Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1C>[C:1]1([C:7]2[O:8][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccc1Br
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1
Yield: 80.7 %

Procedure:
39.2 g of benzyl phenyl ketone, 46.7 g of 1,2-dibromobenzene, g of palladium acetate, 10.5 g of triphenylphosphine, 77.2 g of cesium carbonate, and 400 mL of o-xylene were loaded into a flask, and the mixture was refluxed and stirred under heat under an argon atmosphere for 8 hours. After the completion of the reaction, the reaction solution was filtrated while being extracted with ether. The filtrate was dried with magnesium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography, whereby 43.2 g of a white crystal were obtained (80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][Si:11]([CH2:14][CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)(=O)C.O.[Cu](I)I.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>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:7][N:6]=1
Reactant: CC[Si](C)(C)C
Reactant: COc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncc(C#C[Si](C)(C)C)cn1
Temperature: 60 °C
Yield: 98.2 %

Procedure:
To a solution of 5-bromo-2-methoxypyrimidine (500 mg, 2.7 mmol) in ethyl acetate (2 mL) and water (0.2 mL) was added trimethylsilylethane (0.41 mL, 3 mmol), triethylamine (0.75 mL, 5.4 mmol), copper iodide (25 mg, 0.13 mmol) and bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol). The solution was heated to 60° C. for 16 h. Ethyl acetate (100 mL) was added and the solution was washed with water (3×10 mL), dried over MgSO4 and treated with decolorizing charcoal. Ethyl acetate was removed in vacuo to give the title compound as a clear oil (547 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 2H), 4.01 (s, 3H), 0.24 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.CN(C(ON1N=[N:28][C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:28][C@@H:23]2[CH2:24][CH2:25][N:27]([CH3:26])[CH2:22]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC[C@@H](NC(=O)c2cc(Cl)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 300 mg, 1.58 mmol), HATU (903 mg, 2.37 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 325 mg, 2.37 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.2 mL, 7.12 mmol) added. The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a pale orange solid (333 mg, 77%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].O.[CH3:13]O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CO
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C#N)nc1
Reaction time: 0.17 h

Procedure:
6-Cyanonicotinic acid (500 mg) was dissolved in dichloromethane (25 ml), water-soluble carbodiimide (776 mg), methanol (0.164 ml) and 4-dimethylaminopyridine (49 mg) were added thereto, and the mixture was stirred for 2 hr 10 min. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound. The same reactions were repeated using 6-cyanonicotinic acid (547 mg) to give the title compound (total 951 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1>C(O)C.C1CCCCC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.54 g, 1.75 mmol) in ethanol (10 ml) and cyclohexene (20 ml) was added 10% palladium-on-charcoal (400 mg) and the solution was refluxed for 7 hours. A further quantity of catalyst (200 mg) was added and the solution was refluxed overnight. The solution was filtered and washed through with methanol. To the filtrate was added hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) and the solution was stirred for 30 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (5:1, 4:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a crystalline solid (150 mg, 36%), m.p. 156°-158° C.; λmax (H2O) 242 and 303 nm; λmax (KBr) 3320, 3210, 1640, 1610, 1580, and 1430 cm-1 ; δH [(CD3)2SO] 1.47 (1H, m, 3'-H), 1.78 (2H, q, J 7.2 Hz, 2'-H), 3.3-3.5 (4H, m, 2×4'-H), 4.12 (2H, t, J 7.4 Hz, 1'-H), 4.42 (2H, t, J 5.2 Hz, D2O exchangeable, 2×OH), 6.45 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 50.61; H, 6.45; N, 29.62%. C10H15N5O2 requires: C, 50.62; H, 6.37; N, 29.52%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C.O>O1CCCC1>[C:4]1([C:3]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution (100 ml) of N-hydroxybenzenimidoyl chloride (2.25 g) and methyl 4-ethynylbenzoate (2.30 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.30 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-(3-phenyl-5-isoxazolyl)benzoate (3.49 g, yield 87%) as colorless crystals. melting point: 205–206° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C@@H:21]([CH3:22])[CH2:20][N:19]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32]C(OC(C)(C)C)=O)[N:27]=3)=[O:24])[C@H:18]([CH3:40])[CH2:17]2)=[CH:12][C:11]=1[C:41]([F:44])([F:43])[F:42])#[N:9]>ClC(Cl)C>[NH2:32][C:28]1[N:27]=[C:26]([NH:25][C:23]([N:19]2[CH2:20][C@H:21]([CH3:22])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[C:11]([C:41]([F:44])([F:43])[F:42])[CH:12]=3)[CH2:17][C@H:18]2[CH3:40])=[O:24])[CH:31]=[CH:30][N:29]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(NC(=O)OC(C)(C)C)n1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
A 15 ml portion of trifluoroacetic acid was added to 60 ml of dichloroethane solution containing 2.8 g of (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-N-[2-(1,1-dimethylethoxycarbonyl)amino-4-pyrimidyl]-2,5-dimethylpiperazine-1-carboxamide synthesized in Example 6-2, and the mixture was stirred at room temperature for about 12 hours. The reaction solution was evaporated under reduced pressure, and the thus obtained residue was mixed with saturated sodium bicarbonate solution and extracted with chloroform. The thus obtained organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the crude product obtained by evaporating the solvent was subjected to a silica gel column chromatography to obtain 1.97 g of the title compound from chloroform-methanol (30:1, v/v) eluate. Thereafter, this was crystallized from ethyl acetate-hexane to obtain 1.51 g of the title compound as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2-fluoro-5-methylphenol (23.8 g, 0.19 mol) and bromine (9.7 ml, 0.19 mol) are combined in 50 ml of glacial acetic acid and stirred at RT for one hour. Acetic acid was removed under vacuum. The liquid was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-bromo-2-fluoro-5-methylphenol (38 g, 98% yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98 (s, 1H) 2.22 (s, 3H) 6.81 (dd, J=9.15, 0.54 Hz, 1H) 7.17 (d, J=9.88 Hz, 1H)
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20](Br)[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32]N(C)P(N(C)C)(N(C)C)=O.C[Sn](C)(C)C>[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Pd+2]>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([CH3:32])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Pd+2]
Agent: C[Sn](C)(C)C
Agent: [CH2-]c1ccccc1
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1C
Temperature: 140 °C
Yield: 30.6 %

Procedure:
A mixture of 5-bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid (S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (2a, 20.0 mg, 0.0414 mmol) 07), hexamethylphosphoramide (0.500 mL, 2.87 mmol), tetramethyltin (22.8 uL, 0.166 mmol) and benzylbis(triphenylphosphine)palladium(II) chloride (1.44 mg, 0.00190 mmol) was heated at 140° C. under microwave irradiation for 90 min. It was partitioned between water (2 mL) and ethyl acetate (3×2 mL). The combined organic solution was washed with brine (1 mL), dried (MgSO4) and evaporated. The title compound (5.3 mg, yield 31%) was separated by flash chromatography on silica gel. LC-MS (m/z) 419.8 (MH+); tR=1.59 (method C).). 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.72 (overlapping s, 3H, Me), 1.78 (overlapping s, 3H, Me), 1.74-1.84 (overlapping m, 4H), 1.88 (overlapping m, 1H), 1.99 (overlapping s, 3H, Me), 2.06 (overlapping br. m, 1H), 2.66 (m, 1H, CH of Cb), 4.93 (t, J=9.2 Hz, CH—N), 7.01 (dt, J(d)=2 Hz, J(t)=8.5 Hz, 1H), 7.11-7.20 (m, 4H), 7.34 (q (unresolved dt), J(d)=6.5 Hz, J(t)=7.7 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H, para-H of Ph), 7.52 (br. t, 2H, two meta-H of Ph), 8.60 (br. d, J=8.3 Hz, 1H, NH).
Reaction SMILES: [C:1]([C:3]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)[CH2:5][CH2:4]1)#[N:2].[N-:24]=[N+:25]=[N-:26].[Na+].Cl.C(N(CC)CC)C>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)C>[NH:2]1[C:1]([C:3]2([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]3)[CH2:4][CH2:5]2)=[N:26][N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)C1(CCCCCCCCCCCCC2(c3nnn[nH]3)CC2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
To a solution of Step 3 product of Example 19 (0.38 g, 1.8 mmol) in nitrobenzene (4 mL) were added sodium azide (0.46 g, 7.1 mmol) and triethyl amine hydrochloride (0.98 g, 7.1 mmol) at room temperature. The reaction mixture was allowed to stir at 130° C. over a period of 24 h. The reaction mixture was diluted with diethyl ether (50 mL) and extracted with 2% NaOH solution (50 mL×2). The combined aqueous layer was acidified to PH=5 (1N HCl), extracted with ethyl acetate (50 mL×2), dried over sodium sulphate. The residue obtained upon evaporation of the solvent was purified through silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product as Off-white solid 120 mg (27%). mp −133.2° C.-135.0° C.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([C:69]#[N:70])([CH3:68])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:69]([C:44]1([CH3:68])[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[N:58]([CH3:67])[S:59]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1)#[N:70]
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C#N)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a solution of triphenylphosphine oxide (0.68 g) in acetonitrile (10 ml) was slowly added trifluoromethanesulfonic anhydride (0.21 ml) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-2-cyanopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.43 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.27 g, yield 79%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 178-179° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22]3[S:23][C:24]([Br:27])=[CH:25][N:26]=3)[CH2:17][CH:16]2[CH3:28])[CH:6]=1.[OH-].[Na+].CO.O1CCCC1>[Cl-].[Na+].O.O>[Br:27][C:24]1[S:23][C:22]([N:18]2[CH2:19][CH:20]([CH3:21])[N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:10]=[CH:9][C:8]=3[CH3:11])[CH:16]([CH3:28])[CH2:17]2)=[N:26][CH:25]=1
Reactant: COC(=O)Cc1ccc(C)c(OCCN2C(C)CN(c3ncc(Br)s3)CC2C)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)O)cc1OCCN1C(C)CN(c2ncc(Br)s2)CC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A mixture of [3-[2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethoxy]-4-methylphenyl]acetic acid methyl ester (8.49 g), 2N aqueous sodium hydroxide solution (22 mL), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 1.5 hours. To the reaction solution were added water and brine. The mixture was washed with ethyl acetate. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to give the title compound (5.81 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([Cl:50])=[C:29]([C:46]([CH3:49])=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:28]1[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[N:36]=2)=[C:46]([CH3:49])[CH:47]=[CH:48][C:27]=1[NH:26][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 49.5 %

Procedure:
Using 3 -(1 cyano-1 -methylethyl) benzoic acid (95 mg, 0.50 mmol), oxalyl chloride (55 μL, 0.63 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 51%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[CH2:10][O:9][C:8]([NH:12][C@H:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cccc3c2COC(N[C@@H]2CCc4ccccc42)=N3)cc1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (171.6 mg, 0.5 mmol), 4-fluorophenyl-boronic acid (84 mg, 0.6 mmol), 1M sodium carbonate solution (1.25 ml, 1.25 mmol), tetarkis(triphenylphosphine)palladium (17.3 mg, 0.015 mmol) in 1,2-dimethoxy-ethane (2.5 ml) was heated at 80° C. for 17 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (164 mg, 92%). MS (ISP) m/e=359.1 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[CH3:16])(=[O:3])[CH3:2].C1C[O:20]CC1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[OH-].[Na+]>O.C(O)(=O)C>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[CH:16]=[O:20])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)c1c(C)[nH]c(-c2ccncc2)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1c(C=O)[nH]c(-c2ccncc2)c1C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole (800 mg, 3.74 mmol) was dissolved with THF (37 mL), acetic acid (45 mL) and water (37 mL). Ammonium cerium(IV) nitrate (8.38 g, 15.3 mmol) was added to the mixture at room temperature and stirred for 1.5 hours. The mixture was neutralized with 2 M aqueous NaOH solution and extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine, dried over MgSO4, and evaporated in vacio. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (2:1) to afford the title compound (190 mg, 22% yield) as a solid.
Reaction SMILES: [CH2:1]([C:19]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(C(OC(C)(C)C)=O)[C:20]([O:22]C(C)(C)C)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([CH:19]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCC(CCCCCCCC/C=C\CCCCCCCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCC(CCCCCCCC/C=C\CCCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A 3 g of this di-t-butyl dioleylmalonate was dissolved in a solution comprising 20 ml of anisole, 20 ml of dichloromethane and 10 ml of trifluoroacetic acid, followed by stirring at room temperature overnight. After reaction, volatile components were distilled off. The residue was then heated at 150° C. for 4 hours to remove carbonic acid, thereby obtaining 2.32 g of α,α-dioleylacetic acid [RF =0.12 (chloroform:methanol=10:1)].
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:34]([OH:36])=O)[CH:13]=[CH:12][CH:11]=1)[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.O[N:38]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[OH:1][CH2:2][CH:3]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:34]([NH2:38])=[O:36])[CH:13]=[CH:12][CH:11]=1)[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
5-{[6-(2-Hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylic acid (64 mg, 0.13 mmol), N-hydroxybenzotriazole (39 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (48 mg, 0.25 mmol), and ammonium chloride (34 mg, 0.63 mmol) were taken up in DMF (4.2 mL) under argon. Diisopropylethylamine (110 μl, 0.63 mmol) was added and the mixture was stirred at room temperature for 36 hours. The solution was then diluted with water to precipitate a white solid that was collected by filtration, washed with water and dried under reduced pressure to afford the title compound as a bright yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.66 (d, 1H), 8.08 (dd, 1H), 7.72 (s, 1H), 7.69 (t, 1H), 7.59 (s, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 4.53 (m, 1H), 3.99 (m, 2H), 3.69 (m, 5H), 3.55 (m, 8H), 2.50 (m, 4H). LRMS (APCI) calc'd for C24H30N7O4S [M+H]+ 512.2, found 512.1