Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([N:26]([CH2:33][CH3:34])[CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:23]([CH3:35])=[C:22]([C:36](=[O:48])[NH:37][CH2:38][C:39]4[C:40](=[O:47])[NH:41][C:42]([CH3:46])=[CH:43][C:44]=4[CH3:45])[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:25]=[C:24]([N:26]([CH2:33][CH3:34])[CH:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:23]([CH3:35])=[C:22]([CH:21]=3)[C:36]([NH:37][CH2:38][C:39]3[C:40](=[O:47])[NH:41][C:42]([CH3:46])=[CH:43][C:44]=3[CH3:45])=[O:48])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 903.1 %

Procedure:
To a stirred solution of tert-butyl(1-(5-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.39 g, 0.058 mmol) in DCM (4 mL) at 0° C., TFA (2 mL) was added and reaction was stirred for 1 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (30 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (50 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.3 g, 90.63%) which was used as such for next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:40])[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:40][C:33]2[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: O=[N+]([O-])c1cc(O)cc(I)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Yield: 73.3 %

Procedure:
A similar procedure as described in Example 12, step 7 was used, starting from 4-[3-(6-bromo-hexyl)-2-(ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (9.39 g, 19.92 mmol) and 3-iodo-5-nitro-phenol (4.8 g, 18.11 mmol) to afford 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-nitro-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (8.7 g, 73%) as a light yellow oil: ES(+)-HRMS m/e calculated for C29H38INO8 (M+H)+ 656.1715, found 656.1721.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[NH:21][C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[N:21]([CH3:29])[C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CI
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4C)c2)CCOCC1
Yield: 42 %

Procedure:
Using a similar procedure to that described in Example 16, (R)(-)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 42% yield, m.p. 107°-109° C. Specific Rotation: [alpha]D =-36.8° (methylene chloride, c=1 g/100 ml, temp.=25° C).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([CH3:20])[CH:22]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1C

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3,4-dimethylphenylboronic acid (step 1) to give 1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 125.1-125.8° C.; NMR (CDCl3) δ 2.16 (s, 3H), 2.23 (s, 3H), 3.04 (s, 3H), 6.69 (dd, J=2, 8 Hz, 1H), 6.86 (S, 1H), 6.95 (d, J=8 Hz, 1H), 7.16-7.26 (m, 3H), 7.29 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 2H); MS (FAB) m/z 379 (M+Li)+; HRMS calc'd for M+ 372.0996, found 372.0978. Anal. calc'd for C20H18F2O2S: C, 67.73; H, 4.87; F, 10.20. Found: C, 67.93; H, 4.92; F, 9.82.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].CN1C=CC=C1C(N1CCOCC1)C#N.[C:24]([O:28]CC)(=[O:27])[CH:25]=[CH2:26].Cl>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:26][CH2:25][C:24]([OH:28])=[O:27])=[O:8]
Reactant: C=CC(=O)OCC
Reactant: Cn1cccc1C=O
Agent: Cl
Agent: Cn1cccc1C(C#N)N1CCOCC1
Product: Cn1cccc1C(=O)CCC(=O)O

Procedure:
As for Example 6, 1-methyl-2-pyrrolecarboxaldehyde is converted to α-(1-methyl-2-pyrrolyl)-4-morpholineacetonitrile. The preceding compound is reacted with ethyl acrylate and the resulting 1,4-addition product is heated at 100° C. with 6 N hydrochloric acid to give 3-(1-methyl-2-pyrrolylcarbonyl)propionic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 93.3 %

Procedure:
A mixture of Example 17C (0.02 g, 0.060 mmol), 2,4-difluorophenol (2) (0.012 g, 0.090 mmol), and cesium carbonate (0.029 g, 0.090 mmol) in DMSO was heated at 110° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (0.025 g, 0.056 mmol, 94% yield).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(C(C)=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(O)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(O)cc2)CC1
Reaction time: 5 h
Yield: 66.8 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 3-hydroxy-2-[3-(4-(4-hydroxyphenyl)-1-piperazinyl)propyl]-1-isoindolinone (4.6 g) in methanol (115 cc), to which 22.7 cc of concentrated sulphuric acid is added in the course of 15 minutes and at a temperature close to 20° C. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 57 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (4×100 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 6 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (97-3 by volume). The first 800 cc are eliminated and the next 3000 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (35 cc). A solution of oxalic acid (0.8 g) in methyl ethyl ketone (20 cc) is added, and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling acetonitrile (200 cc). 1.4 g of 3-methoxy-2-[3-(4-(4-hydroxyphenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 147° C.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][CH2:9][CH:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:23]=[CH:24][C:25](=[O:28])[CH2:26][CH2:27]3)=[C:18]([F:29])[CH:17]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.0 M HCl in 1,4-dioxane (25 mL) is added to {3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (1.05 g, 2.6 mmol), and the mixture is stirred at r.t. for 45 min. The solvent is removed under vacuum. Resulted residue is dissolved in excess MeOH and then evaporated again under vacuum to afford 1-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-2,3-dihydro-1H-pyridin-4-one hydrochloride as hydroscopic orange crystals. Yield 0.8 g (quant). MS (m/z): 306 [M+H]+.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.O1CCCC1.CO.[OH-].[K+]>O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a mixture of ethyl 7-[(methylsulfonyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.81 g), tetrahydrofuran (30 mL) and methanol (20 mL) was added a solution of potassium hydroxide (85%, 1.8 g) in water (20 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light brown solid, which was washed with ethyl acetate-hexane to give the title compound (2.12 g, 98%) as a light orange solid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:56][CH3:57])[C:34]([NH:39][C@H:40]2[C@@H:44]([OH:45])[CH2:43][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:58][C:59]1[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=1B(O)O>>[Cl:58][C:59]1[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=1[C:31]1[N:32]=[C:33]([CH2:56][CH3:57])[C:34]([NH:39][C@H:40]2[C@@H:44]([OH:45])[CH2:43][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl (3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and 2-chloro-4-methoxy phenyl boronic acid, and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.06, 2.35, 2.67, 3.51, 3.57, 3.62, 3.82, 4.35, 4.46, 5.08, 5.42, 5.95, 6.98, 7.11, 7.24, 7.38; IR (diffuse reflectance) 2968, 2351 (w), 2339 (w), 2063 (w), 1951 (w), 1700 (s,b), 1681 (s), 1568 (s), 1482 (s), 1428 (s,b), 1422 (s), 1397, 1359 (s), 1287, 1229, cm−1 HRMS (FAB) calcd for C27H31ClN4O4+H 511.2112, found 511.2115.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:25]([OH:27])[CH3:26]>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:6]=[CH:5][N:4]=[C:3]2[CH:26]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:25]1=[O:27]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CCO
Agent: Cl
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
2M Hydrochloric acid (3 ml, 6 mmol) was added to a solution of 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-3-morpholinopropoxy)quinazoline (295 mg, 0.55 mmol), (prepared as described in Example 5), in ethanol (20 ml) at 80° C. The mixture was stirred for 45 minutes at 80° C. After cooling of the reaction mixture, partial evaporation of the solvents led to the crystallisation of the compound. The solid was collected by filtration, washed with ethanol and then ether and dried under vacuum at 50° C. to give 6-methoxy-7-(3-morpholinopropoxy)-4-(oxindol-3-yl)quinazoline as a hydrochloride salt (207 mg, 84%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(F)c2)c1
Yield: 63.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[C:19]=1[O:26][CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=CC(OC)=CC=1C(C1C=C(OC)C=C(OC)C=1)=O>C(Cl)Cl>[OH:24][C:20]1[C:19]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:23]=[CH:22][C:21]=1[C:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cccc(OC)c1OC
Agent: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2O)cc(OC)c1OC
Yield: 56.5 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (11.07 g, 48.0 mmol), 1,2,3-trimethoxybenzene (8.07 g, 48.0 mmol) in anhydrous methylene chloride (60 ml), and aluminum chloride (7.04 g, 52.8 mmol) were treated in the same manner as described above for the synthesis of (2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)methanone. The crude material was purified via flash column chromatography (25% EtOAc in hexane) to give (2-hydroxy-3,4-dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as a yellow solid (9.44 g, 54%); mp, 135-1370C: 1HNMR (DMSO-d6) δ 11.39 (s, 1H, OH), 7.35 (d, J=8 Hz, 1H, Ar), 6.97 (s, 2H, Ar), 6.70 (d, J=9 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 197.5, 157.6, 154.6, 152.5, 140.8, 136.0, 132.9, 128.7, 115.8, 106.7, 103.6, 60.1, 60.0, 56.0; Anal. Calcd. For C18H20O7: C, 62.06; H, 5.79. Found: C, 62.05; H, 5.55. The product was carried over to the next step.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=1>CO.O>[Cl:11][C:9]1[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([CH3:15])[N:6]=[C:5]([O:2][CH3:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Sodium methoxide (28% solution in methanol, 47.0 g, 244 mmol) was added dropwise to a stirred solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (48.3 g, 232 mmol) in methanol (600 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water, concentrated, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-15% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.9 g, 58.5 mmol, 25%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: CCOC(=O)c1c(C)noc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccncc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of ethyl 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylate (0.95 g) in a mixed solvent of THF (20 mL)/methanol (10 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The obtained aqueous layer was acidified with 1N hydrochloric acid, sodium chloride was added thereto until the mixture became saturated, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.48 g).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH3:9].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[C@@H:6]([CH2:7][CH2:8][CH3:9])[NH2:5]
Reactant: CCC[C@@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCC[C@@H](N)C(=O)OC
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Thionyl chloride (47.7 mL) was added dropwise to methanol (300 mL) under stirring at −5° C. over 2 hours and 15 minutes. D-Norvaline (35.00 g) was added to the resulting light yellow solution under stirring at −4° C. The solution was stirred at room temperature for 18 hours and then methanol was removed under reduced pressure. Disopropyl ether (90 mL) was added to the precipitated crystals, which were filtered and washed twice with diisopropyl ether (30 mL) to give (R)-norvaline methyl ester (47.74 g, 95% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccc(C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CCC(C)O)cc1
Yield: 101.3 %

Procedure:
A solution of 1-(4-methylphenyl)butan-3-one (11.4 g, 70.3 mmol) in methanol (80 ml) was cooled, followed by adding thereto sodium tetrahydroborate (1.51 g, 40.0 mmol), and the resulting mixture was stirred at 0° C. for 2 hours. The reaction mixture was added to 1N hydrochloric acid, and the methanol was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 11.7 g of 1-(4-methylphenyl)butan-3-ol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:20]1[CH2:21][C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=4)[C:11]=3[C:18]=2[CH2:19]1)=[O:29]
Reactant: C#Cc1cccc(Nc2ncnc3sc4c(c23)CNC4)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3sc4c(c23)CN(C(=O)/C=C/CN(C)C)C4)c1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-ethynylphenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 27A (40 mg, 0.12 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (27 mg, 0.17 mmol) to yield 11 mg (22%).
Reaction SMILES: [OH-].[K+].[C:3]1([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NNc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C1=C(c2ccccc2)NN(c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
In a 2000-ml four-necked flask were placed 13.0 g (0.23 mole) of potassium hydroxide and 1004.5 g of ethanol. The mixture was stirred at room temperature until the potassium hydroxide dissolved and 25.8 g (0.12 mole) of chalcone and 26.4 g (0.24 mole) of phenylhydrazine were added at room temperature. After the addition, the mixture was heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with hexane and dried under reduced pressure to give 27.8 g of 1,3,5-triphenylpyrazoline as a white powder.