Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[C:54]([C:59]#[N:60])=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:49][CH:48]=2)[C:19](=[O:45])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si](C(C)(C)C)(C)C)=[CH:28][CH:27]=2)=[C:21]([CH:23]2[CH2:25][CH2:24]2)[N:22]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[C:59]3[NH:60][C:4](=[O:7])[O:5][N:3]=3)=[CH:51][CH:52]=2)[C:19](=[O:45])[C:20]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]([CH3:44])([CH3:43])[CH2:34][OH:35])=[CH:30][CH:31]=2)=[C:21]([CH:23]2[CH2:24][CH2:25]2)[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C2CC2)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)c(-c2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogen carbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.69 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 1.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.29 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23]([CH3:32])=[CH:24][C:25](=[O:31])[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>C(O)C>[CH:27]1([CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:19]([CH3:20])[NH:22][C:23]=2[CH3:32])=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CC(N)=CC(=O)CC1CCC1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 34.7 mg (0.227 mmol) of 4-amino-1-cyclobutylpent-3-en-2-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 36 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:19][C:6]1=2)#[N:2].[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:7]2[O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]([S:4][CH2:3][C:1]3[NH:36][N:35]=[N:34][N:2]=3)[C:6]=2[CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc2c(c1)COc1ccc(OCc3ccc4ccccc4n3)cc1C2SCc1nnn[nH]1

Procedure:
11-Cyanomethylthio-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine, ammonium chloride and sodium azide were used and reacted in the same manner as in Example 32 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:6]([C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:8])[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: Cc1cc(C(=O)O)cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Commercially available 6-chloro-5-methylnicotinic acid (200 mg, 1.29 mmol) was dissolved in dichloromethane (7.0 mL), and azetidine hydrochloride (160 mg, 1.71 mmol), HATU (1000 mg, 2.63 mmol) and N,N-diisopropylethylamine (0.69 mL, 3.96 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-75%) to afford the desired compound (160 mg, yield 64%) as a colorless liquid.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35])=[CH:28][CH:27]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:7]4[N:3]([CH3:2])[N:4]=[N:5][N:6]=4)[CH:9]=3)=[O:16])[CH2:20]2)=[O:35])=[CH:30][CH:31]=1
Reactant: CC(C)(Cc1ccc(F)cc1)C(=O)O
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(C(=O)C(C)(C)Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (100 mg, 284 μmol), 3-(4-fluorophenyl)-2,2-dimethylpropionic acid (56 mg, 284 μmol) and triethylamine (158 μL, 1.14 mmol) in dichloromethane (2 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (177 mg, 341 μmol) and the mixture was stirred at room temperature for 17 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and then with 1.0 N aqueous hydrochloric acid, dried (sodium sulfate) and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% hexane in ethyl acetate, to provide an amorphous white solid. 1H NMR (300 MHz, CDCl3) δ7.83 (s, 1H), 7.58 (d, J=7 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.28 (m, 1H), 7.05 (m, 2H), 6.90 (t, J=9 Hz, 2H), 4.18 (s, 3H), 4.10 (m, 2H), 3.31 (m, 2H), 3.00 (m, 2H), 2.90 (s, 2H), 1.90 (m, 1H), 1.77 (m, 2H), 1.56 (m, 1H), 1.40 (m, 1H), 1.23 (s, 6H). Mass spec (AP+) m/z 494.2 (M+H+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Mg].C[O:18][B:19](OC)[O:20]C.B([O-])([O-])[O-]>C1COCC1.O>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:19]([OH:20])[OH:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Mg]
Agent: [O-]B([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A dry reactor equipped with two addition funnels, nitrogen inlet, and a mechanical stirrer was set up over a dry ice bath. To one of the addition funnels was added a filtered, preformed Grignard reagent from the reaction of 4-(t-butyldimethylsilyloxy)-bromobenzene (28.7 g, 0.1 mol) with magnesium turnings (2.96 g, 0.12 mol) in THF (70 mL). To the other addition funnel was added trimethylborate (12.48 g, 0.12 mol) in THF (50 mL). The reactor was charged with about 10 mL of the borate solution and was cooled to -70° C. About 10 mL of the Grignard solution was then added. The remaining borate and Grignard solutions were then added in aliquots in such a way as to ensure a slight excess of borate. The reaction mixture was stirred at -70° C. for one hour then stirred at room temperature for 20 hours. The reactor was cooled to 0° C. and water (100 mL) was slowly added with vigorous stirring. The mixture was extracted with ether (400 mL). The ether layer was washed with water (2×200 mL), dried over anhydrous MgSO4, then concentrated on a roto-evaporator to afford a light-tan-colored solid (22.0 g, 87 percent). 1H and 13C NMR spectra were consistent with the following structure. ##STR11##
Reaction SMILES: C(OC([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:25])([O:22]CC)[O:19]CC)[O:7]C(OCC)=O)=O)C.Cl.N.C>O.CO.C(O)C>[OH:7][NH:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:19])([OH:22])[OH:25]
Reactant: CCOC(=O)ON(CCCCCP(=O)(OCC)OCC)C(=O)OCC
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=P(O)(O)CCCCCNO
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A mixture of diethyl 5-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)pentylphosphonate (90.0 g.) and conc. hydrochloric acid (630 ml.) was refluxed for 14 hours and concentrated under reduced pressure to give a residue, which was dissolved in water (200 ml.). The aqueous solution was washed with ethyl acetate, treated with activated charcoal and then concentrated under reduced pressure to give an oily residue (53.7 g.). The residue was dissolved in a mixture of water and methanol (1:2). The solution was adjusted to pH 4.0 with 28% aqueous ammonia under ice-cooling to give precipitates, which were separated by filtration, washed with methanol and dried to give crude crystals. The crystals were dissolved in 20-fold volume of water under heating, treated with activated charcoal and then cooled to ambient temperature. To the solution was added ethanol (100 ml.) and then allowed to stand overnight at 4° C. to give crystals, which were separated by filtration and dried to give crystalline 5-(N-hydroxyamino)pentylphosphonic acid (18.8 g.). M.p. 184°-185.5° C. (dec.).
Reaction SMILES: N1C=CN=C1.[H-].[Na+].[H][H].Cl[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]([NH2:23])[CH:17]=1>O1CCCC1.CN(C)C=O.CO>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:11]([O:13][CH3:14])=[O:12])[N:19]=[C:18]([NH:23][C:11]([O:13][CH3:14])=[O:12])[CH:17]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: [H][H]
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)n1
Reaction time: 1 h

Procedure:
A solution of 2.7 g (0.041 mol) of imidazole in 50 ml of dry tetrahydrofuran is treated at 0° C. with 1.8 g (0.041 mol) of 55 to 60 percent sodium hydride. After the hydrogen formation has finished, 3.8 g (0.041 mol) of methyl chloroformate in 20 ml of dry tetrahydrofuran are added dropwise at 0° C., whereupon the suspension obtained is treated dropwise at 0° with a solution of 2.9 g (0.021 mol) of 6-chloro-2,4-diaminopyrimidine and 4.5 g (0.041 mol) of potassium t-butylate in 30 ml of dry dimethylformamide. The mixture is stirred at 0° for 1 hour and then at 50° for 3 hours, whereupon 3 ml of methanol are added thereto and the solvent is evaporated to the largest extent possible. The residue is poured into ice-cold water, adjusted with 1N hydrochloric acid to pH 2 and extracted with methylene chloride and a small amount of methanol. After drying the organic extract over magnesium sulphate and evaporation under vacuum, the residue is recrystallized from ethyl acetate, there being obtained pure dimethyl 6-chloro-2,4-pyrimidinedicarbamate.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13](O)=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:29]2[C:13](=[O:14])[C:12]([C:7]3[NH:6][C:5]4[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)=[C:21]([OH:20])[C@H:23]3[C@@H:28]2[C@H:27]2[CH2:38][C@@H:24]3[CH2:25][CH2:26]2)=[CH:36][CH:35]=1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852; 2.51 g, 6.86 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (2 g, 6.86 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.74 g, 7.2 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (18 mL). N-Methylmorpholine (3 mL, 27.44 mmol) was added and the mixture was stirred at 25° C. for 2 h. Triethylamine (3.82 mL, 27.44 mmol) was added and the mixture stirred at 60° C. for 16 h. Upon cooling, the mixture was slowly added to a 1.0 M aqueous hydrochloric acid solution (200 mL) while stirring. The product precipitated immediately. Stirring was continued for 5 min. The solid was collected by vacuum filtration, rinsed with water (2×60 mL) and dried in vacuo for 16 h to afford the desired product, (1S,2R,3S,4R)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.94 g, 3.27 mmol, 48%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.20-1.23 (1H, m), 1.38-1.61 (5H, m), 2.50-2.53 (1H, m), 2.62 (1H, d, J=3.2 Hz), 2.98 (1H, d, J=9.3 Hz), 3.52 (1H, d, J=9.4 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=14.9 Hz), 7.12-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J=8.6 Hz, J2=1.4 Hz), 8.07 (1H, d, J=1.7 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][C:19]([CH3:26])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][CH:23]([F:24])[O:22][C:21]1[C:13]([C:10]([C:8]2[NH:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([OH:12])[CH3:11])=[C:14]2[C:18](=[C:19]([CH3:26])[CH:20]=1)[NH:17][CH:16]=[CH:15]2
Reactant: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(OC(F)F)c(C(C)(O)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: Cc1cc(OC(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 60 °C

Procedure:
To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.504 mmol) in THF (5 mL) at room temperature, ethylenediamine (0.34 mL, 5.04 mmol) was added followed by TBAF (1M in THF, 5.04 mL, 5.04 mmol) and the reaction was stirred at 60° C. After 2 days the reaction was cooled to room temperature, quenched with sat. aq. WWI and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (s, 1H) 11.12 (br. s., 1H) 8.06 (m) 7.81 (m) 7.65-7.74 (m) 7.46-7.56 (m) 7.29 (t, J=2.78 Hz, 1H) 6.72 (br. s., 1H) 6.68 (s, 1H) 6.65 (t, J=75.8 Hz, 1H) 6.22 (s, 1H) 2.45 (s, 3H) 2.09 (s, 3H). HRMS calcd. for C20H16F2N4O2 (M+H)+ 383.1314. found 383.1321.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:8][CH2:7]1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with dimethlamine to give trans-N-[4-(4-Dimethylamino-butyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 421 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1cccnc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccnc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 78.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 94.8 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl (2S)-N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.00 g; 9 mmol) in methylene chloride (50 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3×). The combined organic extracts were dried and concentrated to yield 2.00 g (95%) of the free amine as a thick oil. 1H NMR (300 MHz, CDCl3): δ 1.87-2.20 (m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m, 2H); 3.84 (m, 1H); 4.24 (m, 2H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[F:9])[CH3:18]
Reactant: Nc1ccc(O)c(F)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 18.3 %

Procedure:
To a solution of 4-amino-2-fluorophenol (2.15 g, 16.9 mmol) in dry DMF (60 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added Cs2CO3 (10.6 g, 25.4 mmol) and the mixture was stirred for 10 min at RT before addition of bromoethane (1.5 mL, 20.3 mmol). The reaction mixture was then stirred for 7 h at RT, concentrated to dryness, and the residue was partitioned between CH2Cl2 (100 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 88:12) gave 4-ethoxy-3-fluoroaniline SMA 44094 as a brown oil (480 mg, 18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: Cc1cc(Br)c2c(c1)C(=O)C(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=Cc2cc(C)cc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 32.5 g (136 mmol) of 4-bromo-2,6-dimethylindan-1-one in 370 ml of a mixture of THF-methanol (2:1, vol.), 11.8 g (312 mmol) of NaBH4 was added in small portions while vigorously stirring for 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 1000 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 700 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 1 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic fractions were evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm, eluent: hexanes). Yield 24.6 g (81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[CH:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([Br:33])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c3ccccc3n(-c3ccccc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 103(a) from 4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 411 (M+H)+.