Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([O:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]3[C:13](=[O:14])[CH:12]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:11][C:10]3=[O:22])=[C:6]([CH3:8])[CH:7]=1)[CH:34]=[CH:33]2
Reactant: Cc1cc(O)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc3cc(Cl)ccc3n2)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Temperature: 140 °C

Procedure:
A suspension of 2-(4-hydroxy-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.104 g, 0.00033 mol), 2,6-dichloroquinoline (0.065 g, 0.00033 mol) and potassium carbonate (0.140 g, 0.00101 mol) in anhydrous N,N-dimethylformamide (3 ml) is heated at 140° C. for 40 minutes under microwave irradiation. After cooling to room temperature the reaction mixture was quenched with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is separated, washed with distilled water then dried over anhydrous magnesium sulfate. The mixture is filtered, the filtrate is evaporated in vacuo and the residue is purified by preparative reverse phase HPLC to afford 2-[4-(6-chloroquinolin-2-yloxy)-2,6-dimethylphenyl]-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:16]#[N:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn].Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:16]#[N:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: N#CC(Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: N#CC(Cc1ccc(N)cc1)c1ccccc1

Procedure:
Analogous to this formula, 5.8 g=95.1% of the theoretical yield or 2.4 g=80.0% of the theoretical yield of 4-aminobenzyl-benzylcyanide is prepared from 7.0 g or 3.4 g of 4-nitrobenzyl-benzylcyanide, with 6.1 or 3.0 g of tin, 95.4 ml or 46.3 ml of ethanol and 27.7 ml or 13.5 ml of hydrochloric acid, 32%. The two raw products are combined and chromatographed (silica gel 0.063-0.2 mm, developing agent diethyl ether: petroleum ether--2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:12][C:13](=[N:17][OH:18])[C:14](=O)[CH3:15].Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]([CH3:15])=[C:13]([CH3:12])[N+:17]=2[O-:18])[CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)C(C)=NO
Agent: Cl
Solvent: O=CO
Product: Cc1oc(-c2cc(Cl)c(O)c(Cl)c2)[n+]([O-])c1C

Procedure:
2-(3,5-Dichloro-4-hydroxyphenyl)-4,5-dimethyloxazole N-oxide was prepared from 19.1 g 3,5-dichloro-4-hydroxybenzaldehyde and 10.1 g butanedione mono-oxime in formic acid in the presence of hydrogen chloride gas. There was obtained 12.2 g of product, m.p. 221°-223° C.
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C@:32]1([OH:38])[C:33]2[N:34]([CH:35]=[N:36][CH:37]=2)[C@@H:30]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[F:21])[CH2:31]1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc([C@H]2C[C@](O)(c3nc4ccccc4s3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a 1.6 M solution of n-BuLi in hexane (0.29 mL, 0.46 mmol) cooled to −78° C. was added a solution of benzo[d]thiazole (56 mg, 0.42 mmol) in THF (1 mL). The crude was stirred at −78° C. for 1 hr. This solution was then cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) cooled at −78° C. After stirring at −78° C. for 2 hrs, the crude was warmed to room temperature. The crude was stirred at room temperature for 1 hr. The crude was quenched with sat. NH4Cl. The crude was diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 18 mg of the entitled product as the major diastereomer. MS 377.0 (M+H); LCMS condition A, retention time 1.23 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.09 (dd, 1H), 3.84 (dd, 1H), 5.96 (d, 1H), 7.02 (s, 1H), 7.24-7.53 (m, 6H), 7.85 (d, 1H), 7.93 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CC#N>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[O:9][CH2:8][C:7]3=[O:10])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A microwave vial was charged with (S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.047 g, 0.13 mmol) and 3-butyl-8-azabicyclo[3,2,1]octane (0.039 g, 0.23 mmol) in MeCN (2 mL) and sealed. After microwave irradiation, 100° C., 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK05) (0.017 g, 33%). 1H NMR (CD3OD) δ 7.34-7.30 (m, 1H), 6.80-6.75 (m, 2H), 4.61 (ABq, J=18.8 Hz, J=15.1 Hz, CH2), 4.04 (dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.93 (dd, J=14.3 Hz, J=8.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.36-2.23 (m, 2H), 2.03-1.85 (m, 3H), 1.62-1.45 (m, 5H), 1.36-1.14 (m, 8H), 0.92-0.87 (m, 2 CH2); 13C NMR (CD3OD) δ 166.2, 160.4 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.3 (d, J=2.9 Hz), 118.1 (d, J=9.7 Hz), 109.8 (d, J=22.9 Hz), 105.7 (d, J=26.5 Hz), 68.6, 62.5, 61.2, 58.3, 46.4, 39.0, 37.9, 32.1, 30.2, 29.0, 27.8, 27.2, 23.9, 17.2, 14.4.
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[C:24]([SH:37])=[CH:25][C:26]([CH3:36])=[C:27]([O:29][S:30](=[O:35])(=[O:34])[N:31]([CH3:33])[CH3:32])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][S:30](=[O:34])(=[O:35])[N:31]([CH3:32])[CH3:33])[C:26]([CH3:36])=[CH:25][C:24]=1[S:37][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)N(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and addition funnel were added tosyl bromide (1.64 g, 7.0 mmol), CCl4 (25 mL), and NEt3 (0.98 mL, 7.0 mmol). The ensuing slurry was then cooled to 0° C. A solution of 1.07 g (3.5 mmol) of dimethyl-sulfamic acid 5-tert-butyl-4-mercapto-2-methyl-phenyl ester (prepared in Example TTT) in CCl4 (25 mL) was added dropwise to the slurry. Addition was complete in 1.0 hour. After addition was complete, the ice bath was removed and the reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2, washed with brine, dried (MgSO4), and concentrated. The residue was taken up in a small amount of EtOAc and triturated with hexane. The product was filtered and dried under high vacuum to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 2.23 (s, 3 H), 2.37 (s, 3 H), 3.02 (s, 6 H), 7.19 (d, 2 H), 7.22 (s, 1 H), 7.33 (s, 1 H), 7.40 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1.Br[CH2:20][CH2:21][CH3:22].[H-].[Na+]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:20][CH2:21][CH3:22])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[CH:10]1
Reactant: Cc1cn(Nc2ccncc2Cl)c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1Cl)n1cc(C)c2ccccc21

Procedure:
The title compound was prepared from N-(3-chloro-4-pyridinyl)-3-methyl-1H-indol-1-amine and 1-bromopropane with the aid of NaH in substantially the same manner as in Example 4, m.p. 68°-70°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O-:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.O1CCCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)[O-])cc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (0.58 g, 1.952 mmol in methanol (12 mL) and tetrahydrofuran (3 mL) was added 3 N NaOH (3.25 mL, 9.76 mmol) via syringe and stirred for 3 h at RT. The volatiles were removed in vacuo then diluted with water and slowly acidified with 1 N HCl to pH 4-5. The contents were extracted with 20% THF/EtOAc (3×). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.52 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 13.54 (s, 1H) 8.36-8.43 (m, 2H) 7.82 (d, J=1.52 Hz, 1H) 5.11 (quin, J=6.57 Hz, 1H) 1.48 (s, 3H) 1.47 (s, 3H); LC-MS (ES) [M+H]+ 283.4/285.2
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([O:26]CC)=[O:25].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.95 g (4.73 mmol) of ethyl 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]pyridine-3-carboxylate Example 90A were initially charged in 30 ml of methanol, 3.28 g (10.4 mmol) of barium hydroxide octahydrate were added and the mixture was stirred at RT for 3 days. The suspension was diluted with 30 ml of water and adjusted to pH 6 using 1 M aqueous hydrochloric acid. The solid was filtered off, washed with 50 ml of water and dried under reduced pressure at 70° C. for 2 h. This gave 1.64 g of the target compound (90% pure, 81% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccc(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(CCCBr)c1
Yield: 87.9 %

Procedure:
Compound 75-2 (4.45 g) was dissolved in methylene chloride (95 ml), triphenylphosphine (8.13 g) and N-bromosuccinimide (5.51 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.44 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:16])=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:17]1([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:32])=[CH:27][CH:26]=2)=[O:23])[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][CH:15]=[C:3]([CH2:2][N:36]2[CH2:37][CH2:38][N:33]([C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([NH:24][C:22]([NH:21][CH:17]4[CH2:18][CH2:19][CH2:20]4)=[O:23])=[CH:26][CH:27]=3)[CH2:34][CH2:35]2)[C:4]=1[F:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NC(=O)c1cccc(CBr)c1F
Reactant: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)NC1CCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)c1F
Temperature: 70 °C
Yield: 44 %

Procedure:
A stirred mixture of 3-(bromomethyl)-N-tert-butyl-2-fluorobenzamide (0.36 mmol, 105 mg), 1-cyclobutyl-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.33 mmol, 620 mg) and triethylamine (2.5 mmol, 0.35 mL, 253 mg) in tetrahydrofuran (2 mL) was heated to 70° C. for 16 hours. After this time the volatiles were removed under vacuum. The residue was purified by strong cation exchange chromatography and basic reverse phase HPLC to yield the title compound (74 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:12][N:11]([CH2:13][CH3:14])[CH2:10]1.ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:12][N+:11]([O-:21])([CH2:13][CH3:14])[CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1CC(O)(c2cccc(F)c2F)C1
Solvent: ClCCl
Product: CC[N+]1([O-])CC(O)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
To a stirred solution of 3-(2,3-difluorophenyl)-1-ethylazetidin-3-ol (0.622 g, 2.91 mmol) in dichloromethane (30 mL) was added 3-chloroperoxybenzoic acid in portions (77%, 0.98 g, 4.37 mmol). The resulting mixture was stirred at ambient temperature for 5 h. The reaction mixture was poured onto a column of basic alumina, the column was washed with dichloromethane and eluated with methanol. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 10:90 to 30:70) gave the title compound (0.160 g, 23.9%). The N-oxide was converted to the hydrochloric acid salt and recrystallized from methanol/acetonitrile. The product was analyzed by LCMS (Qtrap, Applied Biosystems, Q1 MS): MS (m+1)/z; 231 (M+1, bp).
Reaction SMILES: [CH3:1][C:2]([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]2[N:32]=[C:33]([C:35]#[N:36])[S:34][C:30]=2[CH:29]=1>C1COCC1>[C:35]([C:33]1[S:34][C:30]2[CH:29]=[C:28]([NH:27][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]3[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=3[CH3:18])[CH3:7])[CH:38]=[CH:37][C:31]=2[N:32]=1)#[N:36]
Reactant: N#Cc1nc2ccc(N)cc2s1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc3nc(C#N)sc3c2)=C(C)C1=O
Yield: 10 %

Procedure:
To the solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanoic acid (0.72 g, 3.09 mmol) and isobutyl chloroformate (0.44 g, 3.24 mmol) in 10 ml of dry THF, N-methyl morphorline (0.34 ml) was added at 0° C. The resultant mixture was stirred for 30 minutes at 0° C., and 6-amino-2-cyanobenzothiazole (0.36 g, 2.06 mmol) added. The resultant mixture was stirred overnight. The compound was directly purified with flash silica column using heptane and ethyl acetate as eluent to give a yield 10%. 1H NMR (300 MHz, CD2Cl2) δ 8.57 (d, J=2.0, 2H), 8.06 (d, J=9.0, 2H), 7.67 (s, 1H), 7.40 (dd, J=2.1, 8.9, 1H), 3.08 (s, 2H, CH2), 2.22 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.50 (s, 6H, CH3). MS (m/e): 408 (M+).
Reaction SMILES: [Br: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][CH2:20][F:21]>CN(C=O)C.O>[Br: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][CH2:20][F:21]
Reactant: FCCBr
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 16A (475 mg, 2.179 mmol) was dissolved in DMF (1 mL) and to this solution was added potassium carbonate (903 mg, 6.54 mmol) and 1-bromo-2-fluoroethane (415 mg, 3.27 mmol). The reaction mixture was stirred at 100° C. for 3 hours, cooled, diluted with water (20 mL) and then extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 16B was obtained as a pale yellow semi-solid (570 mg, 2.159 mmol, 99% yield). MS (ES): m/z=199.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.47-4.51 (m, 1 H) 4.55-4.59 (m, 1 H) 4.73-4.78 (m, 1 H) 4.85-4.91 (m, 1 H) 7.77-7.83 (m, 1 H) 7.91 (d, J=2.51 Hz, 1 H) 7.94 (d, J=8.53 Hz, 1 H).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:9][C:10]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:15][CH:14]=1.Cl.O1CCCC1>O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[O:9][C:8]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:7][C:6]=2[CH2:5][OH:4])=[CH:14][CH:15]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2CO)cc1
Yield: 30.1 %

Procedure:
A mixture of 4-[(methoxymethoxy)methyl]-5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole (0.80 g), 1N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) was heated under reflux for 20 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give [5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]methanol as colorless crystals (0.22 g, yield 29%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]CCC1)[CH3:2].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:25]([F:27])([F:26])[F:24])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CCCCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: -25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
1.05 g (3.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate and 0.74 ml (5 mmol) of (trifluoromethyl)-trimethylsilane in 7 ml of THF are mixed with 62 mg of tetramethylammonium fluoride at −40° C. It is stirred for 2 hours at −25° C., and then another 0.35 ml (2.4 mmol) of (trifluoromethyl)-trimethylsilane and 62 mg of tetramethylammonium fluoride are added. After another 2 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 800 mg of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 40 ml of diethyl ether at 0° C. with 150 g (4 mmol) of lithium aluminum hydride, and it is stirred for 2.5 more hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added at 0° C. to the batch, and it is vigorously stirred for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-1 5%), 630 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([I:11])[C:8]([OH:12])=[C:7]([Br:13])[CH:6]=1)[CH3:2].[CH2:15](O)[CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([I:11])[C:8]([O:12][CH2:15][CH2:16][OH:17])=[C:7]([Br:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(O)c(I)c1
Reactant: OCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCCO)c(I)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
To a mixture of 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 255 mmol) in 1 L of dry THF was added ethylene glycol (63.2 mL, 1.02 mol) and triphenylphosphine (87 g, 322 mmol). The solution was cooled to 0° C. and diisopropyl azodicarboxylate (60.2 mL, 306 mmol) was added dropwise with stirring. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete after 3 h. Worked up by removing ˜½ of the THF via concentration in vacuo, adding water, and extracting with ethyl acetate several times. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, decanted, and concentrated in vacuo to give a viscous oil which solidified on standing. The major portion of the solid byproducts were removed by stirring with 50% ethyl acetate/hexane. The solid byproduct was filtered off and the liquid was concentrated in vacuo to give a solid which was further purified. Flash chromatography eluting with 5–15% ethyl acetate hexane gave pure 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (65 g, 62%). 1H NMR (300 MHz, CDCl3) δ 1.37 (t, J=6.5 Hz, 3H, —CO2CH2CH3), 3.95 (t, J=5 Hz, 2H, —OCH2CH2OH), 4.19 (t, J=5 Hz, 2H, —OCH2CH2OH), 4.32 (t, J=6.5 Hz, 2H, —CO2CH2CH3), 8.18 (d, 1H, arom), 8.37 (d, 1H, arom).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1onc(-c2ccncc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccncc2)c1CBr
Yield: 21.9 %

Procedure:
Ethyl 4-methyl-3-(pyridin-4-yl)isoxazole-5-carboxylate (5.1 g, 22.0 mmol), NBS (4.7 g, 26.4 mmol), and benzoyl peroxide (0.53 g, 2.2 mmol) were added to 140 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography (10-60% EtOAc/hexanes) to afford 1.5 g of the title compound. MS: (+) m/z 311, 313 (M+1, 79Br/81Br).