Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.CN(C=O)C.[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>O>[Br:7][C:5]1[N:6]=[C:2]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2nc(Br)cs2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 1 L flask equipped with a mechanical stirrer and a thermometer was charged with 2,4-dibromothiazole (60 g, 0.247 mol) and DMF (480 mL). After dissolution, cis-2,6-dimethylmorpholine (33.65 mL, 0.272 mol) and DIPEA (61.23 mL, 0.37 mol) were added under a stream of nitrogen. The reaction mixture was heated to 70° C. under nitrogen and stirred overnight. The reaction mixture was cooled to 10° C. in an ice/water bath. Then water (1 L) was added dropwise in a temperature range of 10-20° C. A slightly exothermic reaction was observed, with formation of an off-white precipitate. After the addition, the reaction mixture was stirred for 30 min. The precipitate was then filtered and washed with water (50 ml). The collected solid was dried in a vacuum oven at 50° C., yielding 52.8 g (77%) of Intermediate 1 as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([O:9][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH3:1])[CH:8]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Cl)c1ccccc1
Product: Cc1cc(OC(=O)c2ccccc2)ccc1O
Yield: 68.2 %

Procedure:
Using 5.0 g of methylhydroquinone and 5.6 g of benzoyl chloride, the procedure of Reference Example was followed. Recrystallization from ethanol-isopropyl ether gave 6.2 g of 4-benzoyloxy-2-methylphenol as white crystals, m.p. 120-122. Then, using 6.2 g of thus obtained white crystals, 5.1 g of benzyl bromide and 4.1 g of anhydrous potassium carbonate, the procedure of Reference Example was followed to give 7.6 g of 1-benzyloxy-2-methyl-4-benzoyloxybenzene as white crystals, m.p. 118-119° C. Then, using 7.6 g of thus obtained white crystals, 15 ml of 2N NaOH and 100 ml of methanol, the procedure of Reference Example was followed to give 3.8 g of 4-benzyloxy-3-methylphenol as white crystals, m.p. 70-71° C. Then, using 2.1 g of thus obtained white crystals, 1.4 g of anhydrous potassium carbonate, 4.6 g of chloromethyloxirane and 1.9 g of 1-(2-methoxyphenyl)piperazine, the procedures of Examples 1-A and 2 were followed. Recrystallization from methanol-ethyl acetate gave 3.0 g of white crystals, m.p. 214-216° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].II.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[C:13]#[N:14].[Cl-].[NH4+]>O1CCCC1.[Zn]>[NH2:14][C:13]([C:12]1[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=1[F:19])=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(F)cccc1F
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(N)c1c(F)cccc1F
Temperature: 25 °C
Yield: 404.3 %

Procedure:
3.0 g of ethyl α-bromoacetate and a trace amount of iodine were added to a solution of 18.3 g of zinc in 250 ml of tetrahydrofuran under reflux and vigorously stirred to start the reaction. The reaction solution was cooled to room temperature and added with a 30 ml tetrahydrofuran solution of 13.9 g of 2,6-difluorobenzonitrile at one time. Then 17.8 g of ethyl α-bromoacetate was added dropwise at such a rate that slow refluxing would continue. The reaction solution was further refluxed for one hour, cooled, added into 350 ml of an aqueous solution of 50.0 g of ammonium chloride and extracted with 300 ml of diethyl ether. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 16.5 g of ethyl 3-amino-3-(2,6-difluorophenyl)-2-propenoate.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:20])[CH2:15][NH:16][CH:17]2[CH2:19][CH2:18]2)=[CH:6][C:5]=1[Br:21].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:20])[CH2:15][NH:16][CH:17]2[CH2:18][CH2:19]2)=[CH:6][C:5]=1[Br:21]
Reactant: Nc1c(Br)cc(C(=O)CNC2CC2)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(Br)cc(C(O)CNC2CC2)cc1C(F)(F)F

Procedure:
m.p. 141.5°-142.5° C., m.p. of the hydrochloride: 195°-195.5° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-cyclopropylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]=[C:18]([CH3:21])[NH:19][CH:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[NH:17][C:18]([CH3:21])=[N:19][CH:20]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1ncc(C#Cc2c(-c3ccccc3)noc2C)[nH]1
Yield: 13 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted using (4-iodo-2-methyl-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 14 mg, 13%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(OCCCN(C(N)=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.1 %

Procedure:
Methyl 4-[3-[N-carbamoyl-N-(4-chlorophenyl)amino]propoxy]benzoate (1.5 g) was dissolved in dioxane (30 ml), and thereto was added a solution of sodium hydroxide (0.33 g) in water (6 ml), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was neutralized with conc. hydrochloric acid (0.7 ml), and the mixrure was concentrated under reduced pressure. The residue was crushed in aqueous methanol, and collected by filtration to give the desired product (1.27 g). mp. 172°-174° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH2:13][CH2:14]O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>O>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:13][CH2:14][Cl:24])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cccc(C2CCCCC2)c1
Solvent: O
Solvent: c1ccncc1
Product: ClCCc1cccc(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.1 g of β-(m-cyclohexyl-phenyl)-ethanol are mixed with 13.3 ml of absolute pyridine. 12.5 ml of thionyl chloride are added dropwise to this mixture, whilst cooling with ice. Thereafter the reaction mixture is slowly heated to 100°-110°C and is kept at this temperature for 2 hours. The reaction solution is again cooled to room temperature, 29 ml of water are added and the whole is extracted with a mixture of ether and chloroform. The organic phase is washed twice with 2 N sodium carbonate solution, three times with 2 N hydrochloric acid and finally once with 2 N sodium carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue, a brown oil, is distilled in a high vacuum. Hereupon, β-(m-cyclohexyl-phenyl)-ethyl chloride is obtained as a light yellow oil of boiling point 103°-8°C/0.1 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:27]=3)[C:22]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:27]=3)[C:22]3([CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:15][CH2:14]1)=[N:7]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N2CCN(S(C)(=O)=O)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-(5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.093 mmol) in DCM (5.0 mL) was treated with triethylamine (0.019 mL, 0.140 mmol) and methanesulfonyl chloride (7.3 μL, 0.093 mmol) and the reaction was stirred at rt overnight. After this time the reaction was partitioned between EtOAc and water. The separated organic layer was dried over MgSO4 and evaporated in vacuo. Purification by reverse-phase HPLC (10% to 95% acetonitrile in water) gave 1′-(5,7-difluoro-3-methyl-2-(4-(methylsulfonyl)piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.57 (1H, d, J=2.3 Hz), 7.37 (1H, dt, J=9.8, 1.3 Hz), 6.78 (1H, ddd, J=11.8, 9.0, 2.4 Hz), 5.65 (1H, d, J=2.3 Hz), 4.04-4.25 (2H, m), 3.83-3.97 (2H, m), 3.69-3.78 (4H, m), 3.30-3.65 (10H, m), 2.90-3.09 (4H, m), 2.86 (3H, s), 2.26-2.39 (2H, m), 2.25 (3H, s), 1.78 (1H, d, J=13.3 Hz), 1.64-1.75 (1H, m). Mass Spectrum (ESI) m/e=615.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1CCCCC=1>[Pd].CO.C(Cl)Cl>[NH2:14][C:6]1[CH:5]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cc(OC)c(OCCOC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1=CCCCC1
Solvent: CO
Product: CCOC(=O)c1cc(OC)c(OCCOC)cc1N
Yield: 87.4 %

Procedure:
A mixture of ethyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (10.24 g, 34 mmol), cyclohexene (30 ml) and 10% palladium-on-charcoal catalyst (2.0 g) in methanol (150 ml) was heated at reflux for 5 hours. The reaction mixture was allowed to cool and diluted with methylene chloride. The catalyst was removed by filtration and the volatiles removed from the filtrate by evaporation. The residue was recrystallised from ethyl acetate/hexane to give ethyl 2-amino-5-methoxy-4-(2-methoxyethoxy)benzoate (8.0 g) as a buff solid. Formamide (80 ml) was added to this product and the mixture heated at 170° C. for 18 hours. About half the solvent was removed by evaporation under high vacuum and the residue was left to stand overnight. The solid product was collected by filtration, washed with ether and dried to give 6-methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (5.3 g, 62% over two steps) as a grey solid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.N1CCCCC1.[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:2]2[C:1](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:10])=[CH:20][CH:19]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1CC(=O)c2ccccc21
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccncc2)C(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of indane-1,3-dione (5.85 g), piperidine (0.46 ml) and pyridine-4-carboxaldehyde (4.31 g) was stirred in IMS (40 ml) at ambient temperature for 50 minutes. The mixture was cooled in an ice-bath but no crystallization occurred. The solution was allowed to warm to ambient temperature and then the solvent was removed under reduced pressure to give a residue which was partially purified by flash column chromatography on silica using 10% industrial methylated spirit in dichloromethane followed by 20% industrial methylated spirit in dichloromethane as the mobile phases. The leading fractions were collected, combined and evaporated to give a solid which was triturated with ice-cold diethyl ether and filtered to give 2-(4-pyridylmethylene) indan-1,3-dione, m.p. 152-157° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:21]([CH2:22][OH:23])=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:21]([CH:22]=[O:23])=[C:20]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[C:19]2[CH:18]=[C:17]3[O:32][CH2:33][CH2:34][O:35][C:16]3=[CH:15][C:14]=2[N:13]=1
Reactant: CN1CCN(Cc2c(CO)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A 3-necked 4-L round-bottom flask is equipped with a mechanical stirrer and a 250-mL addition funnel. Under nitrogen, the flask is charged with methylene chloride (800 mL), followed by addition of oxalyl chloride (28.8 mL, 330 mmol). The solution is cooled to -78° C. and dimethyl sulfoxide (46.7 mL, 660 mmol) is added over 6 min. The temperature of the solution increases to -58° C. during the addition and is cooled back to about -70° C. After stirring for 3 min, [7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol (100 g, 275 mmol), prepared as in example 13e, is added as a solution in 140 mL of methylene chloride over 10 min. The yellow slurry is stirred for 45 min, then anhydrous triethylamine (153 mL, 1.10 mol) is added over 4 min. Stirring is continued for 10 min at -78° C., then the cooling bath is removed. The reaction mixture is allowed to warm to -5° C. and poured into 2 L of water. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×1.5 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo yielding 7-chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a dark solid. This crude product is used for the next step without further purification. Recrystallization from CH2 Cl2 --MeOH (5:1) provided an analytical sample as a light yellow solid:140°-142° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ2.30 (s, 3H), 2.45, 2.59 (m, 8H), 3.98 (s, 2H). 4.41(s, 4H), 7.46 (s, 1H), 7.53 (s, 1H), 10.4 (s, 1H). Elemental analysis: Calculated for C18H20ClN3O3 : C 59.75, H 5.57, N 11.61. Found: C 59.78, H 5.62, N 11.64.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2].[OH2:17]>CC(C)=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]
Reactant: CCc1cc(=O)c2cc(CCO)ccc2o1
Reactant: O
Solvent: CC(C)=O
Product: CCc1cc(=O)c2cc(CC(=O)O)ccc2o1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
This red solution was added dropwise to a stirred solution of 2-(2-ethyl-4-oxo-4H-1-benzopyran-6-yl)ethan-1-ol (3.5g) in acetone (30 mls) maintained at 20° C until a permanent red colouration was obtained. The reaction was stirred at room temperature for a further 11/2 hours. Water was added and the product was extracted with ether (3x). The separated ethereal solution was extracted with sodium bicarbonate which was washed with water, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform solution was washed with a small volume of saturated brine solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the product as an off-white solid (2.2g). Recrystallisation from benzene yielded pale yellow needle crystals mp 171°-172° C (1.1g). The mother liquors were concentrated and a second crop was obtained as a pale yellow solid (0.6g).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCc2ccsc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-20; 0.84 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.92 mmol), potassium carbonate (3.35 mmol) in DMF (4 mL). The product was purified via flash chromatography over silica gel eluting with 10:90 EtOAc:CH2Cl2, mp 63-70° C. MS (APCI): 475 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Cl)(=[O:3])[CH3:2].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([O:17][CH3:18])=[O:16])[CH3:6]
Reactant: CC(=O)OCCCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1C(=O)OC
Temperature: 70 °C
Yield: 91 %

Procedure:
Chloroethyl acetate was slowly added to a mixture of methyl salicylate (100 g, 0.657 mol) and K2CO3 (100 g, 0.723 mol) in DMF (400 mL) at ambient temperature (20-30° C.). The reaction mixture was heated at 65-75° C. for 12-18 h. The progress of the reaction was monitored by HPLC analysis. Upon completion of reaction, the inorganics were filtered off and washed with DMF. DMF was recovered from the filtrate to obtain the product meeting the desired specifications. Yield—91-95%.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:27][C:21]1[CH:20]=[C:19]([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][CH:2]([F:1])[F:29])=[O:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH2:33][CH:32]=[CH2:31]
Reactant: C=CCCBr
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and 4-bromo-1-butene, white powdery 3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].C1(O)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22]
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: Oc1ccccc1
Product: CC(C)=CCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 2-chloro-5-nitrophenol (50.6 g), anhydrous potassium carbonate (44.5 g), tetrabutylammonium bromide (4.7 g) and 4-bromo-2-methyl-2-butene (53.3 g, 90%) in methyl ethyl ketone (263 mL) was stirred at ambient temperature overnight. TLC of the reaction mixture showed traces of phenol remaining. Additional prenyl bromide (1 mL) was then added to the reaction mixture and stirred for 2 hours. The solvent was then removed from the reaction mixture. The residue of the reaction mixture was then treated with water and extracted into diethyl ether. The extract was washed with 2N sodium hydroxide and water, dried (MgSO4), filtered, and evaporated, to leave a brown solid which was recrystallised from ethyl acetate/isopropyl alcohol to give 1-chloro-2-(3-methyl-2-butenyloxy)-4-nitrobenzene, 49.5 g, a beige solid, a single spot on TLC (ethyl acetate:hexane, 20:80).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br:11]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: BrBr
Reactant: CC(C)c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-isopropylphenol (1.39 mL, 10 mmol, 1 eq.) in DCM (8 mL), bromine (0.52 mL, 10 mmol, 1 eq.) was added at r.t. over a period of 10 min. The reaction mixture was stirred at r.t. for 18 hours. The mixture was poured into a mixture of sat. aq. NaHCO3 soln. (25 mL) and ice. The resulting mixture was extracted with AcOEt (2×25 mL). The comb. org. layers were washed successively with water (25 mL) and sat. aq. NaCl soln. (25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 4-bromo-2-isopropyl-phenol as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[C:17]([O:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([O:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OCC(F)(F)C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,3,3,3-pentafluoropropyloxy)phenylacetate (0.40 g, 0.82 mmol) from Step 2 above in MeOH (5 mL) was added a solution of aqueous NaOH (0.82 mL of a 2.0 N solution, 1.6 mmol). The mixture was refluxed for 3 h and then cooled to ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated and washed with H2O (10 mL) and brine (10 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. 4-(N-tert-Butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,3,3,3-pentafluoropropyloxy)phenylacetic acid was obtained as an amorphous solid (HPLC retention time=9.7 min (method A)).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH:20]=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C=CC(N2C3C(=CC=C(OCC4CC4)C=3)C=N2)=CC=1)C1C=CC=CC=1>>[CH:26]1([CH2:25][O:24][C:19]2[CH:20]=[CH:21][C:22]3[C:17]([CH:18]=2)=[N:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:23]=3)[CH2:27][CH2:28]1
Reactant: c1ccc(COc2ccc(-n3cc4ccc(OCC5CC5)cc4n3)cc2)cc1
Agent: c1ccc(COc2ccc(-n3ncc4ccc(OCC5CC5)cc43)cc2)cc1
Product: Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1

Procedure:
Using a mixture of 2-[4-(benzyloxy)phenyl]-6-(cyclopropylmethoxy)-2H-indazole and 1-[4-(benzyloxy)phenyl]-6-(cyclopropylmethoxy)-1H-indazole, and in the same manner as in Example 12, step C, a mixture of the title compound and 4-[6-(cyclopropylmethoxy)-1H-indazol-1-yl]phenol was obtained.