Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][C@H:9](C(C)=C)[CH2:8][C:7](=[O:14])[CH:6]1[CH3:15].O=[O+][O-]>CO>[OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH:6]([CH3:15])[C:7](=[O:14])[CH:8]=[CH:9][CH2:10]1
Reactant: C=C(C)[C@@H]1CC(=O)C(C)[C@@H](CCCO)C1
Agent: O=[O+][O-]
Solvent: CO
Product: CC1C(=O)C=CC[C@@H]1CCCO
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 68729.1 %

Procedure:
A solution of 34 g (0.16 mmole) of the crude (3S,5S)-3-(3-hydroxypropyl)-5-(1-methylethenyl)-2-methylcyclohexanone in 600 ml of MeOH at -78° C. was bubbled with ozone until the blue color persisted. Excess ozone was removed by flushing the solution with argon. The reaction mixture was warmed up to -20° C., added with 64.8 g (0.32 mole) of cupric acetate and stirred for 15 minutes. This was then added with 54.2 g (0.195 mole) of ferrous sulfate heptahydrate in small portions. After the addition, the reaction mixture was stirred at -20° C. for 3 hours, room temperature for 1 hr, quenched with 650 ml of water and extracted with 3×1000 ml ether. The aqeous layer was then acidified with 6N HCl until it became homogeneous and extracted with 2×800 ml of ether. The combined etheral extracts were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give 18.5 g of the crude (5S)-5-(3-hydroxypropyl)-6-methyl-2-cyclohexene-1-one which was used as such for the next step. An analytical sample of the conjugated enone was obtained by further purification of the crude (3S,5S)-3-(3-hydroxypropyl)-5-(1-methylethenyl)-2-methylcyclo-hexanone on a silica gel column (2:1, hexane/EtOAc). IR (CHCl3): 1670, 3625 cm-1. 1H NMR (200 MHz): δ1.04 (d, J=7.3 Hz, 1.5H), 1.17 (d, J=6.9 Hz, 1.5H), 1.43-1.65 (m, 4H), 1.90 (m, 1HO, 2.10-2.27 (m, 2H), 2.34-2.42 (md, 1H), 2.49-2.57 (m, 1H), 3.65 (t, J=6.4 Hz, 2H), 5.98 (mt, 1H), 6.89-6.92 (m, 1H). Mass spectrum m/e: M+ (168). Anal. for C10H16O2 : Calc. for C, 71.39; H, 9.59. Found: C, 71.34; H, 9.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:21]([N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=2[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:28]1[C:36]2[C:31](=[C:32]([NH:37][C:12]([C:9]3[N:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2ncc(C(=O)O)n2c1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)n2c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
6-Methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.154 mmol) was taken up in DCM. Oxalyl chloride (1.1 equivalents) was added followed by a drop of DMF. The reaction was stirred at ambient temperature until bubbling ceased, and then 1-benzyl-1H-indazol-4-amine (34.3 mg, 0.154 mmol) was added followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature overnight. The reaction was concentrated, triturated with ether and purified by Preparative TLC (1 mm) eluting with 10% MeOH/DCM to give 15 mg (25%) of the desired product. MS (ES+APCI) m/z=398.3 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2([O:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]2=[O:14])[C:2]1=[O:15].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:12]1[CH:11]=[CH:10][C:8]2[O:9][C:3]3([C:6](=[O:14])[C:7]=2[CH:13]=1)[CH2:4][CH2:5][O:1][C:2]3=[O:15])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C1OCCC12Oc1ccccc1C2=O
Agent: O=S(=O)(O)O
Product: O=C1OCCC12Oc1ccc([N+](=O)[O-])cc1C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.408 g. of 4',5'-dihydrospiro[benzo[b]furan-2(3H), 3'(2'H)-furan]-2',3-dione in 3 ml. of concentrated sulfuric acid was added a mixture of 0.35 ml. of nitric acid (d=1.42) and 0.36 ml. of concentrated sulfuric acid, dropwise under ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-water and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from ethyl acetate. By the above procedure there was obtained colorless needles of 4',5'-dihydro-5-nitrospiro[benzo[b]furan-2(3H),3'(2'H)-furan]-2',3-dione. m.p. 199°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCCC2)c1C
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-chloro-3-((cyclopentylmethyl)amino)-2-methylbenzoate (1.0 g, 3.5 mmol) in acetonitrile (10 mL), cesium carbonate (2.3 g, 7.1 mmol) and methyl iodide (5.0 g, 35 mmol) were added. The mixture was heated at 80° C. for 12 h. cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford the title compound (1.0 g, 95%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]([CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (180 mg) in THF (4 mL) was added sodium hydride (32 mg, 60%) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. To the reaction mixture was added methyl iodide (0.107 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1[N:10]=[C:11]([NH2:27])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1.[CH:28]1[N:32]=[CH:31][N:30]([C:33](N2C=NC=C2)=[O:34])[CH:29]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:8][C:9]1[N:10]=[C:11]([NH:27][C:33]([N:30]2[CH:29]=[CH:28][N:32]=[CH:31]2)=[O:34])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1
Reactant: Cc1nc(N)sc1-c1csc(C(=O)N2CCOCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Trifluoroacetate salt of 4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-amine, prepared in Step II, described above (142.4 mg; 0.34 mmol; 1 eq.) is suspended in dry DCM (5 ml). CDI (108.8 mg; 0.68 mmol; 2 eq.) and triethylamine (511; 0.37 mmol; 1.10 eq.) are added. Some DMF (0.30 ml) is added to improve the solubility of the starting material. The mixture is stirred overnight at 40° C. A precipitate is formed. It is filtrated, washed with diethyl ether, affording N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (107.1 mg; 79%) which is used as such in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[CH:7]=[CH:8][CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(Cl)c1F
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-fluorobenzaldehyde (2.36 g, 14.88 mmol) in THF (29.8 mL) was cooled down to −78° C. under argon. To the solution was added vinyl magnesium bromide (1 M in THF) (20 mL, 20.00 mmol) via syringe pump over 30 min, while stirring was continued at −78° C. After 2 h, the reaction mixture was warmed to 0° C., quenched with 1 N HCl and adjusted the pH to 4. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine and dried over MgSO4. The solids were filtered off and the filtrate was concentrated under vacuum to yield a yellow oil as the desired product. MS (ESI) m/z: 169.1 (M+H-H2O)+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14]Cl)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].[NH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:19]3([NH2:18])[N:23]=[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]4=[N:20]3)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CC2(N)N=c3ccccc3=N2)cc1
Temperature: 80 °C

Procedure:
The compound described in Example 26, Step 1 [1-(4-cyanobenzyl)-5-(chloromethyl)imidazole hydrochloride] (0.75 mmol, 0.20 g), 2-aminobenzimidazole (0.90 mmol, 0. 12 g) and diisopropylethylamine (2.25 mmol, 0.29 g) were dissolved in acetonitrile and placed in a nitrogen purged sealed tube and warmed at 80° C. for 18 hr. The precipitate was filtered off to yield 1-(4-cyanobenzyl)-5-(2-amino-1-benzimidazolylmethyl)imidazole.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:17]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(OCC)(=O)C>O1CCOCC1.[Pd]>[C:9]([C:11]1([N:17]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)O)CCCCC1

Procedure:
A solution of 2.4 g (4.3 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in 40 ml of dioxan is hydrogenated with the addition of 0.5 g of Pd/C (10%) and worked up, in a manner analogous to that described in Example 73. The N-(1-carboxycyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is thus obtained in the form of colourless crystals (from ethyl acetate) melting between 134° and 136°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].Cl.[NH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:42](=[O:43])[NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:49])=[CH:40][CH:41]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(=O)NCC(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carboxyphenyl)ethyl]benzofuran (0.12 g) in N,N-diemthylformamide (2 mL) were added benzyl 2-aminoacetate hydrochloride (48 mg), 1-hydroxybenzotriazole (32 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg) and triethylamine (0.11 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(benzyloxycarbonylmethylcarbamoyl)phenyl]ethyl}benzofuran (94 mg). This material was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (40 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (82 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1>C(O)C.[C].[Pd]>[NH2:14][C:13]1[C:8]([NH:7][CH2:6][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[N:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCC2OCCO2)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(NCC2OCCO2)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a solution of 2.7 g of N-(1,3-dioxolan-2-ylmethyl)-6-methoxy-3-nitropyridin-2-amine in 30 mL of ethanol, 0.81 g of 10% palladium-carbon was added at room temperature, and mixture was stirred at 40° C. for 2 hours 30 minutes under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble substance was filtered off, and the filtration residue was washed with diethyl ether. The solvent was distilled off under reduced pressure to obtain 2.4 g of 3-amino-2-(1,3-dioxolan-2-ylmethyl)amino-6-methoxypyridine as a purple solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5].[F:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:16](=[O:19])[CH2:17]Br.C([O-])(O)=O.[Na+].Cl>CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]([C:16](=[O:19])[CH2:17][NH:2][C:3]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)(NCC(=O)c1cc(F)cc(F)c1)C(=O)OC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-amino-2-ethylbutanoate hydrochloride from Step A (2.10 g, 11.6 mmol), 3,5-difluorophenacyl bromide (2.99 g, 12.7 mmol), and NaHCO3 (2.43 g, 28.9 mmol) in DMF (20 mL) was stirred at 45° C. for 1 h, and at ambient temperature for 2 h. 1 N aqueous HCl (50 mL) was added and the mixture was extracted with EtOAc (75 mL) and this organic extract was discarded. The aqueous layer was adjusted to pH 10 by addition of saturated aqueous Na2CO3 (150 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were treated with CF3CO2H (1.5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=300 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]CCCC.CCCCCC.C1(OC)C=CC=CC=1.[N:29]1([C:34]2[CH:38]=[CH:37][NH:36][C:35]=2[C:39](OCC)=[O:40])[CH:33]=[CH:32][CH:31]=[CH:30]1.[NH4+].[Cl-]>C1COCC1>[N:29]1([C:34]2[CH:38]=[CH:37][NH:36][C:35]=2[C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[O:40])[CH:30]=[CH:31][CH:32]=[CH:33]1
Reactant: CCOC(=O)c1[nH]ccc1-n1cccc1
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1C(=O)c1[nH]ccc1-n1cccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 2-bromoanisole (1.39 g, 7.43 mmol, 5.63 equiv) in anhydrous THF (5 mL) at −78° C., a 2.5M solution of BuLi in hexane (3 mL, 7.50 mmol, 5.68 eq.) was added dropwise, the resulting mixture was stirred for 1 h. at −78° C. to generate the lithiated anisole. In an oven-dried flask, compound (c) (270 mg, 1.32 mmol, 1 eq.) was dissolved in THF (5 mL) and cooled to −78° C., the lithiated anisole (d) was transferred into the solution containing (c) dropwise via syringe, and the resulting mixture was stirred for 1 h. at −78° C. To the reaction mixture, an aqueous solution of NH4Cl (5 mL) was added, the mixture was extracted with EtOAc, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography (10% EtOAc in Hexane) to give (e) as a light brown solid (0.30 g, 85% yield).
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C.O>[C:10]1([C:3]2[C:2]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncnc(Cl)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: c1ccc(-c2ncnc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 46 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 4.25 g of 5-bromo-4,6-dichloropyrimidine, 6.84 g of phenylboronic acid, 5.95 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.28 g of phenylboronic acid, 1.98 g of sodium carbonate, 0.053 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, the precipitated solid was suction-filtered and washed with water. The obtained residue was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that a pyrimidine derivative Htppm, which was the objective substance, was obtained (white powder, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (1-1) of Step 1 is shown below.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][OH:28])[CH:25]=2)[CH:20]=[C:19]1[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:43])[CH:36]=2)[N:32]=[N:31][C:30]=1[O:44][CH3:45])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[CH:25]=2)[CH:20]=[C:19]1[C:29]1[CH:34]=[C:33]([C:35]2[CH:36]=[C:37]([CH3:43])[C:38]([OH:42])=[C:39]([CH3:41])[CH:40]=2)[N:32]=[N:31][C:30]=1[O:44][CH3:45])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A dry flask is charged with 0.399 mL oxalyl chloride and 69 mL dichloromethane. After cooling to −78° C. 0.304 mL DMSO is added dropwise. After stirring for 15 minutes at this temperature, 2.04 g (6-hydroxymethyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester in 46 mL dichloromethane are slowly added by syringe. After stirring for 60 minutes at −78° C. 2.98 mL triethylamine is added. The reaction mixture is stirred for 60 minutes at −78° C., allowed to warm to 0° C. and quenched by addition of sat. aq. NH4Cl-solution. The reaction mixture is diluted with dichloromethane, washed with sat. aq. NH4Cl-solution and brine, dried (MgSO4) and concentrated in vacuo. 1.96 g (97%) crude 6-formyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2cccc(Br)c2C1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2c(C#N)ncn2-c2cccc(Br)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A suspension of 21.5 g (64.1 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in a mixture of 100 ml of dioxan and 15 ml of pyridine was treated at 7° to 10° with 15 ml of trifluoroacetic anhydride. The suspension was stirred at room temperature for 1 hour and poured into 600 ml of water. After 1 hour the suspension was suction filtered. There were obtained 17.8 g (88%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile of m.p. 226°-228°.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCOc2ccccc2)cc1

Procedure:
A mixture of 12 g of ethyl p-(2-phenoxyethylamino)-benzoate, 12 g of potassium hydroxide and 200 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The solution is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled, filtered and the solid washed with water to give crystals, mp 172°-175° C. Recrystallization from ethanol gives off-white crystals, mp 174°-176° C.