Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)Cl.[C:6]1([CH:12]=[CH:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)C1C=CC=CC=1.CC(=O)CCC.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].Cl>C(OCC)(=O)C.[Zn]>[OH:18][C:14]([CH:13]=[CH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:15][CH2:16][CH3:17])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CBr
Reactant: CCCC(=O)C=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O=Cc1ccccc1
Solvent: CCCC(C)=O
Product: CCCC(O)(C=Cc1ccccc1)CC(=O)OC
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 8.5 g of zinc powder (129 mmol) in 55 ml of ethyl acetate. After 2.4 ml of trimethylchlorosilane (19 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 50° C. Over the course of 8 min, a mixture of 15 g of 1-phenylhex-1-en-3-one, prepared by base-catalyzed aldol condensation of benzaldehyde and pentan-2-one, and 15.8 g of methyl bromoacetate (103 mmol) was added dropwise, the temperature being maintained at 50° C. by external cooling. The mixture was then stirred at 50° C. for 30 min, and following cooling to 0° C., acidified with 60 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was then removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 60 ml of 0.5 N hydrochloric acid and finally washed with 20 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. Methyl 3-hydroxy-3-(2′-phenylethenyl)caproate was obtained in a yield of 20.4 g (95% of theory) and a purity of greater than 97% (HPLC). The compound had a melting point of 43° C. following recrystallization from petroleum ether.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[C:40](O)(=[O:42])[CH3:41].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:1][C@H:2]1[C@@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH3:41])=[O:42])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][C@@H:6]([O:33][CH3:34])[C@:5]2([OH:39])[NH:35][C:36]([O:38][C@H:3]1[CH2:4]2)=[O:37]
Reactant: CC(=O)O
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: ClCCl
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(C)=O)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
A mixture of maytansinol (6.00 mg, 0.01062 mmol), acetic acid (12.75 mg, 0.2124 mmol), Sc(OTf)3 (3.14 mg, 0.00637 mmol) and DMAP (3.89 mg, 0.03186 mmol) in CH2Cl2 (1 mL) was stirred for 0.5 h at −8° C. DIC (29.49 mg, 0.2337 mmol) was added dropwise. The mixture was stirred till completion, quenched with diluted HCl, extracted with CH2Cl2. The organic layer was washed with aq. NaHCO3, brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product ansamitocin P1. LC-MS (M+Na+) calc.: 629.2. found: 629.3.
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].C(N(CC)C(C)C)(C)C>ClCCCl>[C:14]([C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:2]=[CH:3][CH3:4])(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC=Cc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 39.6 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg) in 1,2-dichloroethane (8 ml) was added N,N-diisopropylethylamine (0.24 ml) and refluxed for 40 minutes. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with diluted hydrochloric acid, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. Trituration with diethyl ether gave methyl 3-isobutyryl-2-(1-propenyl)indole-6-carboxylate (55.2 mg).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[F:48][C:49]([F:76])([F:75])[C:50]([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][CH:69](O)[CH3:70])=[C:61]([CH2:72][CH2:73][CH3:74])[CH:60]=1)([O:55]COC)[C:51]([F:54])([F:53])[F:52]>C1(C)C=CC=CC=1.O1CCCC1>[F:48][C:49]([F:75])([F:76])[C:50]([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][CH:69]([N:4]2[C:3](=[O:8])[C:2]([CH3:1])([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=3)[NH:6][C:5]2=[O:7])[CH3:70])=[C:61]([CH2:72][CH2:73][CH3:74])[CH:60]=1)([OH:55])[C:51]([F:52])([F:54])[F:53]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)N1C(=O)NC(C)(c2ccc(OC(C)C)cc2)C1=O
Yield: 88.5 %

Procedure:
5-Methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (25.8 mg), triphenylphosphine (22.8 mg) and a solution of ethyl azodicarboxylate in toluene (2.2 mol/L, 34.7 μL) were added to a mixed solution of 5-[4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyloxy]pentan-2-ol (15.0 mg, 34.7 μmol) in tetrahydrofuran (1 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 19.0 mg of the title compound (yield: 89%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1>C1COCC1.CO.[Ni]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Cl)cc23)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Cl)cc23)cc1

Procedure:
2-(4-(6-Chloro-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation F, 5 g, 13.6 mmol) and Raney-Ni (2 g) were shaken in 100 mL of THF-MeOH (1:1) under 25 psi of H2 for 3 hours at RT. After completion of reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 3.5 g (66%); 1H NMR (DMSO-d6, 300 MHz): δ 8.599 (s, 1H), 7.892 (s, 1H), 7.816-7.846 (d, 1H, J=9 Hz), 7.655-7.663 (d, 1H, J=2.4), 7.312-7349 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.233-7.262 (d, 2H, J=8.7 Hz), 6.510-6.538 (d, 2H, J=8.4 Hz), 5.457 (s, 2H), 1.598 (s, 6H); MS: m/z 337 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH2:20][C:21](O)=[O:22])=[O:18])=[CH:11]2>CCOCC>[N:1]1([C:21](=[O:22])[CH2:20][NH:19][C:17]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=3)=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CCOCC
Product: O=C(NCC(=O)N1CCOCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Morpholine (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1.0 mmol) were coupled according to Procedure A. The resulting solid was suspended in ether, filtered and dried to give a beige solid: Yield, 264 mg, 71%; HPLC (60/40) 3.28 minutes (100%); TSPMS 322/324 (MH+, 100%);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC4C=CC=CC=4)=[CH:18][CH:17]=2)[NH:12][N:11]=[C:10]3[NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:2]=1>C[Si](I)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[NH:12][N:11]=[C:10]3[NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:2]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Agent: C[Si](C)(C)I
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)c(-c3cccnc3)cc12
Yield: 24.3 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 460 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, and the mixture is refluxed for 18 hours. The insoluble material is filtered off, washed with 2×20 cm3 of diethyl ether and taken up in 50 cm3 of tetrahydrofuran and 25 cm3 of ethyl acetate, and the organic phase is washed with 2×100 cm3 of 10% sodium thiosulphate solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure to give 330 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of diisopropyl ether, filtered off, washed with 3×5 cm3 of diisopropyl ether, with 5 cm3 of ethyl acetate and then with 10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 90 mg of N-[5-(3-pyridyl)-6-(4-hydroxyphenyl)-1H-indazol-3-yl]butanamide in the form of cream-coloured crystals melting at 165° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[O:14].Cl(O)(=O)(=O)=O>[Pd].C(O)(=O)C>[F:16][C:2]([F:1])([F:15])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14]
Reactant: O=C1C(=O)N(CC(F)(F)F)c2ccccc21
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2N1CC(F)(F)F
Reaction time: 22 h

Procedure:
A mixture of 1-(2,2,2-trifluoro-ethyl)-1H-indole-2,3-dione (9.2 g, 40 mmol) and 10% palladium on carbon (2.4 g) in acetic acid (100 mL) and 70% perchloric acid (6.4 mL, 80 mmol) was hydrogenated in a Parr apparatus for 22 hours. The mixture was filtered through diatomaceous earth, diluted with water (1.5 L) and the precipitate was collected and dried. mp 155-162° C. Yield 7.5 g (87%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:21])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(OCC)(=O)C>O>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[NH:14][C:13](=[O:21])[C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)Nc1cnccn1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
[(S)-3-Methyl-1-(pyrazin-2-ylcarbamoyl)-butyl]-carbamic acid t-butyl ester (0.645 g, 2.09 mmol) was treated with a 30% trifluoroacetic acid/dichloromethane (10 mL) solution at 0° C. and the resulting mixture allowed to warm to room temperature over 1.5 h. At this time the mixture was partioned between ethyl acetate and water and the layers separated. The aqueous phase was made basic (pH=10) by the addition of solid sodium hydroxide. The basic aqueous phase was extracted with ethyl acetate (3×) and the ethyl acetate layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (0.341 g, 78%).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24](C(OCC3C=CC=CC=3)=O)[CH2:23][CH2:22]2)[C:10]=1[CH3:37])C1C=CC=CC=1.C1COCC1>[Pd].C(O)C>[CH3:37][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1c(/C=C/C2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CCC2CCNCC2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a mixture of benzyl 4-{(E)-2-[4-(benzyloxy)-3-methylquinolin-2-yl]vinyl}piperidine-1-carboxylate (978 mg), THF (6 mL) and ethanol (6 mL) was added 10% palladium-activated carbon (200 mg) under nitrogen atmosphere. The mixture was stirred at room temperature under hydrogen atmosphere of 3 atms, for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd., NH, eluent: chloroform/methanol=97/3˜92/8), and the solvent was evaporated. The residue was washed with ether, and collected by filtration to obtain 3-methyl-2-(2-piperidin-4-ylethyl)quinolin-4(1H)-one (490 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21]CC)=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([C:17]3[C:18]4[C:19](=[O:21])[O:20][CH2:4][C:6]=4[C:7]([OH:33])=[C:8]4[C:16]=3[C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=[CH:9]4)=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1O)OCO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCc2c1c(-c1ccc3c(c1)OCO3)c1c3c(ccc1c2O)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A solution of 33 (45.2 mg, 0.1 mmol) in THF (1 mL) was added dropwise to a suspension of lithium aluminum hydride (7.6 mg, 0.2 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 2 h and quenched with aqueous saturated Na2SO4 solution, and then extracted with CHCl3 (2×30 mL). After evaporation of organic solvent, the residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (20:1, v/v) to give 34 (36 mg, 99%) as a yellow powder. mp 257° C. (decomp.); 1H NMR (DMSO-d6) δ 10.67 (s, 1H, 4OH), 7.94 (d, 1H, H5, J=9.0 Hz), 7.44 (d, 1H, H6, J=9.0 Hz), 6.84 (d, 1H, H5′, J=8.1 Hz), 6.79 (d, 1H, H2′, J=1.5 Hz), 6.66 (dd, 1H, H6′, J=1.5, 8.1 Hz), 6.04 (AB, 2H, 3′,4′-OCH2O—, Δδ=6.0 Hz, J=0.6 Hz), 5.88 (AB, 2H, 7,8-OCH2O—, Δδ=6.3 Hz, J=0.9 Hz), 5.32 (s, 2H, lactone-CH2—); MS (FAB, positive) m/z 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)([C:4]#[N:5])[CH3:3]>[Ni].C(O)C>[NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)([CH3:3])[CH2:4][NH2:5]
Reactant: CC(C)(C)OC(=O)C1(C(C)(N)C#N)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(C(C)(N)CN)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To an ethanol solution (50 mL) of tert-butyl 1-(1-amino-1-cyanoethyl)-1-cyclopropanecarboxylate (1.12 g, 5.30 mmol) was added an ethanol suspension (30 mL) of Raney Nickel catalyst (R-100 manufactured by NIKKO RICA CORPORATION, 10 mL), and the mixture was stirred vigorously under hydrogen atmosphere at room temperature for 6 hours. The catalyst was removed by filtration through celite, and the solvent was removed under reduced pressure to obtain 0.84 g of a crude product of the target compound (3.92 mmol, 74%) as transparent and colorless oil. The obtained crude product was used for the subsequent reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC1>ClCCl>[OH:2][CH:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-formylbenzoate (2.83 g, 17.2 mmoles) at −78° C. in 60 mL of dichloromethane is added 10 mL a 2.0 M solution of phenylmagnesium chloride in tetrahydrofuran (20.0 mmoles) over 7 minutes. After stirring for an additional 20 minutes, the reaction was quenched with methanol then with saturated aqueous ammonium chloride. The aqueous layer was acidified with 1N hydrochloric acid and the phases were separated. The organic portion was washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Removal of the volatiles under reduced pressure and purification over silica gel afforded the title ester.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:42]([NH2:44])=[O:43])[CH2:40][CH2:41]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (6 mmol) and THF (20 mL). Cool using an ice bath. Add a 1M THF solution of tetrabutylammonium fluoride (7 mL) in dropwise fashion. After 30 minutes, concentrate in vacuo to obtain a residue. Add dichloromethane (50 mL) to the residue. Extract with water (3×15 mL), dry over Na2 SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:23][C:24](OC)=[O:25])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].CO.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:23][CH2:24][OH:25])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cn1nc(-c2ccnc(Br)c2)c2cc(OC)c(OC)cc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc2c(-c3ccnc(Br)c3)nn(CCO)c(=O)c2cc1OC
Yield: 75.9 %

Procedure:
To a solution of 2-bromo-4-(6,7-dimethoxy-2-methoxycarbonylmethylphthalazin-1(2H)-on-4-yl)pyridine (4.34 g) in tetrahydrofuran (20 ml) is added sodium borohydride (0.76 g), and further thereto is added dropwise with heating a mixture of methanol (3.2 ml) and tetrahydrofuran (5 ml) under reflux over a period of one hour. The reaction mixture is allowed to stand for cooling, and thereto is added water under ice-cooling. The mixture is extracted with chloroform, and the extract is washed, dried and concentrated. The residue is recrystallized from isopropyl ether to give 2-bromo-4-(6,7-dimethoxy-2-hydroxyethylphthalazin-1(2H)-on-4-yl)pyridine (3.08 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][C:20]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: O=C=Nc1ccccc1
Product: CC1(C)CC(=O)N(C(=O)Nc2ccccc2)CC(C)(C)N1

Procedure:
Using the same conditions as Example 1, 34 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 26 parts of phenylisocyanate afforded 49 parts of 4-phenylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as an almost colourless solid. Crystallisation from petrol ether (40°-60°) yielded crystalline material of melting point 68.5° - 70°C which gave the following elemental analysis by weight:
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[OH:12].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br>CN(C=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3]1
Reactant: BrCC1CO1
Reactant: OC1Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CC(OCC1CO1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 60% NaH (0.18 g, 4.5 mmol) in DMF (10 ml) cooled to 0 degrees was added 2-indanol (0.5 g, 3,73 mmol) in DMF (2 ml) dropwise. After stirring for 30 minutes epibromohydrin (1.11 g, 8.18 mmol) in DMF (1 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 48 h. The solvent was removed in vacuo and the residue was purified using Prep TLC (30:1, DCM:MeOH) to afford compound 6.
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](=[O:11])[C:5](=[O:12])[CH:4]=1.Cl.[Cl:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>ClCCl>[Cl:14][CH2:15][CH2:16][NH:17][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](=[O:11])[C:5](=[O:12])[CH:4]=1
Reactant: NCCCl
Reactant: COC1=CC(=O)C(=O)C=C1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CC(=O)C(=O)C=C1NCCCl
Yield: 31.8 %

Procedure:
4,5-Dimethoxy-1,2-benzoquinone (672.4 mg, 4 mmol) was dissolved in dichloromethane (40 ml) and stirred in a round-bottomed flask equipped with a cylindrical funnel from which a solution of chloroethylamine hydrochloride (1.2 g, 4.4 mmol) and triethylamine (2.4 ml, 16.8 mmol) in dichloromethane (50 ml) was added dropwise into the solution over the course of one hour. The reaction mixture was maintained with stirring at room temperature for 21 hours. After filtration, the remaining solution was washed with 10% hydrochloric acid, distilled water and then distilled water saturated with sodium chloride, and then dried over magnesium sulfate. Evaporation of the solvent gave the black red crude product. Column chromatography with chloroform: methanol (4:0.5, (v/v)) elution gave 4-chloroethylamino-5-methoxy-1,2-benzoquinone 274.3 mg, 31.8% yield) which was recrystallized from ethanol as red needles: mp 150°-152° C.; Found: C,50.17; H,4.77; N,6.44; Cl,16.39. Anal. Calcd. for C9H10ClNO3 : C,50.13; H,4.67; N,6.49; Cl,16.44%. I.R. υmax 3400, 2940, 1660, 1640, 1620, 1580, 1510, 1250, 1180, 810 cm-1. U.V. λmax (95% EtOH) 210 nm (log ε4.35), 304 (4.23), 464 (3.51), 1HNMR (CDCl3) δ, 3.6 (m, 4H, NCH2CH2), 3.9 (S, 3H, O CH3), 5.4 (S, 1H, 6-H), 5.7 (s, 1H, 3-H), 6.2 (br,s, 1H, NH).