Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1.Cl>[C:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:21]([OH:22])[C:20]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]3[C:17](=[CH:18][C:19]=2[CH:23]([CH3:24])[CH3:25])[O:16][C:12]2([CH2:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:26])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under argon, 0.30 g (0.851 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 6 ml of tetrahydrofuran and cooled to −78° C. 2.54 ml (1.28 mmol) of a freshly prepared 0.5 M solution of [4-(tert-butyl)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is briefly stirred at −78° C. and then warmed to 0° C. After about 1.5 h, saturated ammonium chloride solution is added and the mixture is diluted with a little 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified a little at a time by preparative HPLC (method 12). This gives 0.239 g (58% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:22]([O:26][C:27]([N:29]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:41]=1)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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>[C:22]([O:26][C:27]([N:29]([C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])[C:37]1[S:38][C:39]([C:2]2[CH:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[CH:7]=2)=[CH:40][N:41]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cn2cc(Br)cc(-c3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 17.1 %

Procedure:
A solution of ethyl 6-bromo-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (0.10 g, 0.29 mmol) and tert-butyl (tert-butoxycarbonyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.14 g, 0.33 mmol) in toluene (3 mL) and ethanol (1 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and K3PO4 (2 M, 1 mL, 2 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography using ethyl acetate in hexanes (10-30%) as eluent. The product containing fractions were concentrated to give 28 mg (15% yield) of ethyl 6-(2-(bis(tert-butoxycarbonyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a white solid. LCMS (Conditions C): 4.15 min (RT); (M+H)+=565.62 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(-c2nn([C@H]3CCOC3)c3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.34 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.050 mL, 0.34 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD67. ESI-MS m/z [M+H]+ found 469.4, calculated 469.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(OCC)(=O)C.O.CO>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(CO)c(O)c3)ccc21

Procedure:
760 mg (2.2 mmol) of methyl 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate and 20 ml of toluene are introduced into a three-necked flask under a stream of nitrogen. 4.4 ml of diisobutylaluminium hydride (1 M in toluene) are added at -78° C. and the mixture is allowed to return to room temperature. 9 ml of methanol and then 9 ml of hydrochloric acid (1 N) are successively introduced. The reaction medium is poured into an ethyl acetate/water mixture and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and then evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (50/50% by volume). After evaporation of the solvents, 200 mg (30%) of the expected alcohol are collected, with a melting point of 94-5° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]=O)=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:21]=[C:20]([C:39]#[N:40])[C:19]=2[N:18]=[N:17]1.[CH3:41][NH2:42]>C1COCC1.C(OCC)(=O)C>[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][NH:42][CH3:41])=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:21]=[C:20]([C:39]#[N:40])[C:19]=2[N:18]=[N:17]1
Reactant: CN
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(CCC=O)c(C(F)(F)F)c3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaB(OAc)3H (640 mg) was added in portions to the solution of methyl-6-(4-(3-oxopropyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile, methylamine (1.5 ml, 2M in methanol) in THF (5 ml). The mixture was stirred at rt for 3 hours, then diluted with ethyl acetate (100 ml), washed with sodium carbonate (100 ml), brine (100 ml), dried over sodium sulphate, solvent removed. The crude product was used for next step without further purification (260 mg). MS m/z 375 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([O:14]CC)=[O:13].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: COc1cccc(OCC(=O)O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-methoxyphenol (200 mg, 1.61 mmol) in MeCN (5 mL) was added ethyl bromoacetate (402 mg, 2.42 mmol) and K2CO3 (672 mg, 4.83 mmol). The mixture was stirred at 80° C. for 4 hours, filtered and the filtrate concentrated. NaOH (129 mg, 3.22 mmol) and H2O/EtOH (1:1, 10 mL) was added to the mixture. The reaction mixture was stirred at 50° C. for 4 hours then acidified by 1M HCl and then extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated with the residue used directly for the next step. LCMS (m/z): 183.0 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14]C)=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:28](=[O:70])[CH2:29][NH:30][C:31](=[O:69])[CH2:32][N:33]2[CH2:44][CH2:43][N:42]([CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:41][CH2:40][N:39]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:38][CH2:37][N:36]([CH2:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:35][CH2:34]2)[CH2:22][CH2:21]1)=[O:19].O[Li].O>CO>[OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([OH:14])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH2:26][NH:27][C:28](=[O:70])[CH2:29][NH:30][C:31](=[O:69])[CH2:32][N:33]2[CH2:34][CH2:35][N:36]([CH2:61][C:62](=[O:63])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:37][CH2:38][N:39]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:57])([CH3:58])[CH3:59])[CH2:40][CH2:41][N:42]([CH2:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH2:43][CH2:44]2)[CH2:24][CH2:25]1)=[O:19]
Reactant: COC(=O)[C@]12O[C@@H](CNC(=O)C3CCC(CNC(=O)CNC(=O)CN4CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC4)CC3)[C@H](O)[C@H]1OC(C)(C)O2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCC(=O)NCC2CCC(C(=O)NC[C@@H]3O[C@]4(C(=O)O)OC(C)(C)O[C@@H]4[C@H]3O)CC2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 19b (1.5 g, 1.5 mmol) in MeOH (4 mL) was added a solution of LiOH.H2O (63 mg, 1.5 mmol, Aldrich). The resulting solution was stirred at room temperature for 4 h. 30 mg of LiOH.H2O was added and it was stirred at RT for 20 more hours. Solvents were evaporated to obtain crude product 20b (1.45 g; crude yield 99%). The material was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C([O:40][C:41](=[O:54])[C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][C:43]=1[O:49]C(C)(C)C)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([NH:48][C:46]1[CH:45]=[CH:44][C:43]([OH:49])=[C:42]([CH:47]=1)[C:41]([OH:54])=[O:40])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CS)C(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)ccc1OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(CS)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To the solution of 2-acetylamino-3-mercapto-propionic acid (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4 or 5-amino-2-tert-butoxy-benzoic acid tert-butyl ester (3) (3.0 mmol) was added and stirred mechanically for 3 h at 0° C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate 4 was treated with a solution of TFA (40%) in CH2Cl2. After 2 h the solvent was removed to obtain compound (5) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (8/2), from which 4 or 5-(2-Acetylamino-3-mercapto-propionylamino)-2-hydroxy-benzoic acid (5), compound of Formula XI, was obtained (78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) and TBTU (72 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (175 μL, 1.0 mmol). Then 4-aminotetrahydropyran (23 mg, 0.22 mmol) was added and the mixture was stirred at room temperature under Ar for 16 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (62 mg, 73%) as an off white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[N:20][CH:21]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[O:29]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/3=[CH:14]\[NH:15][C:16]2[CH:21]=[N:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[N:18][CH:17]=2)=[CH:30]1
Reactant: CN1CCN(c2ncc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Reactant: OB(O)c1ccoc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(N/C=C3\C(=O)NC(=O)c4ccc(-c5ccoc5)cc43)cn2)CC1
Yield: 55.8 %

Procedure:
(4Z)-6-Iodo-4-({[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (73.5 mg, 0.15 mmol) is mixed with 3-furanboronic acid (33 mg, 0.3 mmol), Pd2(dba)3 (20.6 mg, 0.022 mmol), and cesium carbonate (98 mg, 0.3 mmol). After the solids were degassed, N,N-dimethylformamide (1.05 mL) and P(t-Bu)3 (9.1 mg, 0.045 mmol) were added. The mixture is heated at 100 C for 55 min, diluted with methylene chloride, and filtered. The filtrate is evaporated to dryness and purified by column chromatography to yield 36 mg (55%) of the title compound as a yellow solid. MS (ESI) m/z 431 (M+H)+1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[C:7]([Cl:11])=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:7]([Cl:11])=[N:6][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-6-chloro-nicotinic acid methyl ester (10 g, 40 mmol) in toluene (200 mL) was added 4-chlorophenyl-boronic acid (6.4 g, 40 mmol), [1,1′-bis(diphenylphosphino)ferrrocene]dichlorpalladium(II) dichloromethane complex (1.6 g, 2 mmol) and 2 M sodiumcarbonate solution (60 mL). The reaction mixture was stirred for 2 h at 90° C. After cooling, the phases were separated; the aqueous phase was extracted once with ethyl acetate (200 mL), organic phases were washed once with water and brine (150 mL each), combined and dried over MgSO4. After evaporation of the solvent the crude product was purified by flash column chromatography (dichloromethane/heptane 2:1 to 9:1) to give 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester as a colorless solid, 8.12 g (72% yield). m/z (ES+): 281.1, 283.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:23]1[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC1CCC(N)CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4-methyl-cyclohexylamine following general procedure B to afford 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (290 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (200 mg) following general procedure E. The above ethylamide (0.41 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg). LCMS: m/z 368 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-1H-indole-3-carboxaldehyde (5.00 g, 27.8 mmol), phenylboronic acid (6.79 g, 55.6 mmol), cupric acetate (10.11 g, 55.7 mmol), pyridine (4.40 g, 55.7 mmol), triethylamine (5.63 g, 55.6 mmol), 4 Å molecular sieves (15.0 g) dichloromethane (300 mL) is stirred at room temperature for 4 d. The reaction mixture is filtered through a pad of Celite and the filtrate is washed with water, with 2N aq hydrochloric acid, with sat aq sodium bicarbonate, with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 2-chloro-1-phenyl-1H-indole-3-carboxaldehyde (4.40 g, 88% yield) as a yellow solid. NMR (CDCl3) 12.30 (1H, s), 8.37 (1H, d), 7.58-7.70 (3H, m), 7.43 (2H, d), 7.23-7.40 (2H, m), 7.10 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([NH2:10])=[O:9])[S:5][CH:6]=1.[CH2:11]([O:18][C:19](=[CH:22]N(C)C)[CH:20]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl>O.CN(C=O)C.CO>[CH2:11]([O:18][C:19]1[CH:22]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[C:8](=[O:9])[NH:10][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Reactant: Cc1csc(CC(N)=O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1csc(-c2cc(OCc3ccccc3)c[nH]c2=O)n1
Yield: 73.1 %

Procedure:
2-(4-Methylthiazol-2-yl)acetamide (0.016 mol), 2-benzyloxy-3-(N,N-dimethylamino)propenal (0.017 mol), sodium hydride (0.032 mol), methanol (1.3 ml) and DMF (100 ml) were heated at 70° C. for 4 h. The reaction was cooled, acidified with 5.0N HCl(aq), and poured into water. The resulting precipitate was collected by filtration and dried to give the product as a brown solid (11.7 mmol, 73%). δH (360 MHz; CDCl3) 9.38 (1H, s), 7.47-7.34 (7H, m), 7.09 (1H, s), 5.21 (2H, s), 2.69 (3H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[N:13][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15]2)=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:14]2[N:13]=[C:12]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:11]3[C:16](=[CH:17][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[N:15]=2)=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(Br)cc3n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(N4CCOCC4)cc3n2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 102.1 %

Procedure:
Under a nitrogen atmosphere, 2.26 g (2.47 mmol) of tris(dibenzylideneacetone)dipalladium-(0) and 4.42 g (12.35 mmol) of 2-(dicyclohexylphosphino)biphenyl were dissolved in 1.5 l of toluene, and 215.2 ml (2.47 mol) of morpholine and 269.0 g (0.5 mol) of 7-bromo-2,4-bis(4-methoxybenzyloxy)quinazoline [dissolved in 5 l of toluene] were added successively. 66.47 g (0.7 mol) of sodium tert-butoxide were subsequently added in portions, and the mixture was stirred at 90° C. for 12 h. Conventional work-up gave 249.0 g of 2,4-bis(4-methoxybenzyloxy)-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=488 as oil [crude product; was reacted further directly].