Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1.[OH:16][C:17]([CH3:50])([CH3:49])[CH2:18][C@@:19]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:24][C:23](=[O:25])[N:22]([C@H:26]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH3:27])[CH2:21][CH2:20]1>CN(C)C=O>[OH:16][C:17]([CH3:49])([CH3:50])[CH2:18][C@@:19]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:24][C:23](=[O:25])[N:22]([C@H:26]([C:28]2[CH:29]=[CH:30][C:31]([C:8]3[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=3)=[CH:32][CH:33]=2)[CH3:27])[CH2:21][CH2:20]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)n1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
2 M aqueous Na2CO3 solution (0.75 mL) was added to a solution of 4-bromo-1-isopropyl-1H-pyrazole (0.15 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.25 g) in dimethylformamide (2 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (13 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 6 h. Then another portion of [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (13 mg) was added and the mixture was further stirred at 100° C. overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) followed by chromatography on silica gel (tert-butyl methyl ether/dichloromethane/NH4OH 95:5:0.1) to afford the title compound as a solid. Yield: 23 mg (9% of theory); Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 59 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH:12]=[O:13])=[N:7]2.[Na].CO.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH2:12][OH:13])=[N:7]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (113 mg, 0.37 mmol) and sodium triacetoxyhydroborate (78 mg, 0.37 mmol) in THF (7.5 mL) was stirred at 25° C. for 10 min. MeOH (1.0 mL) was added, and the resulting mixture was stirred at 25° C. for 10 min. Additional sodium triacetoxyhydroborate (78 mg, 0.37 mmol) was added, and the resulting mixture was stirred at 25° C. for 10 min. Further sodium triacetoxyhydroborate (78 mg, 0.37 mmol) was added, and the resulting mixture was stirred at 25° C. for 10 min. Saturated aq. NaHCO3 (10 mL) was then added, and the resulting mixture was partitioned between EtOAc (70 mL) and half-saturated aq. NaHCO3 solution (50 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide (5-bromo-3-(tert-butylamino)quinoxalin-2-yl)methanol (114 mg, 0.37 mmol, 100% yield) as a yellow-brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, d, J=7.6 Hz), 7.76 (1H, d, J=8.0 Hz), 7.20 (1H, t, J=7.9 Hz), 5.10 (1H, br. s.), 4.72 (2H, s), 3.92 (1H, br. s.), 1.62 (9H, s). m/z (ESI, +ve) 310.0/312.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CC(C)=O>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: NC(=O)c1ccccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 16.3 g of 2-aminobenzamide, 82 ml of saturated aqueous sodium acetate solution and 82 ml of acetic acid was added a solution of 21 g of 4-chlorobenzoyl chloride in 14 ml of acetone. The mixture was stirred at room temperature for one hour after addition was complete. The tan precipitate was collected by filtration and recrystallized from ethanol to give 24.1 g of light tan 2-(4-chlorobenzamido)benzamide, m.p. 205°-207°, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].O.CN([CH:15]=[O:16])C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:15](=[O:16])[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To the solution of 4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL), was added CU (23 g, 0.14 mol) as the solid. The reaction solution was stirred at room temperature for 1 hour, then water (500 mL) was added. The precipitated solid was collected by filtration, washed with water, dried thoroughly to afford the titled compound (26.0 g, 90%). The crude product was used in the following reaction without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]2[F:14])[N:6]=1)(=[O:4])=[O:3].C(O)C(O)C.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>O>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]2[F:14])[N:6]=1)(=[O:4])=[O:3]
Reactant: Nc1ccccc1F
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Solvent: O
Solvent: CC(O)CO
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3ccccc3F)nn12
Temperature: 5 °C

Procedure:
A mixture of 12.5 g (46.9 mmol) of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine and 25 mL of 1,2-propanediol was placed in a round bottom flask and cooled to 5° C. under nitrogen. 2-Fluoroaniline (13.7 g, 123 mmol) was added with stirring and cooling over a 10-min period. There was an exotherm. The mixture was allowed to warm to ambient temperature with stirring overnight and was then diluted with 30 mL of water. The mixture was stirred for 30 min and the solids present were then collected by filtration, washed with 2×25 mL of water and 2×25 mL of 2-propanol. The resulting solid was recrystallized from about 175 mL of 2-propanol and dried under reduced pressure at 45° C. to obtain 13.2 g (82.5 percent of theory) of the title compound as a white solid of 99 percent purity. The structure of this compound was confirmed by its proton nuclear magnetic resonance spectrum (300 MegaHertz, D-6 acetone): 9.70(s, 1H), 8.17(d, 1H, J=1.9 Hertz), 7.58(m, 1H), 7.24(m, 1H), 7.16(m, 2H), 4.29(s, 3H) and its C-13 carbon nuclear magnetic resonance spectrum (75 MegaHertz, D-6 acetone): 165.6, 156.8(d, J=244.8 Hertz), 149.1(d, J=26.1), 147.8, 145.7(d, J=252.9), 130.2(d, J=21.8), 128.5(d, J=4.1), 125(m), 116.7(d, J=19.7), 57.6.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]C(OCC)=O)[CH:15]=1.C[O-].[Na+]>Cl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4](=[O:6])[CH2:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 20 h

Procedure:
A mixture of 27.6 g of ethyl 2,4-dichlorobenzoate and 20.81 g of ethyl 3-pyridylacetate at 20°-25° is treated portionwise with 10.59 g of sodium methoxide. The mixture is subsequently heated at 65°-70° and resulting readily volatile products are blown off with dry nitrogen. After 20 hours, the mixture is treated with 40 ml of concentrated hydrochloric acid and heated at reflux temperature for 18 hours. The mixture is washed with diethyl ether and the aqueous phase is made basic by adding concentrated ammonia and extracted with methylene chloride. The organic phase is concentrated and the crude product is chromatographed on silica gel with methylene chloride/methanol (98:2) to yield 2',4'-dichloro-2-(3-pyridyl)-acetophenone, which can be crystallized from diethyl ether/n-pentane and melts at 55°-56°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9](Br)=[CH:8][CH:7]=2.C[S-].[Na+].[CH3:28][S:29]C>>[NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([S:29][CH3:28])=[CH:8][CH:7]=2
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Reactant: CSC
Agent: C[S-]
Agent: [Na+]
Product: CSc1ccc2c(=O)n(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (0.19 g, 0.50 mmol), sodium thiomethoxide (0.043 g, 0.60 mmol) and dimethylsulfide (2 mL) was stirred at 70° C. for 2 h. To the reaction mixture was added another sodium thiomethoxide (0.043 g, 0.60 mmol), and the resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The extracts were combined and washed once each with saturated aqueous sodium hydrogencarbonate (25 mL) and saturated brine (25 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:5 (v/v)) to give 3-(aminomethyl)-2-isobutyl-6-(methylsulfanyl)-4-phenyl-1(2H)-isoquinolinone (0.16 g, 88%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH2:11][CH3:12])[CH2:9][NH:8][C:7](=S)[C:6]1=[O:14].[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29]([NH:31][NH2:32])=O>C(O)CCC>[Cl:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH2:11][CH3:12])[CH2:9][N:8]2[C:29]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][N:23]=3)=[N:31][N:32]=[C:7]2[C:6]1=[O:14]
Reactant: CC[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: NNC(=O)c1cnccn1
Solvent: CCCCO
Product: CC[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of Intermediate 6 (100 mg, 0.29 mmol) and pyrazine-2-carbohydrazide (39 mg, 0.29 mmol) in 1-butanol (3 mL) was heated to 130° C. for 16 h. After cooling to rt, the reaction was concentrated to give a brown oil. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a white solid (94 mg, 75%). MS (ESI): mass calcd. for C19H16ClF3N6O, 436.1; m/z found, 437.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.62 (d, J=1.5 Hz, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.62 (dd, J=2.5, 1.6 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.69 (dd, J=7.8, 1.1 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 5.56-5.42 (m, 2H), 4.54 (d, J=15.5 Hz, 1H), 4.46 (dd, J=14.1, 4.4 Hz, 1H), 3.77 (ddd, J=9.4, 4.6, 3.5 Hz, 1H), 1.87-1.78 (m, 1H), 1.63-1.53 (m, 1H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a 0° C. solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 45.4 mmol), triethylamine (9.47 ml, 68.1 mmol) and dimethylaminopyridine (0.55 g, 4.5 mmol) in CH2Cl2 (150 ml) was added portionwise p-toluenesulfonyl chloride (9.52 g, 49.9 mmol). After 48 hours stirring at room temperature, reaction mixture was acidified to pH 1 with 1N HCl and aqueous phase was extracted with CH2Cl2. Combined organic phases were washed with 1N HCl and H2O, dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 8:2 then 1:1) to provide (S)-3-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (13.1 g, 87%) as a slightly yellow oil, MS: m/e=268.1 (M-OtBu) and [α]D20=+17.55° (c=3.33, diethylether).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[F:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH2:61][CH:62]=[O:63])=[CH:56][CH:55]=2)[CH:50]=[C:51]([F:53])[CH:52]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([C@@H:62]([OH:63])[CH2:61][CH2:60][C:57]1[CH:58]=[CH:59][C:54]([C:49]2[CH:48]=[C:47]([F:46])[CH:52]=[C:51]([F:53])[CH:50]=2)=[CH:55][CH:56]=1)[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: O=C(CCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
In a flame-dried flask, 3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one (0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C. Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise and the reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine (0.36 mL) was added slowly to the reaction mixture and stirred at 0° C. for 20 minutes. A solution of the compound obtained from step e above (0.187 g) in dichloromethane (10 mL) was added slowly and stirring was continued at 0° C. After 3 hours, the reaction was quenched with the drop-wise addition of saturated ammonium chloride solution, and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluant to afford the title compound (0.24 g).
Reaction SMILES: [OH:1][C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>>[CH:17]1([C:20]([O:1][C:2]2[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1cccc(C(=O)CC)c1O
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared in 2 steps. The first step was carried out according to the procedure of Intermediate CXXVII starting from ethyl 2-hydroxy-3-propionylbenzoate instead of methyl 2-hydroxy-3-propionylbenzoate and from cyclopropylcarbonyl chloride (prepared as described by G. B. Payne et al., J. Org. Chem. 22, 1680 (1957)) instead of 2-phenylbenzoyl chloride. The reaction was carried for 2 hours at 80° C. After cooling, to room temperature, the mixture was concentrated (in vacuo) to a small volume and added to water. The crude methyl 2-cyclopropylcarbonyloxy-3-propionylbenzoate so obtained was used for the second step without further purification.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)=[CH:10][C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.O.[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC#N.O.C(Cl)CCl>[CH:1]1([N:7]2[C:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:44][C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[O:18])=[CH:15][CH:14]=3)=[CH:10][C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 44.4 mg product from Step B above, 28.8 mg EDC, 20.3 mg HOBt and 13.4 mg aminotetrazole monohydrate was dissolved in 1 mL DMF. DIEA (44 μL) was added immediately and the resulting solution was stirred at room temperature for five days. The reaction mixture was diluted with a mixture of DMF, MeCN, and water and purified on preparative HPLC using 70˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA. The title compound was obtained as a white solid following lyophilization. 1H NMR (CD3OD, 500 MHz) δ 8.03 (d, J=8.3 Hz, 2H), 7.84˜7.86 (m, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 6.47 (s, 1H), 4.23 (s, 2H), 4.055 (tt, J=3.7 & 11.7 Hz, 1H), 1.88˜1.97 (m, 2H), 1.81˜1.85 (m, 2H), 1.67˜1.73 (m, 3H), 1.25˜1.39 (m, 3H). LC-MS: 2.34 min. (M+H=512.2).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[C:6]1([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([S:12]([NH:15][C:16]([N:4]2[CH2:5][CH:3]2[C:1]#[N:2])=[O:17])(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1CN1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.82 g. 2-Cyanoaziridine are dissolved in 8 ml. toluene and, while cooling with ice, 2 g. phenylsulphonyl isocyanate, dissolved in 10 ml. toluene, are added dropwise thereto. After further stirring the reaction mixture for 45 minutes at ambient temperature, the precipitated crystals are filtered off with suction, washed with diethyl ether and dried in a vacuum. There is thus obtained 1.45 g. (53% of theory) 1-(N-phenylsulphonyl-carbamoyl)2-cyanoaziridine in the form of white crystals; m.p. 103°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].CN(C=O)C.[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O>[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=4[C:10]=3[CH3:16])=[O:15])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27]
Reactant: CCOc1cccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 115 mg (0.46 mmol) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid in 2 mL of oxalyl chloride was refluxed for 4 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 201 mg (0.56 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were then removed under vacuum. Column chromatography with silica gel gave 237 mg (93% yield) of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([OH:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:10][C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: Oc1ccc2cc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridin-6-ol (1.52 g, 11.4 mmol) and potassium carbonate (7.86 g, 57 mmol) in acetone (100 mL) was stirred under nitrogen at room temperature for 1 h. Iodomethane (2.6 g, 18.2 mmol) was added and the resulting mixture stirred at 56° C. for 12 h. The mixture was filtered, and the filtrate was concentrated to half its volume, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 20% ethyl acetate/hexanes) to afford 6-methoxy-1H-pyrrolo[2,3-b]pyridine (0.5 g, 30%): LC/MS m/e calcd for C8H8N2O [M+H]+ 149.17, observed 149.1.