Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])=[O:11].C(Cl)CCl.[NH3:26]>CN(C1C=CN=CC=1)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:26])=[O:16])=[O:11]
Reactant: N
Reactant: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)c1cccnc1NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 2-[(1-benzothien-2-ylcarbonyl)amino]nicotinic acid (112 g, 4.0 mmol), EDC (2.3 g, 12.0 mmol) and DMAP (1.46 g, 12.0 mmol) in anhyd dichloromethane (50 mL) was stirred at room temperature for 2 h. To this mixture was added 40% aqueous ammonia (4.0 mL), and the resulting solution stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was washed with satd NH4Cl solution, NaHCO3 solution, and water. The solid was dried to give product as white powder (0.92 g, 77%). HPLC/MS: (M+H)+298.15 m/z Retention time (LC-MS)=2.44 min. 1H NMR (DMSO-D6): 12.25 (1H, s); 8.54(1H, m); 8.21(1H, s); 8.18(1H, d); 8.07(2H, m); 7.52(2H, m); 7.32(1H, m).
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[S:12][C:13]([CH2:16]O)=[CH:14][N:15]=1.N1C=CC=CC=1>O1CCCC1>[Cl:10][C:11]1[S:12][C:13]([CH2:16][O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:14][N:15]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: OCc1cnc(Cl)s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.28 g of methanesulfonic anhydride are added to 1.0 g of 2-chloro-5-hydroxymethyl-thiazole and 0.63 g of pyridine in 10 ml of tetrahydrofuran and the mixture is stirred for three hours at room temperature. Concentration of the solution yields the title compound in the form of a solid (compound 1.3). 1H-NMR (DMSO-d6, 250 MHz): s, 1H, 7.87 ppm; s, 2H, 5.52 ppm; s, 3H, 2.43 ppm.
Reaction SMILES: [OH:1]C(O)=O.[CH3:5][C:6]1([CH2:14]C#N)[CH2:11][CH2:10][CH2:9][C:8](C)([CH3:12])[O:7]1>>[CH3:5][C:6]([OH:1])([CH2:11][CH2:10][CH2:9][C:8](=[O:7])[CH3:12])[CH3:14]
Reactant: CC1(C)CCCC(C)(CC#N)O1
Reactant: O=C(O)O
Product: CC(=O)CCCC(C)(C)O

Procedure:
Taking an overall evaluation of the second and third reaction (which simulate a plant operating with recycle but without recycling the hydroxyketone), a 2,6,6-trimethyl-2-cyanomethyltetrahydropyran yield of 52.9 mol % is obtained with respect to the 2-methyl-heptan-2-ol-6-one introduced into the reaction. As the hydroxyketone conversion during each test is about 80%, it is foreseeable that the overall pyran nitrile yield would rise to around 66 mol % if the unconverted hydroxyketone was also recycled.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:26]1[N:31]=[C:20]([CH:8]2[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=3)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]2)[O:22][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: CC(C)(C)C(N)=NO
Product: CCc1ccc(C2CC(c3nc(C(C)(C)C)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 26 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 52 mg (65% of theory)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=3[CH:29]=2)O1.[Br:31][C:32]1[CH:45]=[CH:44][C:43]2[C:42]3[C:37](=[CH:38][C:39](Br)=[CH:40][CH:41]=3)[CH2:36][CH2:35][C:34]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(COC)OC>[Br:31][C:32]1[CH:33]=[C:34]2[C:43]([C:42]3[CH:41]=[CH:40][C:39]([C:9]4[CH:10]=[CH:11][C:12]5[N:16]=[C:15]([C@@H:17]6[CH2:21][CH2:20][CH2:19][N:18]6[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[NH:14][C:13]=5[CH:29]=4)=[CH:38][C:37]=3[CH2:36][CH2:35]2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1-2
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: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1
Temperature: 85 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
A mixture of ((S)-tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.49 g, 3.6 mmol), 2,7-dibromo-9,10-dihydrophenanthrene (6.09 g, 18.0 mmol), 2M aqueous potassium carbonate solution (9 mL, 18.0 mmol), tetrakis(triphenylphosphine)palladium(0) (209 mg, 0.18 mmol) and dimethoxyethane (36 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 85° C. After 16 hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (1.16 g, 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(F)c2)c1C

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting solid was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 96.3° C.-98.0° C.).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:29]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)On2nnc3ccccc32)c(C)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In dichloromethane (70 ml) are added 1-hydroxy-1,2,3-benzotriazole (3.4 g) and further triethylamine (3.7 ml). To the solution is added dropwise a solution of 2,4,6-trimethylbenzenesulfonyl chloride (4.5 g) is dichloromethane (20 ml) at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting residue is washed with ethyl acetate-n-hexane (1:1; 50 ml) and dried to give colorless crystals of 1-(2,4,6-trimethylbenzenesulfonyloxy)-1,2,3-benzotriazole (5.5 g), melting point: 128°-130° C. The product is recrystallized from dichloromethane-n-hexane to give colorless prisms, melting point: 130°-131° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cc(C)c(C(C)=O)c(C)c2)cc1
Yield: 89.1 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methoxybenzenethiol (1.01 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.41 g, 4.9 mmol) as yellow oil in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.39 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 6.79 (s, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.13 (s, 6H); ESI-MS: m/z 287.6 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1.O>CN(C)C=O>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N(C)CCO)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 2-methylaminoethanol 100 mg in dimethylformamide 1 ml is added at room temperature to a solution of 2-chloro-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine (120 mg) prepared in above Example 1-(3) in dimethylformamide (1 ml). The mixture is stirred at room temperature for 1 hour and thereto is added water 50 ml. The mixture is extracted with ethyl acetate-chloroform and the extract is subjected to silica gel chromatography (solvent: chloroform-methanol 5%) to give 2-(N-methyl-N-(2-hydroxyethyl)amino)-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine 110 mg as white crystals. mp 166.5–168° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:35]O)[C:22]1[C:31]([O:32][CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([Cl:34])[CH:23]=1>>[Cl:34][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:35]=2)[C:31]([O:32][CH3:33])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1cc(OC)c(C(N)=NO)cc1Cl
Product: COCc1cc(-c2nc(-c3cc(Cl)c(C(=O)OC)cc3OC)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (99.09 mg; 0.39 mmol) and Intermediate 59 (100 mg; 0.39 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as an off-white powder. LC/MS (Method B): 479.2 (M+H)+. HPLC (Method A) Rt 5.86 min (Purity: 98.1%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-[4-(4-Oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.60 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 3.00-3.50 (m, 3H), 3.50-3.70 (m, 2H), 3.85-4.00 (m, 3H), 4.48 (dd, J=9.8, 3.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 3H), 7.04 (d, J=8.6 Hz, 2H), 7.25-7.38 (m, 3H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S(M+): 455.1878. Found: 455.1880.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[F:12][C:13](I)([F:15])[F:14].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([C:13]([F:15])([F:14])[F:12])=[N:8]2)=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(N)c2[nH]cnc2n1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1nc(N)c2[nH]c(C(F)(F)F)nc2n1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
0.15 g (1.0 mmol) of 2,6-diaminopurine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 2,6-diamino-8-trifluoromethylpurine (19F-NMR yield: 45%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 2,6-Diamino-8-trifluoromethylpurine was obtained as a white solid (0.050 g, yield: 23%) by column chromatography.
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[CH2:56][C:57]1[N:62]=[C:61]([F:63])[CH:60]=[CH:59][CH:58]=1>>[F:63][C:61]1[N:62]=[C:57]([CH2:56][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])[CH:58]=[CH:59][CH:60]=1
Reactant: Fc1cccc(CBr)n1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2cccc(F)n2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 52 %

Procedure:
(S)-1-(6-Fluoropyridin-2-yl-methyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18i) was prepared according to the same procedure for compound 11a, except using compound 17 and 6-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 62 mg (52%) of 18i as an orange solid, mp 144.7-146.1° C. 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 8.00 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.82 (m, 1H), 7.27-7.11 (m, 4H), 6.92 (m, 2H), 6.79 (m, 2H). Anal. Calcd for C24H20FN3O5S: C, 59.87, H, 4.19; N, 8.73. Found: C, 59.59, H, 4.27; N, 8.48.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH:29]3[C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)C1NCC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-carbonyldiimidazole (0.59 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45) and collecting 15 cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified using isopropyl ether to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone (0.6 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (1 cc) and adding a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:22]O)=[C:12]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:35])(=O)=O>ClCCl>[Cl:35][CH2:22][C:11]1[O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:13][C:12]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CO)o2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Temperature: 25 °C

Procedure:
2.0 g [2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-yl]-methanol were dissolved in 30 ml dichloromethane and cooled in an ice bath. 0.88 ml triethylamine were added, followed by the addition of 0.49 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 2.5 g of 5-chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 36.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 4.09 (s, 3H), 7.52 (t, J=9.6 Hz, 1H), 7.88-7.68 (m, 6H), 8.25 (s, 8.25 (d, J=6.9 Hz, 1H), 10.37 (s, 1H), 12.74 (s, 1H); MS (m/z): 540.91[M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[Li+].C[Si]([N-:37][Si](C)(C)C)(C)C>C1COCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[Pd]>[CH3:31][O:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH2:37])=[CH:3][C:4]=2[N:10]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Under inert atmosphere, to a solution of 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (0.4 g, 0.94 mmol, see Example 40/Step 1) in anhydrous THF (10 mL) was added SPHOS Pd precatalyst (0.07 g, 0.094 mmol) and LiHMDS (1.0 M solution in Toluene, 1.9 mL, 1.9 mmol) and the contents were heated at 70° C. After 5 h, the reaction mixture was brought back to ambient temperature and quenched with NH4Cl (5 mL). The organic contents were then extracted with EtOAc and the volatiles were then removed under reduced pressure. The residue thus obtained was purified by a flash column chromatography to afford the title compound. H1NMR (CDCl3, 400 MHz): δ 8.38 (s, 1H), 7.29-7.26 (m, 15H), 5.03 (s, 1H), 4.50 (bs, 2H), 3.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(C2CCNCC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (2 g, 6.06 mmol) in DCM (2 mL) was added TFA (3 mL). The solution was stirred at room temperature for 30 min. The reaction solution was concentrated to afford 2,6-dichloro-4-(piperidin-4-yl)pyridine as TFA salt, which was used without further purification. LCMS (ESI) [MH]+=231.1.