Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1>O>[N:22]1([C:8]2[S:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1C(F)(F)F
Temperature: 25 °C
Yield: 287.7 %

Procedure:
A reaction vessel was charged with 150 ml dimethylacetamide, 13.0 g (50 mmol) ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate and 11.8 g (100 mmol) benzimidazole. The reaction mixture was heated at a temperature of 115°-125° C. for 96 hours. The mixture was cooled to room temperature, diluted with water and extracted three times with ethyl ether. The combined ether extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to provide 49.1 g of a dark gold oil. This oil was subjected to Kugelrohr distillation (90° C. @0.5 mm Hg) to provide 31.7 g of a yellow oil product identified in Table I.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2.31 g, 10.03 mmol, 1.00 equiv) in dichloromethane (20 mL) and a solution of thionyl chloride (1.5 mL, 2.00 equiv) in dichloromethane (3 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×25 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×15 mL of sodium bicarbonate aq. and 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 1.16 g (46%) of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate as a off-white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:4]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:11]1[C:12]([NH2:15])=[N:13][CH:14]=[C:9]([C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4]2)[N:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CO[C@H]1CCC[C@@H](c2cnc(N)cn2)C1
Solvent: CC#N
Product: CO[C@H]1CCC[C@@H](c2cnc(N)c(Br)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
(+/−)-N,N-di-Boc-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (184 mg, 0.452 mmol) in DCM (4. 515 mL) was added HCl (4M in dioxane) (4.515 mL, 18.06 mmol). The reaction mixture was stirred at room temperature overnight. After the volatile material was removed in vacuo, the residue was dissolved in EtOAc. The organic layer was washed by NaHCO3 solution, water and brine, dried over anhydrous Na2SO4, and concentrated affording (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 208 (MH+), 0.43 min. To a solution of (+/−)-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine (54 mg, 0.261 mmol) in acetonitrile (4. 008 μL) was added NBS (48.7 mg, 0.274 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. After quenched with NaHCO3, extracted with EtOAc three times. The organic layer was washed by water and brine, dried over anhydrous Na2SO4, and concentrated to afford 75 mg of (+/−)-3-bromo-5-((1R,3S)-3-methoxycyclohexyl)pyrazin-2-amine in quantitative yield. LCMS (m/z): 286 (MH+), 0.73 min.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([NH:14][CH2:16][CH2:17][CH2:18][Cl:19])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCNC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Yield: 100.1 %

Procedure:
A mixture of 0.1 mole of benzhydrylamine, 39.3 g (0.25 moles) of 1-bromo-3-chloropropane, 13.8 g (0.1 mole) of potassium carbonate, 20.0 ml of dimethylformamide and 20.0 ml of water were heated at 75° C. for 2 hr. The organic layer was separated and concentrated on a rotary high vacuum evaporator to give 26 g of title compound of 85-90% purity of title compound containing about 5% each of benzhydrylamine and 1-benzhydrylazetidine. The following 1NNMR analysis was obtained:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[CH3:14][C:15]([CH3:17])=[O:16]>CCOCC>[Br:8][C:4]1[N:3]=[C:2]([C:15]([OH:16])([CH3:17])[CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2,6-dibromopyridine (1.0 eq.) in Et2O (0.2M) at −78° C. was added dropwise n-BuLi (1.05 eq.). The mixture was stirred at −78° C. for 45 min then acetone (1.5 eq.) was added. The final mixture was stirred for an extra 15 min at −78° C. and quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with, brine, dried over MgSO4, filtered and concentrated to afford the title compound as a white solid which was used as such.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH2:6][O:7][C:8](=[O:11])[CH2:9]Br)[CH2:4]1)[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2].[C:27]([O-:32])(=[O:31])[CH:28]([CH3:30])[CH3:29].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:13][C@H:12]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:5]2([CH3:4])[C@H:6]1[O:7][C:8](=[O:11])[CH2:9][O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(COC(=O)CBr)C1
Reactant: CC(C)C(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)C
Yield: 70.8 %

Procedure:
In a mixture of 50 ml of acetone and 10 ml of water are dissolved 1.5 g of 16β-ethyl-bromoacetoxy-4-estren-3-one and 0.8 g of potassium isobutyrate and the solution is refluxed for 6 hours. The acetone is distilled off under reduced pressure and the residue is extracted with 200 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of diisopropyl ether, elution is carried out with 300 ml of ethyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.08 g of the above-identified compound as a viscous oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=[O:6])[CH3:5].O.[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10].[Na].[OH-].[Na+]>C(O)C.O>[CH:2]([C:3]1[CH:15]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=[CH:5][C:4]=1[OH:6])([CH3:7])[CH3:1]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: CC(=O)CC(C)C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Methyl-2-pentanone (4.85 g, 48 mmol) in 40 mL of ethanol was added dropwise to a solution of sodium nitromalonaldehyde monohydrate (7.61 g, 48 mmol) in 40 mL of water. NaOH (48 ml of 1N aqueous solution) was then added to the reaction mixture. The mixture was stirred at room temperature overnight, and solvent was removed under reduced pressure. The residue was diluted with water and neutralized, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography with silica eluting with 15% ethyl acetate in hexanes to yield 4.7 g of 2-isopropyl-4-nitrophenol.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C@@H:17]12[O:25][CH2:24][C@@H:22]([O:23]1)[CH:21]=[CH:20][C@@H:18]2[OH:19]>C(N(CC)CC)C>[C:1]1([NH:7][C:8]([O:19][C@H:18]2[CH:20]=[CH:21][C@H:22]3[CH2:24][O:25][C@@H:17]2[O:23]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)O[C@H]1C=C[C@H]2CO[C@@H]1O2
Yield: 86.4 %

Procedure:
0.56 g of phenyl isocyanate was added at room temperature to 30 ml of a dry toluene solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas. Further, 0.1 ml of triethylamine was added thereto, and the reaction mixture was refluxed under heating for two hours. Completion of the reaction was confirmed by thin layer chromatography, and then the solvent was immediately distilled off under reduced pressure to obtain a syrup crude product. This crude product was purified by silica gel chromatography (ethyl acetate: hexane=1:3) to obtain 0.5 g of the desired product (Compound No. 23). The NMR analytical data of this product are as follows.
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].[OH:23][CH:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:25]([O:27]C)=O>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25](=[O:27])[CH:24]([OH:23])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(O)C(=O)N(CCCCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.00 g, 0.0035 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl 2-hydroxyhexadecanoate (0.94 g, 0.0035 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.8 g). The waxy solid was recrystalized from hot hexane (yield=1.09 g)
Reaction SMILES: CC1N=CC2C(C=1)=C([N+]([O-])=O)C=CC=2.[CH3:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[N+:26]([O-])=O.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:40]=[CH:39][C:34]([CH2:35][N:36]=[C:37]=[O:38])=[CH:33][CH:32]=1>>[CH3:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[NH:26][C:37]([NH:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:42])[F:41])=[CH:40][CH:39]=1)=[O:38]
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2cccc([N+](=O)[O-])c2cn1
Agent: Cc1cc2c([N+](=O)[O-])cccc2cn1
Product: Cc1cc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3)c2cn1

Procedure:
A sample of 3-methyl-5-nitroisoquinoline (Description 44) enriched in the nitration byproduct 3-methyl-8-nitroisoquinoline was reduced according to Description 45 and the mixture of amines reacted with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. Isomer separation of the products gave the title compound. m/z (ES+) 360 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]([OH:36])=O.C(N(C(C)C)C(C)C)C.[C:46]([C:50]1[O:54][C:53]([C:55]2[C:56]([NH2:74])=[N:57][CH:58]=[C:59]([C:61]3[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]4[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]4)[N:62]=3)[N:60]=2)=[N:52][N:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(#N)C>[NH2:74][C:56]1[N:57]=[CH:58][C:59]([C:61]2[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]3[CH2:69][CH2:70][N:71]([C:34](=[O:36])[CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH2:72][CH2:73]3)[N:62]=2)=[N:60][C:55]=1[C:53]1[O:54][C:50]([C:46]([CH3:47])([CH3:48])[CH3:49])=[N:51][N:52]=1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: O=C(O)CCOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C2CCN(C(=O)CCOC3CCCCO3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 106 g, 279.51 mmol), was added portionwise to a stirred solution of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (44.3 g, 254.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (89 mL, 508.21 mmol) dissolved in acetonitrile (600 mL) at 25° C. The resulting solution was stirred at 25° C. for 20 min then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (101 g, 254.10 mmol) was added portionwise washing the last portion into the mixture as a slurry in acetonitrile (300 mL). After stirring for 1 hour the precipitate was collected by filtration, washing with acetonitrile and drying in vacuo to afford 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 91%) as a beige solid. The filtrate was diluted with DCM (600 ml), washed with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 2 to 2.5% 7N ammonia in methanol with dichloromethane. A second crop of the desired product (40 g, 72.2 mmol, 28.4%) was obtained as a cream solid which was combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.29-1.48 (16H, m), 1.48-1.75 (4H, m), 1.83-1.99 (2H, m), 2.48-2.68 (2H, m), 2.68-2.79 (1H, m), 2.87-2.99 (1H, m), 3.07-3.19 (1H, m), 3.32-3.42 (1H, m), 3.47-3.6 (1H, m), 3.64-3.75 (1H, m), 3.75-3.84 (1H, m), 3.84-3.95 (1H, m), 4.24-4.39 (1H, m), 4.47-4.6 (3H, m), 7.84 (2H, s), 8.79 (1H, s): Mass Spectrum [M+Na]+=577.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45]2[C:50]([NH2:51])=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:57])=[O:56])[CH:53]=[CH:54][C:46]=23)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([NH:44][C:45]2[C:50]([NH:51][C:7](=[O:9])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:56])=[O:57])[CH:53]=[CH:54][C:46]=23)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: O=C(O)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 45.1 %

Procedure:
Cyclopentylacetic acid (0.532 ml, 4.24 mmol), diisopropylethylamine (1.5 ml, 8.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g, 4.70 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.00 mmol) in CH2Cl2 (60 ml) at 25° C. The reaction mixture was stirred for 9 h at 25° C., then was partitioned between 1.0 M HCl (125 ml) and CH2Cl2 (125 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 40%) as an off-white solid. LCMS (Method G, ESI): RT=1.15 min, m+H=582.5. This material was used in the next step below without additional characterization.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:31]([NH:30][C:22]2[CH:21]=[C:20]([Cl:19])[CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:32])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 100.9 %

Procedure:
1.0 g (3.66 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 1.12 g (3.66 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 7 to obtain 1.79 g (yield 100%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.57 (9H, s), 3.87 (3H, s), 7.14 (1H, d), 7.40-7.45 (2H, m), 7.85 (1H, d), 7.92 (1H, d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1ccc2ccccc2c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
70 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 115 mg of (2-methoxynaphthalen-1-yl)acetaldehyde were dissolved in 2 ml of tetrahydrofuran. Thereafter, 0.03 ml of acetic acid and 91 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 72 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[C:15]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: Cc1c(N)cccc1NC1=NCCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1cccc(NC2=NCCC2)c1C

Procedure:
The title compound (2.2 g) was prepared by the method of Example 23 using ethyl chloroformate and 3.0 g of the product aniline of Example 45. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].CN(C)C1C=CC=CC=1>>[Cl:25][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.2 g, 4.00 mmol, 1.00 equiv), POCl3 (12.2 g, 80.26 mmol, 20.00 equiv), N,N-dimethylbenzenamine (4.9 g, 40.50 mmol, 10.00 equiv). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 50 mL of water. The pH value of the aqueous solution was adjusted to 7 with sodium bicarbonate (4 mol/L). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 0.5 g (40%) of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C@@H:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of N-[[4-[(4-methylphenyl)thio]-phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 2a (2.4 g ,5.5 mmole) in DMF (50 ml) was added potassium carbonate (2.28 g, 16.5 mmole) and 4-(2-chloroethyl)morpholine hydrochloride (3.07 g, 16.5 mmole). After vigorously stirring at 60° C. for 18 hours, the reaction was worked up by adding water and extracting with ethyl acetate. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give an oil which was purified on silica gel eluting with 50/50 ethyl acetate/hexane to give N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)-ethyl]-D-valine, 1,1-dimethylethyl ester (3.62 g, 100%): anal. calc'd for C28H40N2S2O5 : C, 61.28; H, 7.35; N, 5.10. Found: C, 61.12; H. 7.69; N, 4.91. HRMS MH+ calc'd for C28H40N2S2O5 : 548.2379, found: 548.2386.