Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+].C1COCC1>CO>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-4-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (156 mg, 0.49 mmol) and lithium hydroxide monohydrate (83 mg, 1.97 mmol), according to General Procedure 7. A 1:2 mixture of THF and methanol (15 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-80% EtOAc/Heptane to give the title compound: 135 mg, 90.6%. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.22-2.33 (m, 1H), 2.73-2.82 (m, 1H), 2.82-2.91 (m, 1H), 2.91-3.00 (m, 1H), 4.23 (t, J=7.20 Hz, 1H), 6.56 (s, J=1H), 7.24-7.32 (m, 3H) 7.37-7.43 (m, 2H), 7.50-7.55 (m, 2H), 7.57-7.61 (m, 2H); LCMS-MS (ESI+) 304.2 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 352 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-].[K+].CS([C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][N:13]=1)(=O)=O>O>[CH2:1]([O:5][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C
Reactant: CCCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCOc1ncc(C(=O)O)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 1.5 ml of butanol, 0.72 g (11 mmol) of 85.5% potassium hydroxide powder was suspended, followed by drop-wise adding, under ice-cooling, a 1.5 ml of butanol solution dissolving with 1.22 g (5.0 mmol) of ethyl 2-methansulfonyl-4-methylpyrimidine-5-carboxylate. After the end of the drop-wise addition, the solution was stirred at room temperature for 3 hours. To the reaction liquid, 50 ml of water was added, and the water layer was washed with diisopropyl ether, followed by adding 10% hydrochloric acid to make acidic, and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to obtain 0.87 g (yield: 83%) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:15][CH:16]([CH3:19])[CH2:17]Br>C(C#N)(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:17][CH:16]([OH:15])[CH3:19])[CH2:11][CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)C#N
Product: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 58.8 %

Procedure:
A mixture of 4-(N-Boc-amino)-piperidine (1.0 g, 5.0 mmol), 2-hydroxybromopropane (1.0 g; 7.5 mmol) and TEA (0.76 g, 7.5 mmol) in AcCN (20 mL) was heated at 60° C. for 4 days. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 concentrated under reduced pressure. Purification of the residue by column chromatography on silica (0-5% 2M ammonia-MeOH in DCM) afforded [1-(2-hydroxy-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.76 g, 59%) as an oil. LCMS (Method G; ESI): RT=0.49 min, m+1=259.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)=[O:15].[ClH:42].CO>>[ClH:42].[ClH:42].[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:17]1[CH2:22][C@@H:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH2:20][NH:19][CH2:18]1)=[O:15]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCCO)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixed solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (103 mg), propane-1,3-diol (152 mg) and triphenylphosphine (105 mg) in toluene (5 ml) and THF (5 ml) was added diisopropyl azodicarboxylate (202 μl) at room temperature, and the mixture was stirred at the same temperature for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 10-20% hydrogen chloride-methanol (3 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to give the object product (22 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[NH:11])=[CH:5][CH:4]=1.C([O:15][C:16](=O)[CH:17]([NH:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:18](OCC)=[O:19])C>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[N:12]=[C:16]([OH:15])[C:17]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[C:18]([OH:19])[N:11]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1)C(=O)OCC
Reactant: N=C(N)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 129 %

Procedure:
2.25 g of sodium were dissolved in 140 ml of ethanol at 60° C. to give a solution of sodium ethoxide. 6.9 g of 2-(4-chloro-phenyl)acetamidine hydrochloride were added while the temperature was maintained at 60° C. The mixture was stirred for 10 min, and then a solution of 10 g of 2-(3-fluoro-benzoylamino)-malonic acid diethyl ester in 20 ml of ethanol was added. The reaction mixture was stirred at 60° C. for 3 h and then evaporated to dryness. The residue was dissolved in the minimum amount of water, and the pH was adjusted to 1-2 by addition of concentrated aqueous hydrochloric acid. The precipitate was filtered off and dried in an infrared dryer until constant weight. 8.9 g of the title compound were obtained.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](O)(=O)CC(O)=O.Cl>C(N(CC)CC)C>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])(=[O:5])[CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 281.9 %

Procedure:
A stirred mixture of phthalic anhydride (compound of formula (XII)) (2.3 kg, 1 eq) (commercially available), malonic acid (compound of formula (XIII)) (389 g) (commercially available) and triethylamine (3.2 L) were heated to 80° C. Further portions of malonic acid (5×389 g; 1.94 kg total) were charged at 15 minute intervals and the reaction mixture maintained at 80° C. for 10 hrs. 4M hydrochloric acid (12.2 L) was charged and the reaction stirred for a further 30 minutes before being cooled to 25° C. and the resulting slurry filtered. The damp cake was washed with water (2×4 L) before being dried in vacuo at 50° C. to give the title compound (1.73 kg, 68%); 1H NMR (400 MHz, CDCl3): δ 1.97 (3H, s, CH3), 4.13 (1H, br s, OH) 7.52-7.63 (2H, m, CH Ar), 7.69-7.73 (1H, t, CH Ar), 7.84-7.86 (1H, d, CH Ar); 13C NMR (100 MHz, CDCl3) δ 26.0, 106.6, 122.1, 125.4, 126.0, 130.5, 134.8, 149.8 and 169.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:57]([O:61][C:62]([NH:64][CH2:65][CH:66]1[NH:70][CH2:69][CH2:68][S:67]1)=[O:63])([CH3:60])([CH3:59])[CH3:58].BrCl>CN(C)C=O.ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:70]1[CH2:69][CH2:68][S:67][CH:66]1[CH2:65][NH:64][C:62]([O:61][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:63])=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCC1NCCS1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2CNC(=O)OC(C)(C)C)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 23 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-bromo-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine and rac.-2-(tert-butoxycarbonylaminomethyl)thiazolidine in dimethylformamide. Yield: 23%; Rf value: 0.52 (silica gel: dichloromethane/methanol/glacial acetic acid=9:1:0.1); C26H29BrClN5O4S (622.969); mass spectrum: (M−H)−=620/622/624 (bromo-chlorine isotope).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:14][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CO)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 59A, 277 mg (0.91 mmol) were dissolved in 10 ml of dichloromethane and admixed at 0° C. with 0.7 ml (9.1 mmol) of trifluoroacetic acid, then stirred at room temperature for 1 hour. The mixture was concentrated on a rotary evaporator. The crude product was taken up in 20 ml of toluene and again concentrated on a rotary evaporator under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 124 mg (43% of theory) of the target compound.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1.[CH2:23]([N:25](CC)[CH2:26]C)C.CNC>O1CCCC1.CN(C)C=O>[CH3:23][N:25]([CH3:26])[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)CCC(CCN(C)C)=C2
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Methanesulfonyl chloride (0.0393 ml, 0.469 mmol) was added to a dimethylformamide solution (2 ml) of N-[6-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenyl]acetamide (102 mg, 0.426 mmol) obtained in Reference Example 102 and triethylamine (0.0652 ml, 0.469 mmol) under ice-cooling, which was stirred for 30 minutes. A tetrahydrofuran solution (0.64 ml) of 2N dimethylamine was added to the reaction mixture, which was stirred at 60° C. for 5 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, and extraction was conducted using 1N hydrochloric acid. Potassium carbonate was added to the extract to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina column chromatography (development solvent; ethyl acetate), to give the titled compound (57.5 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])(=[O:4])=[O:3].[OH-].[NH4+:17]>C(OCC)(=O)C>[NH2:17][S:2]([C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([CH3:12])[C:10]=1[F:11])(=[O:4])=[O:3]
Reactant: Cc1cc([N+](=O)[O-])cc(S(=O)(=O)Cl)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1F

Procedure:
The resulting oily residue of compound 26 was taken up in ethyl acetate (100 mL) and stirred with ammonium hydroxide (100 mL, 30% aqueous solution) overnight at room temperature. After the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The dark oily residue was chromatographed (silica gel, hexanes then 10%, 20%, up to 50% ethyl acetate in hexanes to afford 3-aminosulfonyl-4-fluoro-5-methylnitrobenzene (27). LCMS: purity: 89%; MS (m/z): 235 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[I:15].[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[I:15]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1I
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2F)c1I
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution (42 mL) of 5-(2-fluorophenyl)-4-iodo-1H-pyrrole-3-carbaldehyde (400 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 102 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (560 mg) was added dropwise and the mixture was stirred for 30 min. Pyridin-3-ylsulfonyl chloride (340 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→1:1) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 540 mg, 93%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([NH:36][CH2:37][CH2:38][OH:39])[CH3:35]>>[CH2:34]([N:36]([CH2:37][CH2:38][OH:39])[C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[CH3:35]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCNCCO
Product: CCN(CCO)C(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Yield: 7 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of 2-(ethylamino)ethanol as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(O)=O.CC(O)=O.C1CCC([N-]C2CCCCC2)CC1.C1CCC([N-]C2CCCCC2)CC1.[Pd+2]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccc(F)cc3)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 21 h

Procedure:
Add 3 mg (0.01 mmol) trans-bis(dicyclohexylamine)palladium(II) acetate [T. Bin, J. Org. Chem. 2004, 69, 4330-4335] to a mixture of 100 mg (0.22 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester, 47 mg (0.34 mmol) 4-fluorophenylboronic acid and 95 mg (0.45 mmol) potassium phosphate in 5 ml dioxan, and stir for 21 h at 80° C. After filtering off the solid, concentrate the filtrate by vacuum evaporation. Purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 59 mg (57% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:53]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 22.0 mg, 0.036 mmol) in N,N-dimethylformamide (0.3 mL) was added to 5-bromopyridine-3-acetic acid methyl ester (Example 24-(2); 19.2 mg, 0.083 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (3.2 mg, 0.0039 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84° C. for five hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (17.2 mg, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([NH2:16])[CH2:14][CH3:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.C1COCC1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: CCCN
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1ccc(N)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with N-4-aminophenyl-N'-propylurea to generate the title compound. The N-4-aminophenyl-N'-propylurea was prepared by sequentially treating commercial 4-nitrophenyl isocyanate with PrNH2 in THF at 20° C. followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[O:4][N:3]=1.[F:20][CH:21]([F:31])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1>CO>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:2]2[CH2:6][CH:5]([CH2:7][O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)[O:4][N:3]=2)=[CH:27][CH:28]=1
Reactant: O=C1CCc2cc(OCC3CC(Br)=NO3)ccc2N1
Reactant: NCc1ccc(OC(F)F)cc1
Solvent: CO
Product: O=C1CCc2cc(OCC3CC(NCc4ccc(OC(F)F)cc4)=NO3)ccc2N1
Yield: 11.7 %

Procedure:
6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (0.1 g, 0.308 mmol) and (4-(difluoromethoxy)phenyl)methanamine (0.149 g, 0.923 mmol) were heated at 160° C. for 30 min. The reaction mixture was dissolved in methanol, concentrated, and the crude product purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a 0-100% gradient of ACN in 0.1% TFA to give 6-((3-(4-(difluoromethoxy)benzylamino)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (0.015 g, 23%). 1H NMR 400 MHz, DMSO-d6: δ 2.41 (q, J=7.20 Hz, 2H), 2.78-2.85 (m, 3H), 3.08 (q, J=9.60 Hz, 1H), 3.89-3.97 (m, 2H), 4.18 (d, J=6.00 Hz, 2H), 4.62-4.65 (m, 1H), 6.62 (t, J=6.00 Hz, 1H), 6.72-6.78 (m, 2H), 6.81 (d, J=2.00 Hz, 1H), 7.02-7.39 (m, 5H), 9.91 (s, 1H). LCMS: RT 1.501 min; LCMS (ES-API), m/z 418.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12]O>>[N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Product: COC(=O)c1ccc([N+](=O)[O-])s1

Procedure:
To a 500 mL round bottomed flask with a stirring bar, was added 5-nitrothiophene-2-carboxylic acid (4.62 g, 26.68 mmol) and MeOH (100 mL). This solution was cooled in an ice bath and dry HCl gas was bubbled through the solution till saturated. The reaction was equipped with a condensor and a drying tube and refluxed overnight. The solvent was then removed in vacuo to a yellow solid, which was then dissolved in EtOAc. This solution was washed with NaHCO3 (sat, aq) (3×), and brine (2×), dried (MgSO4), and filtered. Removal of the solvents in vacuo and drying of the product in vacuo yielded methyl 5-nitrothiophene-2-carboxylate as a tan solid.