Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH:23][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Product: C[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1

Procedure:
[2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(3-trifluoromethyl-phenyl)-ethylamine. MS (ISP): 352.3 (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.48 (m, 4H), 7.39 (m, 2H), 7.27 (d, 2H), 3.81 (s, 2H), 2.80-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[C-:11]#[N:12].[Na+].O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(CC#N)cc1
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Under an atmosphere of nitrogen, 25.9 g (150 mmol) of 4-(methylthio)benzyl chloride were dissolved in 45.5 g of toluene. 9.29 g (180 mmol) of sodium cyanide, 0.92 g (2.9 mmol) of tetrabutylammonium chloride and 14.4 g of water were then added. The mixture was stirred at 80-85° C. for 2 h. The reaction mixture was admixed with 30 g of toluene and 45 g of water, the aqueous phase was decanted off and the organic phase was concentrated. This gave a residue of 24.6 g of the title product in a yield of >95% (according to NMR) in the form of a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 33 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 330 ml of dichloromethane is mixed at −5° C. with 28.9 g of triphenylphosphine and 36.7 g of carbon tetrabromide and stirred for 0.5 hour. Then, dichloromethane is added, and it is washed with water, saturated sodium bicarbonate and common salt solution. The organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. Then, the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. 28.5 g of 7α-(5-bromopentyl)-11β-fluor-estr-4-ene-3,17-dione with a melting point of 75-76° C. is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 97.7 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2 g), piperazine-1-carboxylic acid tert-butyl ester (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) were heated together at 80° C. under nitrogen for 15 hours. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2M aqueous hydrochloric acid (200 ml), dried (MgSO4), and concentrated to give the sub-title compound (4.05 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][NH:13][C:14]([C@H:16]1[CH2:21][N:20]([C:22]([NH:24]C(C)(C)C)=[O:23])[CH2:19][CH2:18][N:17]1[S:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](=[O:46])[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)(=[O:31])=[O:30])=[O:15])(C)(C)C>>[OH:12][NH:13][C:14]([C@H:16]1[CH2:21][N:20]([C:22]([NH2:24])=[O:23])[CH2:19][CH2:18][N:17]1[S:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](=[O:46])[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)(=[O:30])=[O:31])=[O:15]
Reactant: CC(C)(C)NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NOC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NO)C1
Reaction time: 36 h
Yield: 55 %

Procedure:
Trifluoroacetic acid (15 ml) was added to N-tert-butoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperadine-1-sulfonyl]piperazine-2-(R)-carboxamide (0.45 g, 0.92 mmol) [prepared as described in Step 2 above] and the reaction was stirred for 36 h. The reaction was concentrated in vacuo, and the residue was chromatographed (SiO2, PTLC, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-aminocarbonylpiperazine-2-(R)-carboxamide (55%) as a pale pink solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:23]1([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)[CH2:21][CH2:22]1
Reactant: N#CC(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC2CCN(CC3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (2.0 g), cyclopropyl carboxaldehyde (1.6 ml) and triethylamine (1.99 ml) were stirred in dichloromethane (70 ml) at room temperature. After 10 min sodium triacetoxyborohydride (3.1 g) was added and the reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated potassium carbonate solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine (50 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound (D9) (2.0 g).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:11]=1.ClCCl>O.Cl>[CH3:5][N:6]([N:1]=[O:3])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: O=N[O-]
Reactant: CNCCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(CCCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)N=O
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of sodium nitrite (7.2 g) in water (50 ml) was added slowly to a solution of N-methyl-3-[4-(trifluoromethyl)phenoxy]benzenepropanamine (30 g) and dichloromethane (100 ml) in 10% hydrochloric acid (200 ml). After one hr, the reaction mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (eluted with 50% hexanes-dichloromethane). The appropriate fractions were collected and evaporated to give 28 g (95.4%) of product, mp 75°-76° C. Recrystallization from hexanes gave the analytical sample, mp 76°-77° C.
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][C:8]([N:10]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])(C)(C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:10]([CH2:11][C:12]([F:13])([F:14])[F:15])[C:8](=[O:9])[CH:7]=[C:6]2[OH:23]
Reactant: CC(C)(C)OC(=O)CC(=O)N(CC(F)(F)F)c1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1cc(O)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Yield: 81.4 %

Procedure:
N-(4-Chlorophenyl)-N-(2,2,2-trifluoroethyl)malonamic acid t-butyl ester (2.86 g, 8.1 mmol) was dissolved in methane sulfonic acid (50 mL) under argon with stirring prior to treatment with phosphorus pentoxide (0.51 g). The mixture was heated to 100° C. for 25 minutes. Analysis by LC/MS indicated the reaction was complete and the solution was cooled in an ice bath before quenching with ice and deionized water. The product precipitated and was collected by filtration. The filter cake was washed with ice water followed by cold chloroform and dried on high vacuum to give the title compound (1.83 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.10 (2H, q, J=9.0 Hz), 5.97 (1H, s), 7.63 (2H, m), 7.79 (1H, m), 12.09 (1H, br s).
Reaction SMILES: S(Cl)([Cl:3])=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.Cl>C(O)C>[ClH:3].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[OH:2])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: N=C(O)c1ccc(Br)cc1

Procedure:
Compound [H], 4-bromobenzoic acid is chlorinated with thionyl chloride to yield compound [I], 4-bromobenzoic acid chloride. Compound [I] is reacted with aqueous ammonia to yield compound [J] 4-bromobenzoic acid amide. Compound [J] is dehydrated with thionyl chloride to yield compound [K], a 4-bromobenzonitrile. Compound [K] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [L], 4-bromobenzimidate hydrogen chloride. In ethanol, compound [L] is reacted with gaseous ammonia to yield compound [M], 4-bromobenzamidine hydrogen chloride.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:21]=[CH2:22])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:23][CH3:24])=O)(C)(C)C.Cl.[CH2:26](Cl)Cl>O1CCOCC1>[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:21]=[CH2:22])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:23][CH3:24])(=[O:5])[CH3:26]
Reactant: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(C)=O
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-vinyl-2-ethylbenzoxazole (30 mg, 0.091 mmol), in methylene chloride (1 mL) was treated with 4 M HCl in dioxane (1 mL) and stirred for 2 hours. The solvent was evaporated and the residue was taken up in pyridine (2 mL) and treated with acetic anhydride (100 μL). After stirring for 2 hours, the reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous copper (II) sulfate (2×5 mL). The organic layer was dried with magnesium sulfate and evaporated. The product was purified on a silica gel column and eluted with 25% EtOAc/hexanes to give a clear oil (16 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[Br:19].[CH2:20]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C([O-])(=O)C.[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=2)=[CH:4][C:3]=1[Br:19]
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(N)cc1
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCc1ccc(Nc2cc(Br)c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 24 h

Procedure:
A reactor was charged with 10 g of 1-amino-2,4-dibromoanthraquinone, 15 g of p-octadecyl-aniline, 20 g of pyridine, 0.2 g of copper acetate and 2.5 g of potassium acetate, and the reaction was effected at an elevated temperature of 115°-120° C. for 24 hours under stirring. A blue solid of 1-amino-2-bromo-4-p-octadecylanilinoanthraquinone was obtained by the reaction of the formula: ##STR9##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].OOS([O-])=O.[K+].[CH3:20][OH:21]>>[CH3:20][O:21][C:5](=[O:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([F:13])[F:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(OC(F)F)c(O)c1
Temperature: 52.5 °C
Yield: 70 %

Procedure:
100 g of 3-hydroxy-4-(difluoromethoxy)-benzaldehyde (0.53 mol) were dissolved in MeOH (600 ml), solid Oxone® (325 g, 1.06 mol) was added portion-wise in 1 hour and solution was stirred and warmed to 50-55° C. for 2 hours. The solvent was concentrated under vacuum to 200 ml and water (1 L) was added. The resulting heterogeneous solution was stirred at 50 to 55° C., then toluene (500 ml) was added, and the biphasic mixture vigorously stirred. Aqueous phase was discharged and the organic one was washed with water (500 ml). Active charcoal (10 g) was added and the organic solution stirred for 20 minutes. It was filtered on a celite pad, the solvent was concentrated under vacuum to 2 to 3 volumes, and the obtained solution was warmed to 80 to 90° C. n-Heptane (400 ml) was slowly added. The mixture was cooled to 0° C. and the suspension was stirred at 0° C. over-night. The solid was filtered on a Buchner funnel and washed with n-heptane (100 ml). The obtained white solid was dried under vacuum at room temperature. (yield 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:29].[Ca+2].[OH-:31]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:31])(=[O:29])[C:7]=2[CH:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
800 Mg. 3-cyano-10,11-dihydrodibenzo[b,f]thiepin is dissolved in 75 cc. methylene chloride and 1.73 g. m-chloroperbenzoic acid is added and the solution stirred at room temperature for three hours. An additional 10 cc. methylene chloride is added, followed by a large excess of powdered calcium hydroxide. After stirring for 5 minutes, the mixture is filtered through celite and the filtrate stripped to dryness and the residual solid triturated with ether and filtered to yield 854 mg. (94%) of the desired pure white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35](O)=[O:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)=[O:22])[CH:17]([C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:36])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Reactant: C1COCCN1
Product: O=C(C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1)N1CCOCC1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with morpholine to give 4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 60% yield, m.p. 235-237 ° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Cc1cc(OCc2ncccn2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(OCc2ncccn2)ccc1N
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine (0.18 g, 0.7 mmol) in ethanol (4.0 mL) and water (1.0 mL), iron (0.40 g, 7.2 mmol) and ammonium chloride (0.020 g, 0.37 mmol) were added. The mixture was refluxed for 1.5 h. Cooled to ambient temperature, the reaction mixture was filtered over Celite to remove unneeded materials and the filtrate was concentrated to afford 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.15 g, crude material) as solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl.O>[CH2:32]([O:31][C:29]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:30])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 605.1 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7 g, 24.3 mmol) in CH2Cl2 (40 mL) at rt was added saturated K2CO3 (30 mL), ethyl chloroformate (2.4 mL, 4.0 mmol) and stirred at 25° C. for 0.5 hour. The solution was diluted with water (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, and concentrated to afford tert-butyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (8.7 g, 100%) as an crude oil. MS [M+H]+ 360.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[C@@H:15]1[C@@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][C@H:16]1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]>C1(C)C=CC=CC=1.CO.N(C(C)(C)C#N)=NC(C)(C)C#N>[OH:21][C@@H:20]1[CH2:19][CH2:18][CH2:17][C@H:16]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@H](O)[C@H]1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Yield: 87.9 %

Procedure:
Tributyltin hydride (1.99 ml, 7.40 mmol) and 2,2′-azobis(isobutyronitrile) (8 mg) were added to a solution of 2-[(1R, 2S, 3S)-2-bromo-3-hydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (2.0 g, 6.17 mmol) in a mixture of toluene (40 ml) and methanol (4 ml) at room temperature, and the resulting mixture was refluxed for 3 hours. Tributyltin hydride (1.99 ml, 7.40 mmol) and 2,2′-azobis(isobutyronitrile) (8 mg) were further added thereto, and the resulting mixture was refluxed for 1 hour. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain cis-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.33 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH:18]=[CH2:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C>[C].[Pd].O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH2:18][CH3:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=Cc1cnc(Cl)c(-n2ncc(C(=O)OCC)c2C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2cc(CC)cnc2Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
Next, 1-(2-chloro-5-vinylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.902 g) was added to a mixed solvent of ethanol (10 ml) and 1,4-dioxane (8 ml), the atmosphere in the flask was substituted with nitrogen gas, 10% palladium-carbon (containing ca. 50% water; 0.20 g) was added and the mixture was stirred under hydrogen atmosphere at room temperature for three hours. The reaction mixture was filtered through Celite to remove palladium-carbon, the filtrate was concentrated and the residue was purified with column chromatography (n-hexane/ethyl acetate) to give 1-(2-chloro-5-ethylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.639 g).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH2:7][C:6](=[O:13])[CH:5]=1.OO.O>CO>[CH3:3][C:4]12[O:1][CH:5]1[C:6](=[O:13])[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]2=[O:10]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)C2OC2(C)C1=O
Reaction time: 3 h
Yield: 81.5 %

Procedure:
2 ml of a 6N aqueous solution of NaOH have been added during a period of 15 minutes at 15°C to a mixture of 3,5,5-trimethyl-cyclohex-2-en-1,4-dione (3.7 g) and hydrogen hydroperoxide (8.3 ml of a 30 % solution) in 27 ml of methanol. The mixture was kept under stirring during 3 hours at 20°-25°C, treated with water and extracted with ether. The combined organic extracts were washed with water until neutrality, dried over MgSO4 and evaporated. 3.33g (81.5 %) of the desired product, b.p. 40°C/0.001 Torr, were thus obtained. IR: 1715 cm-1 ; MS: M+ = 168; m/e: 56 NMR (CCl4) : 1.05 (3H,s); 1.25 (3H,s); 1.50 (3H,s); 2.08 (1H,d, J=13 cps); 3.09 (1H,d, J=13 cps); 3.47 (1H,s) δ ppm.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[N:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(c1cnc(-n2ccnc2)nc1)N(C1CCNCC1)C1CC1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-imidazol-1-yl-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.40 min; Mass spectrum (ESI+): m/z=419 [M+H]+.