Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16]C(C)=[N:14][C:13]=3[C:12](=[O:19])[N:11]3[CH2:20][C:21](C)(C)[N:22]=[C:10]23)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH2:16])=[C:13]([NH2:14])[C:12](=[O:19])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[CH:4][CH:3]=1
Reactant: Cc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1=NC(C)(C)CN1C2=O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(N)n(Cc2ccc(Cl)cc2)c2nccn2c1=O
Yield: 70 %

Procedure:
4-[(4-CHLOROPHENYL)METHYL]-6,7-DIHYDRO-2,6,6-TRIMETHYL-3H-IMIDAZO[1,2-a]PURIN-9(4H)-ONE.- The nitroso compound of Procedure 103 was catalytically hydrogenated to the diamino compound and then treated with acetic anhydride according to the method of Procedure 63. There resulted from this process the mono N-acetyl derivative of 8-[(4-chlorophenyl)methyl]-6,7-diaminoimidazo[1,2-a]pyrimidin-5-one, m.p. 155°-159° after recrystallization from isopropanol and drying under vacuum.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][CH2:13][OH:14].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CS(C)=O.C1(C)C=CC=CC=1>O>[C:15]([NH:19][C:7]1[C:2]([F:1])=[C:3]([CH2:12][CH2:13][OH:14])[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])c(CCO)c1F
Temperature: 25 °C
Yield: 1036.1 %

Procedure:
A mixture of 2-(2,3-difluoro-6-nitrophenyl)ethanol (6.00 g, 29.6 mmol), as prepared in the preceding step, tert-butylamine (18.6 mL, 1.77 mmol), DMSO (30 mL), and toluene (5 mL) was heated at reflux for 16 hours. After cooling to ambient temperature the brown solution was poured into H2O (300 mL), and the deposited yellow crystals were filtered and washed with H2O twice. The yellow solid was dissolved in CHCl3 (70 mL), dried over Na2SO4, concentrated, and crystallized from hexane to give the title compound (4.70 g, 62% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J=9.3, 1.5 Hz, 1H), 6.79 (t, J=8.7 Hz, 1H), 4.69 (br s, 1H), 3.96 (dd, J=11.4, 5.9 Hz, 2H), 3.32 (dt, J=6.5, 3.1 Hz, 2H), 1.75 (t, J=5.3 Hz, 1 H), 1.46 (s, 9H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:24])=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[C:15]1[C:14](=[C:23]3[C:18](=[C:17]([Cl:24])[CH:16]=1)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13][S:10]2(=[O:11])=[O:12]
Reactant: Nc1cc(F)c(Cl)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)c(Cl)cc21
Yield: 15.7 %

Procedure:
In the similar fashion using route 16 general procedure 61, 2-amino-5-chloro-N-(5-chloro-quinolin-8-yl)-4-fluoro-benzenesulfonamide (Intermediate 284) (150 mg, 0.38 mmol), t-butyl nitrite (0.07 ml, 0.58 mmol) and AcOH:THF (1.5 ml:1.5 ml) gave the title compound (22 mg, 16%) after purification by column chromatography with chloroform/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([N:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CC(=O)NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4,4-dimethylpiperidine-2,6-dione (2.0 g, 14.2 mmol) in acetone (50 mL) was added K2CO3 (3.92 g, 28.3 mmol) followed by (bromomethyl)benzene (1.85 mL, 15.6 mmol). The reaction mixture was heated at 50° C. for 4 h then cooled to room temperature and stirred overnight. The thick white precipitate present was removed via filtration, rinsing with acetone. The filtrate was concentrated and purified by SiO2 chromatography (10% to 50% EtOAc/hexanes) to afford 3.0 g (92%) of 1-benzyl-4,4-dimethylpiperidine-2,6-dione as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH2:14]([Mg]Br)[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:14][CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A cold (0° C.) solution of 3-bromo-N-methoxy-N-methylbenzamide (3 g, 12.3 mmol) in THF was treated with propylmagnesium bromide (6.15 mL, 12.3 mmol), stirred at room temperature for 1 hour, quenched with aqueous NH4Cl, acidified with HCl (2N) and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated under vacuum. Purification of the resultant residue on silica gel (Biotage) using hexanes/EtOAc (20/1) as the eluting solvents gave 1-(3-bromophenyl)butan-1-one as a tan solid (2.1 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(Cl)cc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(Cl)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 78 mg (0.276 mmol) of the compound of Example 33A gave 101 mg (66% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1>>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: OCCN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(CCO)CC4)sc3n2)cn1

Procedure:
2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol (175 mg) was utilized in a Suzuki coupling with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine according to General Procedure Suzuki to provide 385 (20 mg) after reverse phase HPLC purification. MS (Q1) 457 (M)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([CH:16]=[O:17])[C:3]=1[Cl:18].Cl([O-])=[O:20].[Na+].CC(=CC)C.P([O-])([O-])(O)=O.[Na+].[Na+].Cl>C(O)(C)(C)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([OH:20])=[O:17])[C:3]=1[Cl:18]
Reactant: [O-][Cl+][O-]
Reactant: Nc1c(F)c(-c2ccc(Cl)cc2)nc(C=O)c1Cl
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Temperature: 80 °C

Procedure:
In a typical reaction, 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde is oxidized with an excess of sodium chlorite, between 20-30 equivalents of 2-methyl-2-butene and about 5 equivalents of disodium hydrogen phosphate in a t-butyl alcohol/water mixture. The mixture is heated at about 80° C. until the reaction is complete. After cooling, the mixture is treated with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is separated and dried. The solvent is evaporated to provide crude 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=1[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:2][C:1]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1ccccc1NCc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2n1Cc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 2-acetylamino-N-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]aniline (500 mg), p-toluenesulfonic acid (50 mg) and toluene (50 ml) was heated under reflux while removing the by-produced water therefrom through a Dean-Stark trap. After the by-production of water ceased, the reaction mixture was cooled to room temperature, washed with a saturated sodium carbonate solution and water in order and distilled under reduced pressure to eliminate toluene. The residue was purified by silica gel column chromatography to give 2-methyl-1-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]benzimidazole (433 mg) as a colorless oil. nD25.0 1.5670.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C(Cl)Cl.F[B-](F)(F)F.C([O+](CC)CC)C.Cl.[NH2:38][OH:39]>CO.C(N(CC)CC)C>[OH:39][N:38]=[C:5]1[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:15])[C:2]([CH3:1])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1
Reactant: NO
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(c2ccccc2)SC(=NO)N(Nc2ccccc2)C1=O
Yield: 70.2 %

Procedure:
5-Methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (0.3 g) was added to a 1M methylene chloride solution of triethyloxonium tetrafluoroborate (1 ml) at room temperature with stirring. After stirring the mixture for 24 hrs hydroxylamine hydrochloride (0.1 g) and triethylamine (0.3 g) in methanol (10 ml) were added at 0° C. The reaction mixture was again stirred for 2 hrs at room temperature followed by evaporation of the solvents under reduced pressure. The residue was added to ice water and then extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous ethyl acetate and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate-n-hexane, ½) to yield 2-hydroxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidine-4-one (0.21 g) having a melting point of 62-63° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3([N:24]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:12]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CCO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3([N:24]4[CH2:25][CH2:26][N:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:28][CH2:29]4)[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCC(c2cccc(NC(=O)N3CCC(=O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CCC(c2cccc(NC(=O)N3CCC(O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(oxo)-N-[3-[4-methyl-1-(4-phenyl-1-pipera-zinyl)cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) (34 mg, 0.072 mmol) in anhydrous EtOH was treated with excess NaBH4 (14 mg, 0.36 mmol) and the resulting solution was stirred at room temperature for 1 h. The reaction was quenched with excess saturated NH4Cl (aq.) then extracted with EtOAc (3×). The combined extracts were dried (Na2SO4), concentrated under reduced pressure, and triturated with 30% EtOAc/hexanes to give 4-(hydroxy)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)-cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer), as a white powder. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a white solid which was washed with EtOAc. mp=144-145° C.
Reaction SMILES: CI.[NH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=S.[ClH:27]>C(O)C.C(OCC)(=O)C.C(OCC)C>[ClH:27].[NH:10]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH:3][C:11]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H]1CCCC[C@H]1NC(=S)Nc1ccccc1Oc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc(Oc2ccccc2N=C2N[C@@H]3CCCC[C@H]3N2)cc1
Reaction time: 8 h

Procedure:
3.4 g of methyl iodide were added to a solution of 1.03 g of N-(trans-2-aminocyclohexyl)-N′-(2-phenoxyphenyl)thiourea in 30 ml of ethanol, and the reaction mixture was kept at reflux for 5 hours. The mixture was allowed to stand overnight and the solvent was then distilled off and the residue was treated with water and subsequently made alkaline using saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the organic extraction phase was evaporated, and the oily residue was then chromatographed on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol and 1 part of concentrated aqueous ammonia solution. This gave an oily product which was dissolved in ethyl acetate and acidified using a saturated solution of HCl gas in diethyl ether. The solvent was distilled off and the residue was then dissolved in water and subjected to freeze-drying. This gave 0.49 g of a solid of m.p. 110° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(O)(=O)C.C(#N)C.C(Cl)Cl>[Br:11][C:7]1[S:6][C:5]([NH2:8])=[N:4][C:3]=1[C:2]([F:10])([F:9])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(C(F)(F)F)cs1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(C(F)(F)F)c(Br)s1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-trifluoromethyl-thiazole-2-ylamine (0.2 g; 1.2 mmol) in acetic acid (0.14 mL) and acetonitrile (1.4 mL) at 0° C. was added N-bromosuccinimide (0.23 g, 1.3 mmol). The reaction mixture was warmed to room temperature over 17 h. The reaction was diluted with methylene chloride, washed with saturated NaHCO3, dried, filtered and concentrated under vacuum to give the crude product. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 20% to give the product.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[CH:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
A mixture of racemic trans-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (2.96 g, 11.29 mmol) (Method 195) and triphenylphosphine (3.11 g, 11.85 mmol) in THF (25 mL) was stirred at rt for 7 h. Water (2 mL, 111 mmol) was then added and the mixture then stirred at 50° C. overnight. The mixture was then concentrated under reduced pressure, and the residue was purified via silica gel chromatography (100% DCM to 37:3:60/methanol:Et3N:DCM) to yield the title compound (2.96 g, 11.29 mmol) as an oil. 1H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.38-7.19 (m, 5 H), 5.02 (s, 2 H), 3.89 (brs, 1 H), 3.62 (dd, 2 H), 3.29-3.15 (m, 2 H), 3.12-3.01 (m, 1 H); m/z 236.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CCNCC1.C([O-])(C)(C)C.[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: OC1CCNCC1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard fashion starting, from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO−K+ in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant:heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH:24]([OH:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][OH:26])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: CC(O)Br
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCO)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2) was alkylated with bromoethanol/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-[4-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide as a colorless oil. MS 363.1 ([M+Na]+)
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2.O.C(OCC)(=O)C.[CH3:37][N:38](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:37]([C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:18][CH2:19]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2)#[N:38]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3c(Br)ccc4cccc2c34)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2cccc3c2c1CC3N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[1-(3-Bromoacenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (1.25 g) was dissolved in N,N-dimethylformamide (16 ml), zinc cyanide (380 mg) and tetrakistriphenylphosphinepalladium (1.6 g) were added, and the mixture was stirred at 110° C. for 1 hr. After allowing to cool, water and ethyl acetate were poured into the reaction mixture, and the mixture was subjected to celite filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from acetone to give the title compound (1.0 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([NH2:25])[C:7]2[C:12]([CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[CH:11][O:10][C:8]=2[N:9]=1>CO.CS(C)=O>[NH2:3][C:4]1[N:5]=[C:6]([NH2:25])[C:7]2[C:12]([CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:11][O:10][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc(CCc2coc3nc(N)nc(N)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc(N)c2c(CCc3ccc(C(=O)O)cc3)coc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
About 1.5 ml of 1N sodium hydroxide was added to a solution containing about 0.065 g of Compound 28 in about 10 ml of a mixture of 2:1 methanol/DMSO. The mixture was stirred at room temperature for 18 hours and evaporated to dryness under reduced pressure (oil pump). The residue was dissolved in about 5 ml water and 1N HCl was added dropwise to bring the pH of the solution to 5.5. The suspension was cooled to 5° C. for about 12 hours and filtered. The residue was washed sequentially with water, acetone and ether and dried to yield about 0.05 g of Compound 30.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([CH2:15][NH2:16])=[O:14])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)C.C(NCC)C>[NH:16]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C:13]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCNCC
Solvent: CC(C)O
Solvent: O
Product: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 64.6 %

Procedure:
Production of compound (22) was conducted in substantially the same manner as in step 1 of Example 6. That is, Gly-Phe (manufactured and sold by PEPTIDE INSTITUTE INC., Japan, 1.1 g, 5 mmol) was dissolved in a mixture of 2 ml of H2O, 2 ml of 2-propanol and 1.5 ml of diethylamine, to obtain a solution. To the obtained solution was portionwise added trityl chloride (1.8 g, 6.5 mmol), followed by stirring for one hour. To the resultant reaction mixture was added H2O, to thereby generate a precipitate. The generated precipitate was collected, washed with water and then dissolved into 5 ml of acetic acid, to thereby obtain an acidic solution. The obtained acidic solution was evaporated to dryness under reduced pressure, to thereby obtain 1.5 g of Trt-Gly-Phe.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12](O)=[O:13])[O:3]1)=[O:2].CSC.B>C1COCC1>[C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][OH:13])[O:3]1)=[O:2]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=C1OC(CCO)c2ccccc21
Reaction time: 24 h

Procedure:
A solution of phthalide-3-acetic acid (1 mmole) in THF was treated with borane dimethylsulfide (1.5 mmole) at 0° C. for 1 h, and at 25° C. for 24 h. Extraction and chromatography gave 2-(3-phthalidyl)ethanol as a light yellow oil: Rf=0.25, 50% EtOAc-hexane.