a solution of 7.5 g of 4-hydroxy cinnamic acid in methanol, 0.02 g of Kl was added thereto, and then 10.0 g of 6-bromo-1-hexanol was slowly added dropwise for reaction at 65° C. for 24 hours. 100 ml of distilled water was added thereto to complete the reaction, and then the mixture was cooled to normal temperature. A 10% aqueous HCl solution was added thereto, and the obtained precipitants were filtered to obtain 9.5 g of 4-((6-hydroxyhexyl)oxy)cinnamic acid. (Yield: 60%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(Cl)Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[OH:35])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:35][CH:34]([CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)[C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:41]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A 0.06 gram (0.0004 mole) sample of 4-chlorophenylisocyanate was weighed into a two-dram vial, followed in turn by 1.2 mL of methylene chloride, 0.18 gram (0.0004 mole) of {1-[(4-(2-pyridyloxy)phenyl)methyl](4-piperidyl)}[4-(trifluoromethyl)phenyl]methanol, and 0.06 mL of triethylamine. The vial was tightly capped and gently shaken at 35° C. for 16 hours using a vortex mixer. After this time, the methylene chloride was removed under a nitrogen stream to provide a residue. The residue was purified with column chromatography on silica gel using mixtures of acetone and methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of Compound 227. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6](O)=[O:7])#[N:2].Cl.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][CH2:6][OH:7])#[N:2]
Reactant: CC(C)(C#N)C(O)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
Optically active 4-cyano-3-hydroxy-4-methylpentanoic acid (1.5 g, 9.54 mmol) was dissolved in dry THF (5 mL) and a solution (38.175 mmol) of borane-THF complex was gradually added dropwise thereto at 0° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hr and then 2N aqueous hydrochloric acid solution was added to neutralize the reaction mixture. Ethyl acetate (20 mL) was added thereto and the mixture was stirred vigorously. An organic layer was extracted. Ethyl acetate (20 mL) was further added to an aqueous layer and the mixture was stirred vigorously. The organic layer was extracted again. This step was repeated 3 times and the obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (847 mg, 5.915 mmol) (yield relative to optically active 4-cyano-3-hydroxy-4-methylpentanoic acid: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 52 %

Procedure:
The titled compound (155 mg) was prepared in 52% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethyl-benzene according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.80 (d, 2 H, J=8.6 Hz), 7.61 (m, 4 H), 7.49 (d, 2 H,J=8.0 Hz), 7.32 (s, 1 H), 6.66 (s, 1 H), 4.65 (AB2, 2 H, Δv=17, Jab=64 Hz), 3.88 (m, 1 H), 2.80 (s, 1 H), 2.44 (m, 1 H), 1.79 (m, 1 H), 1.65 (m, 2 H), 1.30 (m, 3 H), 0.92 (m, 1 H); MS m/e 475.01 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1C=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].ClC1C=C(Cl)C=CC=1C(=O)CC1N[CH:33]=[C:34]([CH3:36])[N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[NH:16][CH:33]=[C:34]([CH3:36])[N:35]=1)=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: Cc1c[nH]c(CC(=O)c2ccc(Cl)cc2Cl)n1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Product: Cc1c[nH]c(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 1-(2,4-dichlorophenyl)-2-(4-methylimidazolyl)ethan-1-one (II, 1.0 g, 3.7 mmol) was used. The crude residue was used without purification.