Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23]C#N>>[OH:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][CH2:22][CH2:23][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: N#CCCCN1CCC[C@@H]1CO
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCCN3CCC[C@@H]3CO)cc12
Yield: 7 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.8040 g) and (R)-4-(2-hydroxymethylpyrrolidin-1-yl)butyronitrile (2.75 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (344.1 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2-chloromethyl-5-hydroxy-pyran-4-one (2) (105.0 g, 656.2 mmol) in DMF (600 mL) was added NaN3 (55.45 g, 853.12 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Then, the combined organic layer was washed with water and brine, and dried over Na2SO4 and concentrated under reduced pressure to get 2-azidomethyl-5-hydroxy-pyran-4-one (3) (70.0 g, 63.83%) as a light brown solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[ClH:17]>C(O)C.[Pd]>[ClH:17].[O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH2:11]
Reactant: N#Cc1ccccc1N1CCCCS1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccccc1N1CCCCS1(=O)=O
Reaction time: 24 h
Yield: 95 %

Procedure:
Intermediate 100, 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile, (2.63 g, 11.14 mmol) was dissolved in ethanol (150 mL) and 1N HCl (13 mL). Added to this was 10% Pd—C (0.5 g) and the mixture shaken under H2 at 55 psi for 24 h. Filtration through Celite followed by concentration gave the title compound as a white solid (2.93 g, 95% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 7.61–7.47 (4H, m), 4.30 (2H, q, J=13.7 Hz), 3.96–3.87 (1H, m), 3.49–3.36 (3H, m), 2.40–2.31 (2H, m), 2.05–1.96 (2H, m). LCMS [M+H]+ calcd for C11H17N2SO2: 241.10; found: 241.10.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:17][NH2:18].[BH4-].[Na+]>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 1-(4-carbomethoxyphenyl)propan-2-one (2.25 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.4 g) in benzene (100 ml) was refluxed under Dean & Stark conditions for 2 hours. The resulting adduct was reduced with sodium borohydride and the product was isolated as in part 1). Crystallisation from ether gave the title compound m.p. 73°-88° as a 50:50 mixture of diastereoisomers. Recrystallisation of this mixture from ethyl acetate gave a sample m.p. 82°-85°, predominantly the RS,SR diastereoisomer (12:88).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1.[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[CH2:29]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1)[CH3:30]
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 79.9 %

Procedure:
A mixture of 1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.37 g, 0.99 mmol), acetaldehyde (0.08 mL, 1.4 mmol) and sodium triacetoxyborohydride (0.32 g, 1.51 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 17.5 h. The orange reaction mixture was diluted with saturated aqueous sodium bicarbonate (30 mL) and was extracted with dichloromethane (3×25 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (19:1) afforded 1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.32 g, 80%) as a yellow foam: 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.8, 7.8, 1.4 Hz, 1H), 7.15 (dd, J=7.5, 0.9 Hz, 1H), 7.04 (ddd, J=7.5, 7.5, 0.8 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.45 (s, 1H), 6.41 (s, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H), 3.73 (dd, J=14.0, 7.4 Hz, 1H), 3.60 (dd, J=14.0, 7.1 Hz, 1H), 3.10-2.95 (m, 4H), 2.52 (q, J=7.1 Hz, 2H), 2.14-1.87 (m, 3H), 1.83-1.72 (m, 2H), 1.67-1.52 (m, 2H), 1.15 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ178.2, 161.9, 161.5, 143.0, 132.9, 128.9, 124.1, 123.4, 120.3, 120.0, 118.9, 108.8, 93.4, 80.9, 72.5, 57.8, 52.6, 45.8, 34.5, 29.6, 29.5, 29.2, 11.7; MS (ES+) m/z 405.2 (M+1).
Reaction SMILES: CC([S@]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[CH3:9])=O)(C)C.O1CCOCC1.CCOCC>Cl>[F:18][C:17]([F:19])([F:20])[O:16][C:13]1[CH:12]=[CH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
(R)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.4 mmol) was dissolved by swirling in 4M HCl in dioxane (16.4 ml, 65.6 mmol), at room temperature. The solution was allowed to sit for 1 hr with occasional swirling. To the clear solution was added 45 ml ether and the resulting cloudy solution sonicated for 1 min, upon which time the white solid product precipitates out. The solid was filtered through a Buchner funnel, washed 5 times with ˜20 ml ether and allowed to air dry. Obtained (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (3.2 g, 13.2 mmol, 80% yield), 1H NMR (400 MHz, CD3OD) δ 1.64 (d, J=6.90 Hz, 3H) 4.52 (q, J=6.88 Hz, 1H) 7.38 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.71 Hz, 2H). LCMS m/z 206.1 (M+H)+, Rt 0.52 min.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:46]Cl>C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98 %

Procedure:
1.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of a benzenedioxane (1:2) mixture. To the solution was added 3 g of NaHCO3 and the mixture was stirred at room temperature. Thereto was added dropwise over 3 minutes 1.5 ml of carbon tetrachloride having dissolved therein 2.1 mmol of chlorine and the mixture was stirred for 2 hours. The reaction mixture was extracted with ethyl acetate and the extract was subjected to the same subsequent procedure as in Example 1, affording 1.04 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 98% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][NH:15][CH:12]1[CH2:11][CH2:10][N:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH2:14][CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc(C#N)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccnc(C#N)c2)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 1-(2-cyanopyridin-4-yl)piperidin-4-yl(methyl)carbamate (300 mg, 0.949 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (2 ml) was added at 0° C. and stirring was carried out for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S-:27].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][S:27][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Solvent: CO
Product: CSCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (9.765 g, 26.43 mmol) in methanol (1 00mL) at room temperature was added sodium thiomethoxide (5.557 g, 79.29 mmol, Aldrich). The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken in methylene chloride and washed with water (3×) and brine (1×). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a clear oil as crude product of 4-methylsulfanylmethyl-piperidine-1-carboxylic acid tert-butyl ester (6.37 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][N:29]=1>CN(C)C=O>[C:23]([O:22][C:20]([NH:19][C@@H:15]([CH2:14][CH:11]1[CH2:10][CH2:9][CH:8]([NH:7][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:30][N:29]=2)[CH2:13][CH2:12]1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC(N)CC1)C(=O)O
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC(Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a solution of 161 mg (0.56 mmol) of (S)-3-(4-aminocyclohexyl)-2-tert-butoxycarbonylaminopropionic acid in 3 ml of dimethylformamide, and the mixture was stirred at room temperature. After 30 minutes, a solution of 100 mg (0.38 mmol) of 2-chloro-4,5-diphenylpyrimidine in 2 ml of dimethylformamide was added, and the mixture was stirred at 90° C. for 6 hours. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated under high vacuum. The residue was separated by a preparative HPLC (Purosphere, gradient acetonitrile/(water+0.5% TFA), gradient 20% acetonitrile to 100% in 30 minutes). 22 mg of (S)-2-tert-butoxycarbonylamino-3-[4-(4,5-diphenylpyrimidin-2-ylamino)cyclohexyl]propionic acid were obtained. The product obtained in this way was stirred with 50% trifluoroacetic acid in acetonitrile for 16 hours, mixed with water and freeze dried. 17 mg (11%) of the desired product were obtained.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Cc1nc2ccc(O)cc2s1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2s1
Yield: 43.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (309 mg, 0.942 mmol), 2-methyl-1,3-benzothiazole-6-ol (250 mg, 1.51 mmol), potassium carbonate (390 mg, 2.83 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (151 mg, 44%) was obtained as a pale-yellow powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:21])[CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10](=[O:21])[CH2:9]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Reactant: O=C(O)/C=C/c1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCN(CCN2CCCC2)C(=O)C1
Reaction time: 1 h

Procedure:
3-Oxo-4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 6; 0.03 g, 0.1 mmol) was treated with a hydrogen chloride solution (4 M in 1,4-dioxane, 1 ml) for 15 minutes after which time the solvent was evaporated. The crude salt was dissolved in N,N-dimethylformamide (0.8 ml) with triethylamine (0.06 ml, 0.4 mmol) and (E)-3-naphthalen-2-yl-acrylic acid (0.02 g, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) were added. The mixture was shaken for 1 h after which time it was directly purified by preparative HPLC. MS (ISP)=378.6 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH:33]([CH3:35])[CH3:34]>>[CH3:34][CH:33]([CH3:35])[CH2:32][C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)CC(=O)CBr
Product: CC(C)Cc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 49 mg (0.273 mmol) of 1-bromo-4-methylpentan-2-one (J. Org. Chem., 19, 2005, 4141-4153) were reacted according to the General Method 3. Yield: 50 mg (55% of theory).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][OH:28]>O>[OH:28][N:27]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: ON=C1CC(c2ccccc2)Oc2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one (50.0 g), methanol (535 ml), water (50 ml), potassium carbonate (59.3 g), and hydroxylamine HCl (59.8 g) was heated at reflux for 16 hours, then poured into ice-water; the oxime of 2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one was filtered off, washed with water, then dried in air. Yield: 52 g.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][OH:24])[CH3:5].[CH3:25]I.O>O1CCCC1>[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:5]
Reactant: CCCCOc1ccc(OCCCN(C)C)c(CCCO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1ccc(OCCCN(C)C)c(CCCOC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (51 mg) was added portionwise over a period of 5 minutes to a stirred solution of N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine (330 mg) in tetrahydrofuran (8 ml) at a temperature of 0° C. and under an atmosphere of argon. The reaction mixture was allowed to warm to 25° C. and stirred for a further 0.5 hour. The reaction mixture was cooled to 0° C. and methyl iodide (0.4 ml) added. The reaction mixture was allowed to warm to 25° C. and the reaction mixture was stirred for a further 15 hours. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (4×15 ml). The ethyl acetate extracts were combined, washed with water (10 ml), dried (MgSO4) and evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 75:25:0.2 mixture of ethyl acetate, hexane, and triethylamine as eluent to give N,N-dimethyl-3-[4-butoxy-2-(3-methoxypropyl)phenoxy]propylamine as a yellow oil (70 mg), NMR ([CD3 ]2SO): 0.92(3H,t), 1.42(2H,m), 1.70(4H,m), 2.1(2H,m), 2.5(6H,s), 2.9(2H,m) and 3.2(3H,s), 3.31(2H,t), 3.9(4H,m), 6.7(2H,s), and 6.82(1H,d); m/z 324 (M+H). The N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine used as starting material was prepared as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.N1C=CC=CC=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)Cl>[Cl:14][CH2:15][C:16]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:17]
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To 800 ml of chloroform is added 118 grams (1.12 moles) of 3-amino-5-methylisoxazole followed by 118 grams (1.5 moles) of pyridine. To this solution is added 147 grams (1.3 moles) of chloroacetylchloride with the addition temperature maintained at 0°-10° C. The reaction is then stirred at room temperature for 1 hour, filtered and dried in a vaccum desiccator to give 116 grams (56%) of 3-(chloroacetamido)-5-methylisoxazole, mp 192°-195° C. This material is slightly irritating to the skin and due caution should be exercised.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([OH:7])=O.[CH2:16]([NH:18][CH3:19])[CH3:17]>ClCCl>[CH2:16]([N:18]([CH3:19])[C:5](=[O:7])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(C)C(=O)c1ccc(C=O)cc1
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Thionyl chloride (26 mL, 0.36 mol) was added dropwise to a solution of 4-carboxybenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of dichloromethane:N,N-dimethylfonamide (4:1 mixture). The mixture was stilTed overnight at room temperature. Ethylmethylamine (75.0 g, 1.3 mol) was added dropwise, and stirring was continued at room temperature for 90 minutes. The solvent was removed under vacuum, the residue was dissolved in 500 mL of 0.1M sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum to give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a stirred solution of 7.91 g (53.0 mmol) tert-Butyl-phenyl-amine (Biehl, Smith, Reeves, J. Org. Chem., 1971, 13, 1842) and 5.36 g (58.3 mmol, 1.1 equiv) Et3N in 60 mL DCM is added 11.77 g (58.3 mmol, 1.1 equiv) Bromoacetyl bromide in 40 mL DCM dropwise over 45 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 200 mL DCM, washed with 1N HCl (2×150 mL), dried (MgSO4), and concentrated in vacuo. The crude product is filtered through a pad of 15 g silica gel eluted with 300 mL DCM. The filtrate is concentrated in vacuo to give 12.40 g (45.9 mmol) of 2-Bromo-N-tert-butyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [BH4-].[Na+].[C:3]1([NH:9][C:10]2([CH:24]=[O:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([NH:9][C:10]2([CH2:24][OH:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Yield: 82 %

Procedure:
Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-(2-phenylethyl)piperidine-4-carboxaldehyde (2 g) in methanol (2 g) at room temperature for 2 hours. The mixture was diluted with water, extracted with chloroform and the combined extracts washed, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, using chloroform-methanol 19:1 as eluant, to afford 4-(N-phenylamino)-1-(2-phenylethyl)-4-piperidinylmethanol (1.65 g), m.p. 98°-99° C.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][O:10][C:8]([C:7]1[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1)=[O:9]
Reactant: COC(=O)c1nccnc1Br
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1nccnc1Nc1ccccc1

Procedure:
A mixture of 9.5 g. of methyl 2-bromo-3-pyrazine carboxylate, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water was stirred and refluxed for two hours. The reaction mixture was poured on ice, extracted with ethyl acetate, the organic extracts were dried and concentrated to yield an oil. The crude residue was eluted on a silica gel column with ethyl acetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72°-75° C.