Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:14]=O)[CH:11]=3)[C:4]=2[NH:5][N:6]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][N:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]4)[CH:11]=3)[C:4]=2[NH:5][N:6]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc2c(c1)Cc1c(I)n[nH]c1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2ccc3c(c2)Cc2c(I)n[nH]c2-3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 318 (980 mg, 3.16 mmol) in dichloromethane was added 1-methylpiperazine (0.83 mL, 7.5 mmol) and acetic acid (0.43 mL, 7.5 mmol) and the mixture was stirred at room temperature overnight. To this mixture was added sodium triacetoxyborohydride (1.0 g, 4.7 mmol) followed by methanol (5 mL) and stirring at room temperature was continued for about 2 days. The mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (9:1)+1% ammonium hydroxide as eluent to provide Example 607. MS (ESI): m/z 395 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([Cl:17])=[N:12][C:13](Cl)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([Cl:17])=[N:12][C:13]([CH2:22][C:21]2[C:20]([F:19])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,6-dichloropyridine (from Step B above, 8.5 g) in THF was added 2,6-difluorobenzylzinc bromide (90 mL, 0.5M in THF) and tetrakis(triphenylphosphine)palladium (2 g), and heated to reflux for a couple of hours until reaction completed. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate, washed with 1N NaOH, brine, dried over MgSO4 and concentrated to give title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[O:23]C.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[N:41]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:40]3[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=3[N:38]=2)[CH2:32][CH2:31]1>ClC(Cl)Cl>[C:2]([OH:3])(=[O:1])/[CH:7]=[CH:6]/[C:22]([OH:23])=[O:25].[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:41]2[C:40]3[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=3[N:38]=[C:37]2[NH:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][NH:27][C:8]([C:7]3[C:2](=[O:1])[O:3][C:4]4[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=4[CH:6]=3)=[O:10])[CH2:31][CH2:32]2)=[CH:44][CH:45]=1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: COC(=O)Cl
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1cc2ccccc2oc1=O
Product: O=C(O)/C=C/C(=O)O
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a stirred and cooled (below 10° C.) mixture of 3.8 parts of 2-oxo-2H-1-benzopyran-3-carboxylic acid, 2.2 parts of N,N-diethylethanamine and 225 parts of trichloromethane was added dropwise a solution of 1.9 parts of methyl carbonochloridate in 75 parts of trichloromethane. Upon completion, stirring was continued for 30 minutes at room temperature. This solution was added dropwise to a stirred and cooled solution of 6.6 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 75 parts of trichloromethane at 5° C. The whole was stirred for 1 hour while the mixture was allowed to reach room temperature. The reaction mixture was washed successively with water, a sodium hydroxide solution 10% and again with water. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in methanol. The salt was filtered off and dried, yielding 6.6 parts (47.5%) of N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioate(1:2); mp. 216.8° C. (compound 44).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].ClCO[CH2:17][CH2:18][O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[Na+].CN(C)[CH:32]=[O:33]>O>[C:20]([O:19][CH:18]([O:33][CH2:32][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH:10]=[O:11])=[CH:5][CH:6]=[CH:7][N:8]=2)[CH3:17])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CN(C)C=O
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CC(OCc1[nH]c2ncccc2c1C=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 7-azaindole-3-carboxaldehyde (2 g, 13.7 mmol) in dry N,N-dimethylformamide (30 ml) was added dropwise, under nitrogen atmosphere, to a stirring suspension of 60% sodium hydride (oil dispersion) (0.6 g, 15 mmol) in dry N,N-dimethylformamide (10 ml) keeping the temperature between 5–10° C. (ice-water bath). After addition was completed, stirring was continued at the same temperature for 30 min. Then a solution of benzoyloxyethyl chloromethyl ether (3.8 g, 15 mmol) in dry N,N-dimethylformamide (40 ml) was added dropwise. After addition was complete, a catalytic amount of sodium iodide was added, and the temperature was allowed to rise to room temperature. The reaction mixture was allowed to stand at room temperature under nitrogen for 6 days, with intermittent stirring. Then water (100 ml) was added, and the mixture extracted with dichloromethane (3×100 ml). The organic phase was washed with water (100 ml), dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to give an oil (4.4 g, 99%), which was used without further purification.
Reaction SMILES: C([O:4][C@H:5]1[O:22][C@H:21]([CH2:23][N:24]=[N+:25]=[N-:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(N)C1C=CC=CC=1>C1COCC1>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][N:24]=[N+:25]=[N-:26])[O:22][C@@H:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)O[C@H](CN=[N+]=[N-])[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3,4-tetra-O-acetyl-6-azido-6-deoxy-α-D-glucopyranose (IV, 850 mg, 2.78 mmol) in THF (12 mL) was added benzylamine (0.23 mL) and the mixture was stirred at rt overnight. Solvents were removed under the reduced pressure and the resulting residue was dissolved in dichloromethane (50 mL) and washed with water, saturated ammonia chloride, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 hexane-ethyl acetate, to give V (640 mg, 85%) as a white foam. 1H NMR (500.1 MHz) (CD3Cl) δ: 5.50 (m, 2H), 5.03 (t, J=10.5 Hz, 1H), 4.90 (m, 1H), 4.24 (m, 1H), 3.35 (m, 2H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). 13C NMR (125.8 MHz) (CDCl3) δ: 170.26, 170.23, 169.78, 89.98, 71.09, 69.71, 68.34, 51.05, 20.68, 20.62, 20.58.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[C:25]([NH2:33])([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(COC)OC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[C:25]([NH3+:33])([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: COCCOC
Product: CC(C)(C)CC(C)(C)[NH3+]
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 68.7 %

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (3.0 g, 0.0083 mole) is dissolved in glyme (20 ml) and t-octylamine (1.17 g, 0.0091 mole) is added rapidly while stirring. The solvent is removed in vacuo and the residue triturated with petroleum either (bp 30°-60° C.) and dried to give 2.8 g of product, mp 140°-57° C. Anal. Calcd. for C22H24ClF3N2O5 : C, 53.82; H, 5.33; N, 5.70; Cl, 7.22: F, 11.61. Found: C, 53.50; H, 5.37; N, 6.06; Cl, 6.87; F, 11.10.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].CC(C)(C)C=[C:10]=[CH:11][CH2:12][NH2:13].[CH:16]1C=CC=CC=1>>[CH3:1][C:2]([CH3:4])([CH3:16])[CH:3]=[N:13][CH:12]=[CH:11][CH3:10]
Reactant: CC(C)(C)C=C=CCN
Reactant: c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC=CN=CC(C)(C)C
Yield: 98.5 %

Procedure:
The procedure is carried out as described in Example 1, with the use however in this case of 10 g of potassium tert-butylate, 330 g (2.95 mols) of (2,2-dimethyl-propylidene)allylamine and 450 ml of benzene. After a reaction time of 3.5 hours at 40° C., there is obtained 325 g (2.9 mols) of (2,2'-dimethyl-propylidene)-propenylamine, corresponding to a yield of 98.5% of theory, as a cis/trans isomeric mixture in the weight ratio of 65:35; b.p. 110° C.; nD20 =1.4487.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:49][N:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51](Cl)=[O:52]>C(Cl)Cl>[C:5]([O:4][C:3](=[O:9])[N:2]([CH3:1])[C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:51]([N:50]([CH3:49])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([CH3:7])([CH3:8])[CH3:6]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)N(C)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Intermediate 7 (175 mg, 0.322 mmol) is dissolved in anhydrous CH2Cl2 (15 mL), to which DIEA (70 μL, 0.40 mmol) is added. The solution is cooled to 0° C. and N-methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) is added, the solution is subsequently warmed to room temperature for 4 h. N-Methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) and DIEA (70 μL, 0.40 mmol) are added and the solution is stirred at room temperature for 15 h at room temperature. The solution is diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 and brine. The solution is dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the crude product as an oil. This material is purified by flash chromatography on silica gel (0-5% MeOH/CH2Cl2). The title compound is isolated as a white foam (168 mg, 77% yield): 1H NMR δ (CDCl3) 6.60-7.60 (m, 10H), 4.19-5.20 (m, 5H), 3.62 (“br d”, 1H, Jobs=13.2 Hz), 3.52 (“br d” 1H, Jobs=13.4 Hz), 2.56-3.28 (m, 10H), 1.72-2.10 (m, 5H), 1.47 and 1.45 (s, 9H total), 1.24-1.32 (br m, 3H), 0.88-1.12 (m, 2H), 1.09 (br d, 1H, J=6.7 Hz), 0.90 (dd, 2H, J=7.0, 2.6 Hz), 0.78 (br d, 2H, J=6.7 Hz), 0.66 (br d, 2H, 6.7 Hz; LCMS (APCl+) 678.6 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg]Br>C1COCC1.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]([OH:23])[CH3:24])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=CC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-[3-(benzyloxy)-5-fluorophenyl]-4-formyl-3,4,5,6-tetrahydro-2H-pyran (1.08 g, 3.4 mmol) in THF (16 ml) at room temperature under a nitrogen atmosphere was added on 0.96 M solution of methyl magnesium bromide (5.3 ml, 5.1 mmol) in a dropwise manner. The mixture was stirred overnight, diluted with saturated aqueous ammonium chloride (40 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica-gel, 150 g, ethyl acetate in n-hexane as an eluent increasing the amount of ethyl acetate from 40% to 60%) afforded the titled compound as a colorless liquid (0.71 g, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)#[CH:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:12]1([CH2:2][CH2:1][C:3]2[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: C#Cc1cncc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1cncc(CCN2CCCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 117.6 %

Procedure:
To a solution of 3-ethynyl-5-nitropyridine (250 mg, 1.69 mmol) in ethanol (5 mL) was added pyrrolidine (0.56 mL, 6.76 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled and palladium hydroxide on carbon (20 mg) was added. The flask was charged with H2 (ballon) and stirred at rt for 16 h. The mixture was filtered over celite and the filtrate was concentrated to afford crude product (380 mg) as a dark red oil: ESI MS m/z 192 [C11H17N3+H]+.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1.C[O:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2)=O.O>O1CCCC1.C(NC(C)C)(C)C>[CH2:22]1[C:23]2[C:19](=[CH:18][C:17]([C:15](=[O:14])[CH2:12][C:8]3[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc2c(c1)CCC2
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(Cc1cccnc1)c1ccc2c(c1)CCC2
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
In 80 ml of anhydrous tetrahydrofuran was dissolved 8.86 ml of diisopropylamine. The solution was cooled to -10°, to which was added dropwise 39.5 ml of a hexanoic solution of n-butyl lithium (1.6M). Then, the mixture was stirred for 30 minutes at the same temperature, followed by dropwise addition of 5.34 g of β-picoline. The mixture was stirred for 30 minutes, to which was added dropwise 5 g of 5-methoxycarbonyl indane dissolved in 10 ml of anhydrous tetrohydrofuran. Then, the mixture was stirred for one hour at room temperature, followed by addition of about 25 ml of water. The organic solvent was exaporated off under reduced pressure. The concentrated solution was subjected to extraction with ethylacetate. The extract solution was washed with water, dried on magnesium sulfate and concentrated. The concentrate was crystallized from ethylacetate-isopropylether to give 5.6 g (yield 82%) of 1-(5-indanyl)-2-(3-pyridyl)-ethanone, m.p. 55°-56° C.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.C([CH2:14][NH2:15])O.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:14][NH2:15]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: NCCO
Agent: C=O
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition was prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol was employed in place of the Bisphenol-A, 20.1 g of ethanolamine was employed in place of the 2-(methylamino)ethanol, and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product was dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution was adjusted to 3.0 with phosphoric acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1COCC1.CCOC(C)=O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: OCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)c(OCC(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-4-formyl-benzonitrile (CAS 105942-10-7, 1 g) in THF (25 ml) was cooled to 0° C. under argon. Trifluoroethanol (3.36 g) and potassium tert.-butylate (0.83 g) were added subsequently. The mixture was stirred for 2 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 1:1) to give 4-formyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile. Yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH2:25])[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH:25][C:27](=[O:28])[O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.205 g (0.60 mmol) of trans-3-[5-(6-cylcopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamine is added, in small portions and at ambient temperature, to a solution of 0.110 ml (0.78 mmol) of 4-chlorophenyl chloroformate and 0.205 ml (1.2 mmol) of N,N-diisopropylethylamine in 6 ml of dichloromethane. The mixture is stirred at ambient temperature for 16 hours, then washing is carried out with 5 ml of a saturated sodium bicarbonate solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.176 g of a white solid is obtained.
Reaction SMILES: CO[CH:3]([O:10]C)[C@@H:4]1[O:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(C(O)=O)(F)(F)F.[OH-].[Na+].[BH4-].[Na+]>O1CCOCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][C@@H:6]2[CH2:7][O:8][C@@H:4]([CH2:3][OH:10])[CH2:5]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(OC)[C@H]1C[C@H](O)CO1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@@H](CO)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S-trans)-tetrahydro-5-(dimethoxymethyl)-3-furanol-4-methylbenzenesulfonate, (Compound IV(e), 10.0 g, 31.6 mmole), 1% CF3CO2H (50 mL), and dioxane (80 mL) in a 250 mL round bottom flask fitted with a reflux condenser was warmed to 80° C. for five hours. After cooling to room temperature, the solution was adjusted to pH 7.0 using 1N NaOH, treated with NaBH4 (1.2 g, 31.7 mmole), and allowed to stir at room temperature for an additional 30 minutes. The solvent was partially removed, then extracted with EtOAc (100 mL×3). The organic fraction was dried over MgSO4, filtered, evaporated and purified by flash column chromatorgraphy (60% EtOAc/40% Hexane) to afford 3.6 g or recovered starting material and 2.7 g (49% based on recovered starting material) of Compound IV(c).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 128 mg (86%) of a white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>C(Cl)Cl.O>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
To a solution of 5-(2-methoxyethyl)-2-sulfamoylbenzo[b]thiophene (8.3 g, 0.031 mol) in 550 ml of methylene chloride at -78° C. was added dropwise under nitrogen, 100 ml of a solution of boron tribromide (BBr3) (1M in hexane, 0.1 mol). The reaction was stirred at room temperature overnight (15 hours) following the addition. The mixture was cooled and diluted with 100 ml of cold water. The aqueous phase was separated and extracted 2× with methylene chloride. The original organic phase and the extracts were combined, dried, filtered and concentrated to dryness to yield 8.3 g (86%) of product with m.p. 118°-120° C.