Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:36][CH2:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH is treated with 1-bromo-3-chloropropane (3 equiv) and cesium carbonate (2 equiv). The reaction is heated to 60° C. and stirred overnight. The reaction is then purified on silica gel column (see Prep. 77) chromatography to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[CH:6][CH:7]=1
Reactant: OCCCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Reactant: COc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1OCCCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-pyridinylsulfanyl)-5-oxazolepropanol (340 mg), 2-methoxyphenol (250 mg), tributylphosphine (400 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (500 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-pyridylsulfanyl)oxazole was obtained as an oil (251 mg, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Cc1ccc(N)cc1
Product: C#CC(Nc1ccc(C)cc1)c1ccccc1
Reaction time: 6 h
Yield: 76.6 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-toluidine (0.160 g, 1.5 mmol). The reaction was conducted at room temperature for 6 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be >99/1. The mixture was purified by flash column chromatography on silica gel (2% ethyl acetate in hexanes) to give the title compound (0.166 g, 76%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 ml; TR=24.2 (minor), 32.2 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.44-7.32 (m, 4H), 7.28 (dt, J=7.2, 2.0 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.65 (t, J=7.2 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.08 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.27 (dt, J=17.2, 1.2 Hz, 1H), 5.23 (dt, J=10.4, 1.2 Hz, 1H), 4.99 (t, J=4.4 Hz, 1 H), 3.88 (br s, 1H), 2.20 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>CCO>[CH3:17][O:18][CH2:19][CH2:20][NH:21][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: COCCN
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: COCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), 2-methyoxyethanamine (0.50 ml, 5.8 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 1), 123 (13), 88 (bp), 72 (25), 56 (13).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@:4]([CH3:22])([C:14](=[O:21])[NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][NH:5][C@:4]([CH3:22])([C:14]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[O:21])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)C(=O)Nc1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(C(=O)Nc2nccs2)C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,4S)-tert-butyl 4-hydroxy-2-methyl-2-(thiazol-2-ylcarbamoyl)pyrrolidine-1-carboxylate (0.49 g, 1.5 mmol) in CH2Cl2 was added TFA (1 ml, excess). The reaction mixture was stirred at RT for 14 h and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 228; Ret time (Method F): 0.46 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Yield: 25.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(pyrimidin-5-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.14 g, 0.29 mmol) obtained in step 2 and methanesulfonamide (0.138 g, 1.45 mmol), the title compound (0.04 g, 26%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.CN.O[N:34]1[C:38]2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:34][CH3:38])=[O:18])=[N:14][CH:15]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.25 mmol) in methylene chloride (3 ml), methylamine hydrochloride (19 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.061 ml, 0.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 2 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane and then collected by filtration, to obtain the title compound (73 mg, 0.17 mmol, 67%) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[K+].CO.Cl>C1COCC1>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: [OH-]
Reactant: O=C1CCCCCO1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Caprolactone (100 g) was added to a mixture of potassium hydroxide (145 g), methanol (110 mL), and THF (390 mL). The resulting mixture was stirred at room temperature overnight. The solution was then acidified with HCl and extracted with ethyl acetate. The combined organic layers were washed with water, dried, filtered, and concentrated to obtain 6-hydroxyhexanoic acid. 1H NMR (CDCl3, 500 MHz) δ 1.44 (m, 2H), 1.60 (m, 2H), 1.68 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 5.80 (br, 1H).
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)[CH2:14][CH2:13]1)[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[O:6])=[N+:2]=[N-:3]>O.C(#N)C>[N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1)[C:5](=[O:6])[N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)[Si](OCC1CCC([C@H](N=[N+]=[N-])C(=O)N2CCSC2)CC1)(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=N[C@H](C(=O)N1CCSC1)C1CCC(CO)CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
3-[(2S)-2-Azido-2-(4-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-ethanoyl]-1,3-thiazolidine (isomer II, 130 mg, 0.29 mmol) from Example 6, Step I was dissolved in 3 mL of 15% HF (45% in H2O) in acetonitrile and stirred for 2 h. The solvent was removed and the residue was dissolved in ethyl acetate and then neutralized with aqueous sodium bicarbonate. The organics were separated, dried (Na2SO4) and filtered. Evaporation of the solvent afforded 78 mg of {4-[(1S)-1-azido-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]cyclohexyl}methanol. A portion of this material (24 mg, 0.084 mmol) was dissolved in wet THF and triphenyl phosphine (26 mg, 0.1 mmol) was added to the solution. The mixture was heated in an oil bath at 60° C. for 5 h, cooled, concentrated and purified by preparative TLC on silica gel (eluent: 5 to 10% methanol in CH2Cl2) to give the title compound. 1H NMR (500 MHz, CD3OD, HCl salt) δ 4.71 (dd, 1H, J=3 and 6 Hz), 4.58 (d, 0.45H, J=9.2 Hz), 4.48 (d, 0.55H, J=9.2 Hz), 4.18 (d, 0.45H, J=5.9 Hz), 4.11 (d, 0.55H, J=5.9 Hz), 3.93 (m, 0.55H), 3.88 (m, 0.45H), 3.88 (m, 0.45H), 3.79 (m, 1H), 3.17 (m, 1H), 3.36 (d, 2H, J=6.1 Hz), 3.09 (m, 1H), 1.98–1.78 (m, 4H), 1.40 (m, 1H), 1.26 (m, 1H), 1.11(m, 1H), 1.01 (m, 2H). 3-[(2S)-2-Azido-2-(4-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-ethanoyl]-1,3-thiazolidine (isomer I, 78 mg) was converted to the title compound in a manner identical to that described for isomer II. 1H NMR (500 MHz, CD3OD, HCl salt) δ 4.71 (dd, 1H, J=8 and 10 Hz), 4.58 (dd, 0.45H, J=2 and 9 Hz), 4.48 (d, 0.55H, J=2 and 9 Hz), 4.20 (d, 0.45H, J=6.2 Hz), 4.12 (d, 0.55H, J=6.2 Hz), 3.96 (m, 0.55H), 3.88 (m, 0.45H), 3.88 (m, 0.45H), 3.79 (m, 1H), 3.55 (d, 2H, J=5.9 Hz), 3.14 (m, 1H), 3.09 (m, 1H), 1.98 (m, 1H), 1.80 (m, 3H), 1.58 (m, 3H), 1.39 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].OC1C=CC=CN=1.[C:13]([O:17][C:18](=[O:48])[NH:19][C@H:20]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[CH3:36])[CH2:24][C:23]1([CH3:38])[CH3:37])([CH3:16])([CH3:15])[CH3:14]>O>[C:13]([O:17][C:18](=[O:48])[NH:19][C@@H:20]([CH2:21][N:22]1[CH2:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[CH3:36])[CH2:24][C:23]1([CH3:38])[CH3:37])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:44]([CH3:46])[CH3:45])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: CC(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)C)C(C)C)CC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
0.4 ml of isobutylamine (3.96 mmol) and 8 mg of 2-hydroxypyridine (0.079 mmol) were added to 200 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (70f) (0.39 mmol), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 226 mg of the title compound (yield: 99%).
Reaction SMILES: [CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:35])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)Cl
Reaction time: 2 h

Procedure:
36.0 g of the 2-(2-hexyldecyloxy)benzoic acid was dissolved in 100 ml of methylene chloride, 0.5 ml of N,N-dimethylformamide was added, and 13 ml of oxalyl chloride was added dropwise over about 30 min at room temperature with stirring. After the addition the stirring was continued for 2 hours further and it was concentrated, to obtain 2-(2-hexyldecyloxy)benzoic acid chloride.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-c2cn3cccc(Br)c3n2)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2cn3cccc(N4CCNCC4)c3n2)cc1
Temperature: 115 °C
Yield: 76.1 %

Procedure:
To a flask containing 8-bromo-2-(4-tert-butyl-phenyl)-imidazo[1,2-a]pyridine (0.313 g, 0.951 mmol) was added tris(dibenzylidineacetone)dipalladium(0) (0.087 g, 0.0.0951 mmol), 2-(di-tert-butylphosphino)biphenyl (0.028 g, 0.0951 mmol), sodium tert-butoxide (0.183 g, 1.90 mmol) and piperazine (0.409 g, 4.76 mmol). The solid reagents were then suspended in degassed toluene (22 mL). The mixture was purged with nitrogen and heated to 115° C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude mixture was purified by flash silica gel chromatography, eluting with 15% methanol/chloroform to give 0.242 g (76%) of the title compound. MS (ES) m/z 335.1; HPLC (Method B): r.t.=8.4 min., purity 98.6% at 210-370 nm. HRMS: calcd for C21H26N4+H+, 335.22302; found (ESI, M+H), 335.2236.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH2:7]([Li])CCCCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21](=[O:27])[CH:20]=[CH:19]2>C1COCC1.CCCCCCC>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]([N:22]([CH3:26])[C:21](=[O:27])[CH:20]3[CH2:7][CH:19]32)=[CH:24][CH:25]=1
Reactant: COc1ccc2c(ccc(=O)n2C)c1
Reactant: [Li]CCCCCC
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C1CC1C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
A suspension of 3.35 gm (15.1 mmol) trimethylsulfoxonium iodide in 10 ml of THF at 0° C. under nitrogen was treated portionwise with 5.8 ml (14.6 mmol) of 2.5 M n-hexyllithium in heptane over 30 minutes. The mixture was stirred for 30 minutes at 0° C. and then treated with 1.0 gm (5.02 mmol) 6-Methoxy-1-methyl-1H-quinolin-2-one followed by heating under reflux for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature before quenching with 35 ml of water followed by extraction into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford 1.1 gm of desired product. Mass spectrum APCI m/e 204 (p+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH3:3].[OH-].[Na+]>CO.O>[CH3:15][CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:14]
Reactant: COC(=O)CCc1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(CCC(=O)O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
3-[2,4,6-Tris(1-methylethyl)phenyl]propionic acid, methyl ester (2.12 g, 7.3 mmol) was dissolved in 100 mL methanol and 10 mL water. Sodium hydroxide (0.32 g, 8.0 mmol) was added and the resulting solution was stirred at room temperature for 4 hours. Concentrated in vacuo and partitioned the residue between water and diethyl ether. The aqueous layerwas acidified with concentrated HCl and extracted with dichloromethane. Theorganic extract was dried over MgSO4, filtered, and concentrated to give 1.87 g of 3-[2,4,6-tris(1-methylethyl)phenyl]propionic acid as a white solid, mp 194°-196° C.
Reaction SMILES: C(N(CC)C(=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([Cl:13])[C:7]=1[I:14])C.II>>[Cl:13][C:8]1[C:7]([I:14])=[C:6]([OH:5])[CH:11]=[CH:10][C:9]=1[F:12]
Reactant: CCN(CC)C(=O)Oc1ccc(F)c(Cl)c1I
Agent: II
Product: Oc1ccc(F)c(Cl)c1I

Procedure:
3-Chloro-4-fluorophenol was acylated with diethylcarbamoyl chloride to produce 3-chloro-4-fluorophenyl diethylcarbamate, which was converted to 3-chloro-4-fluoro-2-iodophenyl diethylcarbamate via ortho-metalation followed by treatment with iodine. Basic hydrolysis provided 3-chloro-4-fluoro-2-iodophenol, which was coupled to (2-hydroxyphenyl)boronic acid under Suzuki conditions to give 6-chloro-5-fluorobiphenyl-2,2′-diol. Copper-mediated cyclization provided 4-fluorodibenzo[b,d]furan-1-ol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][Mg]Br.[NH4+].[Cl-]>C(OCC)C>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:2]1([OH:1])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Reactant: Fc1ccccc1C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-oxocyclohexylcarbamate (2 mmol, 426 mg) in ethyl ether (10 mL) was added a solution of (2-fluorobenzyl)magnesium bromide in ether (5 mmol, 0.25 M, 20 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for overnight. The reaction mixture was added to the NH4Cl aqueous solution. The organics were extracted with EtOAc. The EtOAc solution was concentrated. The product, tert-butyl 3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate was purified by column chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: COc1cccc(Cc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Product: COc1cccc(Cc2ccc(N)cc2)c1
Reaction time: 16 h
Yield: 75.9 %

Procedure:
4-(3-Methoxybenzyl)nitrobenzene (0.50 g, 2.10 mmol) was dissolved in ETOH (25 mL) and 10% palladium on carbon (0.50 g) was added under a nitrogen stream. The reaction mixture was hydrogenated on a Parr shaker at 50 psi for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give 0.34 g (77%) of 4-(3-methoxybenzyl)aniline as an oil. 1H NMR (CDCl3) δ7.15 (t, J=8.1 Hz, 1H), 6.95 (d, J=8.1 Hz, 2H), 6.70 (m, 3H), 6.60 (d, J=8.1 Hz, 2H), 3.85 (s, 2H), 3.75 (s, 3H), 3.45 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([CH3:26])=[CH:28][CH:29]=1)=[O:20]
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: Cc1ccc(CNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.700 g, 1.92 mmol), 4-methylbenzylamine (0.330 g, 2.72 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methylbenzyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.741 g, 79.7% yield).
Reaction SMILES: Cl[CH2:2][C@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@H:4]([OH:6])[CH3:5].C[O-].[Na+].O>CO>[O:7]1[C@:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([C@H:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@@H](O)[C@@](O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 1.00 g (4.23 mmol) of (2R,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol in 8 mL of methanol was cooled in ice, and 0.91 g (4.65 mmol) of a 28% solution of NaOMe in methanol was added thereto. The reaction was performed for 2 hours, and 10 mL of water was added to stop the reaction. Then, extraction was performed with 20 mL of ethyl acetate. After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The product was quantitatively analyzed by HPLC (under the same HPLC measurement conditions as those in Example 10). The title compound was obtained in a yield of 97%. 1H-NMR (400 MHz, CDCl3) δ: 1.19 (d, 3H, J=6.3 Hz), 2.22 (s, 1H), 2.91 (d, 1H, J=4.9 Hz), 3.28 (d, 1H, J=4.9 Hz), 4.11 (d, 1H, J=6.3 Hz), 6.80-6.91 (m, 2H), 7.34-7.39 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].CCCC[Sn]([C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)(CCCC)CCCC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Product: CCOC(=O)c1nc(-c2cccnc2)c2onc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 12 from 7-Bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 3-(1,1,1-tributylstannyl)pyridine; ESI MS (m/z): 362.23 (M+H+); 360.13 (M−H+).