Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=2[NH:27][C:28](=[O:37])[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36].[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>ClCCl>[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][C:24](=[O:25])[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[NH:27][C:28](=[O:37])[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36]
Reactant: O=C(O)Cc1c(Br)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1c(Br)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)NCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a mixture of dimethylformamide (17.4 mg) and dichloromethane was added oxalyl chloride (27.7 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 3-bromo-4-carboxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (90 mg) at 0° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2-aminomethylpyridine (107 mg) at 0° C., and the mixture was stirred for 30 minutes at ambient temperature. The mixture was partitioned between dichloromethane and saturated ammonium chloride solution. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and recrystallized from ethanol to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-[(pyridin-2-ylmethyl)carbamoylmethyl]quinoline (58.0 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([C:18]3[CH2:22][C:21]([C:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=4)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:21]2([C:23]([F:25])([F:24])[F:26])[O:20][N:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][CH:9]=[C:8]4[C:6]([OH:7])=[O:5])[CH2:22]2)[CH:32]=[C:31]([Cl:33])[CH:30]=1
Reactant: CC(C)(C)OC(=O)c1cccc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a stirred solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid tert-butyl ester (Example 9.5) (1.0 g) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to give a solid which was washed with cyclohexane to give 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid (0.76 g). 1H-NMR (DMSO, 400 MHz): 8.95 (m, 2H), 8.20 (d, 1H), 7.90 (d, 1H), 7.65-7.80 (m, 5H), 4.50 (q, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH2:18]([NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32](O)=[O:33])[N:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=2)=[O:33])[N:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1csc(NCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Product: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)Cc2csc(NCc3ccccc3)n2)cc1

Procedure:
960 mg of t-butyl 2-(4-aminophenyl)ethylcarbamate and (2-benzylaminothiazol-4-yl)acetic acid were subjected to an amidation reaction to obtain 500 mg of t-butyl [2-[4-[2-(2-benzylaminothiazol-4-yl)acetylamino]phenyl]ethyl]carbamate.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([N:21]([CH2:22][C:23]([F:25])([F:26])[F:24])[C:19](=[O:20])[C:18]1[CH:27]=[CH:28][CH:29]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:15][CH2:14]2)[CH:17]=1)[CH:37]=[CH2:36]
Reactant: O=C(NCC(F)(F)F)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: C=CCBr
Product: C=CCN(CC(F)(F)F)C(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of step (b) of Example 33 was repeated using the compound prepared in step (a) of Example 33, except that allyl bromide was used instead of benzyl bromide. Thus, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.[Cu]Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[Si](C)(C)C#Cc1cncc(Br)c1
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C#Cc1cncc(Br)c1

Procedure:
3-Bromo-5-trimethylsilanylethynyl-pyridine (1.0 eq, 1.22 g, 4.78 mmol), pivaloyl chloride (1.1. eq, 0.647 ml, 5.26 mmol) and copper(I) chloride (0.2 eq, 95 mg, 0.96 mmol) are dissolved in DMF (8 ml). The resulting mixture is heated using microwave radiation at 120° C. for 30 min. The mixture is filtered and washed with EtOAc. The filtrate is concentrated in vacuo and partitioned between sat. aqueous NaHCO3 solution and EtOAc. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+=266/268.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[C:37]4[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]5[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=5[O:52][CH3:53])[C:36]=4[CH:35]=[CH:34]3)[CH2:24]2)[CH3:21])[CH2:17]1.C(O)(=O)C>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH:18]([N:20]([CH2:22][C@@H:23]4[C@H:30]5[O:29][C:28]([CH3:32])([CH3:31])[O:27][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]7[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=7[O:52][CH3:53])[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH3:21])[CH2:19]3)=[N:1][C:2]=2[CH:7]=1)([CH3:10])([CH3:9])[CH3:11]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 86.6 %

Procedure:
A solution of N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.24 g, 0.32 mmol) in Acetic acid (5 ml, 90 mmol) was stirred overnight at 60° C. The volatiles were removed in vacuo and remaining residue partitioned between Na2CO3 (2N) and DCM. The aqueous layer was extracted 3× with DCM and the combined organics dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 94:6) to yield the desired compound (0.20 g) as a solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2]N.C([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])C=C>C1(C)C=CC=CC=1>[O:14]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:2]=[CH:1][NH:4]1
Reactant: C=CCc1ccccc1O
Reactant: NCCN
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 92 %

Procedure:
This compound was prepared according to the method described in the previous examples from ethylene diamine (6.0 g, 100 mmole), paraformaldehade (12.6 g, 420 mmole), 2-allyl-phenol (26.8 g, 200 mmole), and toluene (200 ml). The final product was obtained as a viscous liquid. The yield was 92% of theory.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Br:34])[CH:32]=3)[N:27]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:26]=2)O)=[C:19]([F:44])[N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[C:38]1([S:35]([N:27]2[C:28]3=[N:29][CH:30]=[C:31]([Br:34])[CH:32]=[C:33]3[C:25]([CH2:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:7])=[N:18][C:19]=3[F:44])=[CH:26]2)(=[O:36])=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncc(Br)cc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
In a round bottom flask, {5-[(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (166, 1.15 g, 1.65 mmol) was combined with 50 mL of 1,2-dichloroethane, trifluoroacetic acid (0.635 mL, 8.24 mmol), and triethylsilane (1.32 mL, 8.24 mmol). The reaction was heated at reflux for 20 hours, then concentrated under vacuum. The residue was dissolved in 10 mL of trifluoroacetic acid and stirred at room temperature for 18 hours, then concentrated under vacuum and combined with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (167, 403 mg). MS (ESI) [M−H+]−=460.8 and 462.8.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].CN(C)[CH:14]=[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16](OCC)=[O:17].Cl.CCN(C(C)C)C(C)C>CC(O)C>[OH:17][C:16]1[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccnc(OC)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Temperature: 25 °C

Procedure:
Combined 6-hydrazinylnicotinic acid (167 mg, 1.090 mmol), ethyl 3-(dimethylamino)-2-(2-methoxypyridin-4-yl)acrylate (300 mg, 1.199 mmol), 2-propanol (3632 μl), and hydrochloric acid (1.85% aqueous, 2.15 mL, 1.090 mmol). The reaction was stirred at room temperature. After 1 hour Hunig's base (949 μl, 5.45 mmol) was added to the suspension which became a yellow solution. The reaction was washed with EtOAc (2×15 mL) and the aqueous phase was concentrated in vacuo, yielding a yellow solid. The solid was triturated with 1N HCl (50 mL), collected by filtration, and washed with water. The solid was then slurried in methanol (2×60 mL) and diethyl ether (2×60 mL), the dried under vacuum to give the title compound. MS m/z [M+H]+ 313.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][C@@H:43]([C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1)[CH3:44]>ClCCl>[CH3:57][C:55]([CH3:56])([CH3:58])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([C@H:43]([CH3:44])[CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: C[C@@H](CCN)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CCNC(=O)c1ccon1)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-Isoxazolecarboxylic acid (0.015 g, 0.13 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.05 g, 0.13 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 36-4 (0.03 g, 0.10 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 0-60% ethyl acetate/hexane gradient, followed by 10-90% reverse phase gradient gave 36-5. (0.017 g, 43%). HRMS (M+H)+: observed=386.2189, calculated=386.2187
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:10])[C:5]#[N:6].[CH2:11]([OH:13])[CH3:12]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:13][CH2:11][CH3:12])[CH:7]=[CH:8][C:9]=1[SH:10]
Reactant: N#Cc1ccc(S)c(Br)c1
Reactant: CCO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=N)c1ccc(S)c(Br)c1
Reaction time: 0.5 h

Procedure:
3-Bromo-4-mercaptobenzonitrile (10 g) was dissolved in toluene (50 ml) and chloroform (80 ml), followed by adding thereto ethanol (3.0 ml), and the resulting mixture was cooled to −10° C. Hydrochloric acid gas was bubbled into the mixture through a bubbler for 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was allowed to stand in a refrigerator for 60 hours and then the completion of the reaction was confirmed by HPLC(ODS-A212). Dry nitrogen was bubbled into the reaction solution through a bubbler for 20 minutes and the hydrochloric acid gas was distilled off. The precipitate was collected by filtration, washed with toluene/chloroform and then dried to obtain ethyl 3-bromo-4-mercaptobenzene-carboximidate (13.6 g) as a light-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:35]1[C:40](=[O:41])[N:39]([O:42][C:43]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](ON2C(=O)CCC2=O)=[O:52])=[O:44])[C:37](=[O:38])[CH2:36]1>CN(C=O)C>[C:10]([O:9][C:7](=[O:8])[C@@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C:43]([O:42][N:39]1[C:40](=[O:41])[CH2:35][CH2:36][C:37]1=[O:38])=[O:44])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (0.488 g, 1.0 mmol) in DMF (20 mL) was added dropwise to a solution of suberic acid bis(N-hydroxysuccinimide ester) (1.47 g, 4.0 mmol) in DMF (80 mL) via a syringe pump. After 2 h, the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM to give (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.54 g, 73%). MS (ESI), 741.6 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]=[C:15]1[N:20]([CH2:21][CH:22]=O)[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[O:17][CH2:16]1>C(O)C.C(Cl)Cl>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][N:20]3[C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[O:17][CH2:16][C:15]3=[O:14])[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCN1C(=O)COc2ccccc21
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: O=C1COc2ccccc2N1CCN1CCC(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
Following the procedure of Synthetic Comm. 23 (6), 789-795, 1993, to a solution of 4-phenylpiperidine hydrochloride Compound 1-9 (290 mg, 1.5 mmol) and Compound 1-4 (300 mg, 1.5 mmol) in 10 mL of absolute ethanol was added BAP (154 μL, 1.5 mmol). After stirring for 2 hrs, an additional equivalent of aldehyde Compound 1-4 and BAP was added. The reaction mixture was stirred overnight and concentrated to give an oily residue. The residue was taken up in DCM, washed with saturated sodium bicarbonate solution NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified on silica gel (elution with 30% EtOAc in hexane) to yield Compound 86 as a glass-like oil (287 mg, 57%) of a glass-like oil. 1H NMR (300 MHz, CDCl3) δ 7.25-7.11 (m, 5H), 7.04-6.91 (m, 4H), 4.53 (s, 2H), 4.04 (m, 2H), 3.04 (m, 2H), 2.58 (m, 2H), 2.45-2.40 (m, 1H), 2.15, (t of d, J=11 and 3 Hz, 2H), 1.83-1.64 (m, 4H); MS (ES+) m/z 337.2 (M+1); Anal Calcd. for C21H24N2O2.0.51H2O: C, 73.02; H, 7.29; N, 8.11. Found: C, 72.98; H, 7.11; N, 8.00.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([N:18]([CH2:20][CH2:21][N:22]([CH2:36][CH2:37][CH2:38]Cl)[C:23]([NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=[O:24])[CH3:19])(=[O:17])=[O:16]>CN(C)C=O>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([N:18]([CH2:20][CH2:21][N:22]1[CH2:36][CH2:37][CH2:38][N:25]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=2)[C:23]1=[O:24])[CH3:19])(=[O:16])=[O:17]
Reactant: CN(CCN(CCCCl)C(=O)NCCc1ccc(C#N)cc1)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCN1CCCN(CCc2ccc(C#N)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
31 mg (0.28 mmol) of potassium tert.-butoxide were added to a solution of 0.147 g (0.28 mmol) of 2,3-dichloro-N-(2-{1-(3-chloropropyl)-3-[2-(4-cyanophenyl)-ethyl]ureido}ethyl)-N-methylbenzenesulphonamide in 8 ml of dimethylformamide, and the mixture was stirred at room temperature for 24 hours. The mixture was then evaporated to dryness. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, saturated sodium hydrogen sulphate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/ethanol 40:1).
Reaction SMILES: [CH3:1]S(O)(=O)=O.[OH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:16]=2)[NH:11][C:10]=1[C:24]([OH:26])=[O:25]>CO>[CH3:1][O:25][C:24]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[CH2:8][CH2:7][OH:6])=[CH:16][C:15]([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[CH:14][CH:13]=2)=[O:26]
Reactant: O=C(O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Yield: 93.6 %

Procedure:
2.7 ml (42 mmoles) of methanesulphonic acid were added to a suspension de 6 g (21 mmoles) of the 3-(2-hydroxyethyl)-5-[1,2,4]triazol-1-ylmethyl-1H-indol-2-carboxylic acid in 120 ml of methanol. The mixture was left under stirring at reflux temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 20 ml of a saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness, and the evaporated solid recrystallised from isopropyl alcohol/heptane to give 5.9 g (93%) of the title ester as a yellow crystalline solid.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:14]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].[O-2].[Mg+2]>C1COCC1.CCCCCC>[CH2:14]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNCCCC
Reactant: CC(C)(C)CC(C)(C)CC=CCCl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(CC=CCC(C)(C)CC(C)(C)C)CCCC

Procedure:
10 g (49.5 mmol) of 1-chloro-5,5,7,7-tetramethyl-2-octene, 64 g (495 mmol) of di-n-butylamine and 10 g (248 mmol) of magnesium oxide in 30 ml of THF are refluxed for 4.5 h. The mixture is taken up in 200 ml of hexane, extracted twice with 5% strength methanolic NaOH and once with water and dried at 30° C./1 mbar. Yield: quantitative.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 24, 920.4 mg of the title compound was afforded (quantitative).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[N:11]([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: CSc1nc(SCc2ccccc2)n[nH]1
Product: CSc1nc(SCc2ccccc2)nn1-c1ncccn1

Procedure:
The product of stage (a) (50 g) was treated with 2-chloropyrimidine (24.4 g) in a method analogous to that of Example F, to give, after chromatographic separation of two products, 23.6 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[N:28]1([C:24](=[O:26])[CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: C1CNC1
Solvent: ClCCl
Product: O=C(O)c1c(CC(=O)N2CCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
To a solution of 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (1.0 mmole) in CH2Cl2 (3 ml) was added azetidine(5 mmole) and stirring was continued at 22° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between aqueous HCl and AcOEt. The organic layer was dried, evaporated and the residue triturated with diethylether to give 3-(2-azetidin-1-yl-2-oxo-ethyl)-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 417.4 ([M+H]+).