Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([O:27]CC)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH:8]=[CH:7]3)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3c(ccn3CC(=O)N[C@@H](Cc3ccccc3)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate and 4-tert-butylphenylsulfonyl chloride following the procedures of Example 10 Step 4 & Step 5: MS (ESI) m/z 534; MS (ESI) m/z 532.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]#[N:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]4[N:23]=[N:24][NH:25][N:20]=4)=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1-c1nn[nH]n1
Temperature: 80 °C
Yield: 72 %

Procedure:
A mixture of 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carbonitrile (0.10 g, 0.31 mmol), sodium azide (0.08 g, 1.57 mmol) and ammonium chloride (0.07 g, 1.57 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) was heated at 80° C. for 16 h. The reaction was quenched with the addition of water (2.0 mL) and the solvents were removed in vacuo. The residue was dissolved with ethyl acetate (10 mL), washed with water (2×2 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from methanol and ether to afford the title compound as a colourless solid (0.08 g, 72%): mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.42-7.37 (m, 2H), 7.23-7.17 (m, 2H), 6.17 (br, 1H), 5.02 (s, 2H), 2.75 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6 (d), 158.7, 151.8, 149.7, 148.6, 132.1 (d), 132.0, 129.9 (d), 115.4 (d), 113.6, 47.7, 16.7; MS (ES−) m/z 356.9 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1.[Si]([C:32]([F:35])([F:34])[F:33])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:25])[C:32]([F:35])([F:34])[F:33])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3F)C[C@H]2C)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@@H]1CN(c2ccc(F)cc2F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Yield: 81 %

Procedure:
To a solution of (R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)ethanone (360 mg, 0.87 mmol, prepared according to procedures similar to those described in Example 29A) was added TMSCF3 (5.2 mL, 0.5 M in THF, 2.6 mmol) and TBAF (0.87 mL, 1 M in THF, 1.0 mmol) at 0° C. The resultant mixture was stirred for 6 h then rt overnight. It washed with aq. NH4Cl and aq. layer was extracted with DCM. The organic layer was dried over Na2SO4. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (329 mg, 81%). HRMS: calcd for C20H21F5N2O3S+H+, 465.12658. found (ESI-FTMS, [M+H]1+), 465.12565.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH3:14].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:14])[CH3:9])[CH:7]=1
Reactant: N
Reactant: COc1c(Cl)cc(F)cc1C(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1c(Cl)cc(F)cc1C(C)N
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a stirred solution of 1-(5-fluoro-2-methoxy-3-chlorophenyl)ethanone (1.9 g, 9.38 mmol), titanium(IV) isopropoxide (5.54 mL, 18.76 mmol) and ammonia in ethanol (23.5 mL) was stirred under nitrogen in a capped flask at ambient temperature for 6 h. Sodium borohydride (0.53 g, 14.07 mmol) was added and resulting mixture was stirred at room temperature for 3 h. The reaction was then quenched by pouring into ammonium hydroxide (40 mL), the resulting inorganic precipitate was filtered off, and washed with ethyl acetate (2×40 mL). the organic layer was separated and aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to afford 1-(5-Fluoro-2-methoxy-3-chlorophenyl)ethanamine (1.7 g, 89%): 1H NMR (400 MHz, CDCl3): δ 6.78 (dd, 1H), 6.68 (dd, 1H), 4.25 (m, 1H), 3.82 (s, 3H), 1.42 (d, 3H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH2:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:13][CH2:14]2)([CH3:26])[CH3:27])=[CH:23][CH:24]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: CC(C)(N)c1ccc(Br)cc1
Product: CC1(C)COC2(CCC(O)(CCNC(C)(C)c3ccc(Br)cc3)CC2)OC1
Yield: 75 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and 1-(4-bromo-phenyl)-1-methyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 75% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=440/442 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[C:13]([F:43])=[CH:14][C:15]([F:42])=[C:16]([C:18]2[C:19](=[O:41])[N:20]([CH2:39][CH3:40])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH3:29])[CH:22]=3)[CH:17]=1.[N-]=C=O>C1COCC1.CCOC(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:29])[C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([C:16]4[C:15]([F:42])=[CH:14][C:13]([F:43])=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])[CH:17]=4)[C:19](=[O:41])[N:20]3[CH2:39][CH3:40])=[CH:25][N:24]=2)=[CH:36][CH:35]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: O=C=Nc1cccc(F)c1
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
3-Fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) in THF (5 mL) and the mixture was stirred at RT overnight. The reaction was treated with additional isocyanate (10 mg) and stirred at RT for a further 4 h. The mixture was diluted with EtOAc, washed successively with water, satd. NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to give an aqueous solution. The solution was diluted with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried (Na2SO4) and evaporated at reduced pressure to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207 mg, 79% yield, ˜75% pure) as a light yellow solid, which was used without further purification. MS (ES-API) m/z: 588.2 [M+H]+.
Reaction SMILES: O.Br[C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(=O)([O-])[O-:17].[Na+].[Na+].Cl>S([O-])([O-])(=O)=O.[Cu+2].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].N1C=CC=CC=1>[OH:17][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(O)c(C(=O)O)cc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Water (80 mL) was added to the crude crystals of 2-bromo-4,5-dimethoxybenzoic acid produced in Example 1 (20.0 g) and sodium carbonate (10.1 g). The resultant mixture was stirred under heating at 80° C., and a copper sulfate solution prepared from copper sulfate pentahydrate (1.91 g), water (20 mL), and pyridine (3.1 mL) was added to the mixture. The resultant mixture was further heated and stirred at 90 to 100° C. for one hour. The mixture was cooled to 50° C., and concentrated hydrochloric acid (16.0 g) was added dropwise thereto. After cooling of the mixture, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-hydroxy-4,5-dimethoxybenzoic acid (15.08 g) (yield: 99.3%).
Reaction SMILES: I[Si](C)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26]C)[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11].CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:6][C:7]1[CH:8]=[C:9]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][OH:26])[CH:22]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
Iodotrimethylsilane (5.61 mL, 39.39 mmol) was added to 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (2.5 g, 7.88 mmol) in acetonitrile (25 mL) and the reaction stirred at RT for 20 hours. Methanol (15 mL) was added and stirred for 1 hour then a saturated solution of sodium thiosulphate (10 mL) was added and stirred for a further 20 mins. The volatiles were removed in vacuo and the aqueous residue extracted into ethyl acetate (2×150 mL). The organics were washed with water (100 mL), brine (100 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a white solid (2.03 g). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.48 (s, 3H), 3.44-3.59 (m, 2H), 4.50 (sextet, 1H), 4.87 (t, 1H), 6.53 (t, 1H), 6.98 (s, 1H), 7.11 (s, 1H), 8.36 (s, 1H), 9.25 (s, 1H), 9.75 (s, 1H), 10.89 (s, 1H); m/z 304 (M+H)+
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=O.[Na+].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:2]1
Reactant: c1cnc2sccc2c1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1csc2ncccc12
Temperature: 100 °C

Procedure:
A solution of thieno[2,3-b]pyridine (0.70 g, 5.2 mmoles), prepared as described in Example 1(A), in chlorosulfonic acid, (7 ml) was heated to 100° C. for 15 minutes, then cooled to ambient temperature and added to ice (100 ml). The pH of the aqueous phase as adjusted to 8 with sat. NaHCO3, then extracted with CHCl3 (2×125 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect 0.95 g (78%) of the title compound as a tan solid.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([Cl:10])(=[O:9])[CH:7]=[CH2:8]>>[CH:2]12[CH2:1][CH:5]([CH:7]([C:6]([Cl:10])=[O:9])[CH2:8]1)[CH:4]=[CH:3]2
Reactant: C=CC(=O)Cl
Reactant: C1=CCC=C1
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 0 °C

Procedure:
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, digital thermometer, glass stopper, an addition funnel with a nitrogen gas purge, and a dry-ice cooling bath was charged with freshly distilled cyclopentadiene (248 g, 3.75 mol), which was cooled to 0° C. The addition funnel was charged with freshly distilled acryloyl chloride (317 g, 3.5 mol), which was added drop wise to the reaction over about three hours while maintaining the reaction temperature between 0-10° C. After the acryloyl chloride addition was complete, the cooling bath was removed and the reaction allowed to warm to room temperature overnight. The reaction mixture was distilled under vacuum, collecting 533 g of the title product distilling at 54-56° C. at a pressure of 300 milliTorr.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>O1CCOCC1>[CH3:10][NH:9][CH2:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCC1=CCCCC1
Solvent: C1COCCO1
Product: CNCCC1=CCCCC1
Reaction time: 3 h
Yield: 18 %

Procedure:
To a solution of 2-(1-cyclohexenyl)ethylamine (4.0 g) in 1,4-dioxane (40 mL) was added di-tert-butyldicarbonate (7.7 g). After gas evolution ceased (≈2 h) the reaction was concentrated. A portion of the residue (2 g) was dissolved in THF (10 mL) followed by addition of LiAlH4 (10 mL, 1M THF), which caused an exotherm. After 3 h, more LiAlH4 solution was added (4 mL), and the reaction was warmed to reflux. After 1 h, the reaction was cooled, and quenched cautiously with vigorous stirring by the addition of water (0.57 mL), 1M NaOH (0.6 mL), and more water (1.5 mL). The suspension was filtered through celite, which was washed with ether. The organic solution was concentrated to give the desired product as a volatile oil (0.8 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[I:36]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([I:36])=[C:9]([C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:14]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:13][C:12]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. acetonitrile and N-iodosuccinimide (2.0 eq), followed by ceric ammonium nitrate (0.05 eq) were added, and the solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting gum was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with 9:1 hexane:ethyl acetate, to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][N:16]=1>C(Cl)Cl>[Br:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[O:13])[CH:20]=1
Reactant: Nc1cc(Br)ccn1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Br)ccn1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
4-Chlorbenzenesulfonyl isocyanate (150 mg) was dissolved in CH2Cl2 (2 mL). 2-Amino-4-brompyridine (132 mg) was added to the mixture. After that the mixture was stirred for 18 h at 25° C. The obtained white precipitate was filtered off and washed with CH2Cl2 and dried in vacuo to yield N-[(4-bromopyridin-2-yl)carbamoyl]-4-chlorobenzenesulfonamide (111 mg; 41%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]=[CH2:14])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:14][O:23]1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1CC)COC2=O
Solvent: ClCCl
Product: CCc1c(C2CO2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-ethyl-5-vinyl-2-benzofuran-1(3H)-one (1.1 g, 5.85 mmol) in 50 mL of DCM was slowly added mCPBA (3.60 g, 85% purity, 17.6 mmol) in 50 mL of DCM at 0° C. Warmed to room temperature, the mixture was stirred for 3 days. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were combined, washed with brine and concentrated. The residue was purified by column chromatography to give product 4-ethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.6 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 5.30 (s, 2H), 4.11-4.13 (m, 1H), 3.23-3.25 (m, 1H), 2.75-2.82 (m, 2H), 2.70-2.72 (m, 1H), 1.27 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH:8](P(OCC)(OCC)=O)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH:27](=O)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7]/[C:8](=[CH:27]\[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:9]([OH:11])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=CCCc1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 74785.5 %

Procedure:
A solution of 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (Preparation 164, 100 g, 0.32 mol) in THF (300 ml) was added dropwise over 15 min to a stirred solution of potassium tert-butoxide (110 g, 0.98 mol) in THF (300 ml), between −10 and −5° C., under nitrogen. The mixture was stirred at −10° C. for 15 min and then a solution of hydrocinnamaldehyde (46.8 g, 0.35 mmol) in THF (100 ml) was added dropwise over 15 min, between −13 and −8° C. The mixture was stirred at −10° C. for 30 min and then a solution of citric acid (111 g, 0.58 mol) in demineralised water (500 ml), and ethyl acetate (500 ml), were added. The pH was adjusted to pH 4 with aqueous sodium hydroxide solution (50%) and the phases were separated. The aqueous fraction was washed with ethyl acetate (500 ml) and the combined organic fractions were washed with saturated sodium bicarbonate solution (500 ml), citric acid solution (10%, 500 ml) and demineralised water (500 ml) and then concentrated in vacuo. The resulting solid was slurried in cyclohexane (470 ml) for 1 hour and then the mixture was filtered. The residue was washed with cyclohexane (2×50 ml) and dried in vacuo to leave the title compound as a colourless solid (76 g, 81% yield, 99% pure by HPLC).
Reaction SMILES: [C:1]([C:4]1[CH:56]=[CH:55][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30]([NH:32][C@@H:33]([CH2:44][C:45]([O:47]CC4C=CC=CC=4)=[O:46])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.O.[OH-].[OH-].[Pd+2].[Pd]>[C:1]([C:4]1[CH:56]=[CH:55][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30]([NH:32][C@@H:33]([CH2:44][C:45]([OH:47])=[O:46])[C:34]([OH:36])=[O:35])=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)N[C@@H](CC(=O)O)C(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reaction time: 10 h
Yield: 52.1 %

Procedure:
Crude dibenzyl (S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinate (18 g) was dissolved in a 1:1 mixture of acetic acid and water (800 mL), assisted by sonication. To this solution was added palladium hydroxide on carbon (Pearlman's catalyst, 20 wt % Pd on a dry weight basis, containing 50% water by weight; 7.0 g). The reaction mixture was pressurized to 30 psi with hydrogen and the suspension was shaken on a Parr apparatus for 10 h. The catalyst was removed by filtration and the solvent was removed in vacuo. Crude (S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinic acid was purified by preparative reverse-phase HPLC to give (S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinic acid (7.2 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:28]([NH2:30])=[O:29])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:28]([NH2:30])=[O:29])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Yield: 97 %

Procedure:
A mixture of 7-(benzyloxy)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (880 mg, 2.237 mmol), 10% Pd on carbon (400 mg) and ammonium formate (705 mg, 11.2 mmol) in ethanol (50 mL) was heated at reflux for 1 hr. Filtration followed by removal of the solvent from the filtrate left 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (658 mg, 2.17 mmol, 97% yield) as a yellow solid. MS (ESI) m/z 304.0 (M+H). 1H NMR (500 MHz, DMSO-d6) d ppm 11.30 (1H, br. s.), 9.77 (1H, br. s.), 8.54 (1H, br. s.), 8.30 (1H, s), 8.27 (2H, d, J=7.32 Hz), 8.03 (1H, d, J=8.24 Hz), 7.80 (1H, br. s.), 7.53 (2H, t, J=7.63 Hz), 7.41 (1H, s), 7.36-7.46 (1H, m), 7.14-7.15 (1H, m), 7.14-7.14 (1H, m), 7.12 (1H, d, J=1.83 Hz), 6.75 (1H, dd, J=8.55, 2.14 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:13]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[CH:1]=[O:13]
Reactant: Cc1cnc2ccccc2n1
Reactant: O=[Se]=O
Product: O=Cc1cnc2ccccc2n1

Procedure:
This compound can also be prepared by oxidation of 2-methylquinoxaline with selenium dioxide, as described by Landquist et. al J. Chem. Soc. 2052 (1956).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([NH:21][O:22]C3CCCCO3)=[O:20])[CH:15]=2)[CH2:10]1)=[O:8].Cl>CO>[OH:22][NH:21][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:7](=[O:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:18][CH2:17]2)=[O:20]
Reactant: COCCOCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: COCCOCC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A mixture of 110 mg 2-[(2-methoxyethoxy)acetyl]-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 1 ml methanol and 1.5 ml 0.1N aqueous hydrochloric acid are stirred for 3 h at ambient temperature. Subsequently, the mixture is lyophilized. 85 mg of the title compound are obtained as colorless oil. MH+=309.1