Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[CH:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[CH:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2ccnc(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4ccnc(Nc5ccc(C(=O)N6CCOCC6)cn5)c4)c3CO)ncc2c1
Reaction time: 2 h

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{2-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-pyridin-4-yl}-benzyl ester (200 mg, 0.31 mmol) was dissolved in methanol (10 ml). K2CO3 (86 mg, 0.62 mmol) was added at room temperature, and the mixture was stirred at that temperature for 2 hours. The mixture was poured into water (10 ml), extracted with DCM (100 ml) and then washed with saturated aqueous solution of sodium chloride (100 ml). The combined organic extract was dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:2). The desired product was obtained as a white solid (130 mg, yield 69%). 1H NMR (300 MHz, MeOD): δ 8.36 (d, J=2.6 Hz, 1H), 8.22-8.18 (m, 2H), 7.73 (d, J=1.5 Hz, 2H), 7.65-7.60 (m, 2H), 7.57-7.51 (m, 1H), 7.50-7.46 (m, 1H), 7.38 (d, J=7.6 Hz, 2H), 7.00 (dd, J=5.2, 1.5 Hz, 1H), 4.36 (s, 2H), 3.59 (s, 8H), 1.36 (d, J=5.7 Hz, 9H). LC-MS: 609[M+1]+, tR=1.407 min. HPLC: 97.79% at 214 nm, 99.31% at 254 nm, tR=3.479 min.
Reaction SMILES: CCOP(S)(OCC)=S.[Br:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH:18]=[CH:19][C:20]([OH:22])=O)[CH:14]=[CH:15][CH:16]=1.BrC1C=C(C(=O)CC(SP(OCC)(OCC)=S)C(O)=O)C=CC=1.O.[NH2:48][NH2:49]>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](=[O:22])[NH:48][N:49]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1cccc(Br)c1
Agent: CCOP(=S)(OCC)SC(CC(=O)c1cccc(Br)c1)C(=O)O
Agent: CCOP(=S)(S)OCC
Solvent: CCO
Solvent: O
Product: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
1.12 g (0.006 mole) of O,O-diethyldithiophosphoric acid were added, at room temperature, to a suspension of 1.28 g of 4-(3-bromophenyl)-4-oxo-2-butenoic acid in 10 ml of ethanol, and then the mixture was stirred for 10 minutes. Formation of 4-(3-bromophenyl)-2-diethoxyphosphinothioylthio-4-oxobutanoic acid was confirmed by thin layer chromatography but the compound was not separated from the reaction mixture. 0.3 g (0.006 mole) of hydrazine monohydrate was added to the reaction mixture, which was then stirred overnight at room temperature. At the end of this time, the crystals which had precipitated were collected by filtration and washed with ethanol to give 0.48 g of the desired 6-(3-bromophenyl)-3(2H)pyridazinone. The filtrate was concentrated and then subjected to column chromatography through silica gel eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give a further 0.48 g of the product, a total of 0.96 g (yield 76%) of the product, melting at 202°-204° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([OH:9])(=[O:8])[CH3:7]>C([O-])(=O)C.[Na+]>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: ClCC1CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OCC(O)CCl
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Epichlorohydrin (187 g, 2.0 mol) was added dropwise over a 75 minute period to a mechanically stirred suspension of 10.0 g (0.062 mol) of anhydrous ferric chloride in 138 mL (2.4 mol) of glacial acetic acid at 0°-10° C. After the addition was completed, the reaction mixture was stirred one hour and was allowed to stand at room temperature for two days. Anhydrous sodium acetate (5.1 g, 0.062 mol) was added and excess acetic acid was then removed in vacuo. The mixture was diluted with 200 mL of methylene chloride and filtered through Celite™ (i.e. diatomaceous earth). The solution was washed with 10% potassium carbonate and dried over potassium carbonate and sodium sulfate. Removal of the methylene chloride in vacuo gave 275 g of crude 3-chloro-2-hydroxy-1-propyl acetate, and an additional 9 g was recovered by extracting the potassium carbonate solution with methylene chloride (93% crude yield). This material was used without purification in the subsequent step. 1H NMR (CDCl3) δ2.10 (s, 3H, --COCH3); 3.80 (m, 6H, --CH2CH(OH)CH2 --); IR (film) 3500 (--OH); 1735 cm-1 (--COCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:3]=1.Cl[Sn](Cl)(Cl)Cl.[I:17]I>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:10]([CH2:11][I:17])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=CCc1cc(F)ccc1O
Reactant: II
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2c(c1)CC(CI)O2
Reaction time: 18 h
Yield: 54.7 %

Procedure:
To a solution of 4-fluoro-2-(prop-2-en-1-yl)phenol (5 g, 32.9 mmol) in dichloromethane (125 mL) was added SnCl4 (4.28 g, 16.5 mmol) and iodine (8.36 g, 32.9 mmol) at room temperature. After an additional 18 hours, the reaction was quenched with water (150 ml) and the pH value was adjusted to ˜8 with aqueous sodium hydroxide solution (2N). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layer was washed with Na2S2O4 (3×100 mL, 5%) to remove iodine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography using 0.5-1% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-fluoro-2-(iodomethyl)-2,3-dihydro-1-benzofuran as a yellow oil (5 g, 54%); 1H NMR (300 MHz, DMSO): δ 7.03-7.08 (dd, J=5.7 Hz, 8.4 Hz, 1H), 6.93-6.86 (dt, J=2.7 Hz, 8.7 Hz, 1H), 6.76-6.70 (m, 1H), 4.88-4.79 (m, 1H), 3.49-3.60 (m, 2H), 3.41-3.32 (dd, J=7.2 Hz, 16.5 Hz, 1H), 2.96-2.88 (dd, J=7.2 Hz, 16.5 Hz, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[NH2:9].Cl.[Sn](Cl)Cl>O.C(O)C>[CH3:25][C:11]1[CH:10]=[C:8]([NH:9][NH2:1])[CH:7]=[C:6]([CH3:5])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:23])[CH3:24])[CH:15]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2c(C)cc(NN)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of sodium nitrite (155 mg, 2.24 mmol) in water (1 mL) was added to a suspension of 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-aniline (J. Med. Chem. 38:695 (1995), 640 mg, 2.24 mmol) in ethanol (3 mL) and concentrated hydrochloric acid (12 M, 1.12 mL, 13.44 mmol) at 0° C. The yellow heterogeneous solution slowly turns to an orange clear solution. After stirring at 0° C. for 30 minutes, a solution of tin dichloride (1.53 g, 8.06 mmol) in hydrochloric acid (12 M, 1.3 mL, 15.68 mmol) was added. The orange solution turned green and a white precipitate formed. Ethanol (3 mL) was added to dissolve most of the precipitate and the heterogeneous reaction mixture was stirred at 0° C. After 2 hours, water was added and the precipitate collected by filtration. The sticky solid was dissolved in ethyl acetate and washed with water, 1 N sodium hydroxide then brine. The organics were dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 95/5 to 90/10) to give 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-phenyl hydrazine (305 mg, 45%): 1H NMR (300 MHz, CDCl3) δ 6.77 (d, J=3.0 Hz, 1H), 6.67 (d, J=9.0 Hz, 1 H) 6.58 (s, 2H), 6.37 (dd, J=9.0, 3.0 Hz, 1H), 3.77 (s, 3H), 3.27 (heptuplet, J=6.9 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J=6.9 Hz, 6H); TLC conditions: Merck silica gel, 250 microns; Mobile phase=dichloromethane-methanol (9:1), Rf=0.6.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@@:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])([CH3:12])[CH2:10][CH2:11][C:6]=2[C:5]([CH3:29])=[C:4]([OH:30])[CH:3]=1.[C:31]([O-])(=O)C.C([O-])(=O)C1C=CC=NC=1.C([O-])(=O)CCC([O-])=O.CC(C)=CCC/C(/C)=C/CC/C(/C)=C/CCC1(C)OC2C=CC(O)=CC=2CC1>>[CH3:31][C:3]1[C:2]([CH3:1])=[C:7]2[C:6]([CH2:11][CH2:10][C@:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])([CH3:12])[O:8]2)=[C:5]([CH3:29])[C:4]=1[OH:30]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(O)c(C)c2c1O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])c1cccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
d,l-α-tocopherol; d-β-tocopherol; d,l-β-tocopherol; d-η-tocopherol; and d,l-η-tocopherol (including acetate, hemisuccinate, nicotinate, and succinate-PEG ester forms of each of the foregoing); tocotrienol isomers, and their esters;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][C:12]([CH2:15]Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[N:18]([CH2:15][C:12]1[N:11]=[C:10]([CH3:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(CCl)ccc1OCc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN=[N+]=[N-])ccc1OCc1ccccc1

Procedure:
A solution of 3-benzyloxy-6-chloromethyl-2-methylpyridine (8.02 g) and sodium azide (5.98 g) in 400 ml of ethanol is heated at 80° for 4 hours. The reaction mixture is cooled, filtered and evaporated to yield a residue which is partitioned between ice-cold 0.5N NaOH (150 ml) and ether (150 ml). The organic phase is dried over sodium sulfate and evaporated to yield 6-azidomethyl-3-benzyloxy-2-methylpyridine, NMR: (CDCl3) 2.47 (3H), 4.27 (2H), 4.95 (2H). Lithium aluminum hydride (1.27 g) is added to a solution of 6-azidomethyl-3-benzyloxy-2-methylpyridine (7.18 g) in 120 ml of dry ether at room temperature. After stirring for 45 minutes, 1.3 ml of water, 1.3 ml of 15% sodium hydroxide and 3.8 ml of water are added sequentially. The salts are filtered off and the filtrate is evaporated to yield 6-aminomethyl-3-benzyloxy-2-methylpyridine; NMR: (CDCl3) 1.67 (2H), 2.47 (3H), 3.8 (2H), 4.95 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].CCN(CC)CC.[C:20](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>C1COCC1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl) aniline (3a) (0.5 g, 2.55 mmol) in dry THF (8 mL), cooled to 0° C., Et3N (0.4 mL, 2.76 mmol) followed by PivCl (0.34 mL, 2.8 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water (30 mL). The organic layer was separated dried over Na2SO4 and concentrated under reduced pressure to give the crude material which was triturated with n-hexane to afford the desired amide 3b (0.45 g, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.OO.C=CCCCC.C(=O)([O-])[O-:32].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:32])[NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: OO
Agent: [Na+]
Solvent: C=CCCCC
Solvent: CO
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
50 mg (0.16 mmol) of N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 2 ml of methanol. 0.58 ml of hydrogen peroxide (30% strength), 0.16 ml of 1-hexene and 11 mg of sodium carbonate are added and the reaction mixture is stirred for 14 hours at RT. The product is isolated by filtration, washed (methanol:water=1:1) and dried at 50° under HV. N-(3-chloro-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine is obtained in the form of a yellow powder; m.p. 245°-247°, Rf =0.23 (n-hexane:ethyl acetate=1:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+]>CCO.Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)cc(OC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of methyl 3-cyano-5-isopropoxybenzoate (1.19 g, 5.4 mmol) in EtOH (4 mL) was added 5N NaOH (3 mL, 15 mmol). After stirring at room temperature for 4 h, the reaction mixture was diluted with 1N HCl and extracted with EA. The combined organic layers were dried over Na2SO4 and concentrated to provide 920 mg (83%) of 3-cyano-5-isopropoxybenzoic acid as a white solid. LCMS-ESI (m/z) calculated for C11H11NO3: 205.2; found 206.1 [M+H]+, tR=2.97 min. 1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=1.4 Hz, 1H), 7.80 (dd, J=2.6, 1.4 Hz, 1H), 7.35 (dd, J=2.6, 1.4 Hz, 1H), 4.71-4.56 (m, 1H), 1.38 (dd, J=6.1, 2.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl>O>[F:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1cccc(F)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
28.0 g (103 mmol) dimethyl 2-(3-fluoro-2-nitro-phenyl)-malonate were added to 120 mL water and 120 mL conc. hydrochloric acid and refluxed for 5 h. The mixture was cooled to RT and extracted several times with EtOAc. The combined organic phases were dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with PE/EtOAc=3/1 and suction filtered.
Reaction SMILES: [CH2:1]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+].Cl[CH2:41][CH:42]([OH:45])[CH2:43][OH:44]>O.CCOCC>[CH2:1]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])=[O:25])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC=CCCCNc1ccc(CC(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCC=CCCCNc1ccc(CC(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.35 g. of 4-(4-pentadecenyl)aminophenylacetic acid in 50 ml. of hexamethylphosphoramide is treated with 4.80 g. of 25% aqueous sodium hydroxide followed by 11.0 g. of 3-chloro-1,2-propanediol and then is heated at 140° C. for 6 hours. The mixture is diluted with water and ether and filtered to yield a white solid. Recrystallization from acetonitrile and then from carbon tetrachloride affords the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].IC.[C:16]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:16]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A mixture of 608 mg (2.4 mmol) of 2-bromo-4-trifluoromethoxyphenol, 0.35 mL (5.6 mmol) of iodomethane and 775 mg (5.6 mmol) of K2CO3 in 2 mL of DMF was stirred at rt for 2.5 h. The reaction mixture was partitioned between 100 mL of hexanes and 100 mL of H2O and the layers were separated. The organic layer was washed with 2×100 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using hexanes as the eluant afforded 579 mg (89%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H), 6.88 (d, J=9.2, 1H), 7.15-7.18 (m, 1H), 7.45 (app d, J=3.2, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25]#[C:26][CH3:27])[CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:6](=[O:28])[C:5]2([CH3:30])[CH3:29].Cl.O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25]#[C:26][CH3:27])[CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[C:6](=[O:28])[C:5]2([CH3:30])[CH3:29]
Reactant: CC#CC(CC(=O)OC)c1ccc(OCN2C(=O)C(C)(C)c3cc(Br)ccc32)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CC(CC(=O)O)c1ccc(OCN2C(=O)C(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
730 mg of methyl 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]-hex-4-ynoate were dissolved in a mixture of THF/MeOH/2N NaOH=1:1:1 (5 ml of each) and stirred at room temperature. After 1 hour, the mixture was acidified to pH 1 by addition of 2N HCl. 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4, then concentrated under reduced pressure and purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 620 mg of 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]-hex-4-ynoic acid.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([OH:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=O>CO.O>[NH2:5][CH2:6][CH2:7][CH:8]([C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[OH:24]
Reactant: O=C(NCCC(O)c1cccc(C#CC2(O)CCCCC2)c1)C(F)(F)F
Solvent: CO
Solvent: O
Product: NCCC(O)c1cccc(C#CC2(O)CCCCC2)c1
Reaction time: 8 h

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide was conducted following the method used in Example 18, except that the solvent was 90% MeOH-water and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and partitioned into EtOAc and water. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude material was crystallized from hot EtOAc. After cooling, the product was collected by filtration, washed with EtOAc and hexanes, and dried. Example 99 was isolated as a white solid. Yield (0.210 g, 47%): 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.26 (m, 4H), 5.45 (br s, 1H), 4.68 (t, J=8.4 Hz, 1H), 2.62 (br s, 2H), 1.83-1.88 (m, 2H), 1.48-1.67 (m, 9H), 1.15-1.34 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ccccc1OC
Yield: 53.6 %

Procedure:
A suspension of 6.2 g (50 mmol) o-anisidine M10, 7.5 g (55 mmiol) 1-bromobutane M17, 7.6 g (55 mmol) K2CO3 and 0.91 g (5.5 mmol) KI in 25 ml DMF was heated at 95° C. for 24 hours. DMF was evaporated and the residue was dissolved in 100 ml CHCl3 and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 9.4 g crude oil. This oil was purified by a plug packed with 45 g silica gel 100 using cyclohexane as eluant, wherein 4.8 g pure product were obtained (yield: 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]2[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=2)(=[O:71])=[O:70])=[CH:61][CH:60]=1)[C:45]([N:47]1[CH2:52][CH2:51][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH2:48]1)=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:58][C:59]5[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]6[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=6)(=[O:71])=[O:70])=[CH:61][CH:60]=5)[C:45]([N:47]5[CH2:48][CH2:49][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:51][CH2:52]5)=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)N=[N+]=[N-])CC1
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)n2cc(COc3ccc4nc(S(=O)(=O)NC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)sc4c3)nn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (91 mg, 0.159 mmol) and the tosylate 145 (87 mg, 0.159 mmol) in THF (1 mL) was added copper(I) iodide (3 mg, 0.0159 mmol) then diisopropylethylamine (30 μL, 0.175 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatography on silica gel using hexanes/ethyl acetate on a Biotage purification system yielding the desired product as a white, crystalline solid (145 mg, 82%).