Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26](I)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41][CH:42]=[CH:43][N:44]=1)CCC>[Cu]=O.O>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26]([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cc2c(Oc3ccc(C)nc3I)ccnc2cc1OCc1ccccc1
Agent: O=[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxyquinoline (100 mg), tetrakistriphenylphosphine palladium (23 mg), tri-n-butyl-(thiazol-2-yl)-tin (113 mg), and copper(II) oxide (32 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (43 mg, yield 46%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:13]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: Nc1cc(Cl)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carbonyl chloride (1 eq) in anhydrous methylene chloride was added to the flask and brought to 0° C. To this was added the solution containing 4-chloropyridin-2-amine (1 eq), and diisopropylethylamine (5 eq) in anhydrous methylene chloride, which was stirred for 1 hour at 0° C. Reaction concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on silica gel, 10% methanol in methylene chloride to yield N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide as a slightly yellow crystal solid. HPLC=2.39 min; MS: MH+=254.
Reaction SMILES: O[CH2:2][C:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:11])[CH3:10])[CH2:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:2][C:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:11])[CH3:10])[CH2:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCC(CO)=C(c2ccccc2)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(CCl)=C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
To a solution of 1-(4-(hydroxymethyl)-3-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (86 mg, 0.37 mmol) in DCM (2 mL) was added SOCl2 (0.67 mL, 9.25 mmol). After stirred at RT for 15 min, the mixture was concentrated and was diluted with Sat. NaHCO3 and EtOAc, organic layer was separated and the aqueous layer was extracted with EtOAc, organic layer ere combined, washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 25:75) to give 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=CCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C=CCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C(O)c1ccc(CC=Cc2ccccc2)cc1
Solvent: CO
Product: O=C(O)c1ccc(CCCc2ccccc2)cc1

Procedure:
A mixture of regioisomeric olefins 54 (100 mg, 0.42 mmol) and Pd 10% on C (10 mg) in methanol (4 mL) was vigorously stirred under H2 atmosphere (14 psi). The mixture was stirred for 2 hours at room temperature, filtered through Celite and evaporated to afford 55 as an oil. Flash chromatography of the residue gave 55 (88 mg, 88%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(C)cc(Br)c1
Reactant: OB(O)c1cccs1
Product: COC(=O)c1cc(C)cc(-c2ccsc2)c1

Procedure:
Following the general procedure of EXAMPLE 766 and making non-critical variations but using 2-thiopheneboronic acid and methyl 3-bromo-5-methylbenzoate, methyl 3-methyl-5-(3-thienyl)benzoate is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:24][OH:25])[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of 1′-benzylspiro[indene-1,4′-piperidin]-3(2H)-one lab (38 g, 0.15 mol) in EtOH (300 mL), hydroxylamine hydrochloride (18 g, 0.30 mol) and sodium acetate (19.5 g, 0.275 mol) were added. The mixture was refluxed for 4 hours and the solvent removed under reduced pressure. The residue was diluted with 150 mL water and 100 mL CH2Cl2. After the mixture was stirred for 10 min, the resulting white solid was collected by filtration. The organic phase in the filtrate was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation of the solvent under reduced pressure, a yellow oil was obtained. The oil was crystallized from EtOAc to yield 1′-benzylspiro[indene-1,4′-piperidin]-3(2H)-one oxime 1ac as an off-white solid. 1H NMR (CD3OD, 400 MHz) δ 7.64 (d, J=8.0 Hz, 1H), 7.55-7.57 (m, 2H), 7.38-7.50 (m, 5H), 7.29-7.33 (m, 1H), 4.25 (s, 2H), 3.41 (d, J=12.4 Hz, 2H), 3.08 (t, J=12.0 Hz, 2H), 2.95 (s, 2H), 2.20-2.28 (m, 2H), 1.68 (d, J=14.4 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>C1(C)C=CC=CC=1.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>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:4]2[N:5]=[N:6][CH:7]=[C:2]([CH:15]=[CH2:16])[CH:3]=2)[N:9]=1
Reactant: Cc1nc(C)n(-c2cc(Cl)cnn2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cnnc(-n2nc(C)nc2C)c1
Temperature: 120 °C

Procedure:
To a solution of 5-chloro-3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazine (23-2, 730 mg, 3.48 mmol, 1.0 eq.) in toluene (24 mL) were added tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol, 0.05 eq.) and tributyl(vinyl)tin (1.30 mL, 4.52 mmol, 1.3 eq.). The mixture was heated at 120° C. for 3 hours. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (30% ethyl acetate in hexanes) to afford 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-vinylpyridazine (23-3) as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.15 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=1.8 Hz), 6.73 (dd, 1H, J=17.7, 10.8 Hz), 6.23 (d, 1H, J=17.7 Hz), 5.78 (d, 1H, J=10.8 Hz), 2.95 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH2:8]([O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[CH:39]([CH:41]1[CH:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1)=O.O>O1CCCC1>[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:17]=[CH:39]\[CH:41]2[CH:46]3[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]3)[CH2:42]2)=[CH:37][CH:38]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1ccc(/C=C\C2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium-tert-butoxide (2.46 g) was added to a stirred, ice-cooled suspension of (4-butoxybenzyl)-triphenylphosphonium bromide (10.1 g) in dry tetrahydrofuran (300 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -10° C. and a solution of 3-formylquinuclidine (750 mg) in dry tetrahydrofuran (20 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature overnight and water (1.0 ml) was then added. The tetrahydrofuran was evaporated and the residue was triturated several times with ether and filtered. The ether extracts were combined and evaporated to give an oil which was purified by flash column chromatography, using 10% methanol in dichloromethane containing 1% 0.880 ammonia as eluent, to give Z-3-[2-(4-butoxyphenyl)vinyl]-quinuclidine (Rf=0.3). This was dissolved in ether and an excess of a solution of hydrogen chloride in ether added to give a solid which was collected by filtration. There was thus obtained Z-3-[2-(4-butoxyphenyl)vinyl]quinuclidine hydrogen chloride as a colourless solid, m.p. 146°-149° C. (220 mg); microanalysis, found: C, 68.2; H, 8.4; N, 4.2%; C19H27NO.HCl.0.75H2O requires: C, 68.06; H, 8.8; N, 4.18%; NMR (DMSO-d6): 0.9-0.97(3H, t), 1.35-1.49(2H, m), 1.66-2.16(8H, m), 2.82-2.95(1H, m), 3.08-3.3(4H, m), 3.41-3.58(1H, t), 3.9-4.03(2H, t), 5.65-5.78(1H, d of d), 6.43-6.53(1H, d, J=11 Hertz), 6.9-7.0(2H, d) and 7.16-7.26(2H, d); m/Z 286 (M+H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[Cl:15]CCCl.CC(O)C>O=P(Cl)(Cl)Cl>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(O)c2ccccc12
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Temperature: 102.5 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
Stir a slurry of 1-hydroxy-4-nitroisoquinoline (62.2 g, 327 mmol) in POCl3 (180 mL) mechanically under nitrogen and heat to 100-105° C. for 1 hour resulting in a homogeneous dark brown solution. Exchange the condenser for a short-path distillation head, and remove excess POCl3 under reduced pressure (ca. 10-30 torr) resulting in a pot temperature of 55° C. To this mixture add 1,2-dichloroethane (150 mL), and warn the mixture to 70° C. to obtain a homogeneous solution. Cool the solution to 15° C., then add i-PrOH (450 mL) over 5 minutes resulting in an exotherm to 33° C. Stir the slurry for 3.5 hours at 15° C. then filter and wash with i-PrOH (3×100 mL). Air-dry the resulting solid overnight to afford 1-chloro-4-nitroisoquinoline (52.08, 76% yield) as a tan solid. (ES+): m/z 209/211 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:26])=[N:4][C:5]([CH3:25])=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=1.[C:27](Cl)(=O)[CH2:28][CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl.C(OCC)(=O)C>[Cl:26][C:3]1[C:2]2[N:1]=[C:27]([CH2:28][CH3:29])[N:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:13][CH:14]=3)[C:7]=2[CH:6]=[C:5]([CH3:25])[N:4]=1
Reactant: Cc1cc(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c(N)c(Cl)n1
Reactant: CCC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(Cl)nc(C)cc2n1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 34.4 %

Procedure:
A mixture of tert-butyl 2-{4-[(3-amino-2-chloro-6-methyl-4-pyridinyl)amino]phenyl}ethylcarbamate (step 2, 238 mg, 0.63 mmol), propionyl chloride (70 mg, 0.76 mmol) in toluene (4.6 ml) and dichloromethane (0.6 ml) was heated at reflux temperature for 1 h. After cooling, the mixture was diluted with ethyl acetate (100 ml) and washed with 1N aqueous NaOH solution (30 ml×2) and brine (30 ml). The organic layer was dried (MgSO4), and concentrated. The residue and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) in toluene (5.0 ml) was heated at reflux temperature for 16 h. After cooling, the mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous NaHCO3 solution (30 ml) and brine (30 ml). The organic layer was dried (MgSO4), and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1:1) to afford 90 mg (34%) of the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:4]([Cl:14])[N:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:37]([O:41][C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][NH2:47])([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[C:37]([O:41][C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:13])[CH2:10][CH2:9][S:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([NH2:1])[N:7]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Nc1nc(Cl)cc(SCCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)CCSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
3-(2-Amino-6-chloropyrimidin-4-ylsulfanyl)propionic acid (240 mg) obtained in Step 1 above and N-hydroxybenzotriazole (180 mg, 1.33 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (4.0 ml) was added thereto. 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (255 mg, 1.33 mmol), 3-aminopropylcarbamic acid tert-butyl ester (155 mg, 0.89 mmol), and diisopropylethylamine (0.79 ml, 4.52 mmol) were added to the solution. The resulting mixture was stirred at room temperature for 4 hours. The reaction was stopped with 1N hydrochloric acid, and the solution was extracted with ethyl acetate. The ethyl acetate solution was sequentially washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure to yield {3-[3-(2-amino-6-chloropyrimidin-4-ylsulfanyl)propionylamino]propyl}carbamic acid tert-butyl ester (175 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)=[O:26])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(Oc2cccnc2Br)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2cccnc2Br)nc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
The 6-(2-bromopyridine-3-yloxy)pyridine-3-amine (200 ml, 1.24 mmol) and indole-3-carboxylic acid (200 mg, 1.24 mmol) were dissolved in DMF (5 ml), DCC (280 mg, 1.37 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (100 mg, 20%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:16])=[C:12]([CH3:15])[N+:13]=2[O-])=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]([CH3:16])=[C:12]([CH3:15])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)c(C)o2)cc1
Yield: 80.3 %

Procedure:
Zinc dust (325 mesh, 60 g) was added in portions over 15 minutes to a solution of 43.8 g of 2-(4-methoxyphenyl)-4,5-dimethyloxazole N-oxide in 400 ml of acetic acid, stirred and heated on a steam bath. After an additional 15 minutes of heating, the reaction mixture was filtered and concentrated in vacuo. The residue was stirred with concentrated ammonium hydroxide and ethyl acetate. The layers were separated, the aqueous layer extracted with ethyl acetate, and the combined ethyl acetate solutions dried and concentrated to yield 32.6 g of 2-(4-methoxyphenyl)-4,5-dimethyloxazole as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[CH2:33](N(CC)CC)[CH3:34].C(I)C>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][CH2:33][CH3:34])=[CH:23][CH:24]=3)=[C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(N)cc3)c12
Solvent: ClCCl
Solvent: CC#N
Solvent: CCI
Product: CCNc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)OC)c23)cc1
Yield: 19.9 %

Procedure:
Put 29.2 mg (0.068 mmol) 6-({5-[4-aminophenyl]-6-phenylfuro[2,3-d]pyrimidin-4-yl}amino)-hexanoic acid methyl ester in 0.5 ml acetonitrile with 14 μl (0.102 mmol) triethylamine and add an excess of ethyl iodide in portions at 45° C. in closed apparatus over a period of 12 h. After cooling, dilute the reaction mixture with dichloromethane, wash successively with satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate by vacuum evaporation. After preparative RP-HPLC (gradient: acetonitrile/water), 6.2 mg of the target compound (19.9% of theor.) is isolated from the raw product mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)Cl.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[C:40]3[CH2:46][CH2:45][NH:44][CH2:43][C:41]=3[N:42]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26].C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[C:3]([C:8]([N:44]2[CH2:45][CH2:46][C:40]3[C:39]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[N:38][C:37]([C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[CH:36][CH:35]=4)=[N:42][C:41]=3[CH2:43]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2nccnc2Cl)C3)cc1
Reaction time: 3 h

Procedure:
3-Chloropyrazine-2-carboxylic acid (0.0648 g, 0.000409 mol) in dry Methylene chloride (1.50 mL, 0.0234 mol) was added N,N-Dimethylformamide (0.00200 mL, 0.0000258 mol) followed by Oxalyl chloride (0.040 mL, 0.00047 mol) dropwise. The reaction mixture was stirred for 3 hours then concentrated, added 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.102 g, 0.000267 mol), N,N-Dimethylformamide (1.80 mL, 0.0232 mol), and N,N-Diisopropylethylamine (0.180 mL, 0.00103 mol) and stirred overnight. The reaction mixture was filtered and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.76 (dd, J=5.6, 2.5, 1H), 8.70-8.60 (m, 2H), 8.17 (dd, J=39.6, 8.8, 2H), 7.47 (dd, J=23.6, 8.8, 2H), 6.17 (dd, J=13.2, 5.7, 1H), 4.79 (s, 1H), 4.42 (s, 1H), 3.91 (t, J=5.4, 1H), 3.80-3.66 (m, 4H), 3.54-3.41 (m, 5H), 3.19-3.05 (m, 2H), 2.81 (t, J=5.1, 1H), 2.69 (t, J=5.0, 1H), 1.06 (q, J=7.2, 3H). LC/MS-m/z+523.2 (M+H)+.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][O:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[OH:33])=[C:26]([N+:46]([O-:48])=[O:47])[CH:25]=1.C(Cl)Cl>CCOCC>[CH3:22][O:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([C:32]([C:34]2[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:33])=[C:26]([N+:46]([O-:48])=[O:47])[CH:25]=1
Reactant: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
Powdered 4 Å molecular sieves (583 mg) and pyridinium dichromate (2.17 g, 5.77 mmol) were successively added to a stirred solution of intermediate 241 (1.46 g, 3.84 mmol) in of anhydrous DCM (38.5 mL) at 0° C. The mixture was stirred at rt for 15 h. More PDC (290 mg, 0.770 mmol) was added and the mixture was stirred for another 4 h, The diluted with ether and filtered through a celite pad. The filtrate was concentrated and the brown solid was purified by flash chromatography using EtOAc/DCM (7:93) affording the title compound 242 (551 mg, 41%) as a yellow solid. 1H NMR (CDCl3) δ (ppm): 7.72 (s, 1H), 6.99 (s, 2H), 6.86 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.93 (s, 3H), 3.84 (s, 6H). m/z: 378.4 (MH+).
Reaction SMILES: [OH:1][C:2]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=1)([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4].CO.[OH-].[Na+].Cl>O>[OH:1][C:2]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=1)([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4]
Reactant: COC(=O)c1ccc(C(O)(CO)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)(CO)c3ccc(C(=O)O)cc3)s2)c1
Yield: 69.1 %

Procedure:
A microwave vial was charged with the product of Step 2 (50 mg, 0.094 mmol), MeOH (666 μl) and then NaOH (700 μl, 0.700 mmol). The mixture was irradiated in the microwave for 20 minutes at 100° C. The pH was adjusted to 3-4 with 1M HCl, then diluted with water and extracted with 10% IPA/CHCl3. The combined organics were washed with water, dried (NaSO4), filtered and concentrated to afford racemic-4-{1,2-dihydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}benzoic acid (33.4 mg, 0.065 mmol, 68.6% yield). MS ESI: [M+H]+ m/z 517.1. 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.24 (s, 1H), 8.82 (d, J=4.8, 1H), 7.99 (s, 1H), 7.93-7.85 (m, 3H), 7.74 (d, J=8.3, 2H), 7.45 (s, 1H), 7.26 (d, J=4.8, 1H), 7.12 (s, 1H), 6.73 (s, 1H), 5.11 (t, J=5.8, 1H), 4.10 (dd, J=5.6, 11.2, 1H), 4.04-3.89 (m, 1H), 2.31 (s, 3H).