Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][N:35]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][OH:50])[CH:44]=2)[C:36]3=[O:41])=[O:30])=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.N1C=CC=CC=1>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][N:35]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:49]=[O:50])[CH:44]=2)[C:36]3=[O:41])=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(Nc1cccc2c1CN(Cc1cccc(CO)c1)C2=O)c1ccc(Cl)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(CN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dess-Martin periodinane (1.9 g, 4.6 mmol) is added to a solution of 5-chloro-N-{2-[3-(hydroxymethyl)benzyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide (1.6 g, 3.8 mmol) in dichloromethane (38 ml) and pyridine (1.5 ml) and the mixture is stirred at room temperature for 6 h, and saturated aqueous sodium bicarbonate solution is then added. After addition of ethyl acetate and phase separation, the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (dichloromethane/methanol mixtures). Yield: 1.5 g, 97% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.[OH-].[Na+]>C(O)(=O)C>[SH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC1CCC(OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Sc1ccc(-n2cccc2)cc1

Procedure:
A 1-liter 3-neck flask equipped with stirrer, condenser, heating mantle, addition funnel and thermometer is charged with 25 g (0.2 mole) of 4-aminothiophenol, 26.4 g (0.2 mole) of 2,5-dimethoxytetrahydrofuran, and 150 ml of glacial acetic acid. The reaction mass is refluxed for 30 minutes, cooled and made alkaline to a pH of 9 with 130 ml of 50% aqueous sodium hydroxide while maintaining the temperature of the reaction mixture below 25°C with a cooling bath.
Reaction SMILES: O.O.[F-].[K+].[CH3:5][N:6]1[CH:10]=[C:9]([C:11]([OH:19])([C:13]#[C:14][Si](C)(C)C)[CH3:12])[N:8]=[CH:7]1>CO>[CH3:5][N:6]1[CH:10]=[C:9]([C:11]([OH:19])([C:13]#[CH:14])[CH3:12])[N:8]=[CH:7]1
Reactant: Cn1cnc(C(C)(O)C#C[Si](C)(C)C)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC(C)(O)c1cn(C)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 15-mL Schlenk tube, was placed a suspension of potassium fluoride dihydrate (940 mg, 10.00 mmol, 2.50 equiv) and 2-(1-methyl-1H-imidazol-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol (888 mg, 3.99 mmol, 1.00 equiv) in methanol (10 mL). The resulting solution was stirred for 2 h at 50° C. Then most of solvent was concentrated under vacuum and the resulting mixture was diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 2×10 mL of water and 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 255 mg (43%) of 2-(1-methyl-1H-imidazol-4-yl)but-3-yn-2-ol as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and tridecanoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-tridecanoyloxy-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=532; RT=7.113 min; LC-MS Method V
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>CN(C=O)C>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:16][CH2:15]1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
Step 1 A stirred suspension of tert-butyl ethyl malonate (2.01 mL, 10.6 mmol), 1,2-dibromoethane (1.01 mL, 11.7 mmol), potassium carbonate (3.67 g, 26.6 mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate (0.198 mL, 1.06 mmol) in DMF (26.6 mL) was heated to 55° C. for 20 hours. Upon cooling the mixture was filtered and the solid residue was washed with Et2O. The mixture was diluted with Et2O and washed with water (×2). The organic phase was dried (Na2SO4), filtered and concentrated giving 1-tert-butyl 1-ethyl cyclopropane-1,1-dicarboxylate which was used without further purification, 2.24 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([F:31])=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[C:18]=3[Cl:28])[CH:14]=2)=[N:6][CH:7]=1.[S-:32][C:33]#[N:34].[K+].BrBr>C(O)(=O)C>[NH2:34][C:33]1[S:32][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:24][CH2:25]4)[C:18]=3[Cl:28])[CH:14]=1)[N:6]=2
Reactant: N#C[S-]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)c(F)cc3F)c2Cl)CC1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2,4-difluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (4.25 g, 9.64 mmol) and potassium thiocyanate (3.75 g, 38.6 mmol) in acetic acid (50 mL) was added dropwise bromine (2.11 g, 13.1 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and triturated with diethyl ether to give the title compound (4.05 g, 84%) as a pale-yellow amorphous.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:21]=2)=[C:14]([Cl:36])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[Cl:18][C:16]1[CH:17]=[C:12]([N:6]([CH2:5][C:4]([OH:37])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:13]=[C:14]([Cl:36])[C:15]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27](=[O:35])[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH:21]=1
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(O)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N(CC(=O)O)c1cc(Cl)c(Oc2ccc(O)c(C(=O)c3ccc(Cl)cc3)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
The ester (2.27 g, 4.0 mmol) was dissolved in MeOH (14 mL) and to that solution of NaOH (0.48 g, 12 mmol) in H2O (7 mL) was added and it was stirred at 60° C. for 1 hr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. The aqueous layer was acidified to pH 4 using 10% HCl solution and extracted with ethyl acetate The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give pure product ({3,5-Dichloro-4-[3-(4-chloro-benzoyl)-4-hydroxy-phenoxy]-phenyl}-ethoxycarbonyl-amino)-acetic acid. (1.7 g, 79% yield)
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH:7]2[N:8]3[CH:9]=[N:10][CH:11]=[C:12]3[CH2:13][CH2:14][CH:15]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=CCCc1cncn1Cc1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cncn2C1c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
A solution of 1.27 g of ethyl 5-[1-(4-cyanobenzyl)imidazol-5-yl)-1-pent-2-enoate in 27 ml of tetrahydrofuran at 5° under nitrogen is treated with 0.52 g of potassium tert-butoxide. The reaction mixture is stirred at 5° for 2 h and 10 ml of 1N hydrochloric acid is added. The layers are separated. The organic phase is extracted with 1N hydrochloric acid (2×10 ml). The combined aqueous layers are extracted with ether, adjusted to pH=8 and extracted with methylene chloride (3×15 ml). The organic phase is dried and evaporated to yield the product which is treated with one molar equivalent of ethereal hydrogen chloride. The resulting solid is recrystallized from acetone to yield 5-(4-cyanophenyl)-6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, m.p. 126°-127°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I>CN(C=O)C>[I:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (154.2 mmol) 5-nitroindole (Aldrich N1, 760-2) and 21.7 g (386.7 mmol) potassium hydroxide were dissolved in 270 ml DMF. To this solution 39.5 g (155.6 mmol) iodine dissolved in 250 ml DMF were added drop wise during one hour. The resulting mixture was subsequently stirred for 1.0 h at room temperature. Afterwards the reaction mixture was poured on 2.5 l of sludge. The formed precipitate was collected by filtration and washed twice with water. The residue obtained was dried in a vacuum (yield: 43.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CN1C(C(C2C=CC([N+]([O-])=O)=CC=2)=O)=CN=C1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1>>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared by using (4-chlorophenyl)(4-nitrophenyl)methanone, (Intermediate 21: step a) in place of (1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methanone, (Intermediate 20: step b) then following the procedure described for the preparation of (4-aminophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 20: step c).
Reaction SMILES: C(Cl)CCl.N1([C:10]2[N:11]=[CH:12][C:13]3[CH:18]([C:19](O)=O)[CH2:17][CH2:16][C:14]=3N=2)C=NN=N1.FC1C(C#N)=C(C)C([C@@H]2OC[C@H]3CNCCN3C2)=CC=1>ClCCl>[NH:11]1[C:10]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C1CCc2nc(-n3cnnn3)ncc21
Agent: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Solvent: ClCCl
Solvent: ClCCCl
Product: c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
EDC (2.24 g, 11.68 mmol) was added to a suspension of 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid [I-67] (2.51 g, 9.73 mmol) and 6-fluoro-2-methyl-3-[(3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile [I-40C-1] (2.81 g, 10.21 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at RT for 1.5 hours. Most of the solvent was evaporated. The residue was dissolved in EtOAc and washed with water, NaHCO3 solution and brine, dried (Na2SO4), filtered, and the solvent evaporated to afford a crude mixture of the two diastereomers. The crude product was purified on silica (220 g cartridge) with gradient elution from CH2Cl2 (solvent A) to 50% CH2Cl2:MeOH 90:10 (solvent B) to afford a mixture of the title diastereomers which were separated by chiral preparative SFC HPLC (SFC on Chiralpak IC column, Diacel Chemical Industries, LTD., 30×250 mm, 60% 2:1 MeOH:MeCN/CO2, 70 mL/min., 100 bar, sample in DCM/MeCN, 35C, 254 nm) to afford the separated aza-indane diastereomers: Isomer 2A, faster eluting, and Isomer 2B, slower eluting. Stereochemical assignment at the aza-indane chiral center was made by X-ray crystallography of the slower eluting isomer. Isomer A was dissolved in 1 mL acetonitrile and 1 eq. 1 M HCl in ether was added, and. the solid was filtered to yield the hydrochloride salt. Isomer 2A HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.04 (s, 1H); 8.72 (s, 0.4H); 8.68 (s, 0.6H); 7.81-7.88 (m, 1H); 7.25-7.31 (m, 1H); 5.12 (t, 1H); 4.63-4.75 (m, 1.5H); 4.40-4.46 (m, 1H); 4.33-4.38 (dd, 0.5H); 4.23-4.28 (dd, 0.5H); 3.72-3.90 (m, 2H); 3.42-3.52 (m, 3H); 3.14-3.28 (m, 3H); 2.84-3.1 (m, 2H); 2.86-2.97 (m, 1H); 2.73-2.82 (m, 1H); 2.60 (s, 3H); 2.50-2.35 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 462 (M+H−N2): The HCl salt of Isomer 2B was made in a similar fashion. Isomer 2B HCl salt: NMR 500 MHz (CD3OD+D2O) (mixture amide rotamers) 10.0 (s, 1H); 8.7 (s, 1H); 7.82-7.86 (dd, 1H); 7.29 (t, 1H); 5.26 d, 1H); 4.66-4.76 (m, 1H); 4.49-4.54 (m, 1H); 4.45-4.59 (m, 1H); 4.35 (d, 0.5H); 3.90-4.03 (m, 1H); 3.76-3.88 (m, 0.5H); 3.11-3.43 (m, 5.5H); 2.88-3.00 (m, 0.5H); 2.70-2.82 (m, 1H); 2.63 (s, 3H); 2.21-2.40 (m, 1H); LC/MS 512 (M+Na), 490 (M+H), 42 (M+H−N2).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH:11]=C)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[O:20]=[O+][O-]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:9]([CH2:10][CH:11]=[O:20])=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(F)c(C#N)c1Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1c(F)ccc(CC=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-fluoro-3-(prop-2-en-1-yl)benzonitrile (450 mg, 2.296 mmol) in 0.37 mL pyridine (363 mg, 4.592 mmol) and 40 mL DCM/MeOH (V/V=1:1) was bubbled O3 at −78° C. for 15 min. Then N2 was bubbled for another 15 min. at −78° C. and 5 mL of Me2S were added. The mixture was stirred at r.t. overnight and then concentrated to dryness. The residue was dissolve in EtOAc (50 mL) and washed with 1 N HCl (aq.) and brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 64.5 %

Procedure:
A mixture of 30.3 g (0.10 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 16.1 g (0.11 mole) of 3-bromo-1-propanol (95% purity, Aldrich), 37.1 g (0.35 mole) of anhydrous sodium carbonate and 1.0 g of potassium iodide in 300 ml of DMF was heated on a steam bath for 20 h. The mixture was converted and the residue partitioned between water and benzene. The benzene layer was washed with water and brine, dried (sodium sulfate) and concentrated to give a gummy solid. The solid was recrystallized from 2-propanol/isopropyl ether to yield 23.3 g (65%) of a white solid, mp 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1Br.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:49][C:50]1([CH3:65])[CH2:55][CH2:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH2:51]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:53]1[CH2:54][CH2:55][C:50]([CH3:65])([CH3:49])[CH2:51][CH:52]=1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(=O)c1ccc(N)c(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(C2=CCC(C)(C)CC2)c1
Reaction time: 3 h
Yield: 64 %

Procedure:
To a slurry of 1-(4-amino-3-bromo-phenyl)-ethanone (20.5 g, 0.960 mol, as prepared in the previous step), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (3.94 g, 9.60 mmol), and K3PO4 (61.0 g, 0.280 mol) in 250 mL of toluene was added 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (24.9 g, 0.100 mol) followed by Pd2(dba)3 (4.39 g, 4.80 mmol). The resultant mixture was heated to 100° C. with vigorous stirring. After 3 h, the reaction was filtered and concentrated in vacuo. Purification of the residue by column chromatography (20% EtOAc-hexane) afforded the title compound (15.0 g, 64%). Mass spectrum (ESI, m/z): Calcd. for C16H21NO, 244.1 (M+H). found 244.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(Br)cc2ccccc12
Temperature: 0 °C

Procedure:
To a solution of 5.10 g (19.2 mmol) of the above methyl 3-bromo-1-naphthoate in 20 mL of anhydrous tetrahydrofuran at −78° C. under an atmosphere of nitrogen was added 48 mL (48 mmol) of a 1.0 M solution of diisobutylaluminum hydride in toluene. The resulting solution was allowed to gradually warm to 0° C. over 90 min and quenched with a saturated aqueous solution of potassium sodium tartrate (25 mL). The resulting suspension was vigorously stirred with gradual warming to ambient temperature over 2 h and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid which was used without further purification LC/MS 237.0 (M+1) and 239.0 (M+3).
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]([CH2:15][NH2:16])=[CH:11][CH:10]=1)#[N:2].[C:17]([NH:22][N:23]=[C:24](OCC)[CH2:25][CH2:26][CH2:27][CH3:28])(OCC)=[O:18]>C(O)C>[CH2:25]([C:24]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:14][CH:13]=2)[C:17](=[O:18])[NH:22][N:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: CCCCC(=NNC(=O)OCC)OCC
Solvent: CCO
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 400 mg (1.923 mmole) of [(2'-cyanobiphenyl-4-yl)methyl]amine, 457 mg (2.12 mmole) of ethyl valerimidate carbethoxyhydrazone (from Example 2, Step A), and 7 mL of ethanol was stirred under N2 in an oil bath at 50° C. for 3 hours and then at 80° C. for 2 days. The mixture was cooled and concentrated. The residue, re-concentrated from toluene, was flash chromatographed over silica gel (gradient elution with 1.5-5% methanol in CH2Cl2) to give the desired product, homogeneous in TLC (90:10 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 333 (M+1)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:12]([NH:20][C:7](=[O:10])[CH:8]=[CH2:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCCCCCCCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
A 500 ml four-necked flask equipped with a thermometer, mechanical stirrer, calcium sulfate-filled drying tube, and pressure-equalizing addition funnel is charged with a solution of 45.3 g of acryloyl chloride (0.5 mole) in 180 g of dichloromethane. The solution is cooled to 0° C. and to it is then slowly added a mixture of 66.6 g of n-octylamine (0.5 mole), 50.6 g of triethylamine (0.5 mole), and 125 g of dichloromethane, over a period of 2.5 hrs., at such a rate that the temperature does not exceed 5° C. Upon completion of the addition, the mixture is allowed to warm gradually to ambient temperature. The product is then stored at -15° C. overnight to complete crystallization of the byproduct triethylamine hydrochloride. After removal of the salt by filtration, the filtrate is washed successfully with 250 g of deionized water. The product is then dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to afford 85 g of N-(n-octyl)acrylamide, bp. 119°-120° (3 mm).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(C(=O)Cl)cc1
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Br)c23)cc1

Procedure:
The above 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole and 4-ethylbenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound, 4-bromo-3-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)indole as a colorless powder. APCI-Mass m/Z 476/478 (M+H). 1H-NMR (DMSO-d6) δ 1.15 (t, J=7.6 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.23 (td, J=9.0, 5.5 Hz, 1H), 3.39 (td, J=8.8, 5.1 Hz, 1H), 3.43-3.47 (m, 2H), 3.61-3.69 (m, 2H), 4.26 (s, 2H), 4.53 (t, J=5.3 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.1 Hz, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 7.09-7.14 (m, 4H), 7.21 (d, J=7.5 Hz, 1H), 7.23 (s, 1H), 7.59 (d, J=8.3 Hz, 1H).