Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([O:27][CH2:28][CH2:29][OH:30])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(N(CC)CC)C>CN(C=O)C.O>[C:17]1([S:14]([C:10]2[C:9]3[C:13]4[N:12]([CH2:2][CH2:3][O:4][C:5]=4[CH:6]=[C:7]([O:27][CH2:28][CH2:29][OH:30])[CH:8]=3)[N:11]=2)(=[O:16])=[O:15])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(OCCO)cc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2ccccc12)c1nn2c3c(cc(OCCO)cc13)OCC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 2-[7-(2-chloroethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]ethanol (1.18 g, 2.65 mmoles) and triethylamine (0.4 ml, 2.65 mmoles) in DMF was stirred overnight at 70° C., cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 5% CH3OH/EtOAc to afford the title compound (1.03 g, 2.5 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:22]4[O:21][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1ccco1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccco2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 35.3 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.050 g, 0.140 mmol) and 2-furanylboronic acid (0.020 g, 0.182 mmol) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.097, 0.70 mmol) was added and the solution was degassed with Argon. PdCl2(dppf) (0.017 g, 0.024 mmol) was added and the reaction was heated in a microwave at 100° C. for 10 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/0.1% NH4OH/H20. The desired fractions were concentrated, giving 0.017 g (36%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C.O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:21][OH:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CSc1ccc(CC(=O)c2ccc(Br)cc2)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CSc1ccc(CC(=NO)c2ccc(Br)cc2)cc1F
Temperature: 75 °C
Yield: 99.6 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone (1.50 g, 4.42 mmol) in a mixture of ethanol (12 ml) and water (6 ml) were added hydroxylamine hydrochloride (615 mg, 8.84 mmol) and anhydrous sodium acetate (715 mg, 8.84 mmol) at room temperature. The mixture was heated for 2 h at 75° C. and then diluted with diethyl ether (200 ml), washed with water (50 ml×2) and saturated sodium bicarbonate (50 ml×2), and dried over magnesium sulfate. Removal of solvent gave 1.56 g (˜100%) of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime as an orange solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])=[O:21].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:16])([F:17])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:24][CH3:25])=[O:26])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (2.61 g, 6.43 mmol) was added to a stirred solution of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, methyl ester (2.61 g, 6.43 mmol) in dry THF (95 mL) at room temperature under a dry N2 atmosphere. After 1 hour, tert-butyl bromoacetate (1.56 mL, 1.5 eq) was added and the reaction mixture was heated at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and the THF was removed. Water (100 mL) was added and the resulting solid was filtered. The resulting solid was washed with water and then petroleum ether and dried in vacuo to provide the title compound as a white solid (2.81 g, 84%). A small portion was recrystallized from petroleum ether:ether, m.p. 126°-128° C.
Reaction SMILES: ClC1C=C([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N+]=[N-])=[C:12](C(F)(F)F)[CH:11]=2)C=CC=1.[H][H]>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH2:8])=[O:23])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(N)cc1

Procedure:
The N-3-chlorophenyl 4-azido-3-trifluoromethylbenzamide compound from Step 18c was reduced under 1 atm of hydrogen in the presence of Pd/ in ethanol to the give the corresponding 4-aminobenzamide, which was used without purification in Step 72b.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[SH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C(#N)C.CCOCC>[CH3:23][CH:22]([CH3:24])[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]1[CH:10]=[CH:9][N:8]=[C:7]([S:6][C:2]([F:4])([F:3])[F:1])[N:12]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S)n2)c1
Reactant: FC(F)(F)I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(SC(F)(F)F)n2)c1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
2 g trifluoromethyl iodide was condensed into a solution of 0.57 g (0.002 mol) N-[2-(2-mercapto-4-pyrimidinyl)-4-methylphenyl]-2-methylpropanamide and 2.5 g triethylamine in 20 mL anhydrous acetonitrile, and the reaction mixture was stirred under a dry ice condenser while exposed to a sun lamp for 4 h. The reaction mixture was diluted with 100 mL ether and washed successively with water, 1N sodium hydroxide solution, and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 40:1 chlorobutane/ethyl acetate mixture as eluent to yield 0.52 g of the title compound as yellow crystals melting at 114°-116° C. 1H NMR (CDCl3): δ 1.21 (d,6H), 2.40 (s,3H), 2.55 (m,1H), 7.40-8.70 (5H), 10.7(s,1H,NH).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of Example 1C (1 g, 4.69 mmol) in methanol (20 mL) was added potassium carbonate (3.89 g, 28.1 mmol) and the mixture was stirred for 30 minutes. Dimethyl 1-diazo-2-oxopropylphosphonate (3.60 g, 18.76 mmol) was added and the mixture was stirred for 12 hours. The mixture was filtered through diatomaceous earth with methanol, concentrated and purified by column chromatography on silica gel (Isco®, Redi-Sep® column), eluting with 15% ethyl acetate in hexane to afford the title compound. LCMS: 110 (M+H-Boc)+.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]([CH3:27])([CH2:24][CH:25]=[CH2:26])[CH2:5][N:6]([CH3:23])[C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([O:13]CC)=[O:12])=[O:8]>CO.O.C1COCC1>[CH3:3][C:4]([CH3:27])([CH2:24][CH:25]=[CH2:26])[CH2:5][N:6]([CH3:23])[C:7]([NH:9][C@@H:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: C=CCCCCC[C@H](NC(=O)N(C)CC(C)(C)CC=C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)N(C)CC(C)(C)CC=C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (66 mmol) was added to a solution of ethyl (2S)-2-({[(2,2-dimethylpent-4-en-1-yl)(methyl)amino]carbonyl}amino)non-8-enoate (2.35 g, 6.67 mmol) in MeOH (20 mL), water (10 mL) and THF (30 mL). The reaction mixture was stirred for 3 hours at RT and then concentrated. A solution 5% potassium bisulfate was added, and the mixture was extracted with EtOAc (3×). The combined organic were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound. LRMS (M+H)+=325.3.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: Cc1cc(C)cc(N2CCN(C(=S)Nc3cc4ccccc4nc3C)CC2)c1
Yield: 81 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10](S(C1C(C)=CC=CC=1)(=O)=O)[S:11]([C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:4].[OH-].[Na+].Cl>O1CCOCC1.CO.O>[C:15]1([CH3:20])[C:14]([S:11]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1N(S(=O)(=O)c1ccccc1C)S(=O)(=O)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 85 °C
Yield: 94.3 %

Procedure:
To a stirred mixture of 3-(bis-(Toluene-2-sulfonyl)-amino)-thiophene-2-carboxylic acid methyl ester (2.5 g, 5.35 mmol) in 1,4-dioxane/MeOH/water (3:1:1; 62.5 mL) was added aq. 1 N NaOH solution (16.05 mL, 16.05 mmol, 3.0 eq) and heated at 85° C. for 3.5 h and it was then cooled to rt. To the reaction mixture was added 1.2 N HCl (16.0 mL), extracted with CHCl3 (3×30 mL), washed with brine and dried. Evaporation of the solvent gave 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (1.5 g, 99%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) 7.94 (dd, J=7.9 Hz, 1.3 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.55 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.42-7.37 (m, 2H), 7.1 (d, J=5.5 Hz, 1H), 2.57 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][S:35]([NH:38][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:31])[F:32])=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:28])(=[O:37])=[O:36]
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a suspension of 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (39.4 mg, 0.085 mmol) in methylene chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4-dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCl (16.4 mg, 0.085 mmol) was added. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified by flash column chromatography using a linear gradient of ethyl acetate containing 1% acetic acidin hexanes (20% to 100% in 15 minutes) to give the desired compound as a pale yellow solid (16.5 mg). 1H-NMR is consistent with the desired structure. LRMS for C23H22F3N5O5S (m/e) calcd 537.13, obsd 538.1 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:9]=O>C=CCCCCCC.C(O)CC.O.Cl[Pd]Cl>[CH2:6]([C:7]([CH3:8])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: O=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCCO
Product: CCCCCCC(C)=O
Reaction time: 6 h

Procedure:
The autoclave described above was charged with 17 g of ME containing 1-octene as compound to be oxidized and having the following composition (in % by weight including catalyst): 54% of 1-octene, 7.7% of Igepal, 1.9% of Triton 100, 19.2% of n-propanol, 10.7% of water and 0.8% of PdCl2 /5.7% of Fe(NO3)3 as catalyst. The oxidation was carried out for 6 hours at 50° C. and 1 bar using pure oxygen. Methyl hexyl ketone was obtained as product. The selectivity was 54% at a conversion of 14%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[C:18](=O)[CH3:19]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[C:18]([CH3:19])[C:17]([CH3:16])=[N:1]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: CC(=O)C(C)=O
Solvent: O
Product: Cc1nc2c(Cl)cc3nc(O)c(O)nc3c2nc1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 10 ml water was at 50° C. added a solution of 0,4 g (4,6 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50° C. for 24 h. After cooling to 25° C., the precipitate was filtered off and washed with water and ethanol to give 0,3 g (50%) 6-chloro-2,3- dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6) 8.47 (1H,s), 2.60 (3H,s), 2.53 (3H,s).
Reaction SMILES: BrC1C=C(N[C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])C=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[O:37])[O:35][N:34]=[C:33]([CH3:38])[C:32]=2[CH:39]=1.C1(C2(CC(=O)C(O)=O)CC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:27][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[O:37])[O:35][N:34]=[C:33]([CH3:38])[C:32]=4[CH:39]=3)=[O:26])[CH2:17][CH2:24]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1cc(Br)c2c(c1)C(=O)OC2)c1ccccc1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Agent: O=C(O)C(=O)CC1(c2ccccc2)CC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC3(c4ccccc4)CC3)cc12

Procedure:
was obtained analogously to the process that is described for 4-bromo-6-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one and 3-(1-phenyl-cyclopropyl)-2-oxo-propionic acid, melting point 197-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:38])=[C:14]([N:18]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:19][CH2:20][O:21][CH3:22])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:19][CH2:20][O:21][CH3:22])[C:13]=2[CH3:38])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from 4-chlorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)s1
Temperature: 100 °C
Reaction time: 14 h
Yield: 74.1 %

Procedure:
Commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (850 mg, 4.3 mmol) was dissolved in 1,2-dimethoxyethane (30 mL), and commercially available ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.50 mL, 3.35 mmol), palladium (II) acetate (38.0 mg, 0.169 mmol), triphenylphosphine (176 mg, 0.671 mmol) and an aqueous potassium carbonate solution (3M, 2.20 mL, 6.60 mmol) were added, followed by stirring at 100° C. for 14 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (800 mg, yield 74%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.COCCOC.[OH-].[Na+]>O.[Na+].[Cl-].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>[OH:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: OCCNc1ccc2ncc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCCNc1ccc2ncc(-c3ccc(O)cc3)n2n1
Temperature: 90 °C
Reaction time: 19 h
Yield: 44.8 %

Procedure:
85 mg (0.33 mmol) of 2-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)ethanol (Example 1.5), 69 mg (0.5 mmol) of 4-hydroxybenzene boronic acid and 76 mg (0.066 mmol) of tetrakis(triphenylphosphine)palladium(0) were mixed under argon with 3.4 ml of dimethyl glycol and 2 ml of an aqueous NaOH solution (a stock solution of 190 mg of NaOH in 10 ml of water). The mixture was stirred at 90° C. for 19 hours. After cooling, the mixture was diluted with sat. NaCl solution and extracted 2× with ethyl acetate. The combined organic phases were washed with sat. NaCl solution, filtered through a silicone filter (from Whatman) and concentrated. The resulting crude product was recrystallized from methanol. 40 mg of the desired product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15]/[CH:16]=[CH:17]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (0.152 g, 0.49 mmol), iodobenzene (0.06 mL, 0.49 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.05 mmol), and triethylamine (0.68 mL, 4.9 mmol) were combined in DMF (4 mL) and the mixture was purged with N2 (g) for 5 minutes. The reaction was then sealed and stirred at 100° C. overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](O)C(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Yield: 53.9 %

Procedure:
(S)-3-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (96 mg, 0.350 mmol, 1.0 eq), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (115 mg, 0.385 mmol, 1.1 eq), and 10-camphorsulfonic acid (89 mg, 0.385 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 40 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a pale yellow solid (101 mg, 54%). LCMS (m/e) 535 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.09 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.11 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.48-7.42 (m, 1H), 7.40 (s, 1H), 7.31-7.26 (m, 1H), 7.14-7.08 (m, 1H), 7.05 (d, 1H, J=8.0 Hz), 6.91 (s, 1H), 6.21 (bs, 1H), 4.42 (bs, 1H), 4.10-4.02 (m, 1H), 3.05 (d, 3H, J=4.6 Hz), 3.00-2.80 (m, 7H), 2.78-2.64 (m, 3H).