Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]O>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C@H:17]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C[C@@H](CCC(=O)O)[C@@H]2O
Product: COC(=O)CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1O

Procedure:
Compound 33 was prepared by esterification of crude 32 (436 mg) with MeOH as described for the preparation of 9. Purification of the residue by flash chromatography on a 3×21 cm column of silica gel using hexanes/EtOAc (2:1) as eluent gave 268 mg (52%, three steps) 33 as a white solid. Data for 33: TLC, T-5, Rf0.76. 1H NMR (500 MHz, CDCl3) δ 0.81 (s, 3H, H-1 8), 2.84 (m, 2H, H-6), 3.31 (d, 1H, J=7.3 Hz, H-17α), 3.69 (s, 3H, OCH3), 5.04 (s, 2H, benzylic), 6.72 (d, 1H, J=2.8 Hz, H-4), 6.79 (dd, 1H, J=8.6, 2.8 Hz, H-2), 7.21 (d, 1H, J=8.6 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C29H36O4Na (M+Na+) m/e 471.2511, found m/e 471.2513.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)(O)O.[NH2:25][NH:26][C:27]([NH2:29])=[NH:28].C(=O)=O>O>[C:1]([NH2:25])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:25][NH:26][C:27]([NH2:29])=[NH:28]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: N=C(N)NN
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(N)=O
Temperature: 120 °C

Procedure:
In a large reaction vessel was placed oleic acid (3,382 g, 11.97 mols), aminoguanidine bicarbonate (1,500 g of 90%, 9.92 mols), 5-W process oil (1,000 g) and a silicon anti-foamant (1 g). The mixture was stirred vigorously under nitrogen and heated to a temperature of 120° C. The aminoguanidine bicarbonate was observed to dissolve as the temperature of the reaction mixture neared 120° C. As the reaction progressed, carbon dioxide was evolved. The volume of the reaction mixture was expanded by approximately 40% due to foaming related to this gas evolution. Water was also evolved in the reaction. The reaction mixture was heated at 120° C. until a total of 308 ml of water collected. The mixture was then cooled and additional process oil was added sufficient to dilute the product to 50% activity. The final product had the following analysis: % Nitrogen, 7.02; Activity, 50%; viscosity (100° C., cSt), 19.11; TBN (mg KOH/g), 67.9; Infra-red absorbance, mm-1 (1675 cm-1, 24.9% in methyl cyclohexane), 8.57.
Reaction SMILES: C([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)([O-])O.[K+].O>ClCCl>[CH2:28]([O:27][C:25]([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1Nc2ccccc2C1CCN(CCO)Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1Nc2ccccc2C1CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
3-[2-[N-Benzyl-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (463 mg) was dissolved in dichloromethane (9.2 ml), added with benzyl chloroformate (0.51 ml) and potassium hydrogencarbonate (358 mg) and stirred at room temperature for 24 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 ml), added with 1 N aqueous sodium hydroxide (2.2 ml) and stirred for 30 minutes. The reaction mixture was added with water (50 ml) and extracted twice with dichloromethane (40 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 272 mg of the title compound. Yield: 52%.
Reaction SMILES: C1(COC(=O)[NH:10][C@H:11]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1>C(O)C.[Pd]>[CH3:27][C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][C@@H:11]([NH2:10])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Reaction time: 48 h
Yield: 116 %

Procedure:
A mixture of (S)-[1-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-phenylethyl]carbamic acid phenylmethyl ester (2.89 g,7.51 mmol) and 10% Pd-C (0.171 g) in ethanol (70 ml) was stirred under hydrogen for 2 days. The reaction mixture was filtered through celite and the filtrate was evaporated to leave the title compound (2.18 g) as a solid, nmr(δ,CDCl3) includes 1.43(s,9H), 2.5-2.62 and 2.83(m and dd,2H), 3.0 and 3.1-3.25(m,2H), 3.25-3.4(m,1H), 5.0-5.15(m,1H), 7.15-7.35(m,5H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:30]([O:29][C:27]([NH:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(NC(=O)OCc3ccccc3)c2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the product from Step A (133 mg) in dichloromethane (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.21 mL) followed by benzyl chloroformate (0.1 mL). The reaction mixture was stirred at 0° C. for 90 min, then diluted with dichloromethane (10 mL) and poured into saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 80% ethyl acetate/hexanes gradient) to give the title compound. LC/MS 359.3 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)C1[S:45]C=CC=1)CCC>>[ClH:1].[ClH:1].[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[S:45][CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccs3)cc2C1
Yield: 10 %

Procedure:
Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:19][OH:20])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([C:6]2[O:20][CH2:19][CH:4]([C:3]([O:2][CH3:1])=[O:21])[N:5]=2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc([N+](=O)[O-])c(OC)c2)=N1
Yield: 74.3 %

Procedure:
The same operation as in Example (97b) was performed using N-(3-methoxy-4-nitrobenzoyl)serine methyl ester obtained in Example (102a) (2.46 g, 8.26 mmol), the Burgess reagent (2.56 g, 10.7 mmol) and THF (50 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 1/2) gave 1.72 g of the title compound as a light yellow solid (74%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([C@H:17]([NH2:39])[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:19])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:14]1([C@H:17]([NH:39][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:16][CH2:15]1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
4-nitrophenyl chloroformate (171 mg, 0.85 mmol, 1.5 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 200 mg, 0.564 mmol, 1 equiv) and N,N-diisopropylethylamine (172 μL, 0.988 mmol, 1.75 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 30 minutes. Additional 4-nitrophenyl chloroformate (1.0 equiv) and N,N-diisopropylethylamine (1.0 equiv) were added and the mixture was stirred for 2.5 hours, then partitioned between water (55 mL) and dichloromethane (2×45 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-nitrophenyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (26-1) as a light yellow oil. LRMS m/z (M+H) 520.4 found, 520.2 required.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([N:28]=CN(C)C)(=[O:27])=[O:26])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].O>CCO.Cl>[Cl:1][C:2]1[N:3]=[C:4]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([NH2:28])(=[O:26])=[O:27])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Yield: 72.7 %

Procedure:
230 mg of 2-[4-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)benzenesulfonyl]-N-dimethylaminomethylenebenzenesulfonamide are refluxed for 2 h in 3 ml of EtOH and 3 ml of a saturated aqueous HCl solution. The reaction mixture is allowed to cool and poured onto 10 ml of water, and the product is filtered off. Chromatography on silica gel using MTB yields 151 mg of an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]2[O:17][CH:18]=[N:19][CH:20]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 121 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25-7.35 (m, 5H), 7.45-7.49 (m, 4H), 7.63-7.71 (m, 4H), 7.95 (s, 1H), 9.67 (s, 1H). MS: m/z 484.3 (M++1).
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([OH:9])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc([C@@H](CC2CCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: Cc1cc([C@@H](CC2CCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
In a flask (R)-3-cyclobutyl-2-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (88 mg, 0.30 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate) to afford (R)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 72%) as a white foam: [α]2958932 −14.7° (c=0.19, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9 H, CH and 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.73 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.64 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.42 (m, 2H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.84 (d, Jo=8.6 Hz, 1H, Ar), 10.70 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:33])([CH3:32])[CH2:22][N:23]4[C:26](=[O:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:19][CH:18]=3)[C:10]2=[O:34])[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]([CH3:40])[C:37]([NH2:39])=[O:38].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][N:28]([CH3:30])[CH2:27][C:26]([N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:11]3[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:37](=[O:38])[N:36]([CH3:40])[CH3:35])[CH:7]=4)[C:10]3=[O:34])[CH:25]=2)[C:21]([CH3:33])([CH3:32])[CH2:22]1)=[O:31]
Reactant: CN(C)C(N)=O
Reactant: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(NC(=O)N(C)C)c4)C(C)(C)C3=O)cc21
Temperature: 25 °C
Yield: 19.9 %

Procedure:
To a solution of 242 mg of 1-(2-chloropyridin-4-ylmethyl)-3-[1-(2-dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-imidazolidine-2,4-dione obtained in stage a) of Example 31B in 10 mL of dioxane are successively added, under argon, 33 mg of N,N-dimethylurea, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 22 mg of palladium acetate and 652 mg of caesium carbonate. The reaction mixture is refluxed for 6 hours, cooled to room temperature, filtered and washed with three times 10 mL of dichloromethane, and the filtrate is concentrated under reduced pressure. The residue is triturated in 20 mL of water and the precipitate formed is filtered off and purified twice by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (93/7 by volume) to give 40 mg of 3-[4-({3-[1-(N,N-dimethylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl}methyl)-pyridin-2-yl]-1,1-dimethylurea, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:21])[CH2:19][CH:18]([CH2:22][CH:23]4OCC[O:24]4)[CH2:17][C:16]3=[O:28])[CH:9]=2)=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:16](=[O:28])[CH2:17][CH:18]([CH2:22][CH:23]=[O:24])[CH2:19][C:20]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2OCCO2)CC1=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC=O)CC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4′-chloro-4-methylbiphenyl-3-yl)-5-[1,3]dioxolan-2-ylmethylcyclohexane-1,3-dione (0.275 g, 0.69 mmol) in tetrahydrofuran (5 ml) is added 6M hydrochloric acid (2 ml), and the reaction mixture is stirred at room temperature for 1.5 hours. Additional 6M hydrochloric acid (1 ml) is added and the solution is heated at 50° C. for an additional 2 hours. After cooling to room temperature the reaction mixture is concentrated and the residue partitioned between distilled water (20 ml) and dichloromethane (20 ml). After extraction of the aqueous phase with dichloromethane (3×10 ml) all organic fractions are combined then passed through a phase separator. The fitrate is concentrated in vacuo to afford [4-(4′-Chloro-4-methylbiphenyl-3-yl)-3,5-dioxocyclohexyl]-acetaldehyde as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 26 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.03 mL, 0.20 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.10 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([NH:16][NH2:17])=[O:15])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19](N(CC)CC)[CH3:20].C(Cl)(=O)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:19]([CH3:20])=[N:17][N:16]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NN)ccn1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: O
Product: Cc1nnc(-c2ccnc(NC(=O)OC(C)(C)C)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of tert-butyl[4-(hydrazinocarbonyl)-2-pyridyl]carbamate (1.01 g, 4.0 mmol) and triethylamine (0.832 mL, 6.0 mmol) in tetrahydrofuran (20 mL) was added acetyl chloride (0.341 mL, 4.8 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hr. To this reaction mixture were added triethylamine (2.77 mL, 20 mmol) and p-toluenesulfonyl chloride (1.53 g, 8.0 mmol), and the resulting mixture was heated under reflux for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran), and washed with diethyl ether/methanol to give the title compound (448 mg, yield 41%) as pale-brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1cc(CCl)ccc1Br
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(CC#N)ccc1Br

Procedure:
4-Bromo-3-methoxybenzyl chloride (23.5 g, 0.1 m) dissolved in ethanol (500 ml) is treated with potassium cyanide (13 g, 0.2 m) dissolved in water. The mixture is warmed and stirred to give 4-bromo-3-methoxyphenylacetonitrile.