Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
To a solution of 76 g of 1,3-propanediol in 0.5 1 of pyridine, cooled to 0° C., were added 278 g of trityl chloride. The mixture was stirred at room temperature for 18 hours, and then the solvent was evaporated in vacuo. The residue was taken up in 600 ml of ethyl acetate. Unsoluble material was filtered off, and the filtrate was washed with 100 ml portions of 3N hydrochloric acid, water, 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from 0.5 1 of ethyl acetate afforded 167.3 g of 3-trityloxy-1-propanol as white crystals of m.p. 117°-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.NC1C=CC(S(CC)(=O)=O)=C(C=1)CN[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].BrC1C=CC(CCCC(O)=O)=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])=[C:16]([CH:15]=2)[CH2:25][NH:26][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:12])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Agent: O=C(O)CCCc1ccc(Br)cc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CNC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Using a procedure analogous to that used to prepare 6C, except that pyridine was used in place of triethylamine, 15A (0.314 g, 1.00 mmol) was coupled to 4-(4-bromophenyl)butyric acid to give 15B (0.540 g, 100%) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.31 (m, 3 H) 1.41 (s, 9 H) 1.97-2.08 (m, 2 H) 2.37(t, J=7.47 Hz, 2 H) 2.59-2.70(m, 2 H) 3.11-3.23 (m, 2 H) 4.12(q, J=7.03 Hz, 1 H) 4.50 (d, J=6.15 Hz, 2 H) 5.60 (t, J=5.93 Hz, 1 H) 7.06 (d, J=8.35 Hz, 2 H) 7.39 (d, J=8.35 Hz, 2 H) 7.45-7.50 (m, 1 H) 7.83-7.95 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[N:33]=1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:27]([CH3:26])[CH2:28][C:29]3[S:30][CH:31]=[C:32]([CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:33]=3)=[O:23])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1nc(CN2CCCC2)cs1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3nc(CN4CCCC4)cs3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), N-methyl-1-[4-(pyrrolidin-1-ylmethyl)-1,3-thiazol-2-yl]methanamine (30 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method D to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24]4[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[S:29][C:23]=4[C:22]3=[O:37])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl.O1CCOCC1>ClCCl>[ClH:36].[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]2[S:29][C:23]3[C:22](=[O:37])[N:21]([C:18]4[CH:17]=[N:16][C:15]([O:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C1c2sc(-c3ccc(Cl)cc3)cc2CCN1c1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 4-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (5.41 g, 10.02 mmol) to a solution of 1:1 MeOH:dichloromethane (80 mL). Then add 4M HCl in dioxane (18.53 mL, 74 mmol) and stir at RT overnight. Filter the reaction and wash with dichloromethane. Dry thoroughly to yield the title compound quantitatively. MS/ES m/z (35Cl) 440.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 122 (0.37 g, 1.3 mmol) and Pyridine HCl (10 g).was heated. to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chromatography (50% Et OActHex) to give 123 as a solid (0.25 g, 74%): Mp=274–276° C., 1H NMR (DMSO-6) δ 9.96 (br s, 1 H), 9.52 (br s, 1 H), 7.74 (d, 2 H, J=8.4 Hz), 7.17–7.16 (m, 3 H), 6.89 (d, 2 H, J=8.4 Hz),2.64 (s, 3 H); MS 267 (M−H)−
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH2:11][CH2:12][NH2:13])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C1C([N+]([O-])=O)=CC=C(O[C:24]([C:26]([F:29])([F:28])[F:27])=[O:25])C=1.[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].[OH-].[Na+]>N1C=CC=CC=1.O>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH2:11][CH2:12][NH:13][C:24](=[O:25])[C:26]([F:27])([F:28])[F:29])[C:7]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CCCN)C(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)SCC(CCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-acetylthiomethyl-5-aminopentanoic acid (2.05 g.) and p-nitrophenyltrifluoroacetate (5.6 g.) in pyridine (10 ml.) is stirred at room temperature for four hours, and then added dropwise to a vigorously stirred solution of L-proline (1.55 g.) in water (10 ml.) while keeping the pH at 9 with careful addition of 2 N sodium hydroxide. When the consumption of sodium hydroxide stops, the reaction mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The solvent is removed in vacuo and the residue is chromatographed on a silica gel column to yield 1-[2-acetylthiomethyl-5-(trifluoroacetylamino)pentanoyl]-L-proline.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Li][C:11](C)(C)[CH3:12].BrCC>C1COCC1.CCOC(C)=O>[CH2:11]([C:2]1[S:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH3:12]
Reactant: c1cnc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCBr
Product: CCc1cc2cccnc2s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of thieno[2,3-b]pyridine (0.35 g, 2.6 mmoles) prepared according to well known methods [see, Klemm, et al. (1969) J. Org. Chem., 34:347-354; see, also U.S. Pat. Nos. 5,026,700, 4,577,014, 4,406,898, 4,375,544, 4,311,845, and 4,161,599] in THF (10 ml) at -78° C. was added t-BuLi (1.7 M, 2.0 ml, 3.4 mmoles). The reaction solution was slowly warmed to -30° C. over a 45 minute period followed by the addition of bromoethane (0.25 ml, 3.4 mmoles). The solution was stirred 2 hours at ambient temperature then diluted with EtOAc (50 ml) and washed with H2O (75 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 0.41 g (97%) of the title compound as an orange-brown oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC=C)(=[O:21])[CH3:20]>C(COC)OC>[C:19]([O:17][C@H:13]1[C@@H:12]([OH:18])[C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:16][CH:15]=[CH:14]1)(=[O:21])[CH3:20]
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@H]1O)c1ccccc1
Reactant: C=COC(C)=O
Solvent: COCCOC
Product: CC(=O)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@@H]1O
Yield: 80 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylgalactal is taken up in 10-15 ml of dimethoxyethane (DME) and 20-25 ml of vinyl acetate and stirred with 1 g of lipase P at room temperature for 8 h, Filtering off the enzyme and crystallization or chromatography on silica gel (ether/hexane 1:1) yield 3-O-acetyl-6-O-benzoylgalactal in 80-85% yield,
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][NH2:7])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 5 h
Yield: 78.9 %

Procedure:
{2-[4-(3-Trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (354 mg, 0.928 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (355 μl, 5 eq) was added. Reaction mixture was stirred for 5 h. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product 2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (206 mg, yield=64.7%, purity=65%). [M+H]+=282.28 1H NMR (300 MHz; CDCl3) δ/ppm 2.76-2.80 (m, 2H), 2.93-3.04 (m, 2H), 6.92-6.98 (m, 2H), 7.02-7.35 (m, 5H), 7.37-7.45 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=O)=[CH:8]2)=[O:4].Cl.[CH:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14](=[O:16])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1)=[CH:8]2)=[O:4]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 1H-Indole-2,5-dicarboxylic acid 5-methyl ester and 491 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride in 20 ml absolute DMF, 746 mg TOTU and 1.1 ml DIPEA were added and the mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was directly purified by chromatography on silica gel eluting with a gradient of DCM/MeOH 100%->60%. The fractions containing the product were combined and the solvent evaporated under reduced ressure. Yield: 0.73 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](CCNCCCCCCC)[CH:8]=1.C([N:30]([CH2:34][CH3:35])[CH:31]([CH3:33])C)(C)C.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][C:45](Cl)=[O:46].Cl>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:35][CH2:34][N:30]([C:45](=[O:46])[CH2:44][C:38]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=2[F:36])[CH2:31][CH2:33][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:9][CH:8]=1
Reactant: CCCCCCCNCCc1cccc(CC(OCC)C(=O)OC)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 131.8 %

Procedure:
To a solution of 2-ethoxy-3-[3-(2-heptylamino-ethyl)-phenyl]-propionic acid methyl ester HCl salt (43 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.33 mmol, 0.058 mL) in anhydrous methylene chloride (2 mL) was added 2,4-difluorophenylacetyl chloride (0.128 mmol) in anhydrous methylene chloride (2 mL). The mixture was allowed to stir at room temperature for 16 hours. Then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with methylene chloride (1×). The organic layers were combined, washed with 2 M HCl (1×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to give a clear oil. The crude product was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate/hexanes to give 3-[4-(2-{[(2,4-difluoro-phenyl)-acetyl]-heptyl-amino}-ethyl)-phenyl]-2-ethoxy-propionic acid methyl ester as a clear oil (36.5 mg, 66%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 24.3 %

Procedure:
General procedure C was followed using acetylpiperazine (35 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (18 mg, 24%), m.p. 144-146° C.; umax (CHCl3)/cm−1 3008, 2909, 2856, 1638, 1558, 1470, 1441, 1282, 1240, 1152, 1098; m/z (ESI) C11H14Cl2N3O requires 274.0508, found [M+H]+ 274.0513.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:16]1)=[O:5]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C1CC(C(=O)C(F)(F)F)Cc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was then added over about 5 min. The reaction mixture was then stirred at room temperature for 14 h and then was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer washed with 3N HCl, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was then taken up in 70 mL of boiling ethanol/water and allowed to cool to room temperature whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give 32 g, 81% of pure product with mp 48°-49° C. 1H NMR CDCl3 δ2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ72.0. EI GC-MS M+=242.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1C(O)=O.[CH3:12][Mg].CC[O:16][CH2:17][CH3:18].Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:17]([OH:16])([CH3:18])[CH3:12]
Reactant: CCOCC
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: C[Mg]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 mL) was treated at −78° C. under nitrogen with a solution of methylmagnesium brormide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0.5 N aqueous hydrochloride solution (300 mL). The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of solvent in vacuo, the residue was purified by a silica gel flash column chromatography(hexane:ethyl acetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as off-white solid (6 g, 57%): mp 62-63° C.; 1H-NMR (CDCl3) δ 7.19 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:3])=[O:2]
Reactant: COC(=O)c1ncccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0° C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA (2.5 mL, 18.0 mmol) in CH2Cl2 (80 mL). The mixture was stirred at 0° C. for 1 h before it was allowed to warm up to room temperature where it stirred for an additional 1 h. The mixture was then quenched with saturated NaHCO3 solution (40 mL) and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated to give methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e. Cap-174, step a) (3.38 g, 73%) as a dark brown oil (>95% pure) which was used directly without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.72-8.79 (1 H, m), 7.71 (1 H, d, J=1.5 Hz), 7.58-7.65 (1 H, m), 4.04 (3 H, s). Rt=1.93 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+C8H7F3NO5S: 286.00; found: 286.08.
Reaction SMILES: [C:1](#[N:3])[CH3:2].O1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:9](OCC)C>>[CH2:1]([NH2:3])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:3]
Reactant: C1CCOC1
Reactant: CC#N
Reactant: CCOCC
Product: N
Product: NCc1ccccc1

Procedure:
The mixture of O-(hexaacetyl α- and -β-rutinosyl) trichloroacetimidates is obtained by the action of hexacetyl-1-rutinose (obtained by the action of benzylamine or ammonia on heptaacetorutinose in an aprotic solvent such as acetonitrile, tetrahydrofuran or ethyl ether) on trichloroacetonitrile, in the presence of a base, for example potassium carbonate or sodium hydride, in an aprotic solvent such as methylene chloride, chloroform or diethyl ether and under anhydrous conditions. O-[Hexaacetyl-6-O-(α-L-arabinofuranosyl)-α- and -β-D-glucopyranosyl] trichloroacetimidates are obtained in the same manner.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].FC1C=[C:14]([O:16]C)C=C(F)C=1CBr.[CH3:19][O:20][C:21]1[C:26](C)=[CH:25][C:24]([N:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[C:41]([F:42])=[CH:40][C:39](F)=[CH:38][C:37]=3[F:44])[C:31]3[CH:45]=[CH:46][CH:47]=[CH:48][C:30]=3[S:29]2(=[O:50])=[O:49])=[CH:23][C:22]=1C>CN(C=O)C>[CH3:14][O:16][C:22]1[CH:23]=[C:24]([N:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[C:37]([F:44])=[CH:38][C:39]([O:4][CH3:1])=[CH:40][C:41]=3[F:42])[C:31]3[CH:45]=[CH:46][CH:47]=[CH:48][C:30]=3[S:29]2(=[O:49])=[O:50])[CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: O=C([O-])[O-]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(F)c1

Procedure:
The title compound (59 mg, 0.12 mmol) was prepared from (IntA1) (84 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,6-difluoro-4-methoxybenzyl bromide (71 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][CH:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (79 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (39 mg, yield 33%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17](=[O:29])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[O:29])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)C=Cc2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(O)c(C(=O)CCc2cccc(N)c2)c1
Yield: 89 %

Procedure:
A mixture of 15.0 g (0.039 mole) of the title product from Example 120 and 1.5 g 5% palladium on charcoal in 300 ml tetrahydrofuran and 200 ml absolute methanol was shaken in a Parr hydrogenator under 10 psi hydrogen at ambient temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo to yield an oil. Column chromatography of the oil on silica gel eluting with ethyl acetate: hexanes (1:2, v/v) gave 9.42 g (90%) of the title product as an oil; 1H NMR (CDCl3): δ2.98 (t, J=8 Hz, 2H); 3.28 (t, J=8 Hz, 2H); 3.65 (s, br, 2H); 3.77 (s, 3H); 6.65 (m, 3H); 6.93 (d, J=9 Hz, 1H); 7.10 (m, 3H); 11.95 (s, 1H). Analysis calculated for C16H17NO3 : C, 70.83; H, 6.32; N, 5.16. Found: C, 70.51; H, 6.30; N, 4.97.