Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:20][CH2:19][C:18]3[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[N:24][C:15]=4[C:14]=3[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CO>[C:33]([O:37][C:38](=[O:41])[CH2:39][N:17]1[C:18]2[CH2:19][CH2:20][CH:12]([N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH3:25])[CH2:13][C:14]=2[C:15]2[N:24]=[CH:23][CH:22]=[CH:21][C:16]1=2)([CH3:36])([CH3:35])[CH3:34]
Reactant: CN(C1CCc2[nH]c3cccnc3c2C1)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C1CCc2c(c3ncccc3n2CC(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 4-fluoro-N-methyl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-benzenesulfonamide (2.8 g, 7.8 mmol) and DMF (22 mL) was cooled to 0° C. Sodium hydride (340 mg, 8.6 mmol, 60% dispersion in mineral oil) was added at 0° C. and after 30 min, tert-butylbromoacetate (1.3 mL, 8.9 mmol) was added at 0° C. After 1 hour, MeOH was added and the reaction mixture was filtered. The organic layer was concentrated and the residue purified by reverse phase preparative HPLC to afford 700 mg of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid tert-butyl ester. Mass spectrometric data [M+H]+=474.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Cl.CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cncn2)cc1
Yield: 44.5 %

Procedure:
A mixture of 13.8 parts of 1H-1,2,4-triazole, 18.7 parts of 1-bromo-4-methoxybenzene, 5 parts of potassium carbonate, 0.5 parts of copper (I)chloride and 90 parts of N,N-dimethylformamide is stirred and refluxed for 2 days. The reaction mixture is cooled and poured onto water. The product is extracted twice with benzene. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7.8 parts (44.5%) of 1-(4-methoxyphenyl)-1H-1,2,4-triazole; mp. 99.4° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[CH:17]([CH:19]([CH2:21][CH3:22])[CH3:20])[NH:18][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(C)C(N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 77 %

Procedure:
D,L-isoleucyl-L-proline benzyl ester hydrochloride (1.2 g) was dissolved in dichloromethane (10 ml), cooled down to 0° C., and DIEA (860 mg) and benzoyl chloride (477 mg) were added dropwisely. The resulting mixture was allowed to warm up naturally to room temperature to react for 2 h, concentrated under reduced pressure to remove the solvent, and purified on a column to give a pale yellow oil (1.1 g, 79%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21]CC)=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[O:35])=[CH:5]1)[N:16]=[C:15]([C:19]([OH:21])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Agent: Cl
Product: O=C(NCc1ccn(-c2cc3nc(C(=O)O)c(=O)[nH]c3cc2Cl)c1)Nc1ccc(Cl)cc1
Yield: 18.2 %

Procedure:
Using the compound (200 mg, 519 μmol) of Example 5 and 4-chlorophenyl isocyanate (80.6 μl, 622 μmol) and through the process similar to Example 38, 44.6 mg of title compound were obtained as yellowish brown powder. Yield 18%.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:26]2[CH:25]=[N:24][C:23]([NH:22][CH3:21])=[CH:28][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1ccc(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.68 mmol) in toluene (20 mL) and EtOH (7 mL) were added N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 12 (1.44 g, 3.36 mmol in theory) and 2 N Na2CO3 aq. (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.2 g, 0.168 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-2) (0.020 g, 3.2%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[C:7]([CH3:15])[CH:6]=1)=[O:4].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[CH3:15]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)c1ccc(CC(=O)O)c(C)c1
Product: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(C)c1
Yield: 69.6 %

Procedure:
2-(4-(methoxycarbonyl)-2-methylphenyl)acetic acid (295 mg) was treated with resorcinol (190 mg) in BF3Et2O at 90° C. over night. After aqueous work-up with ethyl acetate and column purification, the desired product (296 mg) was isolated as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]1([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc(-c2ccccc2)no1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2cc(-c3nc(-c4ccccc4)no3)c(=O)oc2c1

Procedure:
7.6 parts of 2-hydroxy-4-methoxy benzaldehyde and 11.6 parts of the ethyl ester of 3-phenyl-1,2,4-oxadiazole-5-acetic acid (boiling point: 150° C/0.5 mm) are dissolved in 80 parts of toluene. 0.5 part of piperidine is added and the mixture is heated under reflux for 1 hour. The mixture is cooled, the crystallized product is filtered and then washed in ethanol. 13.7 parts of 7-methoxy 3-(3-phenyl 1,2,4-oxadiazol-5-yl) coumarin are obtained which, after crystallization in an ethanol-dioxane mixture, melts at 215° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-:14].[Na+]>>[Cl:1][C:2]1[NH:3][C:4](=[O:14])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Clc1cnc2nc(Cl)nc(Cl)c2c1
Reactant: [OH-]
Agent: [Na+]
Product: O=c1[nH]c(Cl)nc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4,6-Trichloro-pyrido[2,3-d]pyrimidine (360 mg, crude) was dissolved in 1N NaOH (6 ml) (ultrasonication) and stirred for 30 min at r.t. The obtained suspension was extracted with Et2O. The water layer was separated, acidified (HCl), and again extracted (EtOAc). The organic layer was dried (Na2SO4), filtered and evaporated to give crude 2,6-dichloro-3H-pyrido[2,3-d]pyrimidin-4-one (MS: m/e=214.3 [M−H−]) which was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Cl[C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:15]2[S:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: Cc1nsc(Cl)n1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C)ns2)c(C=O)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
In a microwave vial are combined 2-formyl-4-methoxyphenylboronic acid (432 mg, 2.40 mmol), 5-chloro-3-methyl-1,2,4-thiadiazole (270 mg, 2.00 mmol), potassium acetate (390 mg, 4.00 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (283 mg, 0.40 mmol) in 1,4-dioxane (6 mL) and water (0.50 mL). The reaction vial is sealed and stirred at 100° C. for 20 hours. The reaction mixture is cooled to ambient temperature and poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 5-40% EtOAc/heptane) affords 5-methoxy-2-(3-methyl-1,2,4-thiadiazol-5-yl)-benzaldehyde which is used without further purification.
Reaction SMILES: O=[C:2]1[C:15]2[C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=O)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2>[Zn].[NH4+].[OH-]>[C:14]1([C:16]([OH:18])=[O:17])[C:15]2[C:10](=[CH:9][C:8]3[C:3]([CH:2]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1C2=O
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: O=C(O)c1cccc2cc3ccccc3cc12
Reaction time: 3.5 h

Procedure:
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 9,10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid (90 g, 0.357 mol), Zn dust (Mallinckrodt, 250 g, 3.82 mol), CuSO4.5H2O (Mallinckrodt, 5 g), and 28% NH4OH (Mallinckrodt, 2500 mL). The mixture was heated slowly until a dark-red solution occurred as the temperature reached 85°. After 3.5 h the color of the solution faded to yellow. The reaction was heated an additional 1 h, and then cooled and the excess Zn filtered. The filter cake was washed with more NH4OH (100 mL) and then discarded. The filtrate was carefully acidified to pH 1 with conc. HCl added in portions over 1 h affording a light-green precipitate which was separated by filtration. The solid was washed with H2O (200 mL) and then recrystallized once from methoxyethanol/H2O (with a small amount of HCl) to give 65 g (82%) filtered, and dried at 75° of 1-anthracenecarboxylic acid mp 249°-250°, (C,H), (lit. mp 245°, Chemistry of Carbon Compounds IIIb, edited by E. H. Rodd, 1373 (1956), Elsevier, N.Y.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[N:18]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCCOc1nc(-c2ncccn2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 4tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide was reacted with ethanesulfonylchloride to give 33 mg 4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.25 min, [M+1]+=657.33, [M−1]−=655.45.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of ethyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D86) (204 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (30.7 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E37) (48 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.10 (3H, t), 1.36 (6H, d), 1.76 (2H, m), 2.13 (2H, m), 2.72 (2H, m), 3.07 (4H, m), 3.28 (3H, m), 3.67 (2H, m), 4.91 (1H, m), 7.34 (3H, m), 7.44 (1H, d), 7.85 (1H, s), 8.22 (1H, dd), 8.28 (1H, d), 9.37 (1H, br s), 12.60 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C29H33N3O3S requires 503. found 504.1 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)[O:3]1.I([O-])(=O)(=O)=O.[Na+].Cl>O1CCCC1.O>[OH:5][B:4]([OH:3])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:13][CH2:12]2
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(C#N)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(B(O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.2 %

Procedure:
2.76 g 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile and 4.32 g sodium periodate were dissolved in a mixture of 45 ml tetrahydrofuran and 15 ml water. The mixture was stirred at room temperature for two hours. Then 2 ml 4M hydrochloric acid was added and the mixture stirred at room temperature for one hour. 150 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo to obtain 2.94 g of crude 4-(5-Dihydroxyboranyl-2,3-dihydro-indole-1-sulfonyl)-benzonitrile. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:40][CH:41]([CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:42][S:43][CH2:44][CH2:45][C:46](O)=[O:47])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:46](=[O:47])[CH2:45][CH2:44][S:43][CH2:42][CH:41]([O:40][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-aminobenzoylmethionine t-butyl ester (160 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (163 mg, yield 68%) as a colorless wax-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[CH2:12][C:11]3([N:8]([C:6]([NH:5][CH2:4][C:3]4[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=4[Cl:1])=[O:7])[CH2:9][CH2:10]3)[CH2:14]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CCC12CNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCC12CN(S(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (440 mg, 1.10 mmol) in dichloromethane (7 mL) was added TFA (593 μl, 7.7 mmol). After being stirred 2 h at ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned in toluene (10 mL) and then concentrated; this procedure was repeated twice to give the free amine (468 mg), which was used without further purification in the next step. To a solution of the previously obtained N-(2,4-dichlorobenzyl)-1,6-diazaspiro[3.3]heptane-1-carboxamide in dichloromethane (12 mL) was added at 0° C. triethylamine (217 μl, 1.56 mmol) followed by 4-chlorobenzene-1-sulfonyl chloride (329 mg, 1.56 mmol). The reaction mixture was left to warm to ambient temperature overnight, and was then diluted with dichloromethane (10 mL) and quenched with water (10 mL). The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over sodium sulfate and were concentrated under reduced pressure. Purification by chromatography (SiO2; heptane:ethyl acetate 1:4) afforded the title compound (445 mg, 85%) as a colorless solid. HRMS (EI): 473.0134 (exact mass calculated for C19H18Cl3N3O3S ([M]+)=473.0134).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)(=[O:36])=[O:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 290 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 2,4-difluoro benzene sulfonyl chloride. The compound of example 290 was used directly without isolation, for the preparation of compound of example 291.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)[CH:12]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][NH:23]1>CO>[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:12]=1
Reactant: Cn1cnc2ccc(-c3cccc(OCC4CO4)c3)cc21
Reactant: c1ccc2c(c1)CNC2
Solvent: CO
Product: Cn1cnc2ccc(-c3cccc(OCC(O)CN4Cc5ccccc5C4)c3)cc21
Reaction time: 16 h
Yield: 11 %

Procedure:
To a solution of 1-methyl-6-(3-(oxiran-2-ylmethoxy)phenyl)-1H-benzo[d]imidazole (500 mg, 1.78 mmol) in MeOH (5 mL) was added isoindoline (213 mg, 1.78 mmol) at 25° C., and the mixture was heated to reflux and stirred for 16 h. The reaction mixture was cooled, concentrated and purified by preparative HPLC purification. (80 mg, yield 11%) MS (ESI+) e/z: 400.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.22 (s, 1H), 7.87 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.41-7.19 (m, 7H), 6.97-6.95 (m, 1H), 4.16-4.04 (m, 7H), 3.89 (s, 3H), 3.04-2.87 (m, 2H).