Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[OH:26])=[CH:3][C:4]=2[F:25])[O:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)#[N:21]
Reactant: OB(O)c1ccccc1O
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F

Procedure:
In analogy to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide (example 248.1) was reacted with 2-hydroxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide. Off-white solid. MS 423.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:11]=2[CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])=[O:9])=[CH:4][CH:3]=1.CC(O)=O>C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:29](=[O:34])[C:30]([CH3:32])([CH3:33])[CH3:31])[C:11]=2[CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(OC)n3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc(COc2ccn3c(C(=O)c4ccc(Cl)cc4)c(CC(C)(C)C(=O)O)c(C(=O)C(C)(C)C)c3c2)n1
Yield: 99.8 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-[(6-methoxypyridin-2-yl)methoxy]indolizin-2-yl}-2,2-dimethylpropanoate (20 mg, 0.033 mmol) in THF (2.0 mL) and 10M aqueous NaOH (1.5 mL) is heated at 45° C. for 1.5 h. The mixture is then acidified with HOAc, concentrated in vacuo, and partitioned between EtOAc and water. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (19 mg, quant).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7])#[N:2].C1COCC1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:21]
Reactant: N#Cc1cccc(C(=O)NN)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)NNC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF (40 ml) and DMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at 0° C. followed by chloroacetyl chloride (1.0 ml, 12.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h. The THF was evaporated, water was added to the remaining mixture, followed by filtratation over celite and purification with prep. HPLC to give the title compound (1.6 g, 69%). 1H NMR (DMSO-d6): 10.62 (br s, 2 H), 8.28 (m, 1 H), 8.18 (m, 1 H), 8.08 (m, 1 H), 7.75 (t, 1 H), 4.22 (s, 2 H).
Reaction SMILES: N1CCC[CH2:2]1.C([Li])CCC.[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[CH2:17][C@H:18]([OH:43])[CH2:19][C@H:20]([OH:42])[CH2:21][CH2:22][C@@H:23]1[C@@H:32]2[C:27](=[CH:28][C@H:29]([CH3:40])[CH2:30][C@@H:31]2[O:33][C:34](=[O:39])[C@@H:35]([CH3:38])[CH2:36][CH3:37])[CH:26]=[CH:25][C@@H:24]1[CH3:41].CI.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[CH2:17][C@H:18]([OH:43])[CH2:19][C@H:20]([OH:42])[CH2:21][CH2:22][C@@H:23]1[C@@H:32]2[C:27](=[CH:28][C@H:29]([CH3:40])[CH2:30][C@@H:31]2[O:33][C:34](=[O:39])[C:35]([CH3:2])([CH3:38])[CH2:36][CH3:37])[CH:26]=[CH:25][C@@H:24]1[CH3:41]
Reactant: C1CCNC1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)NCCOC)[C@H]21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)NCCOC)[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (520 ml) and pyrrolidine (90 ml) are mixed and the mixture is cooled to −40° C. n-Butyl lithium in hexane (1.6M, 510 ml) is added under nitrogen atmosphere for 2 hours at −40° C. to −50° C. The contents are stirred for 30 minutes at −35° C. to −40° C. The residue obtained in step 1 is dissolved in tetrahydrofuran (200 ml) and added to the alkali metal amide solution prepared above for 20 minutes at −40° C. to −45° C. The reaction mass is stirred for 1 hour at −40° C. to −45° C. The solution is warmed to −25° C. to −30° C., methyl iodide (29.7 ml) is added for 1 hour at −25° C. to −30° C. and stirred for 30 minutes at −25° C. to −30° C. Saturated ammonium chloride (55 ml) is added to the reaction mass for 10 minutes at −25° C. to −30° C., the solution is then allowed to raise the temperature to 25° C., water (250 ml) is added at 25° C. and stirred for 10 minutes. Then the layers are separated and the organic layer is washed with 100 ml of 2N hydrochloric acid. The organic layer is again washed with water (300 ml), dried on sodium sulfate and concentrated to 150 ml at reduced pressure not allowing the temperature to raise above 50° C. to give N-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2,2-dimethyl-butanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(=O)(O)[O-].[K+].Br[C:20]1[CH:21]=[CH:22][C:23]2[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][C:24]=2[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]2[CH:21]=[CH:22][C:23]3[O:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][C:24]=3[CH:37]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Temperature: 90 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(methoxycarbonyl)phenylboronic acid (6.0 g, 33 mmol), potassium bicarbonate (9.1 g, 92 mmol), 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (10 g, 31 mmol) and DIPEA (16 mL, 92 mmol) in dioxane (27 mL) and water (3 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (1.3 g, 1.8 mmol). The biphasic mixture was then heated at 90° C. for 2 h then partitioned with ethyl acetate and 1M hydrochloric acid. The organic layer was washed with 1M sodium hydroxide solution then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (7.5 g, 64% yield) as a pale yellow solid. MS (EI) for C26H23FN6O3: 384 (MH+).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:35]([S:43][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCS
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Product: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1

Procedure:
Using the procedure of Example 6 with 5-chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and octyl mercaptan, the title compound is prepared.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8].C(OCC)C.[CH3:45][NH2:46]>C(Cl)Cl>[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34](=[O:36])[NH:46][CH3:45])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8]
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)O)cc34)cc2OC)cn1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)NC)cc34)cc2OC)cn1

Procedure:
Oxalyl chloride (0.142 ml) was added to a mixture of N-(1-ethylpyrazol-4-yl)-2-[4-(6-carboxyquinolin-4-yloxy)-2-methoxyphenyl]acetamide (0.15 g) and methylene chloride (6 ml) and the resultant mixture was stirred at ambient temperature for 10 minutes. Diethyl ether (10 ml) was added and the resultant precipitate was recovered and dried under vacuum. The material so obtained was suspended in methylene chloride and methylamine gas was passed into the suspension until a clear solution was obtained. The solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 100:0 to 19:1 of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.102 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 2.85 (d, 3H), 3.61 (s, 2H), 3.78 (s, 3H), 4.07 (q, 2H), 6.7 (d, 1H), 6.87 (m, 1H), 7.01 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.88 (s, 1H), 8.08 (d, 1H), 8.24 (m, 1H), 8.77 (d, 1H), 8.82 (q, 1H), 8.87 (d, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:29]([NH:31][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:30]
Reactant: CCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2CC

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (70.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 435; and 1H NMR (DMSO-d6, 400 MHz): δ 8.45-8.39 (1H, m), 8.29-8.25 (1H, m), 8.12-8.08 (1H, m), 7.82-7.67 (3H, m), 7.57-7.50 (1H, m), 4.26-4.22 (2H, m), 3.31-3.29 (2H, m), 1.35-1.32 (3H, t), 1.17-1.13 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:20]3[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])=[N:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1.[C:43](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[CH3:43][N:13]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[C:11]([O:19][C@@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])=[N:12]1
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A suspension of 4-[(4-metylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (30 mg), potassium carbonate (8.0 mg) and iodomethane (8.2 mg) in tetrahydrofuran (1 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/ethyl acetate=5/1) to give 1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole (13 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>CCO.O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 69.5 %

Procedure:
6-chloro-3-nitropyridin-2-amine (0.910 g, 5.24 mmol) was stirred in 15 ml EtOH. Iodine (1.33 g, 5.24 mmol) was added followed by addition of Ag2SO4 (1.64 g, 5.24 mmol). The reaction was stirred for 18 h and was then diluted with −30 ml of water and was filtered and washed with water. Air-drying afforded 1.09 g of 6-chloro-3-nitro-5-iodopyridin-2-amine. The iodide (1.09 g, 3.64 mmol), phenylboronic acid (0.444 g, 3.64 mmol), Pd(PPh3)4 (0.105 g, 0.091 mmol) and Na2CO3 (1.16 g, 10.9 mmol) were stirred in 4 ml of 3:1 dioxane/water and heated to reflux. After 4 h the reaction was diluted with water and extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was triturated with ether, and the resulting solid was filtered and washed with ether. The resulting solid showed pure 6-chloro-3-nitro-5-phenylpyridin-2-amine (4-1). The filtrate was purified by flash column chromatography by dissolving in DCM and eluting with 95:5 DCM/EA. Afforded an additional 240 mg pure 6-chloro-3-nitro-5-phenylpyridin-2-amine (4-1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 7.46-7.42 (m, 5H).
Reaction SMILES: [C:1]12[CH2:9][O:8][CH2:7][C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2.[N+]([O-])(O)=[O:11].O>C(O)(=O)C>[CH:7](=[O:11])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[O:8]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)COC2
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 50 g of o-xylylene oxide, 43.8 g of 60% by weight nitric acid, 203.1 g of water, and 220.6 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 4 hours. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene oxide was completely absent and that phthalaldehyde was formed in a yield of 50%. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 35% on the basis of o-xylylene oxide. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 93.0%. In addition, phthalide was formed in a yield of 9%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[CH3:16]>CN(C=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([CH3:16])[N:12]=2)=[CH:3][C:2]=1[OH:1]
Reactant: CC(=O)CBr
Reactant: Cc1ccc(NC(N)=S)cc1O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ccc(C)c(O)c2)n1
Yield: 61 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methylphenyl)thiourea (100 mg, 0.59 mmol) and bromoacetone (96 mg, 0.71 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained, after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 61% yield (79 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1([C:16](=[O:31])[CH2:17][C:18]2[NH:23][C:22](=[O:24])[CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.C[N:33](C)C=O>O>[NH2:33][N:23]1[C:22](=[O:24])[CH:21]=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]1[CH2:17][C:16]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:31]
Reactant: CN(C)C=O
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
957 mg of cesium carbonate and 685 mg of o-diphenylphosphinylhydroxylamine are successively added to a suspension of 500 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one (which can be obtained according to the previous step) in 5 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours and then diluted with 10 ml of water and extracted with dichloromethane (3×25 ml). The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05). The fractions of interest containing the product are combined and then evaporated under reduced pressure, and 154 mg of 3-amino-2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=2[CH:10]=1)=[O:2]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A 50 mL round bottom flask was charged with 5-formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol), dimethylformamide (15 mL) and potassium carbonate (2.95 g, 21.39 mmol) and heated to 60° C. for 12 hours. Additional ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and the reaction heated for 16 hours at 75° C. After cooling to room temperature, the reaction was partitioned between H2O and diethyl ether. The organic phase was washed with saturated NaHCO3 solution, KHSO4 solution (0.25 M), brine, treated with decolorizing carbon (warming gently). The resulting black suspension was dried over MgSO4, vacuum filtered through diatomaceous earth, and concentrated in vacuo yielding an orange crystalline mass. This material was recrystallized from hot hexanes yielding the ester (1.51 g, 24%) as orange crystals: mp 84.3-86.2° C. 1H NMR (acetone-d6/300 MHz) 9.96 (s, 1H), 8.06 (d, 1H, J=2 Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.1 Hz), 4.43-4.25 (m, 2H), 1.34 (t, 3H, J=7.3 Hz). FABLRMS m/z 301 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal. Calc'd for C14H11F3O4: C, 56.01; H, 3.69. Found: C, 56.11; H, 3.73.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)cc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,5-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 186 mg (86%) of the title compound as a white solid. mp 129°-130°. FDMS: m/e =333. α[D]589 =+73.31 (c=1.00, chloroform).
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[Br:17]Br>CCO>[Br:17][CH2:16][C:2](=[O:1])[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(CCC(C)=O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(=O)CBr)cc1
Temperature: 25 °C

Procedure:
21-1 (3.13 g, 14.2 mmol) was dissolved in EtOH (30 mL) at 0°, and Br2 (805 μL, 15.6 mmol) was added. After warming to RT for 16 h the reaction was concentrated, diluted with Et2O, washed with water and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% EtOAc/hexane) provided 21-2 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=O>C(Cl)Cl>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[CH2:37][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Reactant: CCCNc1c(N[C@@H](Cc2ccc(N)cc2)C(=O)O)c(=O)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCNc1c(N[C@@H](Cc2ccc(NCc3ccc(OC)c(OC)c3OC)cc2)C(=O)O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.3 %

Procedure:
To the derivatised resin (5), (120 mg) was added DCM (5 ml), DIPEA (0.1 ml, 0.6 mmol) and 2,3,4-trimethoxybenzoyl chloride (138 mg, 0.6 mmol). The solution was agitated for 12 h at RT then filtered and washed thoroughly with DCM. The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (0.5 mg).