Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (26 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (78 mg). 1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 116 part a to d except using 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine (1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 147 part a to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine (32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine (25.2 g, 59%). Oxidative cleavage using a 4% solution of osmium tetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried out in a mixture of THF and water (10:1, 60 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 70 to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g, 56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g). 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[CH:7][CH:8]=3)[N:3]=[CH:2][C:11]=2[C:12]#[N:13])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: COc1ccc2cc(C#N)c(Cl)nc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCCO
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c1

Procedure:
To a suspension of 200 mg (0.91 mmol) of -chloro-7-methoxy-3-quinolinecarbonitrile and 135.5 mg (1.10 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxy ethanol was added 105.6 mg (0.91 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 277 mg (99%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:26]=[CH:25][C:17]3[C:18]([CH3:24])([CH3:23])[O:19][C:20](=[O:22])[NH:21][C:16]=3[CH:15]=2)=[CH:4][CH:3]=1.[OH:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:26]=[CH:25][C:17]3[C:18]([CH3:23])([CH3:24])[O:19][C:20](=[O:22])[NH:21][C:16]=3[CH:15]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)cc3)ccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccc(Cl)cc3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-[4-(4-chlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:40])[N:9]=[C:10](SC)[C:11]([C:25]1[C:26]([F:37])=[C:27]2[C:32](=[C:33]([O:35][CH3:36])[CH:34]=1)[O:31][CH2:30][CH2:29][CH2:28]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C[O:42][C:43]([C:45]1[S:46][CH:47]=[CH:48][C:49]=1[NH:50][NH2:51])=[O:44]>C(N(CC)CC)C>[F:37][C:26]1[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:40])[N:50]([C:49]3[CH:48]=[CH:47][S:46][C:45]=3[C:43]([OH:44])=[O:42])[N:51]=2)=[CH:34][C:33]([O:35][CH3:36])=[C:32]2[C:27]=1[CH2:28][CH2:29][CH2:30][O:31]2
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To 1 ml of a DMF solution containing 100 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)), 35 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.028 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 12 hours under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1.5 ml of methanol, 1.5 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours, and 1 ml of a 5 N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature overnight. Acetic acid (0.3 ml) was added to the reaction mixture, and the resulting mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](O)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:13]>>[C:1]1([N:7]2[C:10](=[O:18])[C:11]3[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:13][C:8]2=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: S=C=Nc1ccccc1
Product: O=c1c2ccccc2[nH]c(=S)n1-c1ccccc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Phenyl isothiocyanate (28.3 g) was added to anthranilic acid (28.7 g) in absolute alcohol (250 ml) and heated at reflux for 4.5 hours. The mixture was cooled to room temperature and the solid removed by filtration to give 32.5 g of 3-phenyl-2,3-dihydro-2-thioxoquinazolin-4(1H)-one, mp 287°-291° C. Sulphuryl chloride (5.4 ml) was added dropwise at room temperature to a suspension of this product (32.5 g) in chloroform (250 ml). The mixture was heated at reflux for 4 hours. When cool it was poured into water (400 ml), filtered and the solid washed with dichloromethane. The organic layer was separated from the filtrate, dried and concentrated in vacuo. The residue was extracted with ether, filtered and the filtrate concentrated in vacuo to give an oil which solidified on standing. This was recrystallised from cyclohexane to give crude 2-chloro-3-phenylquinazolin-4(3H)-one, mp 102°-5° C. (shown to be 90% pure by high pressure liquid phase chromatography (hplc). A mixture of this product (3.85 g), imidazole (1.02 g) and potassium carbonate (2.07 g) in acetonitrile (60 ml) was heated at reflux for 4 hours. The mixture was cooled to room temperature, and concentrated in vacuo. The residue was chromatographed on silica using light petroleum (bp 60°-80° C.)/ethyl acetate (1:1) as eluant. The resulting solid was recrystallised from cyclohexane to give 0.8 g of 3-phenyl-2-(imidazol-1-yl)-quinazolin-4(3H)-one, mp 163°-5° C. (Compound 1).
Reaction SMILES: Cl.[CH3:2][N:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:13](=[O:19])[C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:4].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH:16]([N:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([N:3]([CH3:2])[CH3:4])=[CH:6][CH:7]=2)=[C:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:13]([O:19][C@@H:38]2[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]2[OH:41])=[N:14]1)([CH3:17])[CH3:18]
Reactant: COc1ccc(Cc2c(-c3ccc(N(C)C)cc3)n(C(C)C)[nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)C)c2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a suspension of 5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxyphenyl)methyl-3H-pyrazole-3-on hydrochloride (0.051 g), acetobromo-α-D-glucose (0.16 g) and benzyl(n-tributyl) ammonium chloride (0.12 g) in dichloromethane (3 mL) was added sodium hydroxide (2 mol/L, 0.19 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate). The obtained semi purified 1-isopropyl-4-(4-methoxyphenylmethyl)-5-[4-(N,N-dimethyl-amino)phenyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol, and sodium methoxide (28% methanol solution, 0.02 mL) was added to the solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μM, 20×50 mm, flow rate 30 mL/min linear gradient, water/methanol=90/10-10/90) to give the title compound (0.040 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1CCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and pyrrolidine. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79-1.95 (m, 4 H) 2.33 (d, J=2.44 Hz, 3H) 3.49 (t, J=5.61 Hz, 4 H) 7.42-7.82 (m, 2 H) 7.84-8.76 (m, 4 H). ESI-MS m/z [M+H]+392.3.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:10]C(C)=O.[CH2:14]1[O:22][C:21]2[CH:20]=[CH:19][C:18]([N:23]=[C:24]=[S:25])=[CH:17][C:16]=2[O:15]1.CI>>[O:22]1[C:21]2[CH:20]=[CH:19][C:18]([NH:23][C:24]([S:25][CH3:10])=[C:4]([C:3](=[O:7])[C:2]([CH3:9])([CH3:8])[CH3:1])[C:5]#[N:6])=[CH:17][C:16]=2[O:15][CH2:14]1
Reactant: S=C=Nc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CI
Product: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (0.626 g, 5.0 mmol) in dry acetone (10 ml) first potassium carbonate (1.38 g, 10 mmol) and then 3,4-methylendioxyphenyl isothiocyanate (0.941 g, 5.3 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 72 h, and then filtered. To the filtrate methyl iodide (0.93 ml, 15 mmol) was added. The mixture was stirred at room temperature for 45 min. The precipitate was filtered off and the filtrate was concentrated. The residue was taken up into dichloromethane and water. The organic layer was washed with water (2×), dried (sodium sulfate) and concentrated. Crystallisation from ethyl acetate/heptane 1:1 gave 1.56 g (98%) of the title compound. Mp 139-141° C.; 1H NMR (200 MHz, CDCl3): δ=1.40 (s, 9H), 2.28 (s, 3H), 6.03 (s, 2H), 6.75 (dd, 1H), 6.8 (m, 2H), 13.5 (br s, 1H); EI SP/MS: 318 (M+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:38])[O:30][CH:29]([C:31]2[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=2)[CH2:28][O:27]1.C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:33]3[S:34][CH:35]=[C:31]([CH:29]4[CH2:28][O:27][C:26]([CH3:38])([CH3:25])[O:30]4)[N:32]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2csc(C=O)n2)O1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OCC(c2csc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)n2)O1
Yield: 60 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole-2-carbaldehyde (0.37 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and the title compound (0.47% g, yield 60%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[N:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C@@H:30]([NH2:39])[CH2:29][C@H:28]1[CH2:40][CH3:41])=[O:26])[CH3:23].C(N(CC)CC)C>O1CCCC1>[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[N:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C@@H:30]([NH:39][C:10]([O:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:11])[CH2:29][C@H:28]1[CH2:40][CH3:41])=[O:26])[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1CC
Reactant: C[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(=O)O[C@@H](C)c2ccccc2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 2 h
Yield: 11.8 %

Procedure:
(S)-1-Phenylethyl alcohol (1.0 g) and 1,1′-carbonyldiimidazole (1.33 g) are dissolved in tetrahydrofuran (20 ml), and the mixture is stirred at 80° C. for 2 hours. To the reaction solution are added (2R*,4S*)-4-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1.91 g) and triethylamine (1.14 ml), and the mixture is heated to reflux for 3 days. The reaction solution is partitioned by adding ethyl acetate and a saturated aqueous sodium bicarbonate solution, and then the organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue is purified by column chromatography (silica gel; hexane:ethyl acetate=90:10→70:30). The resulting mixture of diastereomers is recrystallized from hexane to give (2R,4S)-2-ethyl-6-methoxy-4-((S)-1-phenylethoxycarbonylamino)-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (345 mg). The physical property data are the same as the compound obtained in Example 2 (3).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:55])=[CH:46][C:47]3[O:51][C:50]([CH3:53])([CH3:52])[CH2:49][C:48]=3[CH:54]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[C:45]([OH:55])=[CH:46][C:47]3[O:51][C:50]([CH3:52])([CH3:53])[CH2:49][C:48]=3[CH:54]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (25%): MS (ES+) m/z 490.5 (M+1), 492.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.[CH:19]1[C:32]2[CH:31]([C:33]([Cl:35])=[O:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl>CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:33]([CH:31]2[C:32]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:34])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCOC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 3.8 g of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-hydroxy-propane in 40 ml of acetone is added dropwise at 20° C to a stirred solution of 4.9 g of xanthene-9-carbonyl chloride in 30 ml of acetone. The reaction mixture is refluxed for 30 minutes, allowed to cool to 60° C, and then ethanolic hydrochloric acid is added to the mixture until no more crystalline substance separates. The reaction mixture is cooled to 0° C, the separated crude substance is filtered off, and the crude substance is recrystallized from 20 ml of a 1:2 mixture of water and ethanol. 5.3 g (73%) of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-(xanthene-9-carbonyloxy)-propane hydrochloride are obtained; m.p.: 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([OH:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:17][CH:18]=[CH2:19])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOc1nc(Cl)ncc1OC
Temperature: 70 °C
Yield: 99.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (85 g, 475 mmol), and K2CO3 (78.8 g, 570 mmol) in allyl alcohol (320 mL, 4.75 mol) was heated to 70° C. for 5 h before being cooled to r.t. and diluted with DCM, filtered through Celtic (DCM wash) and concentrated to give 95.0 g (99.7%) of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine. 1H-NMR (CDC3, 300 MHz) δ 7.85 (s, 1H), 6.09-5.99 (m, 1H), 5.43-5.38 (in, 1H), 5.31-5.27 (m, 1H), 4.91 (m, 2H), 3.87 (s, 3H). MS (ESI) m/z (M+H)+ 201.0.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:10][C:11]1[CH:16]=[CH:15][C:14](O)=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-:20].[K+].[K+]>CN(C=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:20][C:16]1[CH:15]=[CH:14][C:13]([Cl:18])=[CH:12][C:11]=1[Br:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br

Procedure:
tert-Butyl bromoacetate (2.6 ml) was added to a stirred mixture of 4-bromo-2-chlorophenol (3 g) and potassium carbonate (6.2 g) in DMF (40 ml) at RT. After 16 h the reaction was partitioned between diethylether and water, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 4% EtOAc/iso-hexane. Yield 4.05 g
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3](=[N:7]O)[C:4](=O)[CH3:5].[CH3:10][CH:11]([CH3:16])[CH2:12][C:13](=O)[CH3:14].[N:17](Cl)=O.N=C=O>[Zn].C(O)(=O)C>[CH3:5][C:4]1[C:3]([CH:2]([CH3:9])[CH3:1])=[N:7][C:13]([CH3:14])=[C:12]([CH:11]([CH3:16])[CH3:10])[N:17]=1
Reactant: CC(=O)C(=NO)C(C)C
Reactant: CC(=O)CC(C)C
Reactant: O=NCl
Agent: N=C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(C(C)C)c(C)nc1C(C)C

Procedure:
d. 2,5-Dimethyl-3,6-diisopropyl-pyrazine was prepared by first forming 4-methyl-3-oximino-2-pentanone by reacting 4-methyl-2-pentanone with nitrosyl chloride according to the method of Bouveault, Bull. [3] 31, 1163 (1904). The autocondensation of two moles of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-Dimethyl-3,6-diisopropyl-pyrazine which had a b.p. of 91°C./8 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[C:17]([OH:19])=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[C:17]([O:19][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1
Reactant: N#Cc1cc2c(cc1O)NC(=O)CN=C2c1ccccc1Cl
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=O)CN=C2c1ccccc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A mixture of 0.322 g (0.00103 mole) of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Iqq), 6 mL of dimethylformamide, 0.132 g (0.00124 mole) of sodium carbonate and 0.2028 g (0.00124 mole) of 4-(3-chloropropyl)-morpholine was stirred 50° C. under an atmosphere of argon for 24 hours. The mixture was then cooled and partitioned between ethyl acetate and water. The aqueous phase was reextracted with ethyl acetate and the ethyl acetate extracts were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with acetonitrile-methanol (90:10), to provide 0.199 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ik). MH+/Z=439.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>O1CCCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:26]([OH:29])[OH:27])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500 mL three-neck flask were stirred 29 g (90 mmol) of 3-bromo-9-phenylcarbazole obtained by the above Step 3 described in Synthesis Example 1 and 200 mL of tetrahydrofuran (abbreviation: THF) at −78° C. to provide a solution. Then, 110 mL (69 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped therein, and the mixture was stirred for 2 hours at the same temperature. Furthermore, 13 mL (140 mmol) of trimethyl borate was added therein, and the mixture was stirred for 24 hours at room temperature. After the reaction, 200 mL of 1.0 mol/L hydrochloric acid was added therein, and the mixture was stirred for 1 hour at room temperature. This mixture was washed with water, aqueous sodium hydroxide, and water in this order, and magnesium sulfate was added so that the moisture was removed. This suspending solution was filtered and the obtained filtrate was concentrated. Then, chloroform and hexane were added therein, ultrasonic waves were applied thereto, and then recrystallization thereof was performed. Accordingly, 21 g of a powdery white solid of 9-phenyl-9H-carbazol-3-boronic acid, which was the object of the synthesis, was obtained in a yield of 80% (synthesis scheme (b-1)).