Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.Cl>C1(C)C=CC=CC=1.O.C(OCC)C>[CH:20]1([CH2:19][C@@H:2]([NH2:1])[CH2:3][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:7][CH2:6]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)CC2CCCCC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
The above-described desired (R)-2-amino-3-cyclohexyl-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-1-one (0.83 g, 2.25 mmol) was dissolved in 20 ml of dry toluene and placed in a flame-dried flask under a nitrogen atmosphere. The mixture was heated to reflux and a solution of 0.45 mL of 10M borane-dimethylsulfide complex in 15 mL of dry toluene was added dropwise over ten minutes as reflux was maintained. After complete addition, the reaction mixture was refluxed an additional two hours. The reaction was then cooled to room temperature and 30 mL of 1N aq. HCl was added and the mixture stirred for one hour. Stirring was halted, the mixture was diluted with 20 mL of water and 20 mL of diethyl ether, and the layers were separated. The aqueous layer was washed with an additional 30 mL portion of diethyl ether and then made basic by addition of 50% aq. sodium hydroxide solution. The basic aqueous mixture was then extracted with three 50 mL portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine (0.74 g, 93% yield) as a yellow oil, which was pure enough to use in subsequent experiments; MS (+) ESI m/z=(M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccccc3)C3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-3-benzyl-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step B (110 mg, 0.24 mmol) in acetonitrile (1.5 mL) was added dropwise a solution of ammonium cerium (IV) nitrate (395 mg, 0.72 mmol) in H2O (1 mL). After 3 h at ambient temperature, the precipitate was isolated by filtration and dried in vacuo to afford the title compound. MS: m/z=338 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][CH2:31][CH2:32]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:30][CH2:31][CH2:32][O:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: Oc1cccc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCOc1cccc2nc[nH]c12
Temperature: 23 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
To a solution of 4-hydroxybenzimidazole (3.1 g, 32.4 mmol), triphenylphosphine (12.75 g, 48.6 mmol) and 2-chloroethanol (5.2 g, 64.8 mmol) in tetrahydrofuran (75 mL) at 0-5° C. was added over 30 min a solution of diethyl azodicarboxylate (8.5 g, 48.7 mmol) in tetrahydrofuran (75 mL). The mixture was warmed to 23° C. and stirred for 48 hr. The solvent was removed under vacuum to give a dark brown oil. Purification by chromatography (silica gel, ethyl acetate-1% 2M NH3 in methanol) afforded 2.9 g (63.8%) of a solid residue that was crystallized from ethyl acetate to give the title compound as a white solid, mp 153-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 906.3 %

Procedure:
To 4.6 g (3.03 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 30 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 4.0 mL (33 mmol) of benzenesulfonyl chloride. After stirring at room temperature for 1 hr the reaction mixture was quenched with water (100 mL). The suspension was dissolved in ethyl acetate/ether combination. The organic phase was washed sequentially with 2N HCl and then sodium bicarbonate. The organic phase was dried (MgSO4), and concentrated and triturated from ethyl acetate/hexane ether to give 8.0 g (90%) of the title compound as a colorless solid: NMR (DMSO-d6 ; 300 MHz) δ 10.58 (s, 1H), 7.75-7.84 (m, 3H), 7.52-7.72 (m, 4H), 7.35-7.45 (m, 2H), and 3.82 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[C:20](#[N:24])[CH2:21][C:22]#[N:23].C([O-])(=O)C.[Na+]>O.Cl.C(O)(C)(C)C>[CH3:14][CH:13]1[S:12][C:11](=[O:15])[NH:10][N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][N:16]=[C:21]([C:20]#[N:24])[C:22]#[N:23])=[CH:7][CH:6]=1
Reactant: N#CCC#N
Reactant: O=N[O-]
Reactant: CC1SC(=O)NN=C1c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1SC(=O)NN=C1c1ccc(NN=C(C#N)C#N)cc1
Temperature: 0 °C
Yield: 95 %

Procedure:
(+) 5-(4-aminophenyl)-6-methyl-3,6-dihydro-[1,3,4]-thiadiazin-2-one (1.34 g, 6 mmol) was dissolved in water (23 ml) and 6 N hydrochloric acid (4.5 ml). The solution was stirred and cooled. A cooled solution of sodiumnitrite (0.5 g) in water (5 ml) was added. Then a cooled solution of malononitrile (0.9 g) in t-butanol (54 ml) was added. In the end to the solution was added a cooled solution of sodium acetate (5.4 g) diluted in water (40 ml). The reaction mixture was stirred under cooling (0° C.) for 3 hours. After stirring the crystalline product was filtered and washed with water, yielding (+)-[[4-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)phenyl]hydrazono]propanedinitrile as a crystalline solid (1.7 g) with optical purity of 100%, chromatografic purity 99.3%, m.p. 125-128° C., [a]D25=+1002°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C@@H:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([OH:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OC(C)C)(=O)C.C1COCC1.ClC1C(O)=C(C=C(Cl)C=1)C=O>[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([O-:33])=[O:32])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[CH3:17][C@H:5]1[N:4]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:3](=[O:23])[C@@H:2]([NH3+:1])[CH2:7][C@H:6]1[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[F:16]
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)CC(N)C(=O)N1CC(F)(F)F
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H]([NH3+])C(=O)N1CC(F)(F)F
Product: O=C([O-])C(c1ccccc1)c1ccccc1
Temperature: 57.5 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a mixture of crude material containing (5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one (24, 2.00 g, 5.88 mmol), prepared according to the same method as the previous example, and 3,5-dichloro-2-hydroxybenzaldehyde (0.011 g, 0.059 mmol) in isopropyl acetate (15.0 ml) at 55-60° C. under nitrogen was slowly added a solution of diphenylacetic acid (1.26 g, 5.88 mmol) in THF (10.0 ml) over 2 h. Upon completion of acid addition, a thick salt suspension was agitated at 55-60° C. for another 18 h and then was allowed to cool to ambient temperature. The salt was filtered and washed with isopropyl acetate. After drying at 60° C. in a vacuum oven with nitrogen purge for 8 hours, 25 (2.97 g, 91.4%) was obtained as crystals. 1H NMR (500 MHz, DMSO-d6): δ 7.48 (qd, J=9.4, 4.9 Hz, 1H), 7.32 (d, J=7.7 Hz, 4H), 7.25-7.26 (m, 4H), 7.19-7.17 (m, 3H), 6.79 (br, 3H), 4.95 (s, 1H), 4.67 (dq, J=15.3, 9.7 Hz, 1H), 3.81-3.79 (m, 3H), 3.62 (dd, J=11.6, 6.5 Hz, 1H), 2.66-2.62 (m, 1H), 2.25 (dd, J=12.9, 6.4 Hz, 1H), 1.11 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 174.4, 171.8, 156.9 (ddd, J=244, 7.0, 2.5 Hz), 149.1 (ddd, J=249, 14.4, 8.5 Hz), 147.2 (ddd, J=246, 13.9, 3.2 Hz), 141.4, 129.0, 128.5, 126.7, 125.5 (q, J=281 Hz), 118.0 (dd, J=19.8, 13.8 Hz), 117.1 (dd, J=19.2, 10.6 Hz), 112.3 (ddd, J=26.1, 6.7, 3.3 Hz), 58.5, 57.1, 51.7, 44.8 (q, J=32.7 Hz), 35.3, 27.5 (br t, J=4.6 Hz), 14.5.
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[N:36]([CH2:37][C:38](O)=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:27][CH:26]=1)#[N:24].C(N(CC)C(C)C)(C)C.N>CN(C)C=O>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[N:36]([CH2:37][C:38]([NH2:7])=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:51])[F:50])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (43 mg, 0.13 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 60 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 μL, 0.29 mmol) in N,N-dimethylformamide (0.5 mL). After 20 min aqueous ammonia (32%, 8 μL, 0.13 mmol) added and the mixture is stirred at room temperature for 1 h. The mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 36 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 0.50 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]1)=[O:17]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2Cl)CC1
Yield: 83.6 %

Procedure:
In a manner similar to the procedure described in Example B except that a one liter three-necked Morton flask was used, 39.0 grams (0.14 mol) of ethyl 3-[(2,4-dichlorophenyl)amino]-3-oxopropanoate, 53.9 grams (0.39 mol) of anhydrous potassium carbonate, 125 milliliters of anhydrous dimethylformamide and 13.4 milliliters (0.16 mol) of 1,2-dibromoethane were reacted for a period of 65 hours to give 35.3 grams (0.117 mol) of ethyl 1-(2,4-dichlorophenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 95.0° C.-96.0° C. The total yield was 83 percent. NMR analysis of the product indicated the following:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CO[C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl>C1COCC1>[O:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:5]([C:16]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccncc1
Reactant: COc1cccc([Mg]Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
4-Methoxypyridine (1-1, 0.7 g, 6.4 mmol) in anhydrous THF at −20° C. was treated with 3-methoxyphenyl magnesium bromide (14.1 mL, 7.0 mmol) and benzyl chloroformate (1.09 g, 6.4 mmol) and stirred 4 h at −20° C. The reaction was poured into 1N HCl and stirred 10 min. The reaction mixture was extracted with Et2O (50 mL), washed with brine and dried over MgSO4. The organic extracts were filtered, concentrated under reduced pressure and purified viaflash column chromatography (SiO2, 0-50% EtOAc-hexanes gradient) to give benzyl 4-oxo-2-phenyl-3,4-dihydropyridine-1(2H)-carboxylate (1-2). MS 338.1 found 338.4 (M+H+) required.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:23])[CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:23])[CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:26]
Reactant: CNC
Reactant: C=O
Reactant: O=C(COc1ccc2ccccc2c1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)COc1ccc3ccccc3c1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.200 g (0.651 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2-(2-naphthoxy)ethan-1-one in 20 ml of acetic acid, 0.088 ml (0.98 mmol) of 50% aqueous dimethylamine and 0.079 ml (0.98 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/methanol=9/1 to 6/1) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[C:12]([O:11][C:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#Cc1cccc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cccc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine (0.24 g, 0.46 mmol), iodobenzene (95 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium (II) (35 mg, 0.05 mmol), copper (I) iodide (26 mg, 0.14 mmol), triethylamine (0.57 ml, 4.1 mmol) and anhydrous dimethylformamide (8 ml) was stirred at ambient temperature under nitrogen for 18 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (3 lots of 50 ml) and water (20 ml). The combined organic layers were washed with brine (50 ml), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-phenylethynyl-benzoyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.23 g). 1H NMR (CDCl3, 500 MHz): δ 7.58 (m, 4H), 7.40 (m, 5H), 7.25 (m, (m, 1H), 7.10 (m, 3H), 4.90 (br m, 1H), 4.79 (s, 2H), 3.80 (br m, 1H), 3.15 (br m, 1H), 2.84 (br, m, 1H), 2.78 (br m, 1H), 1.95 (m, 1H), 1.80 (m, 3H), 1.42 (s, 18H). MS(EI): 617(M++Na).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[Br:51][C:52]1[CH:53]=[C:54]([NH2:59])[C:55]([NH2:58])=[CH:56][CH:57]=1.C(O)(=O)C>O1CCCC1>[Br:51][C:52]1[CH:57]=[CH:56][C:55]2[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:59][C:54]=2[CH:53]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(Br)ccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (1.05 g, 2.21 mmol) in anhydrous tetrahydrofuran (4 mL) cooled in an ice water bath was added 4-methylmorpholine (0.365 mL, 3.32 mmol) and isobutyl chloroformate (0.316 mL, 2.43 mmol). The reaction mixture was stirred for 1 hour at 0° C. and then 4-bromo-1,2-benzenediamine (414 mg, 2.21 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours and then stirred an additional 2 hours. The reaction mixture was concentrated in vacuo and dried. To the resulting residue was added acetic acid (12 mL, 210 mmol) and the mixture stirred at 65° C. for 2 hours. The reaction was concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo to give crude product that was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/methylene chloride gradient. This provided the title compound (1.38 g, 61%) as a light tan solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([O:22][CH:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[O:14]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
To a solution of 1.0 g (3.4 mmol) 1′-benzyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one in 34 ml dichloromethane at −78° C. were added 6.8 ml (6.8 mmol) diisobutylaluminum hydride solution (1 M in n-hexane). After 45 min were subsequently added 0.80 ml (10 mmol) pyridine, a solution of 0.83 g (6.8 mmol) 4-N,N-dimethylaminopyridine in 2 ml dichloromethane and 1.9 ml (20 mmol) acetic anhydride. The reaction mixture was stirred at −78° C. for 14 h. The reaction was quenched with 34 ml aqueous saturated ammonium chloride solution and 26 ml 1 M aqueous sodium potassium tartrate solution and stirred for 30 min. Addition of saturated aqueous sodium hydrogen carbonate solution was followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (0.8 g; 70%) as a light yellow solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:21][O:22][C:23]1[C:24](=[O:47])[C:25]([CH3:46])=[C:26]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:42][C:43](=[O:45])[CH3:44])=[C:37]([CH:41]=2)[C:38](O)=[O:39])[C:27](=[O:31])[C:28]=1[O:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:4][C:38](=[O:39])[C:37]2[CH:41]=[C:33]([CH2:32][C:26]3[C:27](=[O:31])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[C:24](=[O:47])[C:25]=3[CH3:46])[CH:34]=[CH:35][C:36]=2[O:42][C:43](=[O:45])[CH3:44])[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: NC1CC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.2 %

Procedure:
Cyclopropylamine (0.0916 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.089 g, 0.215 mmol, 40%).
Reaction SMILES: S([O:5][C@@H:6]([C@H:9](O)[CH2:10][Cl:11])[CH2:7][Cl:8])(O)(=O)=O.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>CN(C=O)C>[Cl:8][CH2:7][C@@H:6]([OH:5])[C@@H:9]([N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])[CH2:10][Cl:11]
Reactant: O=S(=O)(O)O[C@H](CCl)[C@H](O)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1[C@@H](CCl)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A mixture of 1,4-dichlorobutan-2(S),3(S)-diol sulfate (57.2 mg, 0.258 mmol) and phthalimide potassium salt (51.4 mg, 0.272 mmol) in dry DMF (1.3 mL) was stirred under nitrogen atmosphere at rt for 1 h. Solvent was removed under reduced pressure. The residue was dissolved with dry THF (3 mL). To the resulting solution were added conc. H2SO4 (13 μl) and water (5 μl). After 30 min excess sodium bicarbonate (˜52 mg) was added and the reaction mixture was stirred for 30 min. Filtration through a Celite and silica gel bed and concentration of the filtrate under reduced pressure provided N-(1,4-Dichloro-2(S)-hydroxy-3(R)-butyl)phthalimide (77.8 mg) as a colorless oil.