Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:8]([C:7]1[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: C1COCCN1
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1N1CCOCC1

Procedure:
A mixture of 10 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide and 40 ml morpholine is heated for 10 minutes at 70° C.-80° C. Subsequently, the mixture is evaporated to dryness under vacuum at an 80° C. bath temperature and the residue is collected, washed carefully with water and dried at 110° C. The product is refluxed for 1 hour with 150 ml dichloromethane, filtered off with suction, dried once again at 110° C. and crystallized from n-butyl acetate. Yield: 9.27 g (75% of the theoretical yield), with a melting point of 234° C.-236° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:45])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([CH2:18][S:19][C:20]2[N:21]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=3)([CH3:27])[CH3:26])=[CH:23][N:24]=2)=[C:13]([Cl:44])[CH:12]=1)[C:3]([OH:5])=[O:4].C([NH:53][C:54](N1C=CC=N1)=[N:55]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>CO>[Cl:44][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([F:17])[C:14]=1[CH2:18][S:19][C:20]1[N:21]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[C:22]([C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=2)([CH3:27])[CH3:26])=[CH:23][N:24]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][C@H:2]([NH:1][C:54]([NH2:55])=[NH:53])[C:3]([OH:5])=[O:4])=[O:45]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCCC[C@H](N)C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCCC[C@H](NC(=N)N)C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A solution of (S)-2-amino-5-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)pentanoic acid (268 mg, 0.40 mmol), N,N′-di-Boc-1H-pyrazole-1-carboxamidine (135 mg, 0.44 mmol) and triethylamine (175 μL, 1.19 mmol) in MeOH (10 mL) was stirred at 25° C. for 18 h. The reaction mixture was concentrated and reconstituted in EtOAc. The organic layer was washed with 1N HCl (3×5 mL), sat. aq. NaHCO3 (5 mL), dried over Na2SO4 and concentrated to a colorless oil. To the oil was added 4N HCl in Dioxane (10 mL) at 25° C. and stirred for 18 h. Upon completion, the reaction mixture was concentrated and purified by flash chromatography (MeOH/DCM, 0-20%) to give the title product (64 mg, 28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=5.2 Hz, 1H), 7.76 (s, 1H), 7.61 (dd, J=10.1, 1.0 Hz, 1H), 7.50-7.10 (br s, 4H), 7.45 (d, J=6.6 Hz, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 6.95 (t, J=8.4 Hz, 2H), 6.58-6.43 (m, 4H), 4.06 (s, 2H), 3.77 (d, J=4.6 Hz, 1H), 3.67 (s, 3H), 3.23 (s, 2H), 1.71-1.59 (m, 2H), 1.58-1.46 (m, 2H), 1.46 (s, 6H). MS (EI) m/z 719 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][CH3:13])[O:11][C:7]=2[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:22]([NH2:23])=[C:21]([CH3:24])[O:20][N:19]=1>>[CH3:17][C:18]1[C:22]([NH:23][C:14]([C:6]2[C:7]3[O:11][C:10]([CH2:12][CH3:13])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])=[C:21]([CH3:24])[O:20][N:19]=1
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2o1
Reactant: Cc1noc(C)c1N
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C)noc3C)c2o1
Yield: 64 %

Procedure:
Starting from 4-methoxy-2-ethylbenzooxazole-7-carboxylic acid (0.23 g) and 3,5-dimethylisoxazol-4-ylamine (0.1 g). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a cream solid (0.18 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24]>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:5]([C@@H:3]1[CH2:4][C@H:2]1[CH3:1])=[O:7]
Reactant: CNOC
Reactant: C[C@@H]1C[C@H]1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1C[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,2R)-2-methylcyclopropanecarboxylic acid (44 g, 0.44 mol) in dichloromethane (600 mL) was added 1,1′-carbonyldiimidazole (79 g, 0.45 mol) portion-wise at 20° C. The reaction was stirred at 25° C. for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (52 g, 0.53 mol) was added portion-wise and stirring was continued at 25° C. for 16 hours. The reaction mixture was washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 2% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. Yield: 52 g, 363 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.19 (s, 3H), 1.80-1.86 (m, 1H), 1.30-1.38 (m, 1H), 1.17 (dt, J=8.5, 4.3 Hz, 1H), 1.12 (d, J=6 Hz, 3H), 0.64 (ddd, J=8.2, 6.1, 3.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:12]([O:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][CH2:16][C:17]([N:1]1[CH2:4][CH2:3][CH2:2]1)=[O:18])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Azetidine (546 mg, 9.56 mmol) was dissolved in dichloromethane (20 mL) in a 50 mL round bottom flask and treated with triethylamine (1.47 mL, 10.5 mmol) stirring at ambient temperature for 30 minutes. 2-chloro-2-oxoethyl acetate (1.03 mL, 9.56 mmol) was added to the mixture dropwise. The mixture was stirred at ambient temperature for 16 hours. The precipitated salt was removed by filtration and the filtrate was washed with water. The solution was concentrated under vacuum to give 2-(azetidin-1-yl)-2-oxoethyl acetate as a brown oil. Lithium aluminum hydride (10.0 mL, 10.0 mmol, 1 M in THF) in a 100 mL round bottom flask was cooled in an ice-water bath. 2-(Azetidin-1-yl)-2-oxoethyl acetate as a 0.6 M solution in THF was added dropwise to the lithium aluminum hydride solution. The ice bath was removed and the mixture was stirred at ambient temperature for 2 hours. A mixture of 1:1 Celite®/sodium sulfate decahydrate was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filter cake was washed with THF. The filtrated was concentrated under vacuum to give 2-(azetidin-1-yl)ethanol as a viscous, colorless oil (504 mg).
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[Si:12]([O:19][CH2:20][C@@H:21]1[C:26]([CH3:27])=[CH:25][C:24](=[O:28])[CH2:23][N:22]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[BH4-].[Na+]>CO>[Si:12]([O:19][CH2:20][C@@H:21]1[C:26]([CH3:27])=[CH:25][C@H:24]([OH:28])[CH2:23][N:22]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a stirred solution of cerium(III) chloride heptahydrate (6.36 g, 17.07 mmol) and (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-methyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 78, 6.07 g, 17.07 mmol) in MeOH (100 mL) at 0° C., sodium tetrahydroborate (0.646 g, 17.07 mmol) was added as a solid. The mixture was stirred at ambient temp for 1 h. The mixture was concentrated and diluted with NH4Cl(aq), H2O and extracted with ether. The ether layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (5.48 g, 90%) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:11]([O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])[CH:9]=[CH:8][CH:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)Oc1cccc(CCBr)c1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1SCCc1cccc(OC(C)(C)C)c1
Yield: 98.2 %

Procedure:
1-(2-Bromoethyl)-3-tert-butoxybenzene (320 mg, 1.244 mmol) was dissolved in acetonitrile (15 ml). Methyl thiosalicylate (209 mg, 1.244 mmol) was added and then potassium carbonate, anhydrous (258 mg, 1.866 mmol) was added. The mixture was heated to reflux for 3 hours and then evaporated under vacuum to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using ethyl acetate/heptane (5:95) as eluant gave 421 mg desired product, yield 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 25 g of 4-bromo-2-fluorophenol, 19 g of potassium carbonate and 100 ml of acetone was refluxed under stirring for 30 minutes. The reaction mixture was cooled, to which 17.40 g of benzyl chloride were dropwise added taking 15 minutes. The resultant was refluxed under stirring for 7 hours and filtered. The filtrate was distilled to remove acetone. The residue to which water was added was extracted with chloroform. The extract was washed, dried and purified by a silica gel column chromatography using chloroform. The eluate was evaporated under reduced pressure to obtain 22.24 g of the intended benzyl 4-bromo-2-fluorophenyl ether.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1)=[O:2]
Reactant: CCOC(=O)C=Cc1ccc(C=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(C=CC(=O)O)c2ccccc12
Yield: 93.9 %

Procedure:
A suspension of ethyl 4-formylnaphthalene acrylate (391 mg, 1.53 mmol), sodium carbonate (195 mg, 1.84 mmol) in water (10 mL) was refluxed for 16 hr. The cold solution was filtered, and the filtrate was acidified with conc. hydrochloric acid. The precipitate was collected by suction and dried for 48 hr in vacuum to give the product (325 mg, 94%) as a yellow solid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:14][N:13]=1.N.O>CCOC(C)=O>[CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[CH:14][N:13]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(CCc2cnc(Cl)c3ccccc23)cn1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(CCc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1

Procedure:
Under a N2 atmosphere, 600 mg (4.25 mmol) of trans-4-isopropyl-cyclo-hexylamine [for preparation see Arzneim. Forsch. 19 (1969), 140] and 120 mg (0.424 mmol) of 1-chloro-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline are heated to 140° C. in an ampulla for 10 h. The reaction mixture is suspended in EtOAc, and mixed with 0.25 ml of NH3 solution (25%) and water. The separated aqueous phase is extracted twice more with EtOAc, the organic phases washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 1:1) yields trans 1-(4-isopropyl-cyclohexylamino)-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ8.27 (m, 2H), 7.88 (d, 1H), 7.65 (t, 1H), 7.60 (s, 1H), 7.54 (m, 1H), 7.45 (t, 1H), 7.14 (d, 1H), 6.84 (d, 1H), 3.88 (m, 1H), 3.00 (m, 2H), 2.84 (m, 2H), 2.40 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.5-1.0 (m, 6H), 0.86 (d, 6H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O>[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)OCCCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCCCc1ccccc1
Yield: 30.5 %

Procedure:
A solution of vanillin (12.49 g, 82.1 mmoles) in dimethylformamide was added with Na2CO3 (17.4 g, 164 mmoles) and KI (catalytic amount). The mixture was brought to 90° C. then slowly added with methansulfonic acid 5-phenyl-pentyl ester (24.87 g, 103 mmoles) obtained as described in example 11, in dimethylformamide (40 ml). After 1.5 hours the mixture was poured into 1N HCl and thrice extracted with pentane, anhydrified and dried. The residue was purified by silica gel flash chromatography (eluent: petrolatum/ethyl acetate 9:1), so 7.46 g of the title product were obtained (yield: 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCOCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with morpholine to give (2S)-1-(tert-butoxycarbonyl)-2-morpholinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7-2.0 (m, 4H), 2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H), 3.3-3.4 (m, 2H), 3.43.8 (m, 10H); Mass Spectrum: M+H+ 229.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]2[O:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH:32]2[OH:45])[CH:27]=[CH:28][C:29]=1[Cl:30].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]2[O:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:33][C:32]2=[O:45])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Dess-Martin reagent (1.4 g) was added to a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (800 mg) in acetonitrile (10 ml), and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (624 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=1>>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([F:1])[CH:3]=2)=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=O
Reactant: NNC(=O)c1ccc(O)c(F)c1
Product: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=NNC(=O)c1ccc(O)c(F)c1
Yield: 29.8 %

Procedure:
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above 4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:17]([CH3:18])[C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][CH2:9][CH2:8][C:7]([N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:20])=[O:19])[CH2:16][CH2:15]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN[C@H]1CC[C@H](OCCC(=O)N(C)CCCO)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 158 mg (0.5 mmol) of trans-N-(3-hydroxy-propyl)-N-methyl-3-(4-methylamino-cyclohexyloxy)-propionamide-hydrochloride in 3 mL of CH2Cl2 were added 0.44 mL (2.6 mmol, 5 eq) of N,N-diisopropylethylamine followed by 0.14 mg (0.56 mmol, 1.1 eq) of 4-bromo-benzenesulfonyl chloride. The mixture was stirred at RT for 1 h and the organic phase was extracted with 1M KHSO4. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with a gradient of CH2Cl2:MeOH 98:2 to 95:5 yielded 101 mg (40%) of trans-3-{4-[(4-bromo-benzenesulfonyl)-methyl-amino]-cyclohexyloxy}-N-(3-hydroxy-propyl)-N-methyl-propionamide as colorless oil, MS: 491 (MH+,1Br).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13])([CH3:33])[CH3:32]
Reactant: Cc1cc2c(cc1C)C(C(=O)O)c1ccccc1CO2
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: Cc1cc2c(cc1C)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 93.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 0.84 g of 6,11-dihydro-2, 3-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 63 (Compound AB) in place of Compound A and 0.83 g of 2,6-diisopropylaniline in place of aniline to obtain 1.25 g of Compound 48.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.[CH:14]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)[CH3:14]
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccnc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To 4-methyl-2-phenylpyridine (8 g, 47.3 mmol) in dry THF (150 mL) at −78° C. was added dropwise lithium diisopropylamide (LDA) (30.7 mL, 61.5 mmol). The dark solution was stirred for 3 h at −78° C. and then CH3I was added (4.1 mL, 66.2 mmol) dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. Ammonium chloride solution and EtOAc were added and the reaction transferred to a reparatory funnel. The layers were separated, washing the aqueous twice with EtOAc and combined organics once with water. After removal of the solvent, the crude product was chromatographed on silica gel with 9/1 (v/v) hexane/EtOAc to give 5.5 g (63.5%) of 4-ethyl-2-phenylpyridine. HPLC purity: 99.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([N:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:7]2)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([N:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:7]2
Reactant: CCCN(C(=O)CC)C1COc2ccc([N+](=O)[O-])cc2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(C(=O)CC)C1COc2ccc(N)cc2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
A solution of 6-nitro-3-(N-propionyl-N-n-propylamino)chroman (17) (700 mg, 2.40 mmol) in glacial acetic acid (50 ml) was treated with zinc dust (1.0 g). The mixture was stirred at 50° C. for 90 minutes. The solution was filtered and acetic acid evaporated at reduced pressure. The product was dissolved in CH2Cl2 and washed with 5% -aqueous Na2CO3. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated. The crude product was chromatographed on silica (60 g) , with CH2Cl2 --CH3OH (19:1) as eluant, yielding 350 mg (56%) of 6-amino-3-(N-propionyl-N-n-propylamino)chroman (18) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>ClCCl>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:27](=[O:28])[CH2:26][O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:33][CH2:32]1
Reactant: O=C(Cl)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetic acid (150 mg, 0.39 mmol) in dichloromethane (3 mL) is added oxalyl chloride (490 mg, 3.9 mmol) and 1 drop of N,N-dimethylformamide. The mixture is stirred at room temperature for 5 h, concentrated in vacuo, and residual solvents removed by co-evaporation three times with chloroform to yield [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride as a yellow solid. To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride (50 mg, 0.12 mmol) in dichloromethane at room temperature is added 1-methyl-piperazine (62 mg, 62 mmol) and the mixture stirred for 2.5 h. The mixture is partitioned between dichloromethane and water, the organic portion dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 28 mg (48%), as a light brown solid.