Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])C.[Na+].[Cl:13][C:14]1[C:15]([C:24]2[CH:29]=[C:28]([CH:30]=O)[C:27]([Cl:32])=[CH:26][C:25]=2[Cl:33])=[N:16][N:17]([CH3:23])[C:18]=1[O:19][CH:20]([F:22])[F:21]>C(O)C>[Cl:32][C:27]1[CH:26]=[C:25]([Cl:33])[C:24]([C:15]2[C:14]([Cl:13])=[C:18]([O:19][CH:20]([F:21])[F:22])[N:17]([CH3:23])[N:16]=2)=[CH:29][C:28]=1[CH:30]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC#N
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.4 g (21 mmol) of ethyl cyanoacetate and 0.3 g (4.2 mmol) of sodium ethanolate were added to a solution of 7.5 g (21 mmol) of 4-chloro-3-(2,4-dichloro-5-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 70 ml of ethanol. The mixture was stirred for 4 hours then poured into ice-water, after which the solid product was filtered off, washed with n-hexane and then dried. Yield: 4.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:32][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]1
Reactant: CC1CCN(Cc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Product: CC1CCN(Cc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenylamine (Z36b). The crude product was purified by column chromatography (Alox, neutral, act. II-III, petroleum ether/EtOAc 3:1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CS(O)(=O)=O.[CH3:20][OH:21]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH3:20])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Reactant: CO
Agent: CS(=O)(=O)O
Product: COc1cc2c(OC)c[nH]c(=O)c2cc1F
Yield: 91 %

Procedure:
To a solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (6.3 g, 32.6 mmol) in methanol (70 ml) was added iodozobenzenediacetate (10.5 g, 32.6 mmol) followed by methane sulphonic acid (3.76 g, 39.1 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (6.6 g, 91%) as a light red colored solid. MS: MS m/z 224.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[CH3:15][O:16][C:17]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:15][O:16][C:17]1[C:22]([NH:23][C:11]([C@H:3]2[C@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:2]2([CH3:1])[CH3:14])=[O:13])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COc1ncccc1N
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Product: COc1ncccc1NC(=O)[C@H]1[C@H](c2ccccc2)C1(C)C
Yield: 88.4 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (400 mg, 2.1 mmol) and 2-methoxy-3-pyridinamine (261 mg, 2.1 mmol) were reacted as described under General Procedure D to furnish the title compound (550 mg, 88%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.69-8.64 (m, 1H), 7.90 (s, 1H), 7.85-7.83 (m, 1H), 7.32-7.19 (m, 5H), 6.92-6.88 (m, 1H), 4.06 (s, 3H), 2.84 (d, J=5.7 Hz, 1H), 1.90 (d, J=5.7 Hz, 1H), 1.41 (s, 3H), 0.98 (s, 3H). mp 152-154° C. ESIMS m/z [M+H]+ 297.2.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[NH2:33][C@H:3]1[C@@H:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4]1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reactant: CS(=O)(=O)Cl
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1NS(C)(=O)=O
Yield: 28 %

Procedure:
Method 4 was followed using tert-butyl ((3R,4S,5S)-4-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate and methanesulfonyl chloride to give N-(4-((3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonamido)piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 28% yield. LC/MS (m/z)=535.0 (MH+), Rt=0.58 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:11]=1.B(OC(C)C)(OC(C)C)[O:32]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC.C(C1C=CC=CC=1)C.O1CCCC1>[F:9][C:10]1[C:15]([OH:32])=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reaction time: 4 h
Yield: 45.6 %

Procedure:
4.3 ml (8.6 mmol) of a 2-molar lithium diisopropylamide solution in tetrahydrofuran/hexane/ethylbenzene are added dropwise at -78° C. to 2.36 g (7.8 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 2) in 180 ml of tetrahydrofuran, and the mixture is stirred for 4 hours. 2.95 g (17.2 mmol) of triisopropyl borate in 10 ml of tetrahydrofuran are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. After addition of 12.0 ml of 10% hydrochloric acid and stirring at room temperature for i hour, sodium chloride solution is added, the mixture is extracted with ether, the ether phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is taken up in 40 ml of ether, and the resulting mixture is heated to boiling. 8.03 g (23.5 mmol) of a 10% hydrogen peroxide solution are added dropwise, and the reaction mixture is refluxed for 4 hours. After separating off the ether phase, the aqueous phase is extracted with ether. The combined ether phases are washed with sodium sulfite solution and then with sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by chromatography (silica gel, 7:3 hexane/ethyl acetate) gives 1.13 g of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine. ##STR18##
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[CH2:10]([C:15]12[CH2:22][CH2:21][C:18]([C:23]([OH:25])=O)([CH2:19][CH2:20]1)[CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][CH3:14].Cl.CN>C(Cl)Cl>[CH3:1][NH:4][C:23]([C:18]12[CH2:21][CH2:22][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:20][CH2:19]1)[CH2:16][CH2:17]2)=[O:25]
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (1.44 mL, 11.1 mmol) was added to a mixture of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) (1.09 g, 4.45 mmol) and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride (10 mL) was added and the mixture stirred at room temperature for 18 h. After diluting with methylene chloride, the mixture was washed with water, brine, dried (MgSO4) and concentrated in vacuo to give N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C). 1H NMR (500 MHz, CDCl3): δ 0.91 (t, 3H); 1.22 (m, 8M); 1.43 (m, 6H); 1.77 (m, 6H); 2.82 (d, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[N:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:5]=1)[CH3:2].CC1C=CC(NC2CCC[C:28](=[O:32])C=2)=CC=1.C(I)C.C([N-]C(C)C)(C)C.[Li+].C(OCC)=O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH2:9][CH2:8]/[C:7](=[CH:28]/[OH:32])/[C:6](=[N:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:5]=1)[CH3:2]
Reactant: CCOC1=CC(=Nc2ccc(C)cc2)CCC1
Reactant: Cc1ccc(NC2=CC(=O)CCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC=O
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC1=CC(=Nc2ccc(C)cc2)/C(=C\O)CC1
Reaction time: 0.5 h

Procedure:
2.80 g (12.2 mmol) of N-(3-ethoxycyclohex-2-en-1-ylidene)-4-methylaniline (prepared from 3-[(4-methylphenyl)amino]cyclohex-2-en-1-one and ethyl iodide analogously to J. Org. Chem. 1984, 49, 3314) are dissolved in 40 ml of anhydrous tetrahydrofuran and, at −78° C., 7.94 ml of lithium diisopropylamide solution (2 M in tetrahydrofuran, heptane, ethylbenzene, 15.9 mmol) are added and the mixture is stirred for 30 min. At −78° C., 932 mg (12.2 mmol) of ethyl formate, dissolved in 10 ml of tetrahydrofuran, are added. After 1 h of stirring at −78° C., saturated aqueous ammonium chloride solution is added, the mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Purification of the residue by recrystallization (cyclohexane/ethyl acetate) gives 455 mg of (Z)-{4-ethoxy-2-[(4-methylphenyl)imino]cyclohex-3-en-1-ylidene}methanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]#[N:26])=[CH:5][C:4]=2[N:3]=1.[OH-:27].[Na+].OO>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([NH2:26])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC(C)(C)O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COCc1nc2c(N)nc3cc(CCC(N)=O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile (430 mg, 1.30 mmol) in methanol (75 mL) was heated to 50° C. in an oil bath. Aqueous 10% sodium hydroxide (0.33 mmol) and 30% aqueous hydrogen peroxide (516 mg, 4.55 mmol) were added and the reaction was stirred for 18 hours. The mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was slurried in water (70 mL). The aqueous mixture was washed with chloroform (35 mL), concentrated to a wet solid, slurried in methanol (100 mL) and filtered. The filtrate was absorbed onto silica (1 tbsp) and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-25% CMA over 1200 mL). The material was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-9% gradient of methanol in dichloromethane) to provide 102 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanamide as a white solid, mp 228-230° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].[C:16](=O)([O:20]CC)[O:17][CH2:18][CH3:19].Cl>O>[O:11]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH2:10][C:16]([O:17][CH2:18][CH3:19])=[O:20]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4′-trifluoromethylacetophenone (10.0 g), sodium hydride (60%, oil, 2.13 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 90 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and 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, and ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (9.50 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (7.39 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue 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, the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio) were recrystallized from hexane to give ethyl 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.42 g, yield 56%) as a colorless prism. melting point: 53–54° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:13]1[CH2:14][CH2:15][NH:11][CH2:12]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NC1CCNC1

Procedure:
A solution of 467 mg 3-butoxycarbonylamino-pyrrolidine-1-carboxylic acid benzyl ester in 10 ml ethyl acetate was stirred in the presence of 100 mg Pd/C (10%) under an atmosphere of hydrogen (1 bar) for 12 h. The reaction mixture was filtrated, washed with ethyl acetate and concentrated to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:20]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])=[N:21][N:22]=2)[CH:5]=[C:6]([O:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:7]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:19][C@@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]([O:8][C:6]3[CH:7]=[C:2]([CH3:1])[C:3]4[N:4]([C:20]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5[CH3:28])=[N:21][N:22]=4)[CH:5]=3)[CH2:10][CH2:11]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1cc(O[C@@H]2CC[C@H](N)c3ccccc32)cn2c([C@@H]3CCCN3C)nnc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3cc(C)c4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of Intermediate 105e (53 mg, 0.14 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 67 mg, 0.168 mmol) and DIPEA (49 μL, 4, 0.28 mmol) in DMF (2 mL) was stirred at 100° C. for 1.5 h under argon atmosphere. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane followed by 10% [2M NH3 in MeOH] in EtOAc. The product containing fractions were concentrated in vacuo and the resultant residue was purified by HPLC (C18 Phenomenex Gemini column, 5-98% gradient MeCN in H2O, 0.1% NH4OH), to afford the title compound (52 mg, 74%). LCMS (Method 5): Rt 3.76 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.23 (9H, s), 1.75-2.30 (13H, m), 2.32 (3H, s), 2.48 (3H, s), 3.19 (1H, br s), 4.72-4.83 (1H, m), 5.30-5.38 (1H, m), 6.28 (1H, s), 7.03-7.11 (2H, m), 7.20-7.36 (8H, m), 8.00 (1H, s), 8.11 (1H, s).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:32][CH3:33])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:33][O:32][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)C(=O)O
Reaction time: 24 h
Yield: 59.1 %

Procedure:
0.137 g of 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester (0.298 mmol) was dissolved in 2 ml of THF/EtOH=1/1 and treated with 0.745 ml of 2N NaOH. The reaction mixture was kept for 24 h at ambient temperature and then quenched by pouring onto crashed ice/HCl. Twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product, which was purified by twofold crystallisation from AcOEt/hexane to yield 0.076 g of the title compound as a white solid, mp.128-130°.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].C1C[O:12]CC1.S(=O)(=O)(O)O.N>C(Cl)Cl>[NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:4])=[O:12]
Reactant: C1CCOC1
Reactant: CC(C)C(C)(N)C#N
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(C)(N)C(N)=O
Temperature: 0 °C

Procedure:
A solution of 3.0 g of (-)-2-amino-2,3-dimethylbutyronitrile, [α]D =-6.71° (c=0.03307 g/ml THF) in 10 ml methylene chloride is added with stirring at 80° C. to 13.95 g of concentrated sulfuric acid. The solution is heated for one hour, allowed to cool and 14 g of ice is added. Next, 27 ml of concentrated ammonia is added while cooling. The resulting solution is extracted with methylene chloride (5×25 ml). The combined extracts are dried and evaporated to dryness to afford 3.23 g of title product, mp 81°-83° C., [α]D =+53.04° (c =0.0313 g/ml THF).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6]([OH:16])[N:5]=[C:4](SC)[N:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1.Cl>O>[OH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6]([OH:16])[N:5]=[C:4]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=1
Reactant: CSc1nc(O)c(NC(=O)c2ccco2)c(O)n1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(CCNc2nc(O)c(NC(=O)c3ccco3)c(O)n2)cc1
Temperature: 90 °C
Yield: 16.6 %

Procedure:
A mixture of 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-methylthiopyrimidine (2 g, 7.5 mM), p-methoxyphenethylamine (3.4 g, 22.5 mM), and water (25 ml) was heated at 90° C. for 15 hours. The mixture was then poured into water (100 ml) and acidified with concentrated hydrochloric acid until PH<3. The resultant precipitate was removed by filtration and recrystallised from methanol/water (3:1) to afford 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-[(4-methoxyphenyl)ethyl]aminopyrimidine as a white solid (0.46 g, 16.6% yield) m.p. >250° C.; NMR: DMSO-d6 : 2.75(t, 2H, ArCH2), 3.47(brq, 2H, CH2NH), 3.73(s, 3H, OMe), 6.50(brs, 1H, NH), 6.61(m, 1H, furyl-H), 6.87(d, 2H, ArH), 7.16(d, 2H, ArH), 7.17(s, 1H furyl-H), 7.82(d, 1H, furyl-H), 8.64(brs, 1H, NHCO), 10.58(brs, 2H, OH×2); m/e [M+H]+, 371:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.O1CCOCC1>C(OCC)(=O)C>[NH2:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Cn1cc(Br)cc(N=C(c2ccccc2)c2ccccc2)c1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(N)c1=O
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 5-bromo-3-(diphenylmethyleneamino)-1-methylpyridin-2(1H)-one (3.82 g, 10.4 mmol) in ethyl acetate (10 mL) was added 4 MHCl/dioxane (7.8 mL, 31.3 mmol). The reaction mixture was stirred for 0.5 h and concentrated under reduced pressure. The residue was washed with tert-butyl methyl ether and filtered. The solid was dissolved in ethyl acetate (10 mL) and water (10 mL). The pH of the resulting mixture was adjusted to between 7 and 8 by adding K2CO3 gradually. The water phase was separated and extracted with dichloromethane for three times. The combined organic layer was concentrated under reduced pressure to afford 325a as a yellow solid (1.1 g, 52%). MS-ESI: [M+H]+ 202.9.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]>CCOC(C)=O>[F:23][C:7]([F:6])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Chlorosulfonic acid (2 mL) was added to 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (1.0 g, 3.9 mmol) in a single portion, and the reaction was stirred for 20 minutes until gas evolution ceased (exothermic reaction). The solution was poured into a mixture of ice water (200 mL) and EtOAc (20 mL). The organic layer was concentrated and purified via silica gel chromatography using 8/2 hexanes/EtOAc to obtain 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride as a clear oil (1.3 g, 94%). 1H NMR (400 MHz, CDCl3) δ 8.02-8.00 (m, 2H), 7.48-7.45 (m, 2H), 4.78-4.73 (m, 1H), 4.19 (dd, J=14.0, 1.6 Hz, 1H), 3.32-3.25 (m, 1H), 3.02-2.86 (m, 2H), 2.03-2.02 (m, 2H), 1.81-1.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=4[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:24]([F:33])=[C:25]([F:32])[C:26]([F:31])=[C:27]([F:30])[C:28]=4[F:29])(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([OH:35])[CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2n1-c1cc(F)c(Br)cc1O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.0 g, 8.41 mmol) in DCM (56.1 ml) was added boron tribromide (0.811 ml, 8.41 mmol) at room temperature. The resulting mixture was stirred for 48 hr. The crude mixture was transferred to a sep. funnel containing saturated aqueous bicarb and the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to a white solid. The product was concentrated to a solid, redissolved in toluene (100 mls) and heated to 100° C. for 1 hour to racemize the product. The solution was then cooled to room temperature and concentrated to a solid (4.4 g, 89% crude yield). m/z (ESI) 582.0 (M+1)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
Prepared from 4-fluorobenzaldehyde and 1,4-dioxa-8-aza-spiro{4.5}decane.