Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:23][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:4].[Li+].[OH-]>C1COCC1>[C:26]([CH2:25][O:24][C:6]1[C:7]2[S:15][C:14]3[CH:13]=[C:12]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:11]=[CH:10][C:9]=3[C:8]=2[S:23][C:5]=1[C:3]([OH:4])=[O:2])([OH:28])=[O:27]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(NC3CCCCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1cc(NC3CCCCC3)ccc12
Reaction time: 8 h

Procedure:
To a solution of 6-cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (23 mg, 0.05 mmol) in THF/H20 was added 2.OM aq. LiOH solution (0.125 mL, 0.25 mmol) at room temperature. After stirring at this tempterature overnight, the reaction mixture was concentrated, and acidified with 10% HCl. The product was collected by filtration and washed with water as a white solid (13.2 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])([CH2:7][OH:8])[C:4](=[O:17])[O:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])([CH2:7][O:8][S:20]([CH3:19])(=[O:22])=[O:21])[C:4](=[O:17])[O:3]1
Reactant: CC1(C)OC(=O)C(CO)(c2ccc(Cl)cc2Cl)O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(COS(C)(=O)=O)(c2ccc(Cl)cc2Cl)O1
Temperature: 0 °C

Procedure:
63.5 g (0.22 mole) of 2,2-dimethyl-4-(2,4-dichlorophenyl)-4-hydroxymethyl-1,3-dioxolan-5-one are dissolved in 400 ml of pyridine and to this solution are added 28.9 g of methanesulfonyl chloride at 0° to 5° C. The resultant suspension is stirred for 2 hours at the same temperature, then poured into ice-water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. The residual resin is crystallised by addition of a small amount of diethyl ether/hexane and the product is isolated by filtration. Melting point: 98°-100° C.
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[CH3:22])=[O:8]>C1COCC1>[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]1[CH3:22])(=[O:8])[CH3:1]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
3.0 M methylmagnesium chloride in THF (4.50 mL, 13.5 mmol) was added dropwise to a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylpiperidine-1-carboxylate (3.10 g, 10.8 mmol) in THF (50 mL) at 0° C. The reaction was warmed to ambient temperature and stirred for 90 minutes. The reaction was partitioned between ether and 2N HCl, washed the organic layer twice with water, brine, dried, and concentrated to afford the title compound (2.32 g, 84.3% yield) as clear oil.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Cl[C@:11]1(CO)[O:16][C:14]([C:17](=[O:19])C)(O)[C@:13](C(=O)C)([OH:20])[C@:12]1(C(=O)C)[OH:24].CO.N>C(Cl)(Cl)Cl>[CH:9]1[C:8]2[N:7]=[CH:6][N:5]([C@@H:11]3[O:16][C@H:14]([CH2:17][OH:19])[C@@H:13]([OH:20])[C@H:12]3[OH:24])[C:4]=2[N:3]=[CH:2][N:1]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: CC(=O)C1(O)O[C@](Cl)(CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)[C@H](O)[C@@H]1O

Procedure:
Nebularine was prepared by the use of the thallous salt of purine in the procedure of Brown et al., J. Biol. Chem. 204, 1019 (1953), in place of the chloromercuri salt used therein. The thallous salt of purine is condensed with chlorotriacetylribofuranose and the resulting acetyl derivative hydrolyzed to the product with methanol-ammonia. Other experimental conditions were identical. Crystalline nebularine was obtained after chromatography of the crude product on silica-gel with chloroform.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.C([O:19][CH2:20][C@@H:21]([OH:26])[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:26][C@@H:21]([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:19]
Reactant: O[C@H](COCc1ccccc1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: Nc1ccc(F)cc1O[C@H](CO)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-3-benzyloxy-1,1,1-trifluoro-propan-2-ol.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)(=[O:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.Cl>[NH2:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCNc2nc(Cl)ncc2Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 17 h

Procedure:
A solution of 1.35 g (2.99 mmol) of N-[3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-3-nitro-benzenesulfonamide in 100 ml of tetrahydrofuran is mixed under argon at room temperature with 15 ml of a 15% solution of Ti(III)Cl in about 10% hydrochloric acid. After 17 hours, the reaction solution is mixed again with 1 ml of the Ti(III)Cl solution and stirred for another 3 hours. The batch is made basic with 1N NaOH solution and then filtered. The filter cake is rewashed 2× with 100 ml of ethyl acetate/MeOH (30 ml/20 ml) in each case. The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (dichloromethane/MeOH 95:5, Flashmaster II). 624 mg (1.48 mmol, corresponding to 49% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:32][CH:31]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown sticky solid (90%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:20]([CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:20]([OH:21])[CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[CH:27][N:28]([Si:30]([CH3:31])([CH3:32])[CH3:33])[CH:29]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)n1cnc(CCCC=O)c1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCCc2cn([Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.95 g of p-(tert-butylaminocarbonyl)-bromobenzene is dissolved in 175 ml of tetrahydrofuran at -70° under nitrogen and 20.1 ml of a solution of n-butyllithium (2.7M) in hexane is added dropwise. After reacting 30 min, a solution of 5.69 g of 4-(3-formyl-n-propyl)-1-trimethylsilylimidazole in 10 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm slowly to room temperature and 20 ml of ammonium chloride is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound (b).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1>C(Cl)Cl>[F:83][C:81]1[CH:82]=[C:77]([CH:78]=[C:79]([F:84])[CH:80]=1)[CH2:76][C@H:62]([NH:61][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:25][CH2:26][CH3:27])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccn2COCC)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccn2COCC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-[1-(ethoxymethyl)-1H-imidazol-2-yl]benzoic acid (177 mg, 0.47 mmol), diisopropylethylamine (651 mg, 0.5 mmol), and HBTU (209 mg, 0.55 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (196 mg, 0.48 mmol) and diisopropylethylamine (130 mg, 1.0 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound. APCI MS m/z 690.3 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].C(O)C.O.[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30](S)[C:29]=3[CH:36]=[CH:37][CH:38]=2>C(O)C>[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:29]=3[CH:36]=[CH:37][CH:38]=2
Reactant: NCCCCCCCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCCCCCCCn1ccnc1)=N2
Yield: 70 %

Procedure:
A mixture of 2.8 g of 10-(1H-imidazol-1-yl)decanamine, dihydrochloride was treated with 2 ml of 10N sodium hydroxide in an ethanol-water mixture giving the base derivative. To this base was added 25 ml of ethanol, 2.33 g of 6-bromo-benz[cd]indole-2-thiol and 3 g of mercuric acetate. The procedure of Example 1 was then followed, giving 2.8 g of the desired product, mp 115°-116° C.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO[C:11](=N)[C:12]([Cl:15])([Cl:14])[Cl:13].C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[C:11]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1

Procedure:
To a solution of 10 g Benzene-1,2-diamine in 250 mL acetic acid, 22.8 g 2,2,2-Trichloro-acetimidic acid methyl ester were added drop wise at RT. After 2 h 500 mL toluene were added and the solvents were removed under reduced pressure. The residue was codestilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step.
Reaction SMILES: [Li]CCCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.CN1CCCN(C)C1=O.[CH3:22][O:23][C:24]([CH:26]1[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33][C:28]2([O:32][CH2:31][CH2:30][O:29]2)[CH2:27]1)=[O:25].C(Br)C=C>C1COCC1.CCCCCC>[CH3:39][O:38][C:36]([C:34]1([CH2:12][CH:10]=[CH2:11])[CH2:35][CH:26]([C:24]([O:23][CH3:22])=[O:25])[CH2:27][C:28]2([O:29][CH2:30][CH2:31][O:32]2)[CH2:33]1)=[O:37]
Reactant: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Product: C=CCC1(C(=O)OC)CC(C(=O)OC)CC2(C1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A 1.6 M hexane solution of n-BuLi (101 mL, 161 mmol) was added to the stirred anhydrous THF (300 mL) at −78° C., followed by diisopropylamine (16.2 g, 161 mmol). The reaction mixture was stirred at −78° C. for 15 min and at 0° C. for 1 h. The mixture was re-cooled to −78° C., 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPO) (48 g, 372 mmol) was added slowly, and the resultant white suspension was stirred for 30 min. A solution of 1,4-dioxaspiro[4.5]decane-7,9-dicarboxylic acid dimethyl ester (32 g, 124 mmol) in THF (100 mL) was added, the light yellowish solution was stirred for 30 min, then allyl bromide (16.6 g, 137 mmol) was added, the reaction mixture was allowed to warm to room temperature and left stirring at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate; the organic extracts were combined and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 40 g of crude product as viscous oil. Purification by flash column chromatography on silica gel (hexane-chloroform-ethyl acetate 8:1:1) gave 23.8 g (65%) of the title compound, 1-allyl-5,5-difluoro-cyclohexane-1,3-dicarboxylic acid dimethyl ester as colorless oil. 1H NMR (400 MHz, CDCl3), δ: 5.7-5.6 (m, 1H), 5.10-5.00 (m, 2H), 4.0-3.8 (m, 4H), 3.68 (s, 6H), 3.08-2.98 (m, 1H), 2.5-2.3 (m, 2H), 2.15-2.08 (m, 1H), 1.98-1.92 (m, 1H), 1.65-1.58 (m, 1H), 1.45-1.38 (m, 1H), 1.28-1.18 (m, 1H). ES MS: 299.2 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:12]1([C:15]([NH2:17])=[O:16])[CH2:14][CH2:13]1>>[CH:12]1([C:15]([NH:17][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: NC(=O)C1CC1
Reactant: COC(=O)c1ccnc(Cl)n1
Product: COC(=O)c1ccnc(NC(=O)C2CC2)n1

Procedure:
The title compound is prepared in quantitative yield (1.93 g, a pale yellow solid) from methyl 2-chloropyrimidine-4-carboxylate (1.50 g, 8.69 mmol) and cyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.CN(C(ON1N=N[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C(O)CCCCC>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:64][CH2:65][CH2:60][CH2:61][CH2:62][CH3:63])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Agent: F[B-](F)(F)F
Solvent: CCCCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMF was stirred for 1 h at RT. Then 29 μL (0.23 mmol) 1-hexanol were added and the reaction mixture was stirred for 4 days at RT. The mixture was evaporated down i.vac., the residue was taken up in 30 mL EtOAc, the organic phase was washed with 20 mL 5% NaHCO3 solution and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, gradient DCM/isopropanol 95:5 to DCM/isopropanol 90:10). The fractions containing the product were concentrated by evaporation i. vac., the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:24][N:23](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:22][NH:23][CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CNC2)CC1
Reaction time: 48 h
Yield: 76 %

Procedure:
4-[2-(1-Benzhydryl-azetidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (750 mg, 1.5 mmol) and ammonium formate (1.8 g, 30 mmol) were dissolved into methanol (50 mL) at r.t. The solution was added slowly to 10% palladium on carbon (750 mg) in methanol (20 mL) under nitrogen atmosphere. The mixture was stirred for about 48 hours and filtered through a bed of celite. The solvent was removed under reduced pressure to afford the title compound as a colorless oil (380 mg, 60%).
Reaction SMILES: [C:1]([N:20]1[C:24](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[N:23][CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[C].[Pd]>[C:1]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][OH:28])=[N:23][CH:22]=[N:21]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC/C=C/c1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: OCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A stirred solution of E-3(1-trityl-1,2,4-triazol-5-yl)prop-2-en-1-ol (9.5 g, prepared as described in Example 9) in dichloromethane (100 ml) was hydrogenated over 5% palladium-carbon (50 mg) at room temperature and pressure for four hours. The mixture was filtered through Hyflo Super-Cel, evaporated under reduced pressure and chromatographed, using ethyl acetate-hexane (4:1), then ethyl acetate, as eluants, to give 3(1-trityl-1,2,4-triazol-5-yl)propanol (7.1 g, m.p. 150-152° C.). NMR (CDCl3): δ 1.4(2H,m), 2.2(2H,t), 3.45(2H,t), 7.1-7.3(15H,m), 7.9(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cc(F)cc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cc(F)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-chlorophenyl)-2-(6-fluoro-4-(methylsulfonamido)-1H-indol-1-yl)butanoate (0.5 g, 1.14 mmol) in THF (5 mL) was added dropwise lithium aluminum hydride solution (1.4 mL, 1 M in THF) at −78° C. The reaction mixture was stirred for 0.5 hours at −78° C. TLC and LCMS monitored the reaction was over, then 3M HCl solution was added carefully into the reaction to adjust pH=2˜3 in ice bath. The organic layer was separated and the aqueous layer was extracted with EA. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=2:1) to afford the title compound. LC/MS m/z=411.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+].[CH3:12][NH2:13]>CO>[CH3:12][N:13]1[CH:5]2[CH2:4][CH2:3][CH:2]1[C:1]([C:8]#[N:9])=[CH:7][CH2:6]2
Reactant: CN
Reactant: N#CC1C=CC=CC=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C2CC=C(C#N)C1CC2
Temperature: 125 °C
Yield: 70 %

Procedure:
In 2 ml of methanol was dissolved 0.5 g (4.27 mmol) of 2,4,6-cycloheptatriene-1-carbonitrile (4: CHT-CN). A solution of 171 mg (4.27 mmol) of sodium hydroxide in 5 ml of methanol and then 3 ml (about 38 mmol) of 40% methanolic solution of methylamine were added thereto, and the resulting mixture was stirred with heating at 125° C. for 10 hours in a sealed vessel. After standing at room temperature, the methanol was evaporated and the residue was adjusted to pH 2 with 1N sulfuric acid solution, followed by extraction with chloroform (No. of run: 1) or ether (No. of run: 2 to 5) (separation into an organic layer 1 and an aqueous layer 1). The aqueous layer 1 was neutralized with 4N sodium hydroxide solution, followed by extraction with chloroform (No. of run: 1) or ether (No. of run: 2 to 5) (separation into an organic layer 2 and an aqueous layer 2). The organic layer 2 was dried and then the solvent was evaporated therefrom to obtain 0.458 g of a brown oil (1RS)-AECG-CN (yield: 70%).