Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[C:33]([CH3:40])=[CH:34][C:35]([F:39])=[C:36]([OH:38])[CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH2:24]([O:31][C:32]1[C:33]([CH3:40])=[CH:34][C:35]([F:39])=[C:36]([CH:37]=1)[O:38][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc(F)c(O)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(OCc4ccccc4)c(C)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 160 °C
Yield: 26.6 %

Procedure:
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (250 mg, 0.74 mmol) was added to a solution of 5-benzyloxy-2-fluoro-4-methylphenol (257 mg 1.1 mmol) and potassium t-butoxide (125 mg, 1.1 mmol) in DMSO (3 ml) and the mixture heated at 160° C. for 1.5 hours. The mixture was allowed to cool and was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(3-morpholinopropoxy)quinoline (105 mg, 69%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:6]1
Reactant: COC(=O)CCCC(C)=O
Reactant: SCC(S)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCC1(C)SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5 g, 0.0355 mol), methyl 4-acetylbutyrate (5.1 g, 0.0355 mol) and boron trifluoride etherate (1 ml) in methylene chloride (125 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 6.5 g (69%) of product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:44])[C:18](=[O:43])[C:19]3[CH:29]=[C:28]([CH2:30][CH2:31][O:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)[CH:27]=[N:26][C:20]=3[N:21]([CH2:24][CH3:25])[C:22]=2[N:23]=1>C(Cl)Cl>[CH2:24]([N:21]1[C:20]2[N:26]=[CH:27][C:28]([CH2:30][CH2:31][O:32][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N+:36]([O-:9])=[CH:35][CH:34]=3)=[CH:29][C:19]=2[C:18](=[O:43])[N:17]([CH3:44])[C:16]2[CH:15]=[CH:14][C:13]([F:12])=[N:23][C:22]1=2)[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(F)nc21
Solvent: ClCCl
Product: CCN1c2ncc(CCOc3cc[n+]([O-])c4ccccc34)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 51.3 %

Procedure:
Solid mCPBA (457 mg, 2.12 mmol) was added to a solution of 5,11-dihydro-2-fluoro-11-ethyl-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (470 mg, 1.06 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 13 h then was concentrated under reduced pressure. The residue was dissolved in CHCl3 (75 mL), the solution was successively washed with aqueous 10% Na2S2O3 (3×25 mL), aqueous saturated NaHCO3 (3×25 mL) and brine (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CHCl3:MeOH, 19:1 to 9:1) to give the title compound (250 mg, 51% yield) as a white solid: MS (ESI) m/z 460 (MH)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:23])(=[O:3])[CH3:2].[CH3:24][C:25]1[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:29]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:27]3[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:25]([CH3:24])=[N:29][CH:28]=3)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)n1COCC[Si](C)(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2C(Nc2ccc(Cl)cc2)CC1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cnc(C)n3COCC[Si](C)(C)C)cc2C(Nc2ccc(Cl)cc2)CC1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 52.9 %

Procedure:
[Step 1] 44 mg (cis:trans=3:1) of 1-acetyl-6-bromo-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline (compound 74) and 56 mg of 2-methyl-5-(tributylstannyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole were dissolved in 1 mL of DMF, and 6 mg of tetrakis(triphenylphosphine)palladium was added to the solution. The mixture was stirred in a sealed tube for 12 hours at 120° C. After completion of the reaction, DMF was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, and then the solution was filtered through Celite to remove any insoluble materials. The ethyl acetate solution was washed with water, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:aqueous ammonia=1:0.01). Thus, 31 mg (cis:trans=3:1, yield 53%) of 1-acetyl-6-{2-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1 H-imidazol-5-yl}-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a brown oily substance.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:22])[C:6]([C:23]([O:25]CC)=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([F:20])[C:12]=3[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 77.2 %

Procedure:
0.7 g of ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate is refluxed for 3 hours in a mixture of 6 ml of glacial acetic acid, 0.5 ml of water and 0.1 ml of concentrated sulphuric acid. The reaction mixture is treated with 100 ml of water, and the solid is filtered off with suction and dried. 0.5 g of 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (85% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([C:27]3[CH:28]=[CH:29][C:30]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=4)[CH:18]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([C:27]3[CH:28]=[CH:29][C:30]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=4)[CH:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CNCCCc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(CCCNCC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
To a suspension of 3-({3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-propylamino}-methyl)-azetidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in anhydrous DCM (2.8 mL) was added trifluoroacetic acid (1.4 mL). The mixture was stirred at rt under N2 for 3 days. The reaction mixture was concentrated and the crude was dissolved in EtOAc. The organic layer was washed with aqueous, saturated NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC [gradient 15 to 90% ACN/H2O+0.1% TFA]. The product containing fractions were collected, and the TFA was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (6 mg, 9%) as a white solid. 1H NMR (300 MHz, MeOD). 8.39 (s, 1H), 7.85 to 7.82 (m, 2H), 7.65 (s, 1H), 7.36 to 7.33 (m, 5H), 7.24 (d, 1H), 6.56 (s, 1H), 5.67 (s, 2H), 4.02 (t, 2H), 3.78 to 3.75 (m, 2H), 3.05 (t, 3H), 2.87 (d, 2H), 2.70 (t, 2H), 2.02 to 1.98 (m, 2H); ES-MS m/z 467.3 [M+H]+, RT (min) 2.82.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][NH2:45]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:45][CH2:44][C@@H:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NC[C@@H]1CCCO1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (S)-(tetrahydrofuran-2-yl)methanamine (45.6 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent. The fractions containing the title compound were pulled together and the solvent was evaporated yielding (S)-tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (50.0 mg, 21.94%). MS (ES+) m/z 506.4 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[NH:21][CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:27]([OH:29])=[O:28]>C(Cl)Cl>[C:2]([O:29][C:27]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)=[CH:24][N:23]=2)[CH2:18][CH2:19][CH2:20]1)=[O:28])([CH3:7])([CH3:3])[CH3:1]
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21

Procedure:
6-(5-Benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method IV, as illustrated above. It is then used to synthesize 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.C[Si]([N:32]=[C:33]=[O:34])(C)C>ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:33]([NH2:32])=[O:34])[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: NC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Reaction time: 60 h

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in a mixture of 1,2-dichloroethane (1 mL) and THF (1 mL) is added trimethylsilyl isocyanate (0.006 mL, 0.05 mmol) and stirred 60 hours. The reaction is concentrated and purified by column chromatography (silica, 20% methanol/dichloromethane) to provide 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid amide. 1H NMR (300 MHz, CD3OD) d 8.09 (s, 1H), 8.02 (d, 2H), 7.53 (dd, 1H), 3.90 (d, 4H), 3.49 (d, 4H), 3.30-3.24 (m, 2H), 2.65 (dt, 2H), 1.49 (d, 2H), 1.12-0.97 (m, 2H); MS (Ion spray) 471 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[CH3:2].[Cl-].[NH4+]>CO.O.[Zn]>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred solution of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-3-nitro-phenyl)-propionic acid ethyl ester (1.00 g, 2.82 mmol) in methanol (50 mL) was added a solution of ammonium chloride (2.26 g, 42.3 mmol) in water (25 mL) followed by zinc dust (<10 μM particle size) (1.84 g, 28.1 mmol). After stirring at ambient temperature for 30 minutes the reaction mixture was filtered through a pad of Celite® and residual soluble material eluted from the pad with methanol. The filtrate was concentarted in vacuo and the aqueous residue poured into water (100 mL), diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (75 mL), dried over sodium sulfate and concentrated in vacuo to give crude 3-(3-amino-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid ethyl ester as a green viscous solid which was used without further purification (0.89 g, 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:62])[C:3](=[O:61])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][CH2:32][C@H:33]([OH:60])[CH2:34][O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:38][CH:37]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:7][CH:6]=1>C(Cl)(Cl)Cl.CO>[OH:60][C@H:33]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)[CH2:32][NH:31][CH2:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3](=[O:61])[N:2]([CH3:1])[CH3:62])=[CH:6][CH:7]=3)=[O:15])[CH2:17][CH2:18]2)=[CH:28][CH:27]=1
Reactant: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C(=O)Oc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 56.6 %

Procedure:
4-{2-[({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl)carbonyl)amino]ethyl}phenyl dimethylcarbamate (0.22 g, 0.256 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.09 g, 0.145 mmol).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O1CCOCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[CH:1][N:8]([CH3:13])[CH3:9])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of N-Boc-4-piperidone (10 g, 50.19 mmol) and DMF-dimethylacetal (20.16 ml, 150.57 mmol) in 1,4-dioxane (100 ml) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7% MeOH in EtOAc) to give the title compound as an orange oil which crystallized on standing (10.51 g, 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:10]1([CH2:14][C:15]#[N:16])[CH2:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:12][CH2:11]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: N#CCBr
Product: N#CCN1CCC(c2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1,2,3,4,5,6-Hexahydro-[4,4′]bipyridinyl (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=202.2: CtRet=2.41.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>O1CCCC1.CN(C)C=O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
15.5 g of Z-Gly-Phe-Gly-OH [manufactured according to J. R. Vaughan & J. A. Eichler, J.Am.Chem.Soc. 75, 5556 (1953)] are dissolved in 100 ml of absolute tetrahydrofurane and 5.3 ml of absolute triethylamine and 4.64 ml of isobutyl chlorocarbonate are added dropwise to the solution cooled to -20°C, whilst stirring, in such a way that the internal temperature does a way that the internal temperature does not exceed -15°C. Thereafter the mixture is allowed to react for 10 minutes at -10°C, is then again cooled to -20°C, and a solution of 7.6 g of H-Pro-OtBu in 30 ml of dimethylformamide is added dropwise whilst stirring, in such a way that the internal temperature does not exceed 0°C. The mixture is allowed to stand for 18 hours at 0°C, the triethylamine hydrochloride is then filtered off and the filtrate is evaporated at 40°C bath temperature. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with sodium bicarbonate solution, water, 10 % strength tartaric acid solution and water, dried with sodium sulphate and evaporated. The residue is crystallised from ethyl acetate-petroleum ether, melting point 66°- 71°C; [α]D20 = - 45° (c = 1% in chloroform).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:60])([F:59])[C:12]([F:58])([F:57])[O:13][C:14]([F:56])([F:55])[C:15]([F:54])([C:50]([F:53])([F:52])[F:51])[O:16][C:17]([F:49])([F:48])[C:18]([F:47])([F:46])[O:19][C:20]([F:45])([C:41]([F:44])([F:43])[F:42])[C:21]([F:40])([F:39])[O:22][C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)(=O)C.Cl.O>CO>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:35])([F:36])[C:23]([F:37])([F:38])[O:22][C:21]([F:39])([F:40])[C:20]([F:45])([C:41]([F:42])([F:43])[F:44])[O:19][C:18]([F:46])([F:47])[C:17]([F:48])([F:49])[O:16][C:15]([F:54])([C:50]([F:51])([F:52])[F:53])[C:14]([F:55])([F:56])[O:13][C:12]([F:58])([F:57])[C:11]([F:60])([F:59])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(OC(C)=O)cc2)C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)cc2)C(F)(F)F)cc1
Yield: 32 %

Procedure:
To a solution of 4-iodophenyl acetate (7.86 g, 0.030 mole) and 1,14-diiodoerfluoro-5,10-dimethyl-3,6,9,12-tetraoxatetradecane (9.20 g, 0.010 mole) in 45 ml of N,N-dimethylformamide was added copper bronze (5.08 g, 0.080 g atom). This slurry was stirred under nitrogen at 115°-117° C for 96 hours. The cooled reaction mixture was added to a stirred mixture of 150 ml of ether and 200 ml of water. The cuprous salts and excess copper were filtered off and the ether layer was washed repeatedly with water until free from the reaction solvent. The ethereal solution was evaporated to dryness to give a brown oil which was refluxed in 20 ml of acetic anhydride for 15 minutes. The excess acetic anhydride was distilled off and the residue was distilled under reduced pressure to give 3.40 g of 1,14-bis (4-acetoxyphenyl)perfluoro-5,10-dimethyl-3,6,9,12-tetraoxatetradecane, b.p. 180°-185° C/0.30 mm. This water-white oil was refluxed for an hour in a solution of 10 ml of concentrated hydrochloric acid (0.12 mole) in 100 ml of methanol. The solvent was evaporated under reduced pressure and the resultant tan residue was taken up in 600 ml of hexane. This solution was treated with charcoal, filtered, and reduced in volume to give 2.72 g (32% yield) of product (III) as a viscous water-white oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]1=[O:13]
Reactant: Br
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2CC1Br

Procedure:
Analogously to Example 1 (a), reaction of 12.39 g (70.0 mmoles) of 6-nitro-1-indanone in 130 ml of glacial acetic acid, containing 0.5 ml of 48% strength aqueous hydrobromic acid, and 11.2 g (70 mmoles) of bromine in 70 ml of glacial acetic acid, in accordance with the instructions indicated above, gives 2-bromo-6-nitro-1-indanone of melting point 102°-105° C. which, as the pure product after reprecipitation from ethanol/water, has a melting point of 114°-116° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH:21]=[N+:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH:21]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methoxy-benzylidene)-piperidinium chloride.