Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=[C:6]2[C:18]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCO)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCCO)c2cc1OC
Yield: 61.7 %

Procedure:
3-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propanol is prepared by following the procedure described in example 88a, but using 0.24 g of 3-[5,6-dimethoxy-3-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propanol and a solution of 9.3 ml of methanolic potassium hydroxide (0.1 g/ml; 1.78M). After purification by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents), 0.103 g of 3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]propanol is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.[S:15](Cl)([Cl:17])=[O:16].Cl>>[Cl:17][S:15]([N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=1)=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Agent: Cl
Product: CC(C)c1cccc(OC(=O)N(C)S(=O)Cl)c1
Reaction time: 1 h

Procedure:
Four grams 3-isopropylphenyl methylcarbamate were mixed with excess thionyl chloride and heated up to 80° C. until HCl evolution ceased. Excess thionyl chloride was removed by distillation and the residue was subjected to high vacuum (0.1 mm) for 1 hour. NMR of the residue in chloroform-d-TMS gave the following absorptions: δ7.5-6.9 (m, 4H, aromatic protons). δ3.25 (s, 3H, NCH3), δ3.2-2.7 (m, 1H, CH), and δ1.3-1.2 (d, 6H, C(CH3 (2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1[CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:32][CH2:33][O:34][CH3:35])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (86 mmol) is dissolved in THF (300 ml) and triphenylphosphin (2 eq.) and ethyleneglycolmonomethylether (1 eq.) is added at 0° C. After addition of di-tert.-butylazodicarboxylate (2 eq) in THF (100 ml), the reaction is stirred five hours at room temperature. The solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow solid in a yield of 90%. HPLC (method C): 1.59 min; LC-MS (method A): 1.47 min, 233.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 51.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methylpyridine (55 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.15 mmol, 53%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CCCCCC.[CH3:19][C@@H:20]1[CH:27]=[CH:26][CH2:25][C:22]2([CH2:24][CH2:23]2)[C@@H:21]1[C:28](=[O:30])C.C(=O)C.Cl.[Na+].[Cl-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:19][C@@H:20]1[CH:27]=[CH:26][CH2:25][C:22]2([CH2:23][CH2:24]2)[C@@H:21]1[C:28](=[O:30])[CH:7]=[CH:5][CH3:6]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)[C@@H]1[C@H](C)C=CCC12CC2
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC=CC(=O)[C@@H]1[C@H](C)C=CCC12CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
At −78° C. under N2, a solution of diisopropylamine (2.57 ml, 18.2 mmol) in anhydrous THF (13.50 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexane (11.40 ml, 18.2 mmol). The resulting solution was stirred 10 min. at 0° C., cooled to −78° C. and treated dropwise with rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (2.3 g, 14.0 mmol, rel-(4R,5R)-/rel-(4S,5R)-98:2) in anhydrous THF (2.2 ml). The resulting solution was stirred 1 h at −78° C., warmed to −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (4.40 ml, 70.1 mmol) in anhydrous THF (13.5 ml). The resulting solution was stirred for 15 min. at −78° C., warmed to −30° C., cooled to −78° C., and treated slowly with a mixture of 2N HCl (11.62 ml) and of a saturated aqueous solution of NaCl (7 ml). The mixture was then warmed to 0° C., the aqueous phase extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, dried (Na2SO4) and concentrated to give 4.06 g of crude product. A solution of the crude product (2.92 g, 14.0 mmol) in toluene (85 ml) was treated with para-toluene sulfonic acid monohydrate (133.5 mg, 0.702 mmol) stirred at 80° C. for 2 h, cooled, poured into a saturated aqueous solution of NaHCO3. The aqueous phase was extracted three times with Et2O and the combined organic phases washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaCl, and concentrated. FC (500 g SiO2, hexane/Et2O 10:0.5) of the crude product (3.4 g) gave two fractions of rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)but-2-en-1-one (Fraction 1: 0.613 g, 23%, 2 steps, rel-(4R,5R)-/rel-(4S,5R)-93:7; Fraction 2: 1.36 g, 51%, 2 steps, rel-(4R,5R)-/rel-(4S,5R)-99.3:0.7).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C1COCC1.[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To an argon flushed flask was added tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.94 g, 3.50 mmol) and THF (35 ml), followed by a slurry of palladium on carbon (0.75 g, 0.70 mmol) in EtOAc (5 ml). The gas in flask was replaced with hydrogen balloon for three times. The mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through celite plug and concentrated to give tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.80 g, 98% yield) as an off-white solid. m/z (ESI) 524.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:6]3[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:13])[S:9][C:5]=3[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nn(C(=O)OC(C)(C)C)c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.7 %

Procedure:
0.20 g (0.50 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 5 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. A solution of 0.09 g (0.53 mmol) of 4-methoxybenzoyl chloride (prepared according to J. Org. Chem. 1976, 41, 2566) in 2.0 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.05 g of tert-butyl 3-(4-methoxy-benzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.16 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 3-(4-methoxybenzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (s, 9H); 1.71 (s, 6H); 3.86 (s, 3H); 7.10 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 8.07 (d, J=8.5 Hz, 2H); 8.71 (s, 1H); 11.25 (broad s, 1H). LC-MS-DAD-ELSD: 534(−)=(M−H)(−); 536(+)=(M+H)(+).
Reaction SMILES: [Br-].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].Cl.[CH2:21]1[CH2:25]OC[CH2:22]1>>[CH:22]1([C:7]2([OH:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=3)[CH2:21][CH2:25]1
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Product: OC1(C2CC2)c2ccccc2CCc2ccccc21

Procedure:
A solution of cycloprolpylmagnesium bromide in dry THF (prepared from cyclopropylbromide (12.1 g, 0.10 mol), magnesium turnings (2.45 g, 0.10 mol) and dry THF (65 ml)) was placed under an atmosphere of nitrogen. A solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (10.4 g, 0.05 mol) in dry THF (25 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (50 ml) was carefully added. The mixture was neutralized with 2N hydrochloric acid and extracted with diethyl ether (2×200 ml). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated in vacuo to give 13.1 g of crude 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[N:7]([CH3:9])[CH3:8].Br[CH2:20][C:21]1[N:26]=[C:25]([N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:8][N:7]([CH3:9])[C:6]1[CH:5]=[C:4]([C:3](=[N:2][O:1][CH2:20][C:21]2[N:26]=[C:25]([N:27]3[C:28](=[O:37])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]3=[O:36])[CH:24]=[CH:23][CH:22]=2)[C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CN(C)c1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
To a stirred solution of 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline (2.90 g, 11 mmol) in dry acetonitrile (100 mL) were added 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (3.74 g, 11.8 mmol), cesium carbonate (7.33 g, 22.5 mmol) and potassium iodide (0.89 g, 5.36 mmol). The reaction mixture was stirred at room temperature for 24 h, then insolubles were removed by filtration and washed with dichloromethane. The filtrates were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL), washed with water (2×200 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 2-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione as an orange solid [5.28 g, yield 97%; HPLC/MS: m/z=483 (M+H); logP(HCOOH)=3.17].
Reaction SMILES: C1(C2C=CC=CC=2N[N:10]=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.I[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClCCl>O>[C:36]1([N:11]2[N:10]=[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=[N:12]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc(NN=NNc2ccccc2-c2ccccc2)cc1
Reactant: Ic1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-n2nc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
2-phenylazoaniline (3.47 g, 17.6 mmol) prepared above was placed in a 100-mL 1-neck round bottomed flask. Acetic acid (20 mL) and iodobenzene diacetate (6.23 g, 19.4 mmol) were added, in that order, resulting in an exotherm. The reaction was allowed to proceed for 1 hour during which time the mixture cooled to room temperature. Dichloromethane and water were added to the reaction mixture. The organic layer was separated and dried over MgSO4. The solution was filtered and concentrated using a rotary evaporator. The residue was purified on a silica gel column using dichloromethane as eluent. The fractions containing the desired product were combined and solvent removed. The solid was dried in a vacuum oven for 2 h. Yield: 34%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)=[C:11]([C:30]#[N:31])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC(O)=[O:34]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:31])=[O:34])[C:12]3[NH:15][C:16]4[C:17]([C:13]=3[CH:14]=2)=[CH:18][C:19]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:21]=4)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C#N)c2)cc1C
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2)cc1C
Temperature: 130 °C

Procedure:
3′,4′-Dimethyl-4-(4-(morpholine-4-carbonyl)phenylamino)biphenyl-3-carbonitrile (320 mg, 0.777 mmol) and Pd(OAc)2 (0.523 g, 2.331 mmol) were mixed with AcOH (10 mL) in a sealed microwave tube and heated at 130° C. for 12 hrs. The mixture was filtered through a pad of CELITE®, then a ACRODISC® PTFE membrane (0.45 um), rinsed with additional 35 ml AcOH. The filtrate was concentrated and purified using preparative HPLC to give 51.8 mg of titled product. MS (ESI) m/z 428.4 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.59 (s, 1H), 8.74 (s, 1H), 8.38 (bs, 2H), 8.3 (s, 1H), 7.76(d, 1H, J=8.2), 7.71 (s, 1H), 7.63 (d, 1H, J=6.3), 7.57 (bs, 1H), 7.48(d, 1H, J=8.2), 7.27(d, 1H, J=7.6), 3.65-3.59 (bm, 8H), 2.35 (s, 3H),), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH:26](O)[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:26]([CH3:27])[CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COCC(C)O
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCC(C)OC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 97 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.8 g of 1-methoxy-2-propanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 6 hours. After completion of the reation, 50 ml of ether was added to the reaction mixture. The resulting mixture was washed with water by the customary method and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.9 g of 1-methyl-2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16]([N:21]=[N+]=[N-])[C@H:15]([OH:24])[C@H:14]2[OH:25])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]>O1CCOC(CCN)C1(CCN)CCN.[Pd]>[C@H:1]1([O:12][C@@H:13]2[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16]([NH2:21])[C@H:15]([OH:24])[C@H:14]2[OH:25])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Agent: [Pd]
Agent: NCCC1OCCOC1(CCN)CCN
Product: N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate (4) is reacted with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes followed by extraction in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate (6). The azide is hydrogenated at room temperature under pressure in dioxane-triethylamine solution using 10% palladium on carbon catalyst. The product is crystallized from dioxane-ethanol to provide 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[CH:21]=[CH:20][C:13]3[CH2:14][C:15]([NH:17][C:18](=[O:19])[C:12]=3[CH2:11]2)=[O:16])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[CH:21]=[CH:20][C:13]3[CH2:14][C:15]([NH:17][C:18](=[O:19])[C:12]=3[CH2:11]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2C=CC3=C(C2)C(=O)NC(=O)C3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC2=C(CC(=Cc3ccc(O)cc3)C=C2)C(=O)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a stirred solution of 4-(4'-methoxyphenyl)methylenehomophthalimide (279 mg, 1 mmol) in anhydrous dichloromethane (10 ml) is added at -78° C. under nitrogen, over a period of 10 min, a 1.0M solution of boron tribromide in dichloromethane (3 ml, 3 mmol). The resulting mixture is stirred for another 1 h at -78° C. and then allowed to warm to room temperature. After stirring for 1.5 h at 20°-25° C. the mixture is cooled to -10° C. and then quenched by dropwise addition of water (10 ml) over a 10-min period. After addition of ethyl acetate (10 ml) the organic layer is separated, washed with water, dried over Na2SO4 and evaporated under vacuum to dryness. The residue is crystallized from ethanol thus giving pure 4-(4'-hydroxyphenyl)methylenehomophthalimide (186 mg, yield 70%).
Reaction SMILES: [NH2:1][C:2](=[O:8])[CH2:3][CH2:4][C:5](O)=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[C:40]3[C:35](=[C:36]([Cl:42])[CH:37]=[C:38]([Cl:41])[CH:39]=3)[CH2:34][N:33]([CH3:43])[CH2:32]2)[CH:26]=1)(=[O:24])=[O:23]>>[Cl:41][C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([Cl:42])[CH:37]=1)[CH2:34][N:33]([CH3:43])[CH2:32][CH:31]2[C:27]1[CH:26]=[C:25]([S:22]([NH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][C:2]([NH2:1])=[O:8])(=[O:23])=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: NC(=O)CCC(=O)O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(N)=O)c2)C1
Yield: 66.7 %

Procedure:
Compound 247 was prepared following the procedure outlined in Example 215 using 4-amino-4-oxobutanoic acid (7.6 mg, 0.0646 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 50 mg, 0.0646 mmol). Purification by preparative HPLC gave the title compound (27.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88 (d, 1H), 7.75 (s, 1H), 7.64 (t, 1H), 7.55 (s, 1H), 7.51 (d, 1H), 6.84 (s, 1H), 4.78-4.71 (m, 2H), 4.55-4.48 (m, 1H), 3.81-3.75 (m, 1H), 3.63-3.55 (m, 10H), 3.51-4.45 (m, 5H), 3.44-3.41 (m, 3H), 3.38-3.31 (m, 3H), 3.13 (s, 3H), 3.07-3.02 (t, 2H), 2.48-2.43 (m, 4H). MS (m/z): 645.32 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].O[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>>[CH3:28][C:21]([O:20][C:19]1[CH:18]=[CH:17][C:16]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1CO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Made from (5-methyl-2-phenyloxazol-4-yl)methanol [Overman, et al., J. Org. Chem. (1979), 44(13), 2323-25] and ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S. Pat. No. 3,795,691) via an analogous procedure to that reported for Example 2, Step A: 1H NMR (300 MHz, CDCl3) δ 8.03-8.09 (m, 2H), 7.45-7.52 (m, 3H), 6.94 (d, 2H), 6.88 (d, 2H), 4.99 (s, 2H), 4.37 (q, 2H), 2.47 (s, 3H), 1.60 (s, 6H), 1.33 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@@H](C)NCc1ccc(-c2ccccc2C#N)cc1

Procedure:
Reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.34 g of (D)-alanine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(D)-alanine methyl ester after flash chromatography (N3). 1H-NMR (DMSO): 1.21 ppm (d, 3 H), 3.63 ppm (s, 3 H), 3.75 ppm (dd, 1 H), 4.56 ppm (d, 2 H), 4.58 ppm (d, 2 H), 5.31 ppm (t, 1 H), 7.4-8 ppm aromatics.