Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH2:16][O:17][CH3:18].O1CCCC1.[Li+].CCC[CH2-].[C:29](=[O:31])=[O:30]>O.CCCCCC>[CH:8]([C:6]1[C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([CH:7]=1)[C:29]([OH:31])=[O:30])([CH3:10])[CH3:9]
Reactant: O=C=O
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1Br
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Temperature: -60 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
1-bromo-5-isopropyl-2,4-bis-methoxymethoxy-benzene (IM2-a: 12.0 g, 37.8 mmol) and tetrahydrofuran (150 mL) were placed in a 300 mL three-neck flask and cooled to −60° C. To this mixture a hexane solution of N-butyllithium (24 mL, 1.59 M) was added slowly, and after adjusting the temperature of the solution to −40° C. the mixture was stirred for 1 hour. Dry ice powder was added to the reaction mixture and the reaction mixture was allowed to come to room temperature. After completing the reaction, the reaction mixture was mixed with distilled water and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation, the solid material obtained was purified by suspending in hexane to obtain the title compound (IM3-a: 6.6 g, 62%).
Reaction SMILES: [S:1]=[C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[NH:3]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:27][S:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg of 4,5-dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (Example 8) in 10 ml of dry tetrahydrofuran, cooled at 0° C., was added 13 mg of sodium hydride (60% dispersion in mineral oil). The reaction mixture was stirred at 0° C. for 15 minutes, then an excess of methyl iodide was added. The mixture was allowed to warm to room temperature then was stirred for 3 hours. The mixture was quenched with water and extracted with chloroform. Evaporation of the extract in vacuo gave 47 mg of the product of the example as a yellow solid, m.p. 234°-237° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30]CC4C=CC=CC=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]>[Pd].O1CCCC1.CO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OCc4ccccc4)cc3)oc2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A mixture of 2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (8.16 g, 15.8 mmol) and 5% palladium on carbon (1.63 g) in tetrahydrofuran (100 mL) and methanol (100 mL) was purged successively with nitrogen then hydrogen, and then stirred under a hydrogen balloon at room temperature for 18 h. The reaction mixture was filtered through hyflo and solvent was removed from the filtrate in vacuo to give an oil which was dissolved in EtOAc and dried (MgSO4). The solvent was removed in vacuo to afford 6.40 g (95%) of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 8.25 (bs, 1H), 7.32 (d, 2H, J=8.79 Hz), 6.75-6.67 (m, 4H), 6.65 (d, 2H, J=8.79 Hz), 4.17 (q, 2H, J=6.84 Hz), 4.09 (t, 2H, J=6.35 Hz), 2.88 (t, 2H, J=6.35 Hz), 2.30 (s, 3H), 1.45 (s, 6H), 1.21 (t, 3H, J=6.84 Hz); 13C (125 MHz, CDCl3) δ 174.4, 160.2, 159.0, 154.3, 148.9, 144.7, 131.5, 128.1, 122.0, 121.6, 118.7, 115.9, 115.7, 114.9, 79.8, 66.8, 61.3, 25.9, 25.2, 14.1, 10.1; IR (KBr) 2985, 2941, 2809, 2606, 1742, 1731, 1507, 1442, 1277, 1233, 1213, 1170, 1137 cm−1; UV (EtOH) λmax 285 nm (ε 21145), 219 nm (•15842); HRMS (ES+) m/z exact mass calcd for C24H28NO6 426.1917, found 426.1896; Anal. Calc'd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found C, 67.22; H, 6.50; N, 2.79
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].O>C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:25]=[O:26])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COCOCc1coc(-c2ccc(Cl)cc2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOCc1nc(-c2ccc(Cl)cc2)oc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
200 mg (0.91 mmol) of the crude product from Example 40A are initially charged in 3.5 ml of dry diethyl ether and cooled to −78° C. 0.63 ml (1.00 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added dropwise. The reaction mixture is stirred at −78° C. for 1 h. 0.21 ml (2.74 mmol) of N,N-dimethylformamide is then slowly added dropwise. The mixture is allowed to warm to RT and stirred at RT for another 1 h. The mixture is then poured into about 3 ml of water. The mixture is extracted three times with in each case 10 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 20:1→2:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[N:13][NH:14][C:15]=1[CH:16]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:16]([C:15]3[C:11]([Br:10])=[CH:12][NH:13][N:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1[nH]ncc1Br
Product: Brc1cnc2[nH]c(-c3n[nH]cc3Br)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-bromo-1H-pyrazole-5-carbaldehyde.
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[CH2:11][C:12](OCC)=[O:13])=[N:6][CH:5]=1.C(O)C>CCOCC>[Br:3][C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][OH:13])=[N:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)Nc1ncc(Br)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CCO)Nc1ncc(Br)s1
Yield: 58.4 %

Procedure:
A mixture of LiBH4 (44 mg, 2.02 mmol), ethyl 3-[(5-bromo-1,3-thiazol-2-yl)amino]-3-oxopropanoate (340 mg, 1.16 mmol), ethanol (0.082 ml, 2.02 mmol), and Et2O (50 ml) was refluxed for 20 min. The reaction was quenched with 1 N hydrochloric acid with ice-cooling. The mixture was then diluted with water and extracted with dichloromethane. The extract was dried and the solvent was evaporated under reduced pressure. Purification by silica gel chromatography (dichloromethane/methanol=98:2 and then 95:5) yielded the title compound as a white solid (0.17 g; 52%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[C:14]1([C@@H:20]2[CH2:22][C@H:21]2[C:23](O)=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]2[C:12]=1[CH2:11][N:10]([C:23]([C@@H:21]1[CH2:22][C@H:20]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24])[CH2:9][CH2:8]2
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Fc1ccc(Br)c2c1CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCc2c(F)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (200 mg, 0.75 mmol, 1.0 eq.) and the acid (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (122 mg, 0.75 mmol, 1.0 eq.) in DMF (9 mL) was treated with 4-(dimethylamino)pyridine (367 mg, 3.00 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (216 mg, 1.13 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (70 mL). The diluted solution was washed with 1N aq. HCl (3×30 mL), sat. aq. NaCl soln. (1×30 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the desired compound as a pale yellow oil. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([OH:15])(=[O:14])[CH:12]=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:12]2[C:11]([OH:15])=[O:14]
Reactant: O=CC(=O)O
Reactant: OCCc1ccccc1Br
Product: O=C(O)C1OCCc2c(Br)cccc21

Procedure:
A solution of 2-(2-bromophenyl)ethanol (40 g, 0.2 mol) and glyoxylic acid (16 g, 0.22 mol) in 100 mL of trifluoacetic acid was refluxed overnight. The solvent was concentrated. Water and ammonium hydroxide was added to the residue to adjust the pH of the solution over 7. The solution was extracted with diethyl ether, and the aqueous layer was adjusted to about 3 with 1M HCl, and then the solution was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was without purification to give 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 2H), 5.33 (s, 1H), 4.27˜4.33 (m, 1H), 3.99˜4.06 (m, 1H), 2.87˜2.89 (m, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[CH2:18][CH2:17][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[NH:15]1)=[O:13])[CH3:10].[Na].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1.CO.C(O)(=O)C>[CH2:9]([O:11][C:12]([C@H:14]1[CH2:18][CH2:17][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[N:15]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Benzaldehyde (2.46 mL) and acetic acid (3 mL) were added to a tetrahydrofuran/methanol (80 mL, 4/1) solution of (2R,5S)-5-(3,4,5-trifluorophenyl)pyrrolidine-2-carboxylic acid ethyl ester (3.42 g) obtained in Example 14. Stirring was continued for 10 minutes at room temperature. Sodium triacetoxybrohydride (5.15 g) was added to the reaction solution, and stirring was continued for 3.5 days. Ammonium chloride aqueous solution and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine, and the resultant was dried with magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (3.43 g) was obtained. The physical property values are as follows.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([C:25](OCC)=[O:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25][OH:26])=[CH:23][N:22]=[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:20]=3)=[CH:15][C:14]=2[O:38][CH3:39])[N:10]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(COc2nc(-c3ccccc3)ncc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate (3.40 g) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.24 g) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), and sodium sulfate decahydrate (2.0 g) was further added. After removing the precipitate by filtration, the filtrate was concentrated. The obtained crystals were recrystallized from ethyl acetate to give {4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidin-5-yl}methanol as colorless prism crystals (2.20 g, yield 70%). melting point: 150-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)CCc1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 62 %

Procedure:
To a solution of methyl 3-(4-aminophenyl)propanoate (2.69 g, 15.0 mmol) in pyridine (20 mL) was added 2-nitrobenzenesulfonyl chloride (3.99 g, 18.0 mmol) by small portions, and the mixture was stirred at room temperature for 45 hr. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue. The mixture was stirred with heating at 80° C. for 15 min and filtrated through celite. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate/hexane) to give the title compound (3.39 g, yield 62%) as yellow prism crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[ClH:50].[N:51]1([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C(N(CC)CC)C>>[ClH:50].[ClH:50].[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][C:58](=[O:59])[CH2:57][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)CN1CCOCC1
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(O)ccc3C2C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(OC(=O)CN4CCOCC4)ccc3C2C)c1C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride (28.8 mg, 0.158 mmol), and triethylamine (46 μl, 0.330 mmol) to afford the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([C:33]([CH3:35])=[CH2:34])=[CH:21][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:39][C:40]([NH:42][CH3:43])=[O:41]>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([C:33]([CH3:35])=[CH2:34])=[CH:21][C:10]=1[C:11]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:39][C:40](=[O:41])[NH:42][CH3:43])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(F)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CNC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cc(C(=O)N(CC(=O)NC)c2ccc(F)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 116 %

Procedure:
2,4-Bis-benzyloxy-N-(4-fluoro-phenyl)-5-isopropenyl-benzamide (0.1 g, 0.21 mmol) [Using method A2 from (2,4-bis-benzyloxy-5-isopropenyl)-benzoic acid (Preparation B5) and 4-fluoro-aniline] was dissolved in DMF (1 ml), treated with 60% NaH in mineral oil (13 mg, 1.5 eq) and stirred at room temperature for 15 min. 2-chloro-N-methyl acetamide (33 mg, 0.12 mmol) was added and the reaction stirred for a further 60 minutes, then diluted with EtOAc and water. The EtOAc layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude material was purified by flash column chromatography eluting with EtOAc to give 75 mg of title compound. MS: [M+H]+ 539.
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[C:6]2[NH:12][N:11]=[CH:10][C:7]=2[NH:8][CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[C:1]([C:4]1[C:5]([Cl:16])=[C:6]2[NH:12][N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2cn[nH]c2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cnc2cn[nH]c2c1Cl
Temperature: 80 °C

Procedure:
A mixture of 6-acetyl-4,7-dihydro-7-oxo-1H-pyrazolo-[4,3-b]pyridine (D14, 1.6 g, 9 mmol) and phosphorus oxychloride (15 ml) was heated at 80° C. for 30 min. Excess reagent was removed in vacuo, water was added and the mixture was adjusted to pH 9 with 10% sodium carbonate solution. The resulting mixture was extracted with ethyl acetate (4×50 ml), and the extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to leave the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:36])[CH:19](Br)[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:36])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A mixture of 2, 4 difluorophenol (0.28 g, 2.18 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in acetonitrilie (20 ml) stirred for 30 mins. A solution of bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 g, 1.98 mmol) in acetonitrile (5 ml) was added drop wise at room temperature and stirred further for 2 hrs. Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, 1N NaOH (cold, 50 ml), and brine (50 ml) dried over anhydrous sodium sulfate, filtered and concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 gm).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6](C)[CH:5]=2.[CH:12]([Li])(CC)C.C1CCCCC1.C(OC(NC1C=CC(OCC)=CC=1C)=O)(C)(C)C.CON(C)C(=O)C>C1COCC1>[CH3:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [Li]C(C)CC
Reactant: Cc1ccc2cc(C)[nH]c2c1
Agent: CCOc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: CON(C)C(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1cc2ccccc2n1C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
2,6-Dimethyl-1H-indole. A solution of 1.3M sec-butyl lithium/cyclohexane (81.0 ml, 0.105 mol) was added slowly to 11.05 g (0.05 mol) of N-tert-butoxycarbonyl-4-ethoxy-2-methylaniline in 150 ml of THF while keeping the temperature below −40° C. with a dry ice-ethanol bath. After 0.25 hours, 7.21 g (0.07 mol) of N-methoxy-N-methylacetamide in an equal volume of THF was added dropwise. The reaction mixture was stirred for 1 hour, the cooling bath removed and stirred an additional one hour. It was then poured into a mixture of 500 ml of ether and 500 ml of 1N HCl. The organic layer was separated, washed with water and dried over Na2SO4. After removing the solvent there remained 12.5 g of crude 1-(2-tert-butoxycarbonylamino-4-methylphenyl)-2-propanone. This material and 15 g of trifluoroacetic acid in 250 ml of CH2Cl2 was stirred at room temperature for 16 hours. The mixture was washed twice with water, a saturated Na2CO3 solution and dried over Na2SO4. After removing the solvent, the product was chromatographed on silica eluting with toluene to give 3.2 g (44% yield) of 2,6-(dimethyl-1H-indole melting at 74-76° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cn1ccc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.3 %

Procedure:
A solution of 1-methyl-1H-indole-6-carboxylic acid methyl ester (Example 15; 2.52 g, 13.3 mmol) in diethyl ether (50 mL) was added to a suspension of lithium aluminum hydride (0.50 g, 13.2 mmol) in diethyl ether (50 mL) and the mixture was stirred at room temperature for 5 h. Saturated Na2SO4 solution was added (˜5 mL) and the mixture was stirred at room temperature for 30 min, then filtered and the filtrate was dried (MgSO4), overnight. The mixture was filtered and evaporated to furnish 1-methyl-1H-indole-6-methanol (1.70 g, 79% yield) as a colorless oil that solidified on standing, mp 47-49° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=1
Reactant: CSc1nccc(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1ncc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylsulfanyl-3H-pyrimidin-4-one (36 g, 0.25 mol) in glacial acetic acid (500 mL) was cooled to 0° C. in an ice bath and treated with Br2 (15.6 mL, 0.3 mol). The reaction mixture changed in color from yellow to brown within 0.5 hours, and was allowed to warm to room temperature where it stirred overnight. When all the starting material had been consumed (as indicated by TLC and HPLC UV detection at λ=254 nm), the reaction mixture was slowly poured into a mixture of ice/H2O (2 liters). The resulting white precipitate was collected by vacuum filtration and washed with H2O (200 mL) and Et2O (2×250 mL). The off-white solid was then suspended in anhydrous toluene (250 mL) and concentrated to dryness under reduced pressure in a 60° C. H2O bath. 5-Bromo-2-methylsulfanyl-3H-pyrimidin-4-one was obtained as a white solid (30.4 g, 55% yield).