Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]([CH3:64])=[CH:45][CH2:46][CH2:47]/[C:48](/[CH3:63])=[CH:49]/[CH2:50][CH2:51]/[C:52](/[CH3:62])=[CH:53]/[CH2:54][S:55][CH2:56][C@H:57]([NH2:61])[C:58]([OH:60])=[O:59]>C1COCC1.C(OCC)(=O)C>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([NH:61][C@@H:57]([CH2:56][S:55][CH2:54]/[CH:53]=[C:52](\[CH3:62])/[CH2:51][CH2:50]/[CH:49]=[C:48](\[CH3:63])/[CH2:47][CH2:46][CH:45]=[C:44]([CH3:64])[CH3:43])[C:58]([OH:60])=[O:59])=[O:6]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, mono-methyl succinate (132 mg, 1 mmol), 2-(7-Aza-1H-benzotriazole-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 mg, 1.1 mmol) and N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) were mixed in THF (5 mL). The reaction solution was stirred at room temperature for ten minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to reaction mixture. The reaction solution was stirred at room temperature overnight. Ethyl acetate (50 mL) was added and then washed with saturated ammonium chloride aqueous solution (20 mL×2), DI water (20 mL×2) and brine (20 mL×2) sequentially. The ethyl acetate solution was dried by Na2SO4 and concentrated in vacuo to afford a crude Compound N-17. The crude Compound N-17 was purified by HPLC (110 mg, 25%) to yield Compound N-17. 1H-NMR (500 MHz, MeOH-d4): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.58 (s, 3H), 1.85-1.88 (m, 2H), 1.91-1.96 (m, 4H), 1.99-2.03 (m, 2H), 2.46-2.54 (m, 4H), 2.68 (dd, J=7.5, 13.5 Hz, 1H), 2.90 (dd, J=4.5, 13.5 Hz, 1H), 3.09-3.12 (m, 2H), 3.21 (s, 3H), 4.35 (dd, J=4.5, 7.0 Hz, 1H), 4.98-5.02 (m, 2H), 5.14 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 16.12, 16.25, 17.79, 25.94, 27.48, 27.79, 30.40, 30.69, 31.73, 35.49, 40.77, 40.89, 52.24, 55.45, 121.82, 125.22, 125.47, 132.08, 136.15, 139.97, 173.57, 174.80, 177.17; ES-MS: mass calcd for Chemical Formula: C23H37NO5S 439.2. Found (M+Na) m/z 462.2.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[F:11][C:12]1[CH:13]=[C:14]([NH:18]N)[CH:15]=[CH:16][CH:17]=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]2[C:7]3[CH2:8][NH:3][CH2:4][CH2:5][C:6]=3[NH:18][C:14]=2[CH:13]=1
Reactant: O=C1CCNCC1
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Fc1ccc2c3c([nH]c2c1)CCNC3
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Piperidone hydrochloride monohydrate (4.55 g) and 3-fluorophenylhydrazine hydrochloride (4.85 g) were added to ethanol (80 ml) and the mixture was heated under reflux for one hour. Hydrogen chloride gas was bubbled into the mixture and refluxing was recommenced for another 1.5 hours. The solution was cooled to 0° C., the hydrochloride was filtered off, washed with ethanol, dissolved in boiling water, decolourised with activated charcoal and filtered. 2M Sodium hydroxide solution was added to the warm solution until it was neutral when tested with pH paper. The pale cream solid was filtered off, washed with water and dried. Recrystallisation from acetonitrile gave a white solid which was a mixture of 7-fluoro and 9-fluoro-isomers in a ratio of 86:14 respectively (HPLC).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCO)c1
Reaction time: 8 h

Procedure:
A solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (1.08 g, 6.87 mmol) in methanol (34 ml) was evacuated and purged with nitrogen and treated with palladium on carbon (0.1 g, 0.094 mmol). The resulting black suspension was evacuated and purged with a hydrogen balloon and stirred under hydrogen overnight. The mixture was filtered through celite with methanol washes, and concentrated. The residue was flash chromatographed (50 mm; 9% methanol/methylene chloride w/0.1% NH4OH then 10% methanol/methylene chloride w/0.1% NH4OH) to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][C:18]([CH3:23])=[CH:17][CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(OC(c2ccccc2)C(O)C(=O)NC(C)C)cc1

Procedure:
This compound was prepared as in Example 12 from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.), p-cresol (3.3 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.) and acetonitrile (250 ml.). The product melted at 152°-152°, and amounted to 2.4 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][NH2:22])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[CH2:23](OC(OCC)OCC)C>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[C:4]2[N:5]([CH:23]=[N:22][N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Solvent: Cc1ccccc1C
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Yield: 90.1 %

Procedure:
D7 (1 g, 3.409 mmol) and triethylorthoformate (7.577 g, 51.13 mmol) in xylene (25 ml) were heated in a sealed tube at 180° C. for 1 h. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield compound D8 (0.932 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2[CH:35]=[CH:34][CH:33]=[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCCOc1cccc(CN)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCCOc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-[3-(aminomethyl)phenoxy]-N,N-dimethyl-propan-1-amine (25.0 mg, 0.12 mmol). The title compound was obtained as a solid (35.4 mg, 65% yield). MS m/z: 541.06, 543.05 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O-])=[O:15])[N:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[Na+].CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)=[O:17]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(C(=O)[O-])cs1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CO)cs1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
2-(3-(3-fluorobenzyl)ureido)thiazole-4-carboxylate (4.08 mmol) is taken up in THF and solution is cooled to −78° C. Added LiAlH4 (2.6 equivalents, 1M solution in THF). Stir at ambient temperature for 3 hours. Add slowly Na2SO4.10H2O (6.4 g), then NaHSO4 (1.8 g). Stir for 30 hours. Aqueous workup with EtOAc. Crystallized from DCM/hexanes to give 1-(3-fluorobenzyl)-3-(4-(hydroxymethyl)thiazol-2-yl)urea in 79% yield.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.Cl.N([O-])=O.[Na+].O[PH2]=O>O.CCO.C(O)(=O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:5]=1)[CH3:12]
Reactant: CCc1cc(Br)cc(CC)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(Br)cc(CC)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A mixture of 20 g of 4-bromo-2,6-diethylaniline, 160 ml of acetic acid, 100 ml of concentrated HCl solution, 30 ml of water and 100 ml of EtOH is cooled to −5° C., a solution of 6.6 g of sodium nitrite in 25 ml of water is added dropwise and the mixture is left stirring at RT for 30 minutes. The reaction mixture is poured into 170 ml of 50% H3PO2 cooled to 0° C. and is left stirring for 2 hours at 0° C. and then for 48 hours at RT. The reaction mixture is extracted with ether, the organic phase is washed with water, with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with cyclohexane. 18 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)=[C:15]([CH3:29])[N:14]=[C:13]1[CH2:30][N:31]([CH3:33])[CH3:32])=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[C:13]([CH2:30][N:31]([CH3:32])[CH3:33])=[N:14][C:15]([CH3:29])=[C:16]2[CH2:17][N:18]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccccc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccc1Cl)c1ccccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 6-(o-chlorophenyl)-1-[(dimethylamino)-methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1.FC(F)(F)C(NC1C=CC=CC=1)=O>>[CH:10]1([CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccccc1
Reactant: BrCC1CC1
Agent: O=C(Nc1ccccc1)C(F)(F)F
Product: c1ccc(NCC2CC2)cc1

Procedure:
N-(Cyclopropylmethyl)aniline [NMR (200 MHz, DMSO-d6): δ0.21 (m, 2H); 0.51 (m, 2H); 1.01 (m, 1H); 3.63 (d, J=7.3 Hz, 1H); 3.80 (br s, 1H); 5.78 (br s, 1H); 7.18 (t, J=7.2 Hz, 1H); 7.25 (d, J=7.8 Hz, 2H); 7.42 (t, J=7.3 Hz, 2H)] was prepared from aniline and (bromomethyl)cyclopropane via trifluoroacetanilide using the general method described by Hodge (Harland, P. A.; Hodge, P; Maughan, W.; Wildsmith, E. Synthesis, 1984, 941.).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[O:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2)[CH3:22]>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[C:23]([O:21][CH3:22])[CH:24]=4)[NH:28][C:27]3=[O:32])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(OC)cc43)c(C)c2C1=O
Yield: 65 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 5-(2-diethylamino-ethyl)-2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetra hydro-pyrrolo[3,2-c]pyridin-4-one (80 mg, 65.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:27])([C:23]([F:26])([F:25])[F:24])[C:3]([F:22])([F:21])[C:4]1([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[O-:28][C:29]#[N:30].[Na+].FC(F)(F)C(O)=O.O>C(Cl)Cl>[F:17][C:12]([F:18])([C:13]([F:16])([F:15])[F:14])[C:11]([F:19])([F:20])[C:4]1([C:3]([F:21])([F:22])[C:2]([F:1])([F:27])[C:23]([F:24])([F:25])[F:26])[O:8][CH:7]([CH2:9][O:10][C:29](=[O:28])[NH2:30])[CH2:6][O:5]1
Reactant: OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)OCC1COC(C(F)(F)C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)C(F)(F)F)O1
Reaction time: 24 h

Procedure:
A solution of 44.0 grams (0.1 mol) of 2,2-bis(heptafluoropropyl)-4-hydroxymethyl-1,3-dioxolane prepared by the method disclosed in patent application Ser. No. 873,660 filed Nov. 3, 1969, in 250 ml methylene dichloride is treated with 13.0 grams of sodium cyanate while 22.8 grams trifluoroacetic acid is added dropwise. The reaction is carried out at 25°-35° C. for 24 hours. After the reaction is completed, a small amount of water is added to dissolve the salts and the methylene dichloride solution is separated and washed with water. Vacuum-stripping yields the desired product. The product, 2,2-bis(heptafluoropropyl)-4-carbamoyloxymethyl-1,3-dioxolane, is purified by crystallization from a mixture of benzene and hexane.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>C(O)C.C(OCC)C>[CH2:3]([O:10][C:11]1[C:12]([CH2:13][OH:14])=[CH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a well-stirred suspension of 2.0 g (52.7 mmol) of sodium borohydride in 65 mL of ethyl alcohol at 0° C. under a nitrogen atmosphere, was slowly added 15 g (61.9 mmol) of 2-benzyloxy-3-methoxybenzaldehyde, from Step 1, in 100 mL of ethyl alcohol. The reaction mixture was stirred at 0° C. for 10 minutes and then 50 mL of water was added to quench the reaction, followed by 50 mL of diethyl ether. The mixture was slowly added to 60 mL of 10% aqueous hydrochloric acid solution at 0° C. and the resultant mixture was stirred for 1 h and then extracted with 3×200 mL of diethyl ether. The combined ether extracts were washed with aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 15.14 g (100% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:16][NH:17][CH3:18])=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[OH:34][CH2:35][C@@H:36]1[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]2[CH:45]=[C:46]([C:49](O)=[O:50])[CH:47]=[CH:48][C:38]=2[NH:37]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[CH3:18][N:17]([CH2:16][C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:20][CH:19]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:49]([C:46]1[CH:47]=[CH:48][C:38]2[NH:37][C@H:36]([CH2:35][OH:34])[C:42](=[O:43])[N:41]([CH3:44])[CH2:40][C:39]=2[CH:45]=1)=[O:50]
Reactant: CN1Cc2cc(C(=O)O)ccc2N[C@H](CO)C1=O
Reactant: CNCc1cc2ccccc2n1Cc1ccc(O)cc1
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: CN(Cc1cc2ccccc2n1Cc1ccc(O)cc1)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 92.2 %

Procedure:
According to the procedure of Example 1(a), except substituting 1-(4-hydroxybenzyl)-2-(methylaminomethyl)indole (0.40 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2-(hydroxymethyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.34 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.63 g, 92%) was prepared as an off-white solid: MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[C@@H:14]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:13]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:12]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][OH:17])[C@@H:14]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:13]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C@@H:12]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 119.4 %

Procedure:
To a stirred and ice-cooled solution of (2S*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-3-[N-(t-butoxycarbonyl)amino]-5-(t-butyldimethylsilyloxy)methyl-2-phenylpyrrolidine (14.5 g, ca.21.3 mmol) in dry THF (20 ml) was added a mixture of glacial AcOH (1.59 ml, d1.049, 27.7 mmol) and a 1.0M solution of (n-Bu)4NF in THF (Aldrich, 32.0 ml, 32.0 mmol) dropwise. After stirring at room temperature for 6 hours, a further amount of a 1.0M solution of (n-Bu)4NF in THF (15.0 ml, 15.0 mmol) was added dropwise at room temperature. After the stirring was continued for 2 days, the resultant orange mixture was neutralized with sat. NaHCO3 aq. solution, and concentrated in vacuo at a bath temperature of 40 C. The residue was diluted with AcOEt (200 ml), washed with H2O (×2), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a dark red viscous oil (13.9 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 130 g). Elution with n-hexane-AcOEt (20:1→10:1→5:1→4:1→2:1) gave a red solid (10.6 g). This was recrystallized from AcOEt-n-hexane; the crystals were filtered off, washed with AcOEt-n-hexane (1:4, ×1), and dried in vacuo to give the title compound (9.0 g, 78%) as a slightly purple crystals. A portion of it was recrystallized from AcOEt-n-hexane to afford an analytical sample of the title compound: mp 126.5-129.5 C. (white fine needles); IRmax (nujol): 3430(s), 3380(s), 1690(vs), 1518(s), 1498(m), 1100(s), 785(m), 770(s), 747(s), 740(s), 715(s), 695(s) cm-1 ; 1H-NMR δ: 7.45-7.15(m, 17H), 6.94(br.s, 1H), 5.22(d, J=8.1 Hz, 1H), 5.02(br.s, 2H), 4.87(br.s, 1H) 4.52(s), 2H), 4.30(dd, J=19.0, 9.0 Hz, 1H), 4.2-4.00(m, 2H), 4.03-3.90(m, 1H), 3.68-3.50(m, 2H), 2.10-1.85(m, 1H), 1.37(br.s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-(1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chlorophenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (64 mg, 54%).
Reaction SMILES: C=O.[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][C:12]([CH3:14])=[CH:11][CH2:10][N:9]1[C:15](=[O:40])[C@H:16]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1)[NH:17][S:18]([C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][NH:27][CH2:28]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])[CH3:4].[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][C:12]([CH3:14])=[CH:11][CH2:10][N:9]1[C:15](=[O:40])[C@H:16]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=1)[NH:17][S:18]([C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][N:27]([CH3:41])[CH2:28]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C)CC2
Reaction time: 0.75 h
Yield: 93 %

Procedure:
Aqueous formaldehyde solution (37% w/v, 1.4 ml, 17.3 mmol) was added to a stirred solution of 4-methyl-1-[N-(1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanyl]-1,2,3,6-tetrahydropyridine-2(R)-carboxylic acid ethyl ester (Preparation 45; 2.26 g, 4.2 mmol) in dichloromethane (30 ml). After 0.75 hour, sodium triacetoxyborohydride (1.34 g, 6.32 mmol) was added and stirring continued for 4 hours. The reaction mixture was then washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried (MgSO4) and evaporated under reduced pressure, then the residue purified by chromatography on silica gel, using ethyl acetate: diethylamine (98:2) as eluent, to provide the title compound (2.15 g) as a foam. [α]D25 +9° (c=0.1, CH3OH). Found : C,62.81; H,6.28; N,9.53. C29H34N4O5S; 0.30 H2O required C,62.63; H,6.27; N,10.07%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].Cl>CO>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:19])[C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid, methyl ester (intermediate 69-184 mg) and potassium hydroxide (131 mg) in MeOH (2.5 mL) was heated to reflux for 1 hour, then it was allowed to cool to r.t. and acidified to pH=3 with 10% hydrochloric acid solution and extracted with AcOEt (2×10 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt from 8:2 to 6:4) to give the title compound (141 mg) as a white solid.