Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[C:13]([Li])([CH3:16])([CH3:15])[CH3:14].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>CCOCC.CCCCCC>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1)=[O:25]
Reactant: O=Cc1ccccn1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: [Li]C(C)(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(=O)c2ccccn2)cc2c1OCC2(C)C
Reaction time: 0.67 h
Yield: 29 %

Procedure:
To 1.0 g (3.5 mmol) of a stirring solution of 5-bromo-2,3-dihydro-3,3-dimethylbenzo[b]furan in 2.0 mL of ether and 18 mL of dry hexane at -78° C. is added 4.4 mL (7.1 mmol) of t-butyllithium in hexane. The resulting mixture is stirred for 40 min., then 0.5 g (4.6 mmol) of 2-pyridinecarboxaldehyde is added. The reaction is allowed to slowly reach RT and is then quenched with water. The reaction is then diluted with 50 mL of ether, and the organic layer is separated. The remaining aqueous layer is extracted with ether (3×20 mL). The organic layers are then combined, dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue is dissolved in 20 mL CH2Cl2, and to this solution was added 0.1 g (0.4 mmol) of tetrapropylammonium perruthinate followed by 0.6 g (5.3 mmol) of N-methyl morpholine-N-oxide at RT. The reaction is stirred for 3 h, then filtered through silica gel, and the solvent is removed in vacuo. Purification by sgc with 1 ethyl acetate : 5 hexane resultes in about 0.30 g (29%) of a yellow solid. mp 95°-97° C.
Reaction SMILES: [BrH:1].[CH:2]1([N:5]([C:13]2[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=[C:15]([C:24]3[S:25][C:26]([CH2:29]O)=[CH:27][CH:28]=3)[CH:14]=2)C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>ClCCl>[Br:1][CH2:29][C:26]1[S:25][C:24]([C:15]2[CH:14]=[C:13]([NH:5][CH:2]3[CH2:4][CH2:3]3)[N:18]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:17]3[N:16]=2)=[CH:28][CH:27]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2ccc(CO)s2)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Temperature: 40 °C
Yield: 34 %

Procedure:
Hydrogen bromide (48% in water, 5 mL) was added dropwise to tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (980 mg, 2.4 mmol) suspended in dichloromethane (5 mL). The solution immediately became dark brown and homogeneous upon addition. The reaction was heated to 40° C. for 4 hours, then diluted with dichloromethane (10 mL). The liquid was decanted and the gummy residue was washed with dichloromethane (3×10 mL). The combined liquids were washed successively with sat. NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated in vacuo: The residue was triturated with hexanes and then purified via flash column chromatography (10-20% EtOAc/hexanes) to provide 5-(5 -(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (300 mg, 34%) as a yellow solid. LCMS (ES): >95% pure, m/z 378 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].O.[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])#[N:18]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CC#N
Yield: 84.4 %

Procedure:
A mixture of the product of example 32 (˜90% pure, 729 mg, 2.46 mmol) in a mixture of DMF:H2O (3 mL:2 mL) and sodium cyanide (362 mg, 7.4 mmol) was stirred at room temperature overnight. The resulting mixture was quenched with saturated NaHCO3 (12 mL) and extracted with ethylacetate (3×30 mL). The extracts were combined and washed with saturated NaCl (2×30 mL) and water (2×30 mL). The organic layer was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the titled product as a colourless oil (503 mg, 85% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: Cc1cc(Oc2ncccn2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(N)n1
Yield: 16.1 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)ethanone (6-2, 1.54 g, 4.79 mmol) and thiourea (0.370 g, 4.86 mmol) in 95% EtOH (6.9 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-amine (6-3, 0.23 g) as brown solids in 9.1% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=4.5 Hz, 2 H), 7.25 (m, 1 H), 6.99 (bs, 2 H), 6.89 (s, 2 H), 6.41 (s, 1 H), 2.11 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. benzenesulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCCC>CN(C)C(=O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:9]1[C:7](=[O:8])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[O:12][C:10]1=[O:11]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Reactant: OCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1oc2ccccc2c(=O)n1CCCCCCCCCO
Temperature: 77.5 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 6.525 g (40 mmol) of carsalam, 10.26 g (44 mmol) of 9-bromo-1-nonanol, and 5.30 g (50 mmol) of sodium carbonate in 30 mL N,N-dimethylacetamide (DMA) was heated at 75-80° C. for 3 hours. TLC (eluent: ethyl acetate/heptane) indicated the reaction was completed. The reaction was carefully poured into a mixture of ice-water. The resulting white solid was stirred for 1 hour. It was collected on sintered glass funnel, washed with water, hexane and dried in vacuo to yield 9.80 g of 3-(9-hydroxynonyl)-2H-1,3-benzoxazine-2,4 (3H)-dione (80%). To a slurry of 6.11 g (20 mmol) of 3-(9-hydroxynonyl)-2H-1,3-benzoxazine-2,4 (3H)-dione in 10 mL of N,N-dimethylacetamide at room temperature was added 20.4 mL (20.4 mmol) of potassium t-butoxide in THF solution. The clear brown solution became very thick. More DMA (10 mL) was added, and the mixture was heated at reflux for 5 minutes. 0.664 g (4 mmol) of potassium iodide was added, followed by dropwise addition of 3.34 (20 mmol) of ethyl bromoacetate. The reaction was refluxed for 1 hour, cooled to about 35° C. and poured into ice-water. A gum resulted. The supernatant liquid was decanted and fresh water was added. That procedure was repeated twice. The gum was dissolved in THF. The THF solution was carefully poured into hexane. The resulting solid was collected, washed with hexane and dried in vacuo. The weight of the desired product was 2.36 g (35%). HPLC: 4.39 min.; Mp: 125-128° C. HNMR(M DSO d6): δ 1.25 (12H, m), 1.37 (2H, m), 1.53 (2H, m), 3.28 (2H, m), 3.36 (2H, t), 4.85 (2H, s), 7.07 (2H, m), 7.45 (1H, t), 7.88 (1H, d), 8.70 (1H, t). Anal. Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C, 63.71; H, 8.29; N, 4.31.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Cl.C([N:20]=C=NCCCN(C)C)C.CN(C=O)C>O>[NH2:20][C:13](=[O:14])[CH:12]([CH3:16])[O:11][C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1scc(Br)c1OC(C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1scc(Br)c1OC(C)C(N)=O
Yield: 88.9 %

Procedure:
A solution of 2-{[4-bromo-2-(methoxycarbonyl)thiophen-3-yl]oxy}propanoic acid (220 mg), 1H-benzotriazol-1-ol 1 ammonium salt (162 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg) and DMF (4 mL) was stirred at room temperature for 1.5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (195 mg, 89%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[N:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccncc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccncc5)nc34)cc21
Temperature: 150 °C
Yield: 13 %

Procedure:
Prepared similarly to that described in Example 82 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 58 mg, 0.195 mmol), pyridin-4-amine (22.00 mg, 0.234 mmol, Aldrich), BrettPhos precat (Strem, Newburyport, Mass.; 8.25 mg, 9.74 μmmol), Brettphos (Strem, Newburyport, Mass.; 5.70 mg, 9.74 μmmol), and LHMDS (1.0M in THF; 429 μl, 0.429 mmol), heating at 150° C. for 40 min in a microwave (Biotage Initiator). Purification by silica gel chromatography (100% DCM to 10% MeOH/DCM) provided 2-(2-(pyridin-4-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (13% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.85 (t, J=7.04 Hz, 2H) 3.62 (t, J=7.04 Hz, 2H) 6.99 (s, 1H) 7.11 (d, J=9.00 Hz, 1H) 7.39 (t, J=7.73 Hz, 1H) 7.64 (dd, J=8.02, 1.17 Hz, 1H) 7.75 (d, J=6.46 Hz, 2H) 7.94 (dd, J=7.43, 1.17 Hz, 1H) 8.14 (d, J=8.80 Hz, 1H) 8.33 (d, J=6.26 Hz, 2H). MS (ESI, pos. ion) m/z: 356.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:30][CH2:29]1)=[O:27].CO.[H][H].[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>O1CCCC1.[Pd]>[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[((R)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran and methanol (2:1) (6 ml) under a nitrogen atmosphere. 10% palladium on carbon (68.6 mg) was added, and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 16 hours and 30 minutes. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.112 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (185.3 mg, quant.) as a white solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:13]([C:14]([C:16]3([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17]3)=[O:15])[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[CH3:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)[CH:33]=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].ClCCl>C1COCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:10][C@@H:11]([S:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:37][C:38]=3[C:43]([F:46])([F:44])[F:45])[CH2:12][N:13]2[C:14]([C:16]2([C:19]([F:21])([F:22])[F:20])[CH2:17][CH2:18]2)=[O:15])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)NC2(C#N)CC2)N(C(=O)C2(C(F)(F)F)CC2)C1
Reactant: Cc1cc(-c2ccc(S)c(C(F)(F)F)c2)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methanesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (20.5 g, 50 mmol) and 4-(2-methyl-pyridin-4-yl)-2-trifluoromethyl-benzenethiol hydrochloride (17.6 g, 57.5 mmol) in THF (75 mL) was added at 0° C. 25% sodium tert-butoxide in THF (43.2 g, 112.5 mmol) over 30 min and the reaction mixture was stirred at 50° C. for 4.5 h. After cooling to 10° C., the reaction mixture was added to dichloromethane (250 mL) and washed twice with deionized water (2×250 mL). The organic layer was dried (Na2SO4), filtered, and evaporated by rotary evaporation (45° C./≧10 mbar), affording the crude title product (30.9 g, 106%) as a beige, amorphous foam which was used without further purification in the next step. 1H NMR (CDCl3, 400 MHz) δ 1.10-1.35 (m, 6H), 1.47-1.58 (m, 2H), 2.00-2.11 (m, 1H), 2.65 (s, 3H), 2.92-3.01 (m, 1H), 3.92 & 4.02 (ABC, JAB=11.8 Hz, JAC=5.0 Hz, JBC=6.2 Hz, each 1H), 4.17 (quint, J=5.5 Hz, 1H), 4.72 (dd, J1=8.1 Hz, J2=4.8 Hz, 1H), 7.31 (dd, J1=5.1 Hz, J2=1.5 Hz, 1H), 7.37 (s, 1H), 7.62 (s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.80 (dd, J1=8.1 Hz, J2=1.9 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 8.60 (d, J=5.1 Hz, 1H). ESI-MS (m/z) [M+H]+ 583 (40).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([OH:1])([CH3:12])[CH3:11])=[CH:5][CH:6]=1)\[CH3:19])[CH3:14]
Reactant: CC(C)(O)Cc1ccc(O)cc1
Reactant: CC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(CC(C)(C)O)cc1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
To a stirred mixture of 4-(2-hydroxy-2-methyl-propyl)-phenol (0.850 g, 5.11 mmol) and ethyl-2-butynoate (3.45 g, 30.66 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (0.710 g, 5.11 mmol). The mixture was heated in a sealed tube at 80° C. for 5.5 h. The reaction mixture was then cooled to room temperature. The solids were isolated by filtration and washed with a small amount of tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) which afforded (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (1.16 g, 81%) as a viscous colorless oil.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19]([C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(C(=O)c2ccccc2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
30 mg of 5% palladium-carbon was added to a mixed solution of 1.5 mL of methanol and 2 mL of ethyl acetate containing the obtained 0.15 g of 2-(benzamido)-4-benzoylbenzoic acid and stirred under hydrogen atmosphere at room temperature for ten hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 0.11 g of 2-(benzamido)-4-benzylbenzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:29].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(Br)cc3)oc2C)cc1C
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ccccn4)cc3)oc2C)cc1C
Temperature: 25 °C

Procedure:
3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-2-methylphenyl)-propionic acid methyl ester (592 mg, 1.25 mmol) is dissolved in anhydrous toluene (5 mL), degassed, and filled with nitrogen three times. Palladium tetrakis triphenyl phosphine [Pd(PPh3)4, 25 mg, 0.025 mmol] is added, and the degassing procedure is repeated. 2-tributylstannylpyridine (635 uL, 2.5 mmol) is then added via syringe and the reaction is heated to reflux. The reaction is monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester is obtained after column chromatography.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27]N=4)[C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:31]([S-])C.[Na+].O.C(OCC)(=O)C>CN(C)C=O>[N:15]1([C:13]2[N:14]=[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[CH:31]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:11]=3[N:12]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCCN3c2ccncn2)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCCN3c2ccncc2)c1
Temperature: 150 °C
Yield: 43.5 %

Procedure:
A solution of 4-(3-methoxyphenyl)-2-morpholin-4-yl-8-pyrimidin-4-yl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (0.50 g, 1.24 mmol) in dimethylformamide (5 ml) was heated to 150° C., and sodium ethanethiolate (1.04 g, 12.4 mmol) was added for every 15 minutes in 3 portions. After heating at 150° C. for 2 hours, sodium ethanethiolate (1.04 g, 12.4 mmol) was added, followed by heating for further 15 minutes. After cooling the reaction mixture, water (5 ml) and ethyl acetate (20 ml) were added, to filter off the deposited precipitate. The crude product was purified by silica column chromatography (dichloromethane/methanol=95/5), to obtain the desired compound as a pale brown solid (0.21 g, 43% yield).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>CO>[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 15 %

Procedure:
To a solution of sodium methoxide (1.67 g, 30.84 mmol) in 100 ml of methanol is added 3-trifluoromethylphenol (3.75 ml, 30.84 mmol). After thirty minutes the solvent is removed in vacuo and replaced by 150 ml dimethylformamide. After addtion of 2-(chloromethyl)quinoline (5.48 g, 30.85 mmol) the reaction mixture is stirred overnight. The solvent is then removed and the residue is partitioned between water and chloroform. The organic layer is dried over sodium sulfate and the solvent is removed. The residue is passed through a silica gel column (eluting with 5:1 hexane-ethyl acetate) and then recrystallized from toluene to afford white crystals (1.4 g, 15%), m.p. 77°-78° C.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=3)=[CH:20][N:19]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Reactant: Nc1ccc(Br)cn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Nc2ccc(Br)cn2)cn1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
2-chloro-1-methylpyridinium iodide (2.37 g, 18.6 mmol) was added to a suspension of 6-(6-bromonicotinamido)nicotinic acid 4 (2 g, 6.21 mmol) and 2-amino-5-bromopyridine 5 (1.07 g, 6.21 mmol) in THF (100 ml), followed by DIPEA (2.4 g, 18.6 mmol). The reaction mixture was stirred for 4 days at RT. The suspension was filtered off and washed with water (25 ml). The filtrate was concentrated, diluted in chloroform, washed with water and brine, and then dried over Na2SO4. The product precipitated during evaporation and was dried under vacuum to give 6-bromo-N-(5-(5-bromopyridin-2-ylcarbamoyl)pyridin-2-yl)nicotinamide 6 as a yellow solid (400 mg, 14%). Mp. 245-247° C.