Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.[C:29]([O-:32])([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.O1CCOCC1.O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3](=[O:17])[N:4]([CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[N:5]=[CH:6][C:7]=2[C:11]2[CH:16]=[CH:15][C:14]([O:32][CH3:29])=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(c1ccccc1)n1ncc(Cl)c(Cl)c1=O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnn(C(C)c3ccccc3)c(=O)c2-c2ccc(OC)cc2)cc1

Procedure:
Compound 6 is prepared from intermediate 1a and 4-methoxyphenylboronic acid under the conditions described for example 1 using tetrakis(triphenylphosphine)palladium(0), K2CO3 and a mixture of dioxane/water: 3/1. Compound 6 is isolated in solid form (yield: 71%).
Reaction SMILES: [CH3:1][C:2]1([CH:15]=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH:15]=[N:18][OH:19])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: NO
Reactant: CC1(C=O)OCCc2c1[nH]c1ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C=NO)OCCc2c1[nH]c1ccccc21
Reaction time: 16 h

Procedure:
A solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-carboxaldehyde (547 mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5 ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml) is heated at 50°-60° C. for 5 min. and then kept at 4° C. for 16 hr. The precipitate is collected and recrystallized from ethanol water to afford 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde oxime, m.p. 176°-178° C.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=3[CH:14]=2)[O:4][N:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:22]([CH3:37])[C:23]([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]3)=[N:24][N:25]=1>>[ClH:16].[CH3:1][C:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][S:20][C:21]4[N:22]([CH3:37])[C:23]([C:26]5[CH:35]=[CH:34][CH:33]=[C:32]6[C:27]=5[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]6)=[N:24][N:25]=4)[CH2:10][CH2:9][C:8]=3[CH:14]=2)[O:4][N:3]=1
Reactant: Cc1noc2cc3c(cc12)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6onc(C)c6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 3-methyl-6,7,8,9-tetrahydro-5H-isoxazolo[4,5-h][3]benzazepine (0.63 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a faint yellow slightly hygroscopic solid (0.11 mmol).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:34])(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].ON1C(=O)CCC1=O.CC(N=C=NC(C)C)C>CS(C)=O>[CH2:27]([CH:26]([CH2:1][CH2:2][CH2:3][CH2:7][CH2:8][CH3:9])[C:25]([OH:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11]
Reactant: CCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: O=C1CCC(=O)N1O
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: CCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous DMSO (50 mL). Octanoic acid (15.12 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was dialyzed in SpectraPor7 MWCO 1000 dialysis tubing to remove the DMSO and unreacted monomer. The polymer crashed out in water into a thick white liquid. After 3 days of dialysis, the solution was placed into a reparatory funnel and the organic portion was dissolved into chloroform. The water layer was removed and the organic layer was dried with sodium sulfate. The solvent was stripped via rotoevaporation to leave a clear thick liquid product. NMR analysis supported full conversion of hydroxyl groups to the octanoic esters.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution triphenylphosphine (177 mg, 0.68 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (132 mg, 0.74 mmol) in small portions. The reaction mixture was allowed to warm to 25° C. over 30 min and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared in Example 3(A), 200 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 30 min and then treated with 2-amino-5-methylpyridine (154 mg, 1.42 mmol). The resulting reaction mixture was stirred at 25° C. for 1 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide as a red solid. The impure product was further purified by precipitation from 1/1 hexanes/ethyl acetate to afford pure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide (80 mg, 31%) as an off-white solid: mp 184-185° C.; EI-HRMS m/e calcd for C21H26N2O3S (M+) 386.1664, found 386.1664.
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C@H:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Agent: O=O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A 185-ml stainless steel autoclave was charged under argon in a glove box (O2 content<2 ppm) with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (5.00 g, 15.1 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP] (3.8 mg, 5.0 μmol) (S/C 5′000) and methanol (150 mL). The asymmetric hydrogenation was run under 40 bar of hydrogen for 20 h at 30° C. and additional 2 h at 60° C. to complete the conversion (>99.6% conversion and 99.9% ee). After the pressure was released, the white suspension was stirred at 0-5° C. for 2 h, filtered off and the filter cake was washed with cold (0-5° C.) methanol (20 mL) and dried under vacuum at room temperature to yield the title product (4.75 g, 99%) with 99% purity and 99.9% ee. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].ClCCl.C(O)C.ClCl>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12]([CH3:13])=[O:38])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCS(C)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 57 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 57%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O3S (487.02); mass spectrum: (M+H)+=487/489 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:10]1.[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C>CCOC(C)=O.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>[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]([CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[O:25][C:26]([CH3:28])([CH3:29])[CH2:27]3)[CH:12]=2)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1OS(=O)(=O)C(F)(F)F
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
A flask was charged with trifluoro-methanesulfonic acid 2-(2-methoxy-phenyl)-5-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl ester (354 mg, 0.69 mmol) (Example 1, step E),4-(benzyloxy)phenylboronic acid (238.3 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol), 2M Na2CO3 (2.8 mL) and 2:1 toluene/ethanol (10 mL) and the mixture was heated at 80° C. for 6 hrs. The resulting mixture was diluted with EtOAc and washed with sat. NaCl. EtOAc was removed under vacuum and the residue was purified by silica column chromatography to give 257.8 mg (74.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[CH:17][CH:16]=1>ClCCCl.C1COCC1>[CH3:21][C:19]1[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)=[CH:17][CH:16]=[C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[N:20]=1
Reactant: CC(C)(C)C(N)=O
Reactant: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C2CC2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.046 g, 0.457 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.040 mL, 0.457 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, treated with a solution of Example A5 (0.10 g, 0.352 mmol) and TEA (0.098 mL, 0.703 mmol) in THF (2 mL) and stirred at RT for 1 h. The mixture was concentrated to dryness, the residue treated with EtOAc, the solid collected via filtration, washed with water and EtOAc and dried to afford N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (57 mg, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.86 (s, 1H), 10.41 (br s, 1H), 8.19 (d, J=5.6 Hz, 1H), 7.90 (m, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.55 (m, 1H), 6.66 (m, 1H), 2.22 (s, 3H), 1.95 (m, 1H), 1.21 (s, 9H), 0.75 (d, J=5.9 Hz, 4H); MS (ESI) m/z: 412.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[CH2:11](O)[CH3:12]>>[CH2:11]([O:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: OCc1ncccc1O
Reactant: CCO
Agent: [Na]
Product: CCOc1cccnc1CO
Reaction time: 65 h

Procedure:
3-Hydroxy-2-hydroxymethylpyridine (8.5 g) was added to a solution of sodium (1.565 g) in ethanol (100 cc) and the mixture was evaporated to dryness. Dimethylsulphoxide (180 cc) was added to the residue, and bromoethane (7.43 g) in dimethylsulphoxide (24 cc) was added over 20 minutes to the stirred mixture. The mixture was allowed to stand at room temperature for 65 hours, and was evaporated. The residue was partitioned between chloroform and water, and the chloroform extracts were evaporated to an oil which was converted into a crystalline hydrochloride m.p. 190°-191.5° by the addition of ethanolic hydrogen chloride. The hydrochloride was dissolved in water, and aqueous ammonia was added until the mixture was basic, and the mixture was extracted with chloroform. The chloroform extracts were evaporated and the residue crystallised from ethanol/diethyl ether to give 3-ethoxy-2-hydroxymethylpyridine (5.0 g) m.p. 74.5°-76°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.FC(F)(F)C(O)=O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C:6]1[C:7]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=1[O:4][CH2:3][CH2:2][O:1][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1
Reactant: C1=COCCC1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2ccccc2OC)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1

Procedure:
A solution of 110 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p-vinylbenzenesulfonamide in 3 ml of absolute tetrahydrofuran was treated with 0.3 ml of 3,4-dihydro-2H-pyran and 4 drops of trifluoroacetic acid. After boiling under reflux overnight, the solvent was distilled under reduced pressure and the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (9:1). There were obtained 100 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide as a white resin, MS: 460 (M--SO2 +H); 430 (M--SO2 +OCH3).
Reaction SMILES: C(C1[C:5]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([F:20])[CH:16]=[CH:15][CH:14]=3)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)C=C.C[N+]1([O-])CC[O:25]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+].[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>O.O=[Os](=O)(=O)=O>[Cl:10][C:7]1[N:6]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([F:20])[CH:16]=[CH:15][CH:14]=3)[C:38]([CH2:37][CH:36]([OH:25])[CH2:40][OH:39])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 0 °C
Yield: 89 %

Procedure:
A mixture of 2-(3-allyl-6-chloropyridin-2-yl)-4-fluoro-1H-indole (100 mg, 0.35 mmol) and NMO (124 mg, 1.05 mmol) in THF (5 mL) and H2O (2.5 mL) was stirred at 0° C. Then OsO4 (20 mg) was added, and the mixture was stirred at RT overnight. After cooling to 0° C., a.q. Na2S2O3 was added and extracted with CH2Cl2. Then the organic layer was washed with water, brine, dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatography (PE:EA=2:1˜1:1) to give the product of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propane-1,2-diol (100 mg, yield: 89%). 1H-NMR (CDCl3, 400 MHz) δ 9.88 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.12˜7.18 (m, 3H), 7.02 (s, 1H), 6.76 (t, J=8.0 Hz, 1H), 4.12˜4.16 (m, 1H), 3.81˜3.85 (m, 1H), 3.64˜3.67 (m, 1H), 3.07˜3.15 (m, 2H). MS (M+H)+: 321/323.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To a solution of 43 mg (0.22 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 70 mg of TBTU (0.22 mmol) in 3 ml DMF, were added 0.19 ml (1.1 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 81 mg (0.22 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 63 mg (55%) of a light yellow foam. MS (ISP) 479.4 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][C:16]1[C:24]2[CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=3)[C:21](=[O:35])[C:20]=2[C:19]([O:36][CH2:37][CH3:38])=[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=12)[CH3:14].[F:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:13]([O:15][C:16]1[C:24]2[CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:53][S:50]([C:47]4[CH:46]=[CH:45][C:44]([F:43])=[CH:49][CH:48]=4)(=[O:52])=[O:51])=[O:33])=[CH:27][CH:26]=3)[C:21](=[O:35])[C:20]=2[C:19]([O:36][CH2:37][CH3:38])=[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=12)[CH3:14]
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)NS(=O)(=O)c3ccc(F)cc3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of carbonyldiimidazole (13.2 mg, 0.081 mmol) and [4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid (30 mg, 0.074 mmol) in dichloromethane (2 ml) was added 4-fluorobenzenesulphonamide (14.3 mg, 0.081 mmol) and N,N-diisopropylethylamine (10.5 mg, 0.81 mmol). The mixture was stirred at ambient temperature under an atmosphere of nitrogen overnight. The reaction mixture was diluted with dichloromethane (3 ml) and then washed with 2N hydrochloric acid (5 ml). The organic phase was dried (MgSO4) and then concentrated in vacuo to give a brown gum. The residue was purified using mass directed autopurification to give the title compound as a white solid (14.7 mg, 35.3%). MH+563.
Reaction SMILES: C(N=C=O)CN=[C:4]=[O:5].[CH2:9]([CH2:16][CH2:17]N=C=O)[CH2:10][CH2:11][CH2:12][N:13]=C=O.N(C1CCCC1CN=C=O)=C=O.N(C1CC(C)(CN=C=O)CC(C)(C)C1)=C=O.C1(CN=C=O)C=CC(CN=C=O)=CC=1>>[NH2:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:16][CH:17]=1.[CH2:4]=[O:5]
Reactant: O=C=NCCCCCCN=C=O
Reactant: O=C=NCCN=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C=NCC1CCCC1N=C=O
Agent: O=C=NCc1ccc(CN=C=O)cc1
Product: C=O
Product: Nc1ccccc1

Procedure:
Examples of suitable polyisocyanates which may be used include ethylene diisocyanate, 1,4-tetramethylene diisocyanate, 1,6-hexamethylene diisocyanate, 2,4,4-trimethyl-1,6-hexamethylene diisocyanate, 1,12-dodecanediisocyanate, cyclobutane-1,3-diisocyanate, cyclohexane-1,3- and/or -1,4-diisocyanate, 1-isocyanato-2-isocyanatomethyl cyclopentane, 1-iso cyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane(isophorone diisocyanate or HMI), 2,4- and/or 2,6-hexahydrotoluylene diisocyanate, 2,4′- and/or 4,4′-dicyclohexylmethane diisocyanate, a,a,a′,a-tetramethyl-1,3- and/or -1,4-xylylene diisocyanate, 1,3- and 1,4-xylylene dilsocyanate, 1-isocyanato-1-methyl-4(3)-isocyanatomethylcyclohexane, 1,3- and 1,4-phenylene diisocyanate, 2,4- and/or 2,6-toluylene diisocyanate, diphenyl methane-2,4′- and/or -4,4′-diisocyanate, naphthalene-1,5-diisocyanate, triphenylmethane-4,4′,4″-triisocyanate, polyphenyl polymethylene polyisocyanates of the type obtained by condensing aniline with formaldehyde followed by phosgenation, and mixtures of the above-mentioned polyisocyanates.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14]>CN(C)C=O>[OH:14][N:13]=[C:12]([Cl:1])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccccc1C=NO
Solvent: CN(C)C=O
Product: Cc1ccccc1C(Cl)=NO
Reaction time: 2 h
Yield: 73.5 %

Procedure:
N-Chlorosuccinimide (2.22 g, 16.6 mmol, 1.0 equiv) was added to a stirred solution of 2-methyl-benzaldehyde oxime (2.25 g, 16.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) at ambient temperature. Stirring was continued for 2 hours and the reaction quenched (ice-water). The resultant mixture was extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×). The organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2.07 g (74%) of N-hydroxy-2-methylbenzenecarboximidoyl chloride as a green oil. 1H NMR (300 MHz, CDCl3) δ: 8.14 (s, 1H), 7.48-7.44 (m, 1H), 7.37-7.20 (m, 3H), 2.43 (s, 3H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=CC=1.[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1.BrC1C=CC=CC=1>CN(C)C1C=CN=CC=1>[CH3:18][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:31][C:29]2[CH:28]=[CH:27][C:25]3[N:26]=[C:22]([NH2:21])[S:23][C:24]=3[CH:30]=2)[NH:8][N:9]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cc1n[nH]c2nccc(Oc3ccc4nc(N)sc4c3)c12
Temperature: 150 °C

Procedure:
A 20 mL sealable tube was charged with 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (0.500 g, 1.74 mmol; prepared according to the procedure of Example 43, Step E), 2-aminobenzo[d]thiazol-6-ol (0.433 g, 2.61 mmol), N,N-dimethylpyridin-4-amine (0.0425 g, 0.348 mmol), and bromobenzene (4 mL). The reaction mixture was heated under nitrogen to 150° C. for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The crude material was used directly in next step. LRMS (APCI pos) m/e 418.2 (M+1).