Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[CH2:68]Cl>O1CCCC1.C(OCC)(=O)C.ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:44][O:43][C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:30]([CH2:68][C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][N:62]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccccn1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccccn4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine (0.52 g, 0.87 mmol) and tetrahydrofuran (20 mL). Cool to about −65° C. using a dry-ice/acetone bath. Add dropwise a solution of potassium bis(trimethylsilyl)amide in toluene (2.1 mL, 0.5 M, 1.05 mmol) at such a rate that the temperature of the reaction mixture does not rise above about 60° C. After 1.5 hours, add a solution of 2-picolyl chloride (prepared as described in Example 37.2) (0.13 g, 1.05 mmol) in tetrahydrofuran (5 mL). When the addition of 2-picolyl chloride is complete, warm the reaction mixture to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract twice with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with methanol/ethyl acetate 1/1. Evaporate the product containing fractions to give a residue, dissolve the residue in dichloromethane, filter through a fine filter, and evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH2:23][C:24](O)=[O:25]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:17]2[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2c(Cl)cccc2Cl)nn2cccnc12

Procedure:
The product from Example 105B and 2-(2,6-dichlorophenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.89 (d, J=6.4 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 7.46-7.52 (m, 2H), 7.35 (dd, J=7.9 Hz, 1H), 7.01 (dd, J=6.6, 3.9 Hz, 1H), 4.05-4.09 (bs, 2H), 1.48 (s, 9H); MS (ESI) m/z 377, 379 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20].CO.O.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1F
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of methyl 2′-fluoro-2-(methoxymethyl)biphenyl-4-carboxylate (12.0 g, 43.7 mmol) in a mixture of THF (50 ml), MeOH (50 ml) and water (25 ml) was added lithium hydroxide monohydrate (5.50 g, 131.2 mmol) in portions. After 12 hours at RT, the reaction mixture was concentrated and the aqueous residual layer was acidified with a concentrated aqueous solution of HCl, and then extracted with EtOAc. The organic layers were washed with water and brine, combined, dried (Na2SO4) and concentrated under reduced pressure to afford of the title compound as a white solid (10.5 g, 92%). LC/MS (Method B): 259.0 (M−H)−. 1H NMR (DMSO-d6, 400 MHz) δ 13.07 (1H, brs), 8.10 (1H, s), 7.92 (1H, d), 7.48 (1H, m), 7.27-7.37 (4H, m), 4.26 (2H, s), 3.18 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:17][NH:18][CH3:19]>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4]([N:18]([CH3:19])[CH3:17])[N:3]=1
Reactant: CNC
Reactant: Nc1nc(Cl)cnc1-c1cccc(Cl)c1Cl
Product: CN(C)c1cnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to the compound in Example 6 from 2-amino-6-chloro-3-(2,3-dichlorophenyl)pyrazine (Example 2) and dimethylamine (Aldrich). M.p. 147-148° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.ClC1C2C(=CC(OC)=C(OC)C=2)N=CN=1.[F:38]C1C=C(C=CC=1)N>>[F:38][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: Nc1cccc(F)c1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OC
Agent: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3cccc(F)c3)c2cc1OC
Yield: 98 %

Procedure:
Employing the same method used for compound 1, 4-chloro-6,7-dimethoxyquinazoline (113 mg, 0.5 mmol) and 3-fluoroaniline (48 μL, 0.5 mmol) afforded compound 2 as the hydrochloride salt in 98% yield (166 mg). 1H NMR [((CD3)2SO) δ11.59(s, 1H), 8.85(s, 1H), 8.43(s, 1H), 7.7(m, 1H), 7.6(m,1H), 7.5(m, 1H), 7.4(s, 1H), 7.1(s, 1H), 4.1(s, 3H), 3.96(s, 3H). MS, m/e: 300 (M+), 299 [(M-H)+ ]. Anal. Calcd. for C16H15FClN3O2 : C, 57.14; H, 4.46; N, 12.50. Found: C, 57.09; H, 4.53; N, 12.49.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([CH:5]3[CH2:6][CH2:7][CH:2]([O:1][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)#[N:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C(F)(F)F)nn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C(F)(F)F)nn12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.14 g), rhodium(II) acetate (dimer) (88 mg) and toluene (20 mL) was added dropwise ethyl diazoacetate (571 mg) under an argon atmosphere at 80° C., and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless amorphous compound (695 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:15]=[O:16])=[CH:4][C:3]=1[CH:9]1[O:10][CH2:11][CH2:12][O:13]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)c(C2OCCO2)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cl)c(C2OCCO2)c1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
2.0 g of 4-chloro-3-(1,3-dioxolan-2-yl)-aniline in 25 ml of ethyl acetate were added to a solution of 3.0 g of trichloromethyl chloroformate in 50 ml of toluene at about 20-25° C. This mixture was stirred for 2 hours at 20-25° C. and then for a further 5 hours at the reflux temperature. Thereafter, the reaction mixture was evaporated down and the residue was dried under greatly reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][NH:7][C:8]2=[O:13]
Reactant: O=C1NCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CNC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the suspension of 4-nitro-2,3-dihydro-isoindol-1-one (2.40 g, 13.5 mmol) in 100 ml of MeOH was added Pd/C (10 wt %, 0.36 g). The mixture was then placed under H2 from a balloon, stirred at RT for 24 h, filtered through Celite®, and condensed to give the titled compound as a light greenish solid. MS (ES+): 149.1 (M+H)+. Calc'd for C8H8N2O—148.16.
Reaction SMILES: N.[CH3:2][C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][N:6]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[CH:7]=1.[CH3:21][CH:22]([N:26]1[CH:30]=[C:29](C)C(C2C=CC=CC=2)=N1)C(O)=O>>[CH2:22]([N:26]([CH2:30][CH3:29])[C:9](=[O:11])[CH:8]([CH2:12][CH2:13][CH3:14])[N:6]1[CH:7]=[C:3]([CH3:2])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5]1)[CH3:21]
Reactant: CCCC(C(=O)O)n1cc(C)c(-c2ccccc2)n1
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Agent: N
Product: CCCC(C(=O)N(CC)CC)n1cc(C)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting diethylamine for aqueous ammonia and 4-methyl-3-phenyl-α-propylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, there was obtained N,N-diethyl-4-methyl-3-phenyl-α-propylpyrazole-1acetamide having a melting point of 65°-67° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([C:21]1[S:25][C:24]2[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=2[C:22]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])COCC[Si](C)(C)C)(=[O:11])=[O:10])[CH3:2].C(=O)([O-])O.[Na+]>Cl.CO>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:21]1[S:25][C:24]2[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=2[C:22]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:10])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccccc2CC)sc2c1CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2CC)sc2c1CCCC2
Temperature: 25 °C
Yield: 51 %

Procedure:
A solution of ethyl 2-[N-(2-ethylbenzenesulphonyl)-N-(2-trimethylsilylethoxymethyl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 37, 0.107 g) in concentrated hydrochloric acid (1 ml) and methanol (3 ml) was heated at 80° C. for 1 hour. After cooling to room temperature, the mixture was added drop-wise to a mixture of ice and saturated aqueous sodium hydrogen carbonate solution (25 ml) and then extracted with ethyl acetate (3×15 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-(2-ethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.041 g) as a white solid.
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:26])[CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([CH3:24])[CH3:25])=[CH:20][CH:21]=1
Reactant: CC(C)C(O)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 42836.4 %

Procedure:
Azodicarboxylic acid diisopropyl ester (824 mg, 4.1 mmol) was added to the mixture of 1-(4-bromophenyl)-2-methylpropan-1-ol (620 mg, 2.7 mmol), phenol (307 mg, 3.2 mmol), triphenylphosphine (1.07 g, 4.1 mmol) and tetrahydrofuran (15 mL) at 20° C. Then the mixture was stirred at 20° C. for 12 hours. The resultant mixture was washed with water (20 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to gave 1-bromo-4-(2-methyl-1-phenoxypropyl)benzene as a colorless oil (353 g, 44%). 1H NMR (300 MHz, CDCl3): δ 8.07-7.98 (m, 2H), 7.56-7.48 (m, 2H), 7.32-7.28 (m, 2H), 6.84-6.77 (m, 3H), 4.49 (d, J=6.6 Hz, 1H), 2.35-2.30 (m, 1H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1>C(Cl)(Cl)Cl>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20]
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: CC1CCCCN1
Solvent: ClC(Cl)Cl
Product: CC1CCCCN1c1c(-c2c(F)cc(F)cc2F)c(Cl)nc2nccn12
Temperature: 80 °C
Yield: 39.8 %

Procedure:
A mixture of 0.63 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-imidazo[1,2-a]pyrimidine, 0.79 g of 2-methylpiperidine and 2 ml of chloroform was heated at 80° C. for one hour. The reaction mixture was allowed to cool and subjected to silica gel column chromatography to give 0.30 g of 5-(2-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:43][CH2:42][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:11][C:10]=1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CC1CCCCC1

Procedure:
A mixture of 2-(2-benzyl-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.14 g, 3.63 mmol) (see Ex. 35, part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (4.71 mmol) (see Ex. 1, part F), and Cs2CO3 (1.77 g, 5.45 mmol) was heated at 55° C. in DMF (10 mL) for 72 h. The reaction mixture cooled and partitioned between ethyl acetate (30 mL) and H2O (10 mL). The organic layer was washed with brine (15 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate (8:1) to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester: MS (ES) m/e 582.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:20]([O:23]CC=C)[CH:21]=[CH2:22].C(C1C=C(C)C=C(Br)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:3]2[O:9][CH:21]([CH2:20][OH:23])[CH2:22][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CCOCC=C
Reactant: Cc1ccc(O)c(Br)c1
Agent: C=CCc1cc(C)cc(Br)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: C=CCBr
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1cc(Br)c2c(c1)CC(CO)O2
Yield: 43 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.ClC([O-])=[O:34].CCN(CC)CC.O>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH:4]1[O:24][C@:23]2([C:25]([CH2:27][OH:28])=[O:26])[C@@H:6]([CH2:7][C@@H:8]3[C@:22]2([CH3:29])[CH2:21][C@H:20]([OH:30])[C@H:19]2[C@H:9]3[CH2:10][CH2:11][C:12]3[C@:18]2([CH3:31])[CH:17]=[CH:16][C:14](=[O:15])[CH:13]=3)[O:5]1.[CH2:23]([O:24][C:4](=[O:5])[O-:34])[CH2:6][CH2:7][CH2:8][CH2:22][CH2:21][CH2:20][CH2:19][CH2:9][CH2:10][CH2:11][CH2:12][CH2:18][CH2:17][CH2:16][CH3:14]
Reactant: O=C([O-])Cl
Agent: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(=O)[O-]
Temperature: 25 °C

Procedure:
To the solution of budesonide (431 mg, 1.0 mmol) in DCM (4.5 mL) was added heaxdecyl chloroformate (655 μL, 2.0 mmol) and Et3N (512 μL, 3.7 mmol) at room temperature. After reaction mixture was stirred at room temperature over night, it was poured into water (20 mL) and DCM (10 mL); the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude budesonide hexadecylcarbonate. The product was purified by chromatography, eluted with Hexane: AcOEt=9:1 to 3:1 to provide 432 mg of 1:1 mixture of epimers (originated from budesonide) (99.38 area % purity on HPLC). 1H NMR (CDCl3) δ 0.80-2.40 (m, 53H), 2.56 (dt, 1H, 13.1 and 4.6 Hz), 4.30 (t, 2H, 6.7 Hz), 4.5-5.2 (m, 7H), 6.00 (s, 1H), 6.26 (d, 1H, 10.1 Hz), 7.3 (d, 1H, 10.1 Hz). 3C NMR (CDCl3) δ 14.16, 14.18, 14.34, 17.10, 17.27, 17.39, 17.71, 21.21, 22.88, 25.81, 28.79, 29.41, 29.56, 29.70, 29.76, 29.87, 30.54, 31.19, 32.11, 33.08, 33.59, 34.23, 35.19, 37.28, 40.68, 40.98, 44.37, 46.08, 47.52, 50.00, 53.07, 55.39, 55.49, 68.98, 69.73, 69.83, 69.95, 70.04, 82.10, 83.38, 97.71, 98.58, 104.70, 108.51, 122.57, 127.91, 155.08, 156.85, 170.48, 170.59, 186.84, 186.88, 202.10 and 203.38. Mass spectrum (m/e) 699 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][CH2:14][CH2:15][OH:16]>O1CCOCC1>[OH:16][CH2:15][CH2:14][CH2:13][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCCCn1ccnc1

Procedure:
To a solution of 1.7 g of imidazole dissolved in 125 ml of dioxane was added 17.25 g of potassium carbonate, and further, 13.8 ml of 3-chloro-1-propanol was added dropwise, followed by heating under reflux for 7.5 hours. The reaction mixture obtained was filtrated to remove potassium carbonate, the reaction stopped by an addition of water, and the pH adjusted to 2.5 before the reaction mixture was applied to an ion exchange column (Dowex 50 (hydrogen ion form)). Elution was effected successively with water, 30% ethanol, and ammonical 30% ethanol, and the fractions eluted with ammonical 30% ethanol were concentrated, the concentrate was applied to a phosphocellulose column (pH 8), and the fractions passed as such were concentrated to dryness under a reduced pressure, whereby 2.5 g of purified 1-(3-hydroxypropyl)imidazole was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=1)=[O:4].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:20][N:21]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)CCl)cc2)=NN1
Yield: 83.9 %

Procedure:
4.0 g (14.8 millimoles) of β-(p-chloroacetylaminobenzoyl)-propionic acid are refluxed with 0.74 g (14.8 millimoles) of hydrazine hydrate and 70 ml of ethanol for 3 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 3.3 g (84% of theory) of 6-(p-chloroacetylaminophenyl)-4,5-dihydropyridaz-3-one are obtained as pale yellow crystals (identical with the compound from Example 1, according to its melting point and infrared and NMR spectra).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:38]=[CH:37][C:22]([CH2:23][N:24]6[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:38]=[CH:37][C:22]([CH2:23][N:24]6[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3c[nH]c4ncc(-c5ccc(CN6CCNCC6)cc5)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(4-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazine-1-carboxylate (63 mg) was suspended in dichloromethane (2 mL) and treated with TFA (2 mL). The resulting mixture was stirred for 90 minutes at room temperature, after which the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with 10% sodium hydroxide solution, water, and brine. The organic layer was dried over MgSO4, and the solvent was removed in vacuo. MPLC silica gel chromatography (0-20% MeOH in dichloromethane) provided an analytical sample (10 mg, 408 M+H) of the title compound.