Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([O-:3])=[O:2]
Reactant: O=C1OCCC1Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-nitrophenol (20 g, 0.14 mol) and K2CO3 (25.2 g, 0.18 mol) in 280 mL DMF was cooled to 0° C. 2-Bromobutyrolactone was added dropwise, the reaction was stirred for 45 min at 0° C., then stirred at room temperature for 3 hours (h). The mixture was poured into 2 L water containing approx. 200 g salt, and the solution was washed with 6×100 mL of 1:1 diethyl ether/ethyl acetate. The combined organics were washed with 2×100 mL sat'd aq. K2CO3, 5×100 mL water and 100 mL brine, dried (Na3SO4), and filtered. Solvent was removed in vacuo to yield the title compound as an off-white solid (21.88 g, 0.1 mol). 1H (CDCl3): 7.84 (d, 1H, J=7.9), 7.57 (t, 1H, J=7.5), 7.49 (d, 1H, J=7.9), 7.16 (t, 1H, J=7.5), 5.03 (t, 1H, J=7.4), 4.58 (m, 1H), 4.42 (m, 1H), 2.8-2.6 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([Cl:12])[CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.CC([O-])=O.[K+].ClCCl.Cl[C:38]1[N:43]=[C:42]([O:44][CH3:45])[C:41]([C@@:46]2([CH3:53])[CH2:51][CH2:50][CH2:49][NH:48][C:47]2=[O:52])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:12][C:4]1[CH:3]=[C:2]([C:38]2[N:43]=[C:42]([O:44][CH3:45])[C:41]([C@@:46]3([CH3:53])[CH2:51][CH2:50][CH2:49][NH:48][C:47]3=[O:52])=[CH:40][CH:39]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH3:11]
Reactant: Cn1ncc2c(Cl)cc(Br)cc21
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCCNC1=O
Agent: CC(=O)[O-]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1nc(-c2cc(Cl)c3cnn(C)c3c2)ccc1[C@@]1(C)CCCNC1=O
Temperature: 100 °C
Yield: 77.5 %

Procedure:
An oven dried vial was charged with 6-bromo-4-chloro-1-methyl-1H-indazole (507 mg, 2.1 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (649 mg, 1.9 mmol), oven dried KOAc (604 mg, 6.2 mmol), [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (54 mg, 0.066 mmol) and dioxane (10 mL), and purged with nitrogen for 20 min. The reaction was heated at 100° C. for 1 h. The mixture was filtered through a pad of Celite®, and the filter cake was rinsed with dioxane. The filtrate was concentrated under reduced pressure to afford the crude residue (530 mg). To a solution of this crude residue (370 mg) in degassed dioxane (2 mL) was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (300 mg, 1.2 mmol), an aqueous solution of sodium carbonate (2 M, 1.5 mL, 2.9 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (54 mg, 0.066 mmol). The reaction mixture was degassed with nitrogen, and heated at 100° C. for 1 h. The reaction mixture was cooled to r.t., and anhydrous Na2SO4 was added. The mixture was filtered through a pad of Celite®, and the filter cake was rinsed with dioxane. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-100% EtOAc in Heptane to 0-30% EtOH/DCM) to afford (R)-3-(6-(4-chloro-1-methyl-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (358 mg, 79%). 1H NMR (600 MHz, CDCl3) δ 1.68 (d, 1H), 1.74 (s, 3H), 1.88 (d, 1H), 1.97-2.07 (m, 1H), 2.39 (td, 1H), 3.37-3.47 (m, 1H), 3.50-3.60 (m, 1H), 4.12 (s, 3H), 4.15 (s, 3H), 5.81 (brs, 1H), 7.42 (d, 1H), 7.70 (d, 1H), 7.82 (s, 1H), 7.94 (s, 1H), 8.06 (s, 1H). MS (AP+)(M+H) 385.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH3:30])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH3:30])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc([N+](=O)[O-])c(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (51 mg, 0.194 mmol) and 2-methoxy-5-methyl-4-nitroaniline (43 mg, 0.236 mmol) similar to Example 160 and was isolated as off-white crystalline solid (mp 128-133° C., 23 mg, 0.057 mmol, 29%). 1H NMR (CDCl3/MeOH-d4): 9.42 (s, 1H), 8.75 (m, 1H), 8.62 (m, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.42 (dd, J=4.8, 8.1 Hz, 1H), 6.82 (s, 1H), 4.01 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromobenzenesulfonamide [CAS 701-34-8] (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (325 mg, 64%). MS (ISP) 511.3 [(M+H)+]; mp 266-267° C.
Reaction SMILES: [Na+].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]([O-])=[O:32])[C:22]2=[O:34])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:76][O:77][C:78](=[O:82])[C@H:79]([CH3:81])[NH2:80]>ClCCl>[CH3:76][O:77][C:78](=[O:82])[C@H:79]([CH3:81])[NH:80][C:31](=[O:32])[CH2:30][N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[CH:20][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:22]1=[O:34]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C([O-])CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c3ncccc23)c2ccccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c3ncccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 2-[3-(8-benzyloxyquinol-5-ylmethylen)-2-oxindol-1-yl] acetic acid sodium salt (50 mg, 0.11 mmol), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (50 mg, 0.10 mmol) and triethylamine (11 mg, 0.11 mmol) in dichloromethane (10 ml) was added L-alanine methyl ester hydrochloride (20 mg, 0.14 mmol) and the mixture was stirred for 2 h at room temperature. Then dichloromethane was added, the organic layer washed 3 times with water, dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate/cyclohexane (8:2) to give 45 mg (78.5% yield) of title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23].O>CN(C)C=O>[C:1]([N:5]1[C:9]([O:10][CH:22]([F:24])[F:23])=[CH:8][C:7]([C:11]([F:13])([F:14])[F:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(F)(F)F)cc1OC(F)F
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 10.4 g (50.0 mmol) of 1-tert-butyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of N,N-dimethylformamide was added 7.6 g (55.0 mmol) of anhydrous potassium carbonate at room temperature. While the reaction solution was stirred, an excess amount of chlorodifluoromethane was introduced into the reaction solution at 80° C. After the confirmation of disappearance of the starting material, the introduction of chlorodifluoromethane was stopped and the reaction solution was cooled to room temperature. Thereafter, the reaction solution was poured into water and extracted with diisopropyl ether. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled under reduced pressure to obtain 10.8 g (yield: 83.7%) of 1-tert-butyl-5-difluoromethoxy-3-trifluoromethyl-1H-pyrazole as a yellow liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH3:19])=[CH:13][CH:12]=1>O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH3:19])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cccc(F)n1
Reactant: CNCc1ccc(OC)cc1
Solvent: O
Product: COc1ccc(CN(C)c2cccc(F)n2)cc1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.183 mL, 2.00 mmol) and (4-methoxyphenyl)-N-methylmethanamine (0.604 g, 4.00 mmol) in 2 mL of water. The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated to give 470 mg of a crude yellow oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate) to give 400 mg of N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine as a clear, colorless oil. To a solution of diisopropylamine (1.92 mL, 13.6 mmol) in 25 mL of THF at 0° C. was added butyllithium (1.6 M in hexanes, 8.93 mL, 14.3 mmol). The mixture stirred for 30 minutes and was then cooled to −60° C. and N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine (1.760 g, 7.15 mmol) was added dropwise in 10 mL of THF. The reaction stirred for 1 h at −60° C. and then triisopropyl borate (2.88 mL, 12.5 mmol) was added and the reaction allowed to warm up to RT and stirred for 1 h. Ammonium chloride (sat.) was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.13 g of a crude yellow foam, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 750 mg of a off-white solid. ES+=291.2 (M+H)
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:24][OH:25])=[N:7]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:24]=[O:25])=[N:7]2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C=O)ccc2c1Br
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (S)-ethyl 2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate (200 mg, 0.49 mmol) in anhydrous dichloromethane (13 mL) at 0° C. was added Dess-Martin periodinane (248 mg, 0.58 mmol) and the reaction mixture was stirred for 1 hour. Reaction mixture was partitioned between dichloromethane and water and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a white solid (160 mg, 80%). LCMS-ESI+ (m/z): [M+H]+ calcd for C19H23BrNO4: 408.07. found: 408.88, 410.14
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH:17]=[CH2:18])=[CH:12][C:11]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:11]1[CH:12]=[C:13]([CH:17]=[CH2:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]([CH:21]2[CH2:23][CH2:22]2)=[O:25])[CH:7]=1)=[O:20]
Reactant: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Yield: 42.9 %

Procedure:
A solution of N-(2-bromopyridin-4-yl)-2,6-dichloro-4-vinylbenzamide (23 mg, 0.062 mmol), cyclopropanecarboxamide (16 mg, 0.19 mmol), Pd2(dba)3 (6.0 mg, 0.0062 mmol), Xantphos (7.0 mg, 0.012 mmol) and Cs2CO3 (40 mg, 0.12 mmol) in dioxane (2 mL) was heated to 140° C. for 1 hour in a microwave reactor under nitrogen atmosphere. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-vinylbenzamide (10 mg, yield: 43%). 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 7.99-7.97 (m, 2H), 7.74 (s, 1H), 7.37 (s, 2H), 6.64 (m, 1H), 5.86 (m, 1H), 5.47 (m, 1H), 1.52 (m, 1H), 1.09-1.05 (m, 2H), 0.92-0.88 (m, 2H). LCMS (ESI) m/z: 376.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCCCC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.200 g, 0.595 mmol), 1-(2-chloroethyl)piperidine monohydrochloride (0.131 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 mL) was heated to reflux for 1.0 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids filtered off, and the filtrate concentrated in vacuo to give the crude product (0.308 g). This crude material was chromatographed over silica gel (5 g), eluting with 5% and then 10% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.192 g (72%) of the title compound as an off-white solid with mp 169°-170° C.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][C:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)=[O:17])[CH:9]=[CH:8][C:7]=2[CH:6]=1>[C].[Pd].CO>[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][CH:23]=3)=[O:17])[CH:9]=[CH:8][C:7]=2[CH2:6]1
Reactant: CN(C)CCC1=Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCC1CCc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Yield: 20.1 %

Procedure:
A methanol solution (5 ml) of N-[6-[2-(dimethylamino)ethyl] 7,8-dihydro-2-naphthalenyl][1,1′-biphenyl]-4-carboxamide (20 mg, 0.050 mmol) obtained in Example 208 and palladium carbon (10 mg) was stirred under hydrogen atmosphere for 4 hours. After a catalyst was filtered off, the filtrate was concentrated under reduced pressure. The resulting residue was purified by aluminum B column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-hexane (1:3), to give the titled compound (4.0 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]1[CH2:10][CH:9]1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH2:8]1[CH2:10][CH:9]1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:15][CH:14]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(OCC2CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin-3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30° C. After 12 hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=249 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH:9]=[CH2:10])[CH2:6][O:5][CH2:4]1)[CH3:2].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[C:31]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:42]=[C:41]([C:43]3[CH:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]=[CH:47][CH:48]=3)[N:40]=[C:39]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57](Br)[CH:56]=3)[N:38]=2)[CH:32]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:31]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:42]=[C:41]([C:43]3[CH:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]=[CH:47][CH:48]=3)[N:40]=[C:39]([C:55]3[CH:56]=[CH:57][CH:58]=[C:59]([CH2:10][CH2:9][O:8][CH2:7][C:3]4([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]4)[CH:60]=3)[N:38]=2)[CH:32]=1
Reactant: C=COCC1(CC)COC1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1(COCCc2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)COC1
Temperature: 20 °C

Procedure:
13.1 g of 3-ethyl-3-vinyloxymethyloxetane and 11.3 g of 9-BBN dimer (9-borabicyclo(3.3.1)nonane dimer) are dissolved in 200 ml of toluene at room temperature under protective gas and stirred for 20° C. During the reaction, the suspension of 9BBN slowly dissolves. 50 g of 2,4-bis-biphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 50 ml of a 1M NaOH solution are subsequently added to the reaction solution. The reaction mixture is carefully degassed, and 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 hours. The solution is cooled to room temperature. The phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:28])[CH3:27].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.0 g, 2.89 mmol) and ethylamine (2M in THF; 3.6 mL, 7.23 mmol) in CH2Cl2 (10 mL) was added sodium cyanoborohydride (0.587 g, 8.6 mmol), followed by acetic acid (0.1 mL). The reaction was stirred at room temperature until deemed to be complete by analytical HPLC. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give (6-methoxy-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C:16]3[CH:24]=[C:23]([C:25]4[CH:26]=[C:27]5[CH:33]=[N:32][N:31](S(C6C=CC=CC=6)(=O)=O)[C:28]5=[N:29][CH:30]=4)[CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][N:20]4S(C3C=CC=CC=3)(=O)=O)=[O:14])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)(C)C>[N:1]1([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C:16]3[CH:24]=[C:23]([C:25]4[CH:26]=[C:27]5[CH:33]=[N:32][NH:31][C:28]5=[N:29][CH:30]=4)[CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][NH:20]4)=[O:14])[N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CN2CCOCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2cnc3[nH]ncc3c2)cc2[nH]ncc12)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
2-(4-Morpholinylmethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (124 mg, 0.167 mmol) was suspended in Isopropanol (1 mL) and Sodium hydroxide (1 ml, 2.0 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was neutralised with 2 M HCl (aq.) and the solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (2 ml) (insoluble salt was filtered off through a filter tube) and the samples (2×1 ml injections) were purified by mass directed autoprep HPLC (Method F). The product-containing fractions were concentrated under a stream of nitrogen to give the title compound as a cream solid (23 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:25])[O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:14]=[CH:15][C:16]=3[Cl:17])[N:10]=2)[CH:7]=1.[Br-].[CH3:27][O:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:30]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:25])[O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][C:11]=1[C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([O:28][CH3:27])=[O:30])=[CH:37][CH:36]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: COCCOC(=O)Nc1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Reactant: COC(=O)Nc1ccc(B(O)O)cc1
Agent: [Br-]
Product: COCCOC(=O)Nc1ccc(Cl)c(-c2cn3cc(-c4ccc(NC(=O)OC)cc4)cnc3n2)c1

Procedure:
Compound 32 was synthesized using 2-methoxyethyl (3-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-4-chlorophenyl)carbamate (I-12) as the bromide and (4-((methoxycarbonyl)amino)phenyl)boronic acid using a suzuki coupling procedure described in I-13. Purification of the compound was done via mass-triggered reverse phase column chromatography preparative system (15% to 65% (B)). m/z (ESI) for 32: 496 (M+H+), 1H NMR (600 MHz, DMSO-D6) δ 10.01 (s, 1H), 9.86 (s, 1H), 9.30 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 7.72 (d, J=6.0, 2H), 7.62 (d, J=6.6, 2H), 7.50 (dt, J=5.7, 8.5, 2H), 4.24 (s, 2H), 3.70 (s, 3H), 3.59 (s, 2H), 3.30 (s, 3H).