Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:63][C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH2:76])[CH2:72][CH2:71]1)=[O:69])([CH3:66])[CH3:65]>ClCCl.CN(C)C=O>[C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH:76][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[CH:24][CH:25]=2)[CH2:72][CH2:71]1)=[O:69])([CH3:63])([CH3:65])[CH3:66]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
A mixture of 0.10 g (0.23 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-256), 0.093 g (0.92 mmole) of triethylamine, 0.133 g (0.35 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.070 g (0.35 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.095 g of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-259).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7][C@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:5]1.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([CH2:28][N:5]2[C@@H:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]2=[O:3])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)NC1=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 14.4 mg, 0.36 mmol) was added to a solution of tert-butyl (3R,7R)-2-oxo-7-phenylazepan-3-ylcarbamate (100 mg, 0.33 mmol) and cyclopropylmethyl bromide (0.08 mL, 0.82 mmol) in N,N-dimethylformamide (1 mL) at 0 □C, and the mixture was allowed to warm to ambient temperature. After 6 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (82 mg). MS 359 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1)(=[O:47])=[O:46].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26]([C:51]2[CH:52]=[CH:53][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:49][CH:50]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C4COC(C)(C)O4)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(c2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-vinyl ester (620 mg, 1 mmol), bis(triphenylphosphine)palladium(II) chloride (70.1 mg, 0.1 mmol) and 4-(methanesulfonyl)phenylboronic acid (460 mg, 2.3 mmol) in dioxane (6 mL) was added a 2M sodium carbonate solution (1.5 mL) at 25° C. The mixture was subjected to microwave irradiation for 1.5 h at 100° C. The mixture was cooled to 25° C., extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (510 mg, 85%) as a light yellow solid: LC/MS m/e calcd for C32H35N2S2O6 [M+H]+ 607.77, observed 607.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.47-1.62 (m, 4H), 1.52 (s, 3H), 1.60 (s, 3H), 1.71-1.98 (m, 4H), 2.68 (m, 1H), 3.07 (s, 3H), 3.80 (m, 1H), 4.40 (dd, J=6.3 Hz, 8.3 Hz, 1H), 5.22 (m, 1H), 6.35 (d, J=10.1 Hz, 1H), 6.58 (s, 1H), 7.29 (m, 2H), 7.37, 7.39 (2d, J=8.6 Hz, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.74 (m, 2H), 7.78, 7.79 (2d, J=8.6 Hz, 2H), 7.96, 7.97 (2d, J=2.1 Hz, 1H), 8.50, 8.51 (2d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])C[CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:31]([Cl:33])[Cl:32]>C(OCC)(=O)C.C(#N)C>[Cl:32][C:31]1([Cl:33])[C:16](=[O:23])[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH2:19][CH2:18]1)[CH:11]=[CH:12][CH:13]=3
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1(Cl)Cl
Temperature: 95 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.5681 g, 1.87 mmol) in ethyl acetate (10 mL) and acetonitrile (10 mL) is added trifluoroacetic acid (2 mL,). Anhydrous cupric chloride (1.26 g, 9.36 mmol) is added and the mixture is heated to reflux at 95° C. for 2 h. After 5 h, additional anhydrous cupric chloride (0.63 g, 4.68 mmol) is added and the mixture is refluxed an additional hour. The mixture is then poured into CH2Cl2 (150 mL) and filtered. The filtrates are washed with aqueous potassium carbonate. The layers are separated and the organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (70 g silica gel) using ethyl acetate/CH2Cl2/hexane (5:45:50) gave 0.428 g (61%) of 8,8-dichloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[N:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)=[CH:14][CH:15]=2)=[C:7]([CH3:32])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:17]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]=[C:16]1[C:13]1[S:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3-c3ccccc3Cl)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2nc(C(F)(F)F)cn2-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
(4-{5-[1-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-thiophen-2-yl}-3-methyl-phenyl)-acetic acid methyl ester (123 mg, 0.25 mmol) was dissolved in 6 mL mixture of THF and water (3:1, V/V). Lithium hydroxide monohydrate (2.3 mg, 0.55 mmol) was added then. The mixture was stirred at room temperature for 3 hrs. The mixture was neutralized to pH 7 by 1N HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→5% MeOH/DCM) to give a white solid (47 mg, 39% yield). 1H-NMR. (400 MHz, CDCl3): δ 2.35 (s, 3H), 3.64 (s, 2H), 6.83 (s, 2H), 7.13-7.10 (m, 1H), 7.16 (m, 1H), 7.29-7.27 (m, 1H), 7.35 (m, 1H), 7.47-7.46 (m, 2H), 7.57-7.52 (m, 1H), 7.64-7.62 (m, 1H). MS (ES): 477.1, [M+H]+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])[CH2:11][CH2:10]1.C[O:20][C:21](=O)[CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O)(=O)C>O1CCCC1.ClCCl>[C:27]([O:26][C:24]([NH:23][CH2:22][C:21](=[O:20])[CH2:18][P:13]([CH2:12][CH:9]1[CH2:11][CH2:10]1)(=[O:17])[O:14][CH2:15][CH3:16])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOP(C)(=O)CC1CC1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)CNC(=O)OC(C)(C)C)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.97 g of lithium diisopropylamide in 100 ml of anhydrous tetrahydrofuran is cooled to -78° under an inert atmosphere. With constant stirring, a -78° solution of 10.5 g of ethyl cyclopropylmethyl(methyl)phosphinate in 30 ml of absolute tetrahydrofuran is added over 15-20 minutes via a canula under a positive pressure of inert gas. The resulting pale yellow solution is stirred for 1 hour at -78° and a pre-cooled (-78°) solution of 2.06 g of N-tert.-butoxycarbonyl glycine methyl ester in 20 ml absolute tetrahydrofuran is added over 5-10 minutes via a canula. Chromatographic analysis after 15 minutes stirring at -78° C. indicated the reaction to be complete. At -78° 3.75 ml of glacial acetic acid is added and the mixture allowed to warm to room temperature. The reaction mixture is diluted with dichloromethane and washed with water. Drying of the solvent and removal under reduced pressure affords a pale yellow oil. Removal of the excess starting material by distillation and chromatography of the residue on silica gel gives ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(cyclopropylmethyl)phosphinate as a pale yellow oil; 1H-NMR (CDCl3): δ (ppm)=5.40 (1H, Br t, Exch. D2O, NH), 4.14 (4H, m, CH2OP+CH2N) 3.17 (2H, d, J=17.5 Hz, CH2C=O), 1.93-1.68 (2H, m, PCH2), 1.45 (9H, s, tBu), 1.35 (3H, t, CH3), 0.93 (1H, m, CH), 0.62 (2H, m, CH2), 0.27 (2H, m, CH2).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)c1ccccc1Oc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
At 0° C., a solution of N-methyl-2-phenoxybenzamide (22.2 g, 97.7 mmol) in THF (175 ml) was added dropwise to a suspension of sodium borohydride (9.20 g, 244 mmol) in THF (100 ml). The reaction mixture was stirred at 0° C. for 20 min. A solution of iodine (24.8 g 97 mmol) in THF (125 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol 500 ml was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia as eluent, to give 3.04 g of N-methyl-N-(2-phenoxybenzyl)amine.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(=NC(C)C)O[C:24]([CH3:27])([CH3:26])[CH3:25])(C)C.NC(=N)O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Agent: N=C(N)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reaction time: 16 h
Yield: 57 %

Procedure:
A suspension of 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (1 eq., prepared as described in WO2005/023819) in dry CH2Cl2 (0.19 M) was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated to reflux for 20 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to complete conversion. After cooling down the solvent was evaporated in vacuo giving a residue that was purified by flash chromatography (PE:EtOAc, 10:1) affording the title compound (57%). 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 11.12 (bs, 1H), 7.55 (s, 1H), 7.08 (s, 1H), 2.60-2.50 (m, 1H), 1.99-1.67 (m, 5H), 1.51 (s, 9H), 1.45-1.19 (m, 5H). MS (ES+) m/z: 306 [M+H]+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:38])[N:9]([CH3:37])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (45.3 mg, 0.083 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (6.93 mg, 0.165 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 18.6% yield) as a white solid. 1H NMR (CDCl3) δ: 8.82 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=3.0 Hz, 1H), 7.53 (d, J=3.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 4.26-4.20 (m, 4H), 3.71 (s, 3H), 3.58-3.54 (m, 2H), 2.97 (brd s, 1H), 1.96-1.90 (m, 2H). LCMS: MH+ 521 and TR=2.765 min.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]2[N:22]=[C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][NH:1][C:5]4=[N:6][CH:7]=3)[O:12][N:14]=2)[CH:17]=1
Reactant: O=C(O)c1cnc2[nH]ccc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3cnc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Adesis) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.71 (d, J=3.4 Hz, 1H), 7.66 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.70 (d, J=3.4 Hz, 1H), 8.47 (dt, J=8.1, 1.9 Hz, 1H), 8.78-8.86 (m, 2H), 9.05 (d, J=2.0 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27]C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.Cl.CO.ClCCl>CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][NH:15]3)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CCN2c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Reaction time: 48 h

Procedure:
200 mg of product obtained in stage 4 of example 41 are dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. Stirring is carried out for 48 hours at ambient temperature, followed by evaporation to dryness. The residue is chromatographed on a silica column, eluting with 85/15/1.5 dichloromethane/methanol/aqueous ammonia. The product obtained is taken up in 10 ml of a 50/50 methanol/dichloromethane mixture, 6 ml of 1M HCl solution in ethyl acetate are added, the mixture is left to crystallize, filtration is carried out, and 87 mg of expected product are thus recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][C:7]=3[O:11][CH3:12])[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1cccc(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c12
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115° C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47](S(C(F)(F)F)(=O)=O)[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:91]([Si:93]([CH3:96])([CH3:95])[CH3:94])#[CH:92]>N1CCCCC1.[Cu]I.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47]([C:92]#[C:91][Si:93]([CH3:96])([CH3:95])[CH3:94])[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(S(=O)(=O)C(F)(F)F)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C#C[Si](C)(C)C)=CN1C2=O
Reaction time: 8 h

Procedure:
A mixture of 9 (0.150 g, 0.14 mmol), CuI (0.003 g, 0.014 mmol, 0.1 eq), Pd(PPh3)4 (0.0162 g, 0.014 mmol, 0.1 eq) and PPh3 (0.007 g, 0.028 mmol, 0.2 eq) was dissolved in piperidine (9 mL) in presence of molecular sieves under an argon atmosphere. Ethynyltrimethylsilane (0.06 ml, 0.42 mmol, 3 eq) was added to the mixture at 70° C. and the reaction mixture was allowed to stir overnight. The solvent was removed by rotary evaporation under reduced pressure and the resulting brown solid purified by flash column chromatography (silica gel, 90% EtOAc, 10% hexane). Compound 27 was obtained as an orange solid (0.043 g, 30%); Rf 0.69 [EtOAc]; LC-MS (5 min) 4.28 min, ES+1008.28.