Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:22])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:15])[CH2:6][CH2:5]2.[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:24][C:7]([CH3:22])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCCO)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 100 mg (0.311 mmol) of 6-hydroxy-N-(4-hydroxybutyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 375 mg CAN (0.685 mmol) yielded 2-hydroxy-N-(4-hydroxybutyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([PH:9](=[O:13])OCC)([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[CH3:14][Mg]Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:14][PH:9](=[O:13])[C:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])[CH3:5]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: C[Mg]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(C)(OCC)[PH](C)=O

Procedure:
By a procedure analogous to that of Example 1, but using ethyl 1,1-diethoxyethylphosphinate (10.5 g) and 33.5 ml of the methylmagnesium chloride solution and adding 14.1 g of potassium carbonate in 30 ml of water to precipitate inorganic salts, methyl (1,1-diethoxyethyl) phosphine oxide is obtained as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:4]1)[CH3:2].O1CCCC1.[CH2:26]([Mg]Br)[CH:27]([CH3:29])[CH3:28]>O1CCCC1>[CH2:1]([N:3]1[C:7]([CH:8]([OH:9])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C=O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(O)CC(C)C
Yield: 31 %

Procedure:
1-Ethyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-5-carbaldehyde (2.5 g) synthesized in Example 58(2) was dissolved in tetrahydrofuran (20 mL), and 1M isobutylmagnesium bromide tetrahydrofuran solution (12 mL) was added dropwise at 0° C. In the same manner as in Example 1(6), the title object compound (0.9 g, 31%) was obtained as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.O1CCOCC1.[C:18](=O)([O-:20])[O-:19].[Na+].[Na+]>O.CCOC(C)=O>[CH3:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1n[nH]c2ncc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c2ncc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 28.8 %

Procedure:
A microwave tube was charged with 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (515 mg, 2.43 mmol), dioxane (2 mL), Hermann's catalyst (72.1 mg, 0.12 mmol) and a solution of sodium carbonate (772 mg, 7.29 mmol) in water (5 mL). The mixture was stirred for 20 sec, heated at 165° C. for 15 minutes in a microwave reactor at very high absorption setting. The reaction was vented before handling. The mixture was diluted with EtOAc and stirred for 5 minutes before filtering through diatomaceous earth to provide the title compound (124 mg, 29%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:16]1[CH:17]=[C:18]([CH:24](CC)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:20]([F:23])[C:21]=1[F:22])[CH2:14][OH:15]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=[C:16]([C@H:13]([OH:12])[CH2:14][O:15][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[F:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)CO)c1
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: -15 °C
Yield: 79.7 %

Procedure:
p-Toluenesulfonyl chloride (9.03 g, 0.0474 mol) in pyridine (25 mL) was added dropwise to a cooled (−15° C.) solution of ethyl 3-{3-[(1S)-1,2-dihydroxyethyl]-4,5-difluorophenyl}pentanoate (13.02 g, 0.043 mol) in pyridine (50 mL) under N2. The reaction was stirred at −15° C. and warmed to RT overnight. The reaction mixture was quenched with H2O and extracted three times with ethyl ether. The combined ether layers were washed with 1N HCl, sat. CuSO4, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (hexane:ethylacetate, 0-30%) yielded the desired product (14.68 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[F:22].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([Cl:14])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Fc1ccc(I)cc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[C:25]([O:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=O.[CH2:35]([N:37]1[C:41]([OH:42])=[CH:40][CH:39]=[N:38]1)[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CC(C)(O)C#N.O>[CH2:35]([N:37]1[C:41]([OH:42])=[C:40]([C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:24]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:25]([O:26][CH:27]3[CH2:30][O:29][CH2:28]3)[C:17]=2[Cl:16])[CH:39]=[N:38]1)[CH3:36]
Reactant: CCn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OC1COC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OC3COC3)c2Cl)c1O
Temperature: 25 °C

Procedure:
Dicyclohexylcarbodiimide (0.72 g (3.5 mmol) was added at ambient temperature with stirring to a solution of 1.07 g (3.5 mmol) of 2-chloro-4-methylsulfonyl-3-(3-oxetanyloxy)benzoic acid and 0.45 g (4 mmol) of 1-ethyl-5-hydroxypyrazole in 25 mL of dry acetonitrile. The mixture was allowed to react for about one hour and then was filtered. The solids collected were extracted with dry acetonitrile. The filtrate and extract were combined and 0.69 g (5.0 mmol) of potassium carbonate and a few drops of acetone cyanohydrin were added with stirring at ambient temperature. The mixture was stirred overnight and was then poured into water. The resulting solution was extracted with ether and then acidified with aqueous hydrochloric acid. The mixture obtained was extracted three times with dichloromethane and the three extracts were combined, washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The yellow solid residue was recrystallized from ethanol to obtain 0.77 g (55 percent of theory) of the title compound as a nearly colorless solid melting at 206-2080° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Solvent: CCOC(C)=O
Product: OCC[C@@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Yield: 74 %

Procedure:
The title compound was prepared from (3S)-(+)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (13b) by a sequence analogous to that described immediately above. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:4) provided the title compound (74%) as a yellow/brown oil; [α]D22 +188 (c=0.007 gml-1, CHCl3).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[C:12]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCCCCC.CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:12]2([OH:21])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8]1
Reactant: O=C1CCc2ccccc21
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccoc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 2.7 mL (0.027 mol) of 10M n-butyllithium in hexane in 70 mL of ether cooled to -78° C. was added 4 g (0.027 mol) of 3-bromofuran and the mixture was stirred for 15 min. To the above cooled mixture was added 3.17 g (0.024 mol) of indanone in 10 mL of THF and the mixture was allowed to warm to room temperature, and then stirred for 20 min. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 mL), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5 g of crude 1-(3-furyl)-indan-1-ol, as an orange oil, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[NH2:13][NH2:14].O.[ClH:16]>C(O)C>[ClH:16].[OH:6][C:5]1[NH:14][N:13]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 20 mL of ethanol. The resulting solution was cooled to 10° C. or less with stirring, and 6.0 g (0.12 mol) of hydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at the reflux temperature for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water and 20.6 g (0.2 mol) of 35% hydrochloric acid were added thereto. The produced crystal was collected by filtration, washed twice with 10 mL of water and dried by a hot air drier to obtain 12.8 g (yield: 68.1%) of the title compound as a white crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Cl)cc(Br)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-chloro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.4 g, 17.5 mmol) and ytterbium(III) triflate hydrate (1.08 g, 1.75 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (1.59 mL, 17.5 mmol) and water (0.32 mL, 17.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-chloro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (7.67 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrClNO3 M+: 438.8, observed: 438.8, 440.8.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])#[N:2].[CH2:24]([O:26][CH2:27][CH2:28]Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:24][O:26][CH2:27][CH3:28])[CH2:20][CH2:19]1)=[O:17])#[N:2]
Reactant: N#CCCCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCN1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix 1-[(4-cyanobutyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.0 g, 12.91 mmol), 2-ethoxy ethylbromide (2.34 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:14])[NH:4][CH:3]=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: COc1ccc2c(=O)[nH]cc(N3CCN(C)CC3)c2c1
Yield: 59.5 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.25 g, 0.984 mmol) and 1-methylpiperazine (0.197 g, 1.968 mmol) in ethylene glycol (2 ml) was added DIPEA (0.516 ml, 2.95 mmol). The reaction was irradiated in microwave at 140° C. for 1 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get the desired compound (0.16 g, 53.5%) as solid. MS: MS m/z 274.18 (M++1).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:20]I>>[CH3:20][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: FC(F)(F)c1cccc(-c2ccnc(S)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: CSc1nccc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
A solution of 4.75 g. of 2-mercapto-4-(m-trifluoromethylphenyl)pyrimidine in 50 ml. of 1 N sodium hydroxide is cooled to near 0° C. in an ice bath and 2.90 g. of methyliodide is added. After the reaction mixture is allowed to warm to room temperature, the product is removed by filtration, m.p. 89°-90° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.7 %

Procedure:
To an anhydrous dichloromethane (8 mL) suspension of 4-(4-methoxyphenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione (200 mg, 0.63 mmol) was added a 1M boron tribromide/dichloromethane solution (0.94 mL, 0.94 mmol) under cooling in an ice-bath. The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was washed with water and ethanol. The solid was further washed with hexane, and dried to obtain the titled compound as a off-white crystal (285 mg, yield 45%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1.[S:11]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=2)=[CH:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2>C(O)(C)C.ClCCl>[NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:18]2[N:17]=[C:16]([C:15]3[S:11][C:12]4[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=4[CH:14]=3)[CH:21]=[CH:20][N:19]=2)[CH2:5][CH2:4]1
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Reactant: NCC1CCC(CN)CC1
Solvent: ClCCl
Solvent: CC(C)O
Product: NC[C@H]1CC[C@@H](CNc2nccc(-c3cc4ccccc4s3)n2)CC1
Yield: 88 %

Procedure:
4-Aminomethyl-cyclohexylmethyl-amine (cis/trans-mixture, ca. 2:1) (1.28 g, 9.00 mmol) is added to a stirred suspension of 4-benzo[b]thiophen-2-yl-2-chloro-pyrimidine (986 mg, 4.00 mmol) in isopropanol (13 mL) at ambient temperature under nitrogen. The resultant mixture is heated at 110° C. for 20 hours. At ambient temperature the mixture is diluted with dichloromethane (40 mL), washed with 1N NaOH (13 mL), and dried (MgSO4). After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-20%, the title compound is obtained as a 2:1 cis/trans-mixture (1.24 g, 88% yield). ES+(m/z) 353 [M+H].
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Br)(C)C.[CH3:32][C:33]1[C:38]([CH:39]=[O:40])=[C:37]([CH3:41])[CH:36]=[CH:35][N:34]=1>C1COCC1.[Cl-].[NH4+]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:39]([C:38]3[C:33]([CH3:32])=[N:34][CH:35]=[CH:36][C:37]=3[CH3:41])[OH:40])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Cc1ccnc(C)c1C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -20 °C
Yield: 60 %

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (0.494 g, 1 mmol) placed in a 10 mL round bottom flask under nitrogen atmosphere was dissolved in anhydrous THF (5 mL). The solution was cooled to −20° C. The magnetically stirring solution was treated with solution of 2.0 M isopropylmagnesium bromide in THF (1.05 mL, 2.1 mmol) drop wise and after the addition was complete the reaction mixture was allowed to warm to 0° C. and maintained at this temperature for 1 h. The resulting deep purple solution was cooled to −20° C. and treated with a solution of 2,4-dimethyl-pyridine-3-carbaldehyde (0.28 g, 2.1 mmol) in THF (2 mL). The mixture was allowed to warm to room temperature and stirred at room temperature over night. After diluting with saturated ammonium chloride solution (10 mL) the product was extracted with ethyl acetate (3×25 mL). The combined organic extract was concentrated and product purified by flash chromatography on silica gel column (10-30% ethyl acetate in hexanes). Product containing fractions were combined and the solvent evaporated to afford 0.33 g of 4-chloro-N-{5-chloro-2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=550.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.CCOC(C)=O>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][C@@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
N-(t-Butoxycarbonyl)glycine 14-3 (Aldrich) was coupled with 3(R)-methyl-β-alanine benzyl ester 0.5 H2SO4. 11-7 (Celgene) according to the procedure described for the preparation of 14-5. The title product 15-1 was then obtained by chromatography (silica, hexane/EtOAc 2:3).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 64 mg (0.221 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 2.0 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1B1OC(C)(C)C(C)(C)O1)=[O:5])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:41])[CH2:33][NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:28][CH:27]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:24])[C:8]([CH2:22][CH3:23])=[C:9]([C:20]#[N:21])[C:10]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:41])[CH2:33][NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:30][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)c(C#N)c(CC)n1C
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Reaction time: 3 h

Procedure:
Add 4-cyano-5-ethyl-1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.22 g, 0.65 mmol, prepared in preparation 50), to propane-2-sulfonic acid [2-(4-iodo-phenyl)-propyl]-amide (0.20 g, 0.65 mmol, can be prepared as in J. Med. Chem., 43, 4354 (2000)), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(1H) complex with methylene chloride (1:1) (0.013 g, 0.016 mmol), and 2M aqueous sodium carbonate (1.35 mL, 2.7 mmol) in DMF and heat to 80° C. After 3 hours, cool and pour into water. Extract with ethyl acetate. Wash the combined organics with water, and brine, dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography (silica gel), eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (ES+)=446.3 (M+1).