Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCO
Reactant: O=C(O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCOCCOCCCCCC(=O)O

Procedure:
Illustratively, 2-butoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 6-bromohexanoic acid to give 7,10-dioxatetradecanoic acid. So also, 2-ethoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 8-bromooctanoic acid to provide 9,12-dioxatetradecanoic acid.
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:13]3[C:8](=[C:9]([O:41][CH3:42])[CH:10]=[C:11]([C:14]([N:16]4[CH2:21][CH2:20][C:19]5([CH2:30][C:29](=[O:31])[C:28]6[C:23](=[CH:24][CH:25]=[C:26]([C:32]7[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=7)[C:37]([O-:39])=[O:38])[CH:27]=6)[O:22]5)[CH2:18][CH2:17]4)=[O:15])[CH:12]=3)[C:7]([CH3:43])=[CH:6]2)[CH2:4][CH2:3]1.Cl>CO.O>[CH:2]1([N:5]2[C:13]3[C:8](=[C:9]([O:41][CH3:42])[CH:10]=[C:11]([C:14]([N:16]4[CH2:17][CH2:18][C:19]5([CH2:30][C:29](=[O:31])[C:28]6[C:23](=[CH:24][CH:25]=[C:26]([C:32]7[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=7)[C:37]([OH:39])=[O:38])[CH:27]=6)[O:22]5)[CH2:20][CH2:21]4)=[O:15])[CH:12]=3)[C:7]([CH3:43])=[CH:6]2)[CH2:3][CH2:4]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc2c1c(C)cn2C1CC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the compound of Example 23 in MeOH (25 mL) and H2O (25 mL) was added 4 mL of 1N HCl aqueous at 0° C. 60 mL of MeOH was added thereto and the mixture was stirred at r.t. for 3 hours. The precipitate was filtered and dried at 60° C. in vacuo to give the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 13.56 (1H, s), 9.09 (1H, d, J=2.2 Hz), 9.03 (1H, d, J=2.2 Hz), 8.41 (1H, dd, J=2.2, 2.2 Hz), 8.07-8.03 (2H, m), 7.29-7.25 (1H, m), 7.14 (1H, d, J=1.0 Hz), 7.00 (1H, d, J=1.0 Hz), 6.51 (1H, d, J=1.0 Hz), 4.41-4.10 (1H, br m), 3.83 (3H, s), 3.51-3.41 (1H, br m), 3.51-3.26 (3H, br m), 2.96 (2H, s), 2.31 (3H, s), 2.13-1.74 (4H, br m), 1.06-0.85 (4H, m); MS [M+H]+=566.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][C:31]2=[O:35])=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCCN1CCCC1=O
Solvent: C1COCCO1
Product: O=C1CCCN1CCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 27 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 1-(3-aminopropyl)pyrrolidin-2-one (400 μl) was stirred at 120° C. for 17 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, 27%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:19]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Yield: 24.4 %

Procedure:
To solution of (2,4,5-trichloro-phenoxy)-acetic acid (150 mg, 0.59 mmol), 2-amino isonicotinic acid methyl ester (179 mg, 1.18 mmol) and DMAP (144 mg, 1.18 mmol) in DMF 13 mL was added PyBOP (614 mg, 1.18 mmol) at room temperature. Reaction mixture was stared at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:1) to give 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.056 g, 24.45% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:37]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([N:18]2[C@@H:30]3[C@@H:21]([C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=43)[CH2:20][CH2:19]2)=[O:17])=[O:8])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: C1COCCN1
Reactant: O=C(CCCCCBr)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CCCCCN1CCOCC1)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 91.3 %

Procedure:
6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)hexaneamide (166 mg, 0.30 mmol), morpholine (28 μl, 0.331 mmol) and potassium carbonate (207 mg, 1.5 mmol) were heated under reflux for 6 hrs. in acetonitrile (3 ml). Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography and eluted with ethyl acetate to give the title compound (153 mg, 91%) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](NCCCC(OCC)=O)=[N:3]1.Cl.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23].C(N(CC)CC)C>O1CCOCC1>[O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:27][CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])=[N:3]1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1=NS(=O)(=O)c2ccccc21

Procedure:
15.0 g. (74.4 mM) of 3-chloro-1,2-benzisothiazole 1,1-dioxide (prepared as in Example 1), 10.4 g. (74.4 mM) of glycine ethyl ester, hydrochloride and 20.4 ml. (148.8 mM) of triethylamine are refluxed in 250 ml of dioxane for 2 hours. The dioxane is evaporated and the residue is taken up in chloroform which is washed with water (2 x) and evaporated. The residue 2-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]acetic acid, ethyl ester is recrystallized once from 150 ml of methanol/water (1:1) and once from 200 ml. of water to give 2-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]acetic acid, ethyl ester as yellow needles, yield 14.35 g., m.p. 166°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CNCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccccc1)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.56 g of N-methyl benzylamine in 100 ml of chloroform. 2.5 g of N-methyl N-phenylmethyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 128° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC([OH:38])(C)C.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([OH:38])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cn1cnnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Air was bubbled in a mixture of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (see Example B7) (0.0018 mol) in N,N-dimethylformamide (8 ml) at 5° C. for 30 minutes. 2-methyl-2-propanol, potassium salt (0.0036 mol) was added portionwise. The mixture was stirred at room temperature for 1 hour, poured out into water, filtered and washed several times with water. The precipitate was taken up in CH2Cl2. The organic layer was separated dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.75 g, 85%) was crystallized from 2 propanone/DIPE. The precipitate was filtered off and dried, yielding 0.68 g (77%) of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 182° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:32]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:47][CH2:48][CH2:49][CH3:50]>CC#N.ClCCl>[CH2:47]([O:7][C:8]1[CH:9]=[C:10](/[C:14](/[CH2:44][CH3:45])=[C:15](\[C:31]2[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=2)/[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:20]=[CH:19]3)[CH:11]=[CH:12][CH:13]=1)[CH2:48][CH2:49][CH3:50]
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCOc1cccc(/C(CC)=C(\c2ccc(/C=C/C(=O)OCC)cc2)c2ccc3c(cnn3C3CCCCO3)c2)c1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (53 mg, 0.38 mmol) was added to (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl) -1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (101 mg, 0.19 mmol) in CH3CN (1 mL). After stirring for 15 min, iodobutane (24 μL, 0.21 mmol) was added. The reaction was stirred at rt for 15 h. Additional iodobutane (24 μL, 0.21 mmol) was added, and the reaction was stirred at 60° C. for 10 h and then at rt for 48 h. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and purified by silica gel chromatography (0-20% EtOAc in hexanes) to give 97 mg of (E)-ethyl 3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenypacrylate as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.73 (d, 1H), 7.64 (s, 1H), 7.49 (d, 1H), 7.41 (d, 2H), 7.24 (dd, 1H), 7.12 (t, 1H), 6.91 (d, 2H), 6.76 (d, 1H), 6.67-6.72 (m, 2H), 6.48 (d, 1H), 5.86 (d, 1H), 4.15 (q, 2H), 3.86-3.94 (m, 1H), 3.72-3.80 (m, 3H), 2.38-2.46 (m, 3H), 1.96-2.10 (m, 2H), 1.70-1.82 (m, 1H), 1.52-1.63 (m, 4H), 1.31-1.37 (m, 2H), 1.22 (t, 3H), 0.85-0.92 (m, 6H); LCMS: 495 [(M-THP+H)+H]+.
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:9]([C:15]([CH:16]1[CH2:4][CH:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)C=Cc1cccc(O)c1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCC(=O)C1CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a 300 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 0.3 g (0.0069 moles) of powdered sodium hydroxide, 1.5 g (0.0069 moles) of trimethyl sulfoxonium iodide, and 50 mls of anhydrous DMSO. The mixture was then stirred at ambient temperature for 1 hour. The mixture was then cooled to 15° C., and a solution of 1-n-hexyl-3-(3-hydroxyphenyl)-2-propene-1-one (0.8 g, 0.0069 moles) was added dropwise in 5 mls of DMSO. The reaction was stirred for 1 hour at 10-15° C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 200 mls of 0.1 N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 0.64 g of the title compound, 2-(3-hydroxyphenyl)cyclopropyl n-hexyl ketone, as a thick yellow oil in a 76% isolated yield.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[CH3:38]O>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([N:10]3[CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[CH2:12][N:8]([CH2:7][CH2:6][O:5][CH3:38])[C:9]3=[O:37])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CO
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Product: COCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O

Procedure:
A solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethyl methanesulfonate (10.0 mg, 0.0180 mmol) in MeOH (0.3 mL) is heated at 60° C. overnight. After removal of the solvent the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.56-7.44 (m, 4H), 7.30 (d, 2H), 7.23 (d, 2H), 6.86 (m, 4H), 5.22 (dd, 1H), 4.07 (t, 1H), 3.57 (m, 3H), 3.49 (m, 1H), 3.36 (dd, 1H), 3.34 (s, 3H); HPLC-MS calculated for C25H22ClF3N2O3 (M+H+) 491.1, found 491.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[O:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1)#[N:2]
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccc(B(O)O)cc2)ccc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>>[C:3]1([CH2:2][CH2:1][OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: [H][H]
Product: OCCc1ccccc1
Yield: 78.4 %

Procedure:
Recently, gas phase hydrogenation of styrene oxide over pentasile type zeolite phosphate doped with a metal as a catalyst to give 2-phenyl ethanol has been reported. The styrene oxide and hydrogen were passed through a tube reactor packed with catalyst prepared by calcining a borosilicate with Cu(NO3)2 at 540° C. to give 78.4% 2-phenyl ethanol. [Holderich Wolfgang, Goelz Narbert, Hupfer Leopold (BASF) Ger offen DE 3,801,106,(1989)].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Br)cc1C(O)c1ccc(Nc2ccc(F)cc2F)nc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (100 mg; 0.35 mmol) in THF (2.2 ml) is treated at −78 C with nBuLi (0.48 ml of a 1.5M solution in hexane; 0.77 mmol). After 10 min at −78 C, 5-bromo-2-methoxybenzaldehyde (75 mg; 0.35 mmol) in THF (0.3 ml) is added and stirring continued for 30 min. at −78 C. The reaction mixture is poured on water/ice and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; TBME/hexanes 3/7) yields the title compound (60 mg; 40%)
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[OH:28])(=[O:8])[CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[C:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH3:27])=[CH:16][CH:15]=[CH:14][C:13]=2[O:28][CH2:2][CH2:3][OH:4])(=[O:8])[CH2:6][CH3:7]
Reactant: OCCBr
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccc(F)cc1C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
A solution of 2-bromoethanol (5.75 ml, 42 mmol) in acetone (25 ml) was added dropwise to a refluxing mixture of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (1.62 g, 5 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol) and acetone (25 ml) with vigorous stirring. Heating was continued for 18 hours, then water added, the product extracted into dichloromethane, dried and evaporated. Chromatography (silica gel, 2-5% methanol in dichloromethane) and recrystallisation from methanol yielded 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.89 g), m.p. 170°-1.72°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12](N)=[O:13])=[CH:10][C:9]=2[F:18])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22].[O:25]1CCOCC1>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:25])=[O:13])=[CH:10][C:9]=2[F:18])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22]
Reactant: NC(=O)c1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(O)c1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Hydrochloric acid (6M, 20 mL) was added to a solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzamide (Preparation 86, 440 mg, 1.25 mmol) in dioxan (10 mL). The reaction mixture was stirred at 120° C. for 5 h. After cooling the solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (1×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with dichloromethane:methanol (from 98:2 to 85:15) then triturated with heptane to yield the title compound as a white solid (259 mg, 59%)
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]2[O:6][C:7]([CH3:17])([CH3:18])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Yield: 94.5 %

Procedure:
A solution of 6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-trans-4-piperidino-2H-benzo[b]pyran-3-ol (140 mg) in ethanol (30 ml) was hydrogenated over 5% palladium-charcoal (0.1 g) until uptake of hydrogen ceased. The solution was filtered (Kieselguhr) and evaporated to dryness in vacuo to give unstable 6,7-diamino-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (0.12 g) which was used immediately in the following reactions. Rf (0.3) in ethyl acetate-hexane 1:2 (colourless spot) compared with starting material with Rf (0.6) as an orange spot.