Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:22])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[Si:38]([O:22][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of (S)-ethyl 1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (17.0 g, 56.2 mmol) and DIPEA (17.68 ml, 101 mmol) in CH2Cl2 (187 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (16 ml, 69.6 mmol) slowly. The reaction was monitored with HPLC. The reaction completed in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted with DCM. The organic phase was combined and dried with Na2SO4. After concentration, the crude material was further purified on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to afford a purified product (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidine-3-carboxylate (22.25 g, 53.4 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.79 (1H, m), 4.15 (2H, m), 2.88 (1H, m), 2.75 (1H, m), 2.60 (1H, dd), 2.48 (1H, m), 2.40 (1H, dd), 2.33 (1H, tt), 2.12 (1H, tt), 1.90 (1H, m), 1.68 (1H, dt), 1.52 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[C:25](OCC)=[O:26])=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:25](=[O:26])[N:9]2[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: CC(=O)NCCNc1cc(Br)ccc1N
Reactant: CCOC(=O)C(=O)c1ccc(OC)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(Br)cc3n(CCNC(C)=O)c2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of crude N-(2-(2-amino-5-bromophenylamino)ethyl)acetamide from Example 14 in ethanol (0.74 mL) 870 mg of ethyl 2-(4-methoxyphenyl)-2-oxoacetate was added. To that mixture acetic acid was added resulting in of 1% v/v AcOH in EtOH solution. The reaction mixture was stirred at 80° C. for 18 h and allowed to cool to room temperature. The yellow precipitate was collected by filtration and washed with two 5 mL portions of EtOH. The yellow solid was dried under vacuum to provide N-(2-(7-bromo-3-(4-methoxyphenyl)-2-oxoquinoxalin-1(2H)-yl)ethyl)acetamide.
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([S:4][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:3])[CH3:2]
Reactant: Fc1cccnc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Sc1ncccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
181.2 g of isopropylmercaptan are added dropwise at a temperature of 0° to +2° C. in the course of 25 minutes to a suspension of 324 g of anhydrous potassium carbonate and 335.6 g of 2,3-difluoropyridine in 4500 ml of dimethylformamide. After the reaction mixture has been stirred for 18 hours at room temperature, it is poured into a mixture of 8000 ml of ice-water and 4000 ml of ethyl acetate. The organic phase is subsequently separated off and washed with ice-water and then with ethyl acetate. The combined organic phases are dried with sodium sulfate and subsequently concentrated. Purification by column chromatography over silica gel with ethyl acetate/n-hexane (1:9) gives 362.9 g of 2-isopropylthio-3-fluoropyridine in the form of an oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH:10]1([N:13]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)([CH3:36])[CH3:35])[CH2:29][CH2:28]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>ClCCl>[CH:10]1([N:13]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]([F:7])([CH3:36])[CH3:35])[CH2:29][CH2:28]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:11]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (57 μL) is added drop wise to N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (83 mg) in dry dichloromethane (12 mL) at −78° C. and the reaction mixture is stirred at this temperature for 2 h. The mixture is poured on aqueous NaHCO3 solution (15 mL) and the aqueous phase is extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue is triturated with diisopropyl ether, filtered off, and dried to give the title compound. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z =386 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]=[N+:10]([CH:5]2[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]2)[O-:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Product: CN1C(C)(C)CC([N+]([O-])=Cc2ccccc2)CC1(C)C

Procedure:
Following the general procedure of Example 1, the title compound is prepared from 5.0 g (29.4 mmol) of 1,2,2,6,6-pentamethylpiperidin-4-one oxime and 3.1 g [29 mmol) of benzaldehyde in a yield of 2.3 g (30%) of a white solid which after recrystallization from heptane melts at 104°-105° C. 1HMR (200 MHz, CDCl3)δ 8.26 (m, 2H's); 7.45 (s, 1H); 7.40 (m, 3H's); 4.18 (tt, IH); 2.28 (s, 3H's); 2.13 (t, 2H's); 1.93 (dd, 2H's); 1.23 (s, 6H's); 1.10 (s, 6H's). IR (CDCl3) 3020, 2950, 1570, 1550,
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])=[CH:11][CH:12]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)Nc1n[nH]c2cc(N)ccc12
Solvent: c1ccncc1
Product: CC(C)Nc1n[nH]c2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 100 °C
Yield: 9.6 %

Procedure:
N*3*-Isopropyl-1H-indazole-3,6-diamine (0.036 g, 0.19 mmol) was dissolved in 1 mL pyridine and benzenesulfonyl chloride (0.024 mL, 0.19 mmol) was added. The reaction mixture was heated to 100° C. and stirred for an hour, then cooled and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-50%) to give 6.0 mg of N-(3-Isopropylamino-1H-indazol-6-yl)-benzenesulfonamide, MS (M+H)=359.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C:6]1(O)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)C.[C:14](#[N:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)[OH:23]>O>[C:14]([NH:21][C:6]1([CH2:5][C:4]([OH:3])=[O:13])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)(=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC1(O)CCOCC1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1
Solvent: O
Product: O=C(O)CC1(NC(=O)c2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
To a mixture of ethyl(4-hydroxytetrahydro-2H-pyran-4-yl)acetate (6.73 g, 35.8 mmol) and benzonitrile (4.05 ml, 39.3 mmol) was added conc. sulfuric acid (25 ml) under ice-cooling. After stirring at room temperature for 16 hrs., the reaction mixture was added to water (100 ml) under ice-cooling, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated brine and dried over anhydrous MgSO4. After concentration under reduced pressure, ethanol (50 ml) and 50% aqueous potassium hydroxide solution (10 ml) was added to the obtained residue, and the mixture was heated under reflux for 6 hrs. Water (200 ml) was added to the reaction mixture and the mixture was washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5N hydrochloric acid, extracted with ethyl acetate-tetrahydrofuran (2:1, v/v). The extract was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropyl ether to give the title compound (1.64 g, 17%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCOCC1
Yield: 12.8 %

Procedure:
Prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C (200 mg, 0.39 mmol) and morpholine (0.102 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.08 (brs, 1H), 8.56 (s, 1H), 7.58-7.65 (m, 2H), 7.38-7.43 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 4.00 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][S:5][CH:6]=1.[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:4][S:5][CH:6]=4)=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: OC(CCCc1ccccc1)c1cscc1Br
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4cscc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(4-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[O:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C1(C2(CCC3C=CC(C(OC)=O)=C(F)C=3)CC(=O)CC(=O)O2)CCCC1>>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[O:15]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Product: O=C1CC(=O)OC(CCc2ccc(C(=O)O)c(Cl)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to example B(6): where methyl 2-chloro-4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]benzoate (example B(7)) was substituted in place of methyl 4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorobenzoate in that example. 1H NMR (300 MHz, CDCl3): δ 1.38-2.30 (m, 11H), 2.78-3.15 (m, 6H), 7.10 (s, 1H), 7.19 (d, J=1.58 Hz, 1H), 7.62 (d, J=1.56 Hz, 1H) 12.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:14][C:12](=[O:13])[C:3]2[N:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[N:1]=1)[CH3:16]
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](O)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Br)([Br:31])=O.N1C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12]([Br:31])([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(Br)Br
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(c1cccnc1)C(F)(F)C3
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Br)(c1cccnc1)C(F)(F)C3
Temperature: 70 °C

Procedure:
Into a 500 ml flask containing the product from step (a) (5.9 g, 15.20 mmol) in DCE (50 ml), thionyl bromide (5.89 ml, 76.03 mmol) was added, followed by pyridine (123 μL, 1.52 mmol). The stirred reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was then allowed to cool to room temperature and was carefully poured over ice-cold saturated aqueous Na2CO3 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a pale red semi-solid that was used without further purification. MS: ESI (positive): 451, 453 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: C#CCCO
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 459 (0.26 mmol) and but-3-yn-1-ol (0.29 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.9, 163.6 (d), 147.6, 146.3, 141.8 (d), 140.7, 138.3, 135.4, 134.8, 133.8, 132.6, 130.9 (d), 128.7, 122.4, 120.9, 120.0, 117.1, 116.1 (d), 113.7, 110.5 (d), 107.6 (d), 61.6, 28.7, 20.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13][S:14][CH3:15])[N:8]=1)[CH3:6].[CH3:25][I:26]>>[I-:26].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13][S+:14]([CH3:25])[CH3:15])[N:8]=1)[CH3:6]
Reactant: CSCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Reactant: CI
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC[S+](C)C)no1
Product: [I-]

Procedure:
A mixture of 0.2 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-methylthioethyl)-1,2,4-oxadiazole and 2 ml of methyl iodide was stirred and refluxed for 10 hours. After the mixture was concentrated to dryness under reduced pressure, the residue was triturated with diethyl ether, collected by filtration and dried to give [5-(3-fluoro-4-phenyl-α-methylbenzyl)1,2,4-oxadiazol-3-ylethyl]dimethylsulfonium iodide as light yellow fine crystals, m.p. 196.5° C. (decomp.).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6.5 g of pulverised potassium hydroxide and 20 g of methyl 4-hydroxy-α-phenoxypropionate in 250 ml of dry dimethyl sulphoxide are charged at 0° C. into a three-necked flask. With stirring, and at a temperature between 0° and 5° C., 19.5 g of 3,4-dichloro-nitrobenzene are added by small amounts and stirring is continued for 12 hours at room temperature. Thereafter the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried over sodium sulphate and the solvent distilled off to yield an oily product which is then subjected to high vacuum distillation. The resultant substance, viz. methyl 4-(2'-chloro-4'-nitrophenoxy)-α-phenoxypropionate (yield 27 g), boils at 194° C./0.01 Torr (compound 1).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[CH3:25].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCCOc2ccc3ccccc3c2)ccc1C(=O)C(=O)O
Yield: 90.1 %

Procedure:
A solution of 2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.52 g of purified 2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (4:1) hydrate as a colorless solid, mp 129°-131° C.
Reaction SMILES: Br[C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C>C(O)C.[Pd]>[C:8]1([C:5]2[N:4]=[C:3]([C:14]([OH:16])=[O:15])[CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1nc(-c2ccccc2)ncc1Br
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(O)c1ccnc(-c2ccccc2)n1
Yield: 83.6 %

Procedure:
A solution of 500 mg 5-bromo-2-phenyl-4-pyrimidinecarboxylic acid and 1 mL N,N-diisopropylethylamine in 5 mL of ethanol was hydrogenated at 40 psi of H2 for 16 hr using 200 mg of 10% palladium-on-carbon as catalyst. The catalyst was filtered off and the ethanol removed by evaporation under reduced pressure. The residue was dissolved in water, acidified with 3N hydrochloric acid and the precipitate was collected by filtration. This material was air dried to yield 300 mg of 2-phenyl-4-pyrimidinecarboxylic acid as a white solid which was used in the next step without further purification or characterization. A solution of 150 mg of 2-phenyl-4pyrimidinecarboxylic acid in 1 mL of thionyl chloride was heated at 70° C. for 1 hr, cooled to room temperature and the excess thionyl chloride removed by evaporation under reduced pressure to yield 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride which was used in the next step without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[F:11][CH:12]([F:22])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1.Cl[C:24]([N:26]1[CH:31]([CH3:32])[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]1[CH3:40])=[O:25]>>[ClH:19].[CH3:40][C@H:27]1[CH2:28][NH:29][CH2:30][C@@H:31]([CH3:32])[N:26]1[C:24]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH:12]([F:22])[F:11])=[CH:15][CH:16]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:25]
Reactant: OCc1cc(O)ccc1F
Reactant: FC(F)Oc1ccc(CCl)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2ccc(OC(F)F)cc2)ccc1F
Product: Cl

Procedure:
2-Fluoro-5-(4-difluoromethoxybenzyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 4-difluoromethoxybenzyl chloride and 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 52 and 54 to give the product as a white solid (0.224 g, 94% overall); (Found: C, 55.7; H, 5.7; N, 5.9. C22H25F3N2O4.HCl requires C, 55.6; H, 5.5; N, 5.9%); δH (400 MHz, DMSO-d6) 9.8 (1H, br), 9.3 (1H, br), 7.50 (2H, d, J 8.4 Hz), 7.26(1H, t, J 74 Hz), 7.21–7.15 (3H, m), 7.09 (1H, m), 7.03 (1H, m, J 3.2 Hz), 5.12 (2H, s), 5.08 (2H, s), 4.28 (2H, m, J 6 Hz), 3.15 (2H, d, J 13 Hz), 3.06 (2H, dd, J 5 and 13 Hz), and 1.29 (6H, d, J 7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>CN(C=O)C>[Br:35][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([OH:1])[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(CBr)cc1O
Reaction time: 2 h

Procedure:
2-hydroxy-4-hydroxymethylbenzonitrile (0.20 g, 1.34 mmol) was dissolved in DMF (5 mL) and CH2Cl2(5 mL) and then treated with triphenylphosphine (0.53 g, 2.01 mmol) and carbon tetrabromide (0.67 g, 2.01 mmol) at ambient temperature with stirring. After 2 h, the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the organic layer were separated, dried (MgSO4), and filtered to give the title compound after silica gel chromatography (15% EtOAc/hexane to 25% EtOAc/hexane).