Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].[C:27]([OH:30])(=O)[CH3:28].O>CO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][CH2:11][C:8]1[CH:7]=[CH:6][CH:28]=[C:27]([OH:30])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCNc1cc(CNCc2cccc(O)c2)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) and m-hydroxybenzaldehyde (0.45 g) in methanol (7 ml) is refluxed for 16 hours. The resulting solution is cooled to 0°-5° C. whereafter sodium borohydride (0.25 g) is added in portions during 5 minutes while stirring. After stirring at 22°-25° C. for a further 3 hours, acetic acid (0.5 ml) followed by water (20 ml) are added to precipitate crude (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-3-hydroxybenzylamine. After filtration and recrystallization from ethanol, it is obtained with a melting point of 174°-175° C.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CC(C)=O>[CH2:30]([O:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Yield: 64.8 %

Procedure:
To a suspension of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [prepared according to WO09/049851] (67.0 g, 211.7 mmol) in acetone (900 ml) was added potassium carbonate (35.1 g, 254.1 mmol), followed by benzyl bromide (35.3 ml, 50.7 g, 296.4 mmol) dropewise. The suspension was stirred at reflux for one hour, then poured on ice water and ethyl acetate. The resulting precipitate was filtered off, dissolved in methylene chloride, dried over sodium sulfate, concentrated and dried over phosphorus pentoxide under vacuum at 50° C. overnight to afford a first crop of product as a white solid (55.8 g). The layers of the mother liquor were separated, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, filtered and dried to further deliver 22.6 g of product. Yield: 78.4 g of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.4) as a solid, mp 184-186° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>O1CCOCC1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:35])[C:32]([CH3:34])=[CH2:33]
Reactant: C=C(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 45 °C

Procedure:
4-(6-Hydroxyhexyloxy)-4'-nitrobiphenyl (22 g) is dissolved in 500 ml of drydioxane and heated to 45° C. A 14 g quantity of triethylamine is added, then a solution of 10.5 g of methacryloyl chloride in an equal volume of dioxane is added dropwise while maintaining the reaction medium temperature at 45° C.
Reaction SMILES: F[C:2]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1.[ClH:43].CCOCC>CO.O1CCOCC1>[ClH:43].[F:42][C:39]1[CH:38]=[C:3]([CH:2]=[CH:41][CH:40]=1)[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)ccc6F)c5)c4c3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(N6CCNCC6)c5)cc34)cn2)c1
Reaction time: 4 h
Yield: 29.8 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (76 mg, 0.137 mmol) in methanol (5 ml) added saturated HCl in dioxane at 0° C. This gradually brought to RT and stirred for four hours. Reaction mass was cooled and added ether to get solids. Solvents decanted and solids washed by ethyl acetate and dried. This afforded 20 mg (29.8% yield) titled compound. 1H NMR (CD3OD, 400 MHz): δ 9.071-9.067 (d, 1H), 8.778-8.774 (d, 1H), 8.605 (s, 1H), 8.215 (s, 1H), 8.009 (s, 1H), 7.618-7.614 (m, 1H), 7.535-7.496 (t, 1H), 7.460-7.441 (m, 1H), 7.405-7.351 (m, 1H), 7.272-7.248 (m, 1H), 7.174-7.155 (m, 1H), 7.086-7.030 (m, 2H), 5.530 (s, 2H), 3.682-3.656 (m, 4H), 3.497-3.471 (m, 4H), 3.339 (s, 3H). MS: m/z=453.4 (M+1); HPLC: 89.28% in method A.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:2]([CH3:20])[CH:3]=[N:4]1
Reactant: CCCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: CN(C)C=O
Product: CCCc1sc(C(=O)OC)cc1-c1c(C)cnn1C

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (242 mg, 0.71 mmol). PdCl2(dppf) (52 mg, 0.07 mmol), potassium carbonate (487 mg, 3.53 mmol) and trimethylboroxine (0.20 ml, 1.41 mmol) in N,N-Dimethylformamide (3.5 ml) was stirred at 110° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (184 mg, 0.60 mmol, 84° A yield) as a yellow oil: LCMS (ES) m/z=279 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][CH3:14])[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][CH3:14])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: CCn1nc([N+](=O)[O-])cc1C(=O)OC
Solvent: CO
Product: CCn1nc(N)cc1C(=O)OC
Reaction time: 8 h

Procedure:
To 2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526, 1.30 g, 6.53 mmol) in methanol (60.0 mL) was added 20% Pd(OH)2C (0.1 g). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was filtered and concentrated to give a light yellow solid (527, 1.0 g, 90.6%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[C:15](C(OCC)=O)=[N:14]2)=[CH:9][C:8]=1[C:30]([O:32]C(C)C)=[O:31]>O>[Cl:6][C:7]1[C:8]([C:30]([OH:32])=[O:31])=[CH:9][C:10]([N:13]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)c(C(=O)OC(C)C)c2)c(=O)c(C)c1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)c(C(=O)O)c2)c1=O
Temperature: 150 °C
Yield: 89.8 %

Procedure:
Twenty mililiters (20 ml) of a mixture of sulfuric acid and water (v/v=1/1), and 7.3 g of 2-(4-chloro-3-isopropoxycarbonylphenyl)-6-ethoxycarbonyl-4-methyl-5-trifluoromethylpyridazin-3-one (the present compound 1-109) were mixed and heated for 7 hours on a 150° C. oil bath. The reaction solution was cooled to room temperature, poured into 100 ml of water. The precipitated crystals were filtered off, washed with 50 ml of water 3 times, dissolved with 200 ml of ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford 4.88 g of 2-(4-chloro-5-carboxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (yield:89%).
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][C:18]4[CH:29]=[CH:28][C:21]([C:22]([O:24]CC=C)=[O:23])=[CH:20][CH:19]=4)=[O:16])=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd].O1CCOCC1>[C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:28][CH:29]=4)=[O:16])=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C=CCOC(=O)c1ccc(OC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: COCCOCOc1cc(C(=O)Oc2ccc(C(=O)O)cc2)ccc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
2.46 g (4.3 mmol) of allyl 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzoyloxy]benzoate, 40 ml of dioxane and 492 mg of palladium-on-charcoal (10%) were introduced into a reactor. The mixture was hydrogenated at 40° C. and at a pressure of 7 bar for three hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The solid obtained was recrystallized from methanol, filtered off and dried. 1.57 g (76%) of the expected acid, having a melting point of 212°-4° C., was recovered.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1.[N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]=[S:26]>CS(C)=O>[C:18]([O:17][C:16]([NH:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[F:23])[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[S:26])=[N:7][CH:6]=1)=[O:22])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1F
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)OC(C)(C)C)c2)cn1
Yield: 79.6 %

Procedure:
In the same manner as in Reference Example 30 and using tert-butyl {5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}carbamate (9.60 g, 30.1 mmol), DMSO (60 mL) and ethyl isothiocyanatoformate (4.73 g, 36.1 mmol) as starting materials, the title compound (10.8 g, 80%) was obtained as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14](O)=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3].[CH3:28][NH:29][CH3:30].CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14]([N:29]([CH3:30])[CH3:28])=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]

Procedure:
A solution of Example 122E (411 mg, 1 mmol), 2M dimethylamine in THF (1 mL), EDCI (296 mg, 1.5 mmol), and DMAP (10 mg) in DMF (10 mL) at room temperature was stirred for 16 hours, diluted with ethyl acetate (200 mL), washed sequentially with 1N HCl (50 mL), water (50 mL), and brine (20 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide the desired product. MS (ESI(+)) m/e 439 (M+H)+.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].[C:8]1([C:14]2[C:18]3[C:19]([O:23]C)=[N:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(OCC)(=O)C>C(#N)C.O.C1COCC1>[C:8]1([C:14]2[C:18]3[C:19](=[O:23])[NH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: COc1nccc2c1c(C1=CCCCC1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1[nH]ccc2c1c(C1=CCCCC1)nn2C1CCCC1
Reaction time: 0.08 h

Procedure:
To a solution (1.0 mL) of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (29.2 mg) obtained in Step C of Example 12, 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.7 mg) and tetrakistriphenylphosphine palladium (18.5 mg) in DME was added 2N sodium carbonate (120 μl), and the mixture was reacted at 100° C. for 6 hr. To the reaction mixture were added ethyl acetate (4 mL), THF (1 mL) and water (1 mL), the mixture was stirred for 5 min, and the organic layer was separated, and concentrated by air-blowing. The residue was purified by preparative high-performance liquid chromatography (C18, mobile phase: acetonitrile/10 mM aqueous ammonium bicarbonate solution) to give 3-(cyclohex-1-en-1-yl)-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridine. A solution (1.0 mL) of chloro(trimethyl)silane (10.2 μl) and sodium iodide (12.0 mg) in acetonitrile was added to 3-(cyclohex-1-en-1-yl)-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridine, and the mixture was reacted at 60° C. for 1 hr. To the reaction mixture were added ethyl acetate (4 mL), THF (1 mL) and water (1 mL), the mixture was stirred for 5 min, and the organic layer was separated, and concentrated by air-blowing. The residue was purified by preparative high-performance liquid chromatography (C18, mobile phase: acetonitrile/10 mM aqueous ammonium bicarbonate solution) to give the title compound (13.0 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][CH:7]=1.CCO.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(C=NNc2ccc(I)cn2)c1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2nnc3ccc(I)cn23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 5-iodo-2-(2-(3-(trifluoromethyl)benzylidene)hydrazinyl)pyridine (1.60 g, 4.09 mmol) in DCM (10 mL)/EtOH (1 mL), was added PhI(OAc)2 (1.845 g, 5.73 mmol). The mixture was stirred at RT for 5 h, then the solvent was removed in vacuo. The residue was dissolved in DCM and purified on SiO2 column chromatography with 80% 15% MeOH/EA in hexane to afford the title compound (1.21 g, 76% yield) as an off-white solid. MS (ES+, m/z): 390.3 (M++1).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:25][CH2:26][CH3:27])[C:5]1=[O:6])[CH2:2][CH3:3].[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:27][CH2:26][CH2:25][N:7]1[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:13](=[O:14])[C:12]2[C:8]1=[N:9]/[C:10](/[N:11]=2)=[C:15]1/[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:33][C:32]2[CH:34]=[CH:35][C:36]3[O:37][CH2:28][O:29][C:30]=3[CH:31]=2)=[O:23])[NH:18][O:19]/1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Reactant: Nc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc4c(c3)OCO4)NO1)N=2

Procedure:
Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]#[N:26].[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]#[N:26])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: N#CCCl
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Temperature: 70 °C

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (1.65 mmol, 500 mg) and chloroacetonitrile (1.65 mmol, 0.125 g) in THF (30 mL) and DMF (5 mL) was added sodium hydride (60%, 2.48 mmol, 0.099 g) and heated to 70° C. for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (125 mg, 22.1% yield). Calculated MS=341.4. found MS (ESI) m/e 342.9 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.472 min.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([OH:20])[CH:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[N:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16]1)[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[C:18]([Cl:19])[C:2]([N:1]=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:3][C:4]=1[OH:20])[CH2:10]2
Reactant: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl

Procedure:
Following the procedure of Example 1, the title compound is prepared from 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide and N,N-dimethylformamide dimethylacetal.
Reaction SMILES: C(O)C.[C:4]1([CH:10]([CH3:13])[C:11]#[N:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:14].[H][H]>C(OC)(C)(C)C>[ClH:14].[C:4]1([CH:10]([CH3:13])[CH2:11][NH2:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C#N)c1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC(CN)c1ccccc1
Yield: 76.2 %

Procedure:
Charge to an autoclave hydrogenation apparatus under nitrogen water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). Stir the mixture rapidly and pressurize to 75 to 78 psi with hydrogen. Heat the mixture 50° C. to 64° C. for 3 hours. Depressurize and filter the reaction mixture to afford two lots of filtrate. Concentrate filtrates under reduced pressure to approximately 400 mL each. Add methyl tert-butyl ether (MTBE) (2.2 L each) to each lot. Stir the precipitate overnight. Filter and wash solids with fresh MTBE (100 mL) and dry overnight. Combine the lots to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2%) as a white powder.
Reaction SMILES: [CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:24])[CH:12]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[CH:1]([CH:8]1[CH:13]2[CH:9]1[CH2:10][CH:11]([OH:24])[CH:12]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC=CC1C2CC(O)C(CCCCCCC(=O)OC)C12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC=CC1C2CC(O)C(CCCCCCC(=O)O)C12
Temperature: 0 °C

Procedure:
A solution of methyl 6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]-hexane-2-heptanoate (17 mg.) from Example 25 in 5 ml. of methanol containing 0.5 ml. of 10% aqueous sodium carbonate solution is heated at 55° C. for 2 hours. The resulting mixture is then cooled to 0° C., acidified with hydrochloric acid to pH 2, and extracted with diethyl ether. The diethyl ether solution is washed, dried with anhydrous sodium sulfate, and evaporated to give 6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]hexane-2-heptanoic acid. I.R. 1745 and 1700 cm-1.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:8][C:7]1=C=O)(C)(C)C.OC1C=C(OC)C=CC=1C(OC)=O.OC1CCN([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])CC1>>[C:50]([O:49][C:47]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]1)=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OC)cc1OC1CCN(OC(C)(C)C)C(=C=O)C1
Agent: COC(=O)c1ccc(OC)cc1O
Product: COC(=O)c1ccc(OC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using a procedure similar to that used in Example 21-C, methyl 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-methoxybenzoate (10.38 g, 71%) was prepared from methyl 2-hydroxy-4-methoxybenzoate and 4-hydroxy-1-tert-butoxycarbonylpiperidine.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][C:16]([NH2:18])=[O:17])=[C:9]2[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1)(=[O:21])=[O:20])(=[O:5])[CH3:4].O>O1CCCC1>[OH:5][CH:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH2:15][C:16]([NH2:18])=[O:17])=[C:9]2[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=1)(=[O:21])=[O:20])[CH3:4]
Reactant: CC(=O)c1ccc2[nH]c(CC(N)=O)c(S(=O)(=O)c3cc(C)cc(C)c3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc(C(C)O)cc23)c1
Yield: 80.9 %

Procedure:
Sodium borohydride (0.03 g, 0.0008 mol) was added to a mixture of 5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (0.30 g, 0.0008 mol) in tetrahydrofuran (8.5 mL) containing 0.1 mL of water, then reaction was refluxed for 1 hour. After cooling, water was added while stirring for a few minutes, then the mixture was extracted with ethyl acetate, washed with brine and dried. Removal of the solvent furnished 0.25 g (83%) of satisfactory pure title compound, mp 260-260° C. (ethanol).
Reaction SMILES: [CH2:1]([C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:2][SH:3].[CH3:29][N:30]([CH3:40])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[C:36]([CH3:38])=[CH2:37].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[C:4]([CH2:1][CH2:2][S:3][CH2:38][CH:36]([C:35]([NH:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:40])[CH3:29])=[O:39])[CH3:37])([C:5]([C:6]([C:7]([C:8]([C:9]([C:10]([C:11]([F:14])([F:13])[F:12])([F:16])[F:15])([F:17])[F:18])([F:19])[F:20])([F:21])[F:22])([F:23])[F:24])([F:25])[F:26])([F:27])[F:28]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: C=C(C)C(=O)NCCCN(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: CC(CSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)NCCCN(C)C
Yield: 78.2 %

Procedure:
1,1,2,2-Tetrahydroperfluorodecanethiol (12.04 g, 0.025 mole), N-(3-dimethylaminopropyl)methacrylamide (3.88 g, 0.023 mole), and benzyltrimethylammonium hydroxide in methanol (4 drops) were heated overnight at 70° C. The resultant mixture was stripped of volatiles and distilled at 150°/≠0.1 mm Hg to yield 11.7 g of pale-yellow liquid (78.1% theory) which subsequently crystallized to a solid, m.p. 47°-50° C. NMR showed proton resonances at δ1.05, 3 protons, CH CH3 ; δ1.55, 2 protons, NHCH2CH2CH2N(CH3)2 ; δ2.10, 6 protons, 2 × NCH3 ; δ2.00-δ2.80, 10 protons, CF2CH2CH2SCH2 + NHCH2CH2CH2N; δ3.05; 1 proton, CH(CH3)CO; δ7.50, 1 proton, NH.