Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C1(C)C=CC=CC=1>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:28][C@@H:26]2[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:30][C@@:18]4([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:19][C:20](=[O:29])[C@@H:21]3[CH2:27]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: C1CN2CCN1CC2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Reaction time: 0.25 h

Procedure:
A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (22.1 g, 44.8 mmol) and DABCO (8.5 g, 76.7 mmol) in toluene (88 mL) was stirred at room temperature. To this solution was added a solution of 4-bromobenzene-1-sulfonyl chloride 17.2 g, 67.2 mmol) in toluene (44 mL). After the addition was complete the reaction mixture was quenched with 10% aqueous sodium carbonate (110 mL) and the mixture stirred for 15 min. Tetrahydrofuran (44 mL) was added and the mixture was washed with 0.5 M HCl, water, and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure and dried to provide the title compound (27.7 g, 87% yield), which was used without further purification.}
Reaction SMILES: O[CH:2]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25].[K+].[Br-]>ClCCl.C(OCC)(=O)C>[F:22][C:23]([F:34])([F:33])[C:24]([O:26][CH2:5][CH2:4][CH2:3][CH2:2][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:17](=[O:19])[C:20]=2[CH:21]=1)=[O:25]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC(O)c1ccc(OCc2ccsc2C(=O)O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1c2cc(CCCCOC(=O)C(F)(F)F)ccc2OCc2ccsc21
Reaction time: 48 h

Procedure:
A stirred suspension of 14.33 g (0.468 mol) of 3-[4-(1-hydroxybutyl)phenoxy]methyl-2-thiophenecarboxylic acid and 150 ml of anhydrous CH2Cl2 was treated with one portion of trifluoroacetic anhydride (22.60 g, 0.107 mol). The suspended material rapidly dissolved and the stirred solution was heated under reflux for four hours. After standing two days at ambient temperature, the reaction was quenched with water (70 ml) and washed with 50 ml of 5% NaHCO3 solution. The dried (Na2SO4) organic phase was concentrated to an oil, which was further dried by azeotropic distillation of toluene. The oil was dissolved in approximately 15 ml of isopropanol, seeded with product previously prepared on a smaller scale, and stirred until a thick crystalline mass formed. The mass was triturated with isopropanol, followed by vacuum filtration. The filter cake was dried in vacuo at 40° C. to afford 15.08 g (83.8%) of almost colorless crystals, m.p. 65.5°-67° C. The material appeared pure by TLC (siica gel, ethyl acetate, Rf =0.70; dichloromethane, Rf =0.51) and the IR (KBr), 1H-NMR (CDCl3) and MS (M+, 384) were consistent with structure.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
Add TFA (6.54 g, 57.4 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acid tert-butyl ester (1.05 g, 2.87 mmol) in DCM (20 ml) and stir at ambient temperature for four hours. Concentrate mixture on rotary evaporator and purify on cation exchange column (10 g, Varian) to give the title compound (519 mg) as a white solid. Mass spectrum (ion spray): m/z=284 (M+1); 1HNMR (DMSO-d6): 8.58 (s, 1H), 8.21 (d, 1H), 8.06 (br s, 1H), 7.44 (br s, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 3.05 (m, 1H), 2.84 (m, 2H), 2.77 (m, 1H), 2.62 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.71 (br s, 2H).
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18](F)=[O:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[CH:21]([CH2:26][OH:27])([CH2:24][Br:25])[CH2:22][Br:23]>>[CH:21]([CH2:26][O:27][C:18]([C:12]([O:11][C:8]([C:5]([C:1]([F:2])([F:3])[F:4])([F:6])[F:7])([F:10])[F:9])([C:14]([F:16])([F:17])[F:15])[F:13])=[O:19])([CH2:24][Br:25])[CH2:22][Br:23]
Reactant: OCC(CBr)CBr
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Product: O=C(OCC(CBr)CBr)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
CF3CF2CF2OCF(CF3)COF obtained in Example 1-7 is reacted with (BrCH2)2CHCH2OH under the same conditions as the above esterification reaction to obtain (BrCH2)2CHCH2OCOCF(CF3)OCF2CF2CF3. Employing the obtained (BrCH2)2CHCH2OCOCF(CF3)OCF2CF2CF3, the same reactions as in Example 1-3 to 1-7 are carried out to obtain (FSO2CF2)2CFCOF and CF3CF2CF2OCF(CF3)COF.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O.C(OCC)(=O)C>[CH2:34]([N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[C:16]2[N:15]=[C:14]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:4]([Cl:3])[CH:5]=3)[O:18][N:17]=2)[C:24]([CH2:28][CH2:29][C:30]([O:32][CH2:5][CH2:4][CH2:9][CH3:8])=[O:31])=[CH:25]1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCI
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCc1cn(CCCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (65 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodobutane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford butyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg). δH (CDCl3, 400 MHz): 0.73 (3H, t), 0.92 (3H, t), 1.03 (2H, m), 1.34 (2H, m), 1.45 (8H, m), 1.59 (2H, m), 2.71 (2H, t), 3.12 (2H, t), 4.08 (2H, t), 4.16 (2H, t), 4.72 (1H, m), 6.94 (1H, s), 7.07 (1H, d), 7.19 (1H, t), 7.53 (1H, dd), 7.76 (1H, dd), 8.08 (1H, dd), 8.25 (1H, d); MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH2:10])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32](F)[N:31]=1)[CH3:23].CCN(C(C)C)C(C)C>CS(C)=O>[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:10][C@H:8]([C:6]2[N:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)[CH3:9])[N:31]=1)[CH3:23]
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([C@H](C)Nc2nccc(N3C(=O)OC[C@@H]3[C@H](C)F)n2)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A solution of (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (28.1 mg, 0.1 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (22.9 mg, 0.100 mmol) and DIPEA (52.4 μl, 0.300 mmol) in DMSO (Volume: 500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt, and RP-HPLC (acetonitrile:water) purification provided a white solid. This material was purified again with flash column chromatography (0-10% MeOH/EtOAc) to give 14 mg (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (dd, J=5.0, 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=5.8 Hz, 1H), 5.08 (br s, 1H), 4.73 (br d, J=26.0 Hz, 1H), 4.56-4.27 (m, 3H), 2.32 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.12 (br s, 3H); HRMS (B) m/z 491.1782 (M+H)+. Anal. RP-HPLC tR=3.42 min. Purity 100%/100%.
Reaction SMILES: ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N.[Br:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([N+:26]([O-])=O)[C:20]=1[Cl:29]>>[Br:18][C:19]1[C:20]([Cl:29])=[C:21]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[NH2:26]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1Cl
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: Nc1cc(Cl)cc(Br)c1Cl
Yield: 24 %

Procedure:
This material was prepared according to the procedure used for SM-9, step 2 using 1-bromo-2,5-dichloro-3-nitrobenzene. Purification by flash chromatography (SiO2, 0-30% EtOAc in heptane) provided 3-bromo-2,5-dichloroaniline (24%): LCMS (m/z) 239.9 (MH+), tR=1.03 minutes; 1H NMR (400 MHz, CDCl3) δ 4.28 (br s, 2H) 6.71 (d, J=2.4 Hz, 1H) 7.02 (d, J=2.4 Hz, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[NH2:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CC(=O)Nc2sccc2C(N)=NO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS(ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1.[I-:20].[Na+].COC(C)(C)C>CC(C)=O>[I:20][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: [I-]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CI

Procedure:
A suspension of 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (3.2 g, 11 mmol; example 19 a]) and sodium iodide (8.25 g, 55 mmol) in acetone (56 ml) was heated under reflux conditions for 30 min. Tert butyl methyl ether was added, the solid was filtered off and the filtrate was brought to dryness under reduced pressure. The residue was dissolved in tert butyl methyl ether, washed with ice water/brine 1/1 and the aqueous layer was extracted two times with tert butyl methyl ether. The combined extracts were washed with aqueous sodium thiosulfate solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: Cc1ccc(CCl)c(SC(C)C)n1
Product: Cc1ccc(COc2ccc(CCC(=O)O)cc2Cl)c(SC(C)C)n1
Yield: 49.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine (34 mg, 0.17 mmol) obtained in Step D of Preparation Example 9 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 58%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].N1([CH:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:27][C:28](=[O:30])[O-:29])C=CC=N1>>[C:34]([O:33][C:32](=[O:38])[N:31]=[C:26]([NH:27][C:28]([O:29][C:5]([CH3:6])([CH3:20])[CH3:4])=[O:30])[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([CH2:8][CH2:9][C:10]([OH:17])([CH2:11][CH2:12][CH3:13])[CH2:14][CH2:15][CH3:16])[CH:6]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CCCC(O)(CCC)CCc1cccc(CCCN)c1
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Product: CCCC(O)(CCC)CCc1cccc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate following the method described in Example 168 gives tert-butyl(tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(CN2CCC(Cc3ccc(F)cc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(CC2CCN(CC3CCNC3)CC2)cc1
Reaction time: 14 h

Procedure:
To a stirring solution of 3-[4-(4-flourophenylmethyl)piperidinomethyl]-N-(benzyloxycarbonyl)-pyrrolidine (600 mg, 1.47 mmol) and 5% palladium on carbon (60 mg, Aldrich) in MeOH (50 mL) was added 50 psi of hydrogen. The reaction was stirred for 14 h. The reaction was filtered and the filtrate was conc. in vacuo to a colorless oil. The oil can be used without further purification. MS (ESI) 277 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:13]([OH:15])(=[O:14])=[O:12])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)O
Yield: 22.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2,4-difluoronitrobenzene (2.0 g, 12.0 mmol) in EtOH (24 ml) and Na2SO3 (3.6 g, 28 mmol) in EtOH:water (32 ml: 40 ml) at 70° C. for 14 h gave the title compound (0.6 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccc(OS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
In a reaction flask 5 mg of palladium on charcoal were added to 50 mg of 4-isopropylbenzenesulfonic acid 6-(4-allyl-piperazin-1-yl)-pyridin-3-yl ester from example 59(0.12 mmol) in dry ethyl acetate (5 ml). The atmosphere was then charged with hydrogen gas and the reaction mixture was stirred at room temperature for 1 hour. Thereby, 4-isopropyl-benzenesulfonic acid 6-(4-propyl-piperazin-1-yl)-pyridin-3-yl ester were obtained in 58% yield. The compound was converted into its hydrochloride salt by addition of HCl in ether.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:69]=[C:70]1[CH:74]=[CH:73][C:72](=[O:75])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH2:84])=[O:82].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>CN(C=O)C>[O:75]=[C:72]1[CH:73]=[CH:74][C:70](=[O:69])[N:71]1[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][C:81]([NH:83][NH:84][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:68])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:24]([O:62][CH3:63])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:60][CH3:61])[C@@H:34]([CH3:59])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:82]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 mg (9.5 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 72) were dissolved in 1000 μl of DMF and then admixed with 10 mg (38 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide, 7.2 mg (19 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 8 μl of N,N-diisopropylethylamine, and the reaction mixture was stirred at RT for 1 h. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization, 6.4 mg (58% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]3)[C:7]=2[N:13]=1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Yield: 67.1 %

Procedure:
6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 204, 0.085 g, 0.48 mmol) was deprotonated with sodium hydride (0.030 g, 60% in oil, 0.7.5 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.05 mmol) as described for Intermediate 2. Chromatography on silica gel with 0-25% acetone in dichloromethane gave 0.13 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1(C)C=CC=CC=1>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Reactant: CCCCNCCCC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 41.5 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.66 g of dibutylamine in 100 ml of toluene. After chromatography and recrystallization in petroleum ether, 1.5 g of N,N-dibutyl 1-phenyl isoquinoline 3-carboxamide melting at 62° C. is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][C:5]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
NaH (0.177 g, 4.42 mmol) was added to 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.450 g, 2.95 mmol) in dimethylformamide (“DMF”; 5 mL) at 0° C. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was then cooled to 0° C. Chlorotriisopropylsilane (0.945 mL, 4.42 mmol) was added to the mixture. The reaction mixture was warmed to 70° C. and stirred for 2 hours. Next, the reaction was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The resulting residue was purified by column chromatography (10:1 hexanes:DCM) to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.55 g, 60.4% yield).