Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.O[C:7]1([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8]1.[OH-:18].[Na+].[C:20](#[N:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([NH:27][C:7]1([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8]1)(=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(C)C1(O)CCC1
Reactant: N#Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)C1(NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
H2SO4 (3.90 mL, 73.2 mmol) was slowly added to a mixture of ethyl 2-(1-hydroxycyclobutyl)propionate (12.5 g, 72.6 mmol) and benzonitrile (75 mL) at room temperature. The mixture was stirred for 1 hour at room temperature, then 80° C. for 1 hour. The mixture was cooled in an ice-water bath and 2N NaOH solution was added until the mixture reached pH=7. The mixture was extracted with ethyl acetate, the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a pale yellow solid (9.24 g, 46%). 1H-NMR (400 MHz, CDCl3) δ 1.25 (3H, t, J=7.3 Hz), 1.30 (3H, d, J=7.3 Hz), 1.73-1.87 (1H, m), 1.98-2.09 (2H, m), 2.21-2.32 (1H, m), 2.53-2.63 (1H, m), 2.84-2.94 (1H, m), 3.11 (1H, q, J=7.3 Hz), 4.08-4.20 (2H, m), 6.88 (1H, brs), 7.40-7.52 (3H, m), 7.75-7.80 (2H, m).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH2:28][CH3:29]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CO>[CH2:28]([C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9])[CH3:29]
Reactant: CCc1c(N)cc(C)c2nc[nH]c12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(N=C=S)cc(C)c2nc[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of di-2-pyridyl thionocarbonate (0.72 g, 3.11 mmol) and 4-dimethylaminopyridine (0.02 g) in ethyl acetate (50 mL) is added dropwise a solution of 5-amino-4-ethyl-7-methylbenzimidazole (0.42 g, 2.39 mmol) in ethyl acetate (20 mL) and methanol (5 mL). The mixture is stirred at room temperature for 3 hours, then rotary evaporated. The residue is purified by filtration on a short pad of silica gel, eluting with ethyl acetate, to afford 4-ethyl-5-isothiocyanato-7-methylbenzimidazole as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=S)[NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=S)Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A stirred slurry of 8 g (0.04 mole) of 4-(3-chlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 6.8 g (0.04 mole) of ethyl 2-chloroacetoacetate. The reactants quickly dissolved but a precipitate soon formed. After stirring at room temperature for 2 hr the reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr, then filtered while hot to remove the insoluble sulfur. The filtrate on cooling yielded 3.5 g of yellow solid and an additional 4.7 g was obtained when the filtrate was concentrated in vacuo. Recrystallization from benzene/ligroin gave 4.2 g of pale yellow brown product. Additional ligroin added to the filtrate gave, upon cooling at ~7°-10° C. for ~16 hr, additional crystals but also some oil; this tri-phase mixture was filtered to yield 1.5 g of additional product. Both solids had identical spectra. They were combined and recrystallized twice from benzene/ligroin and finally from benzene by dissolving the solids and reducing the volume until crystallization began. Upon cooling, 3.93 g of beige plate-like crystals were collected, mp 159.5°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(O)C1CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and cyclopropyl carboxylic acid; MS: m/e=374.4 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH3:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:23]([OH:27])[OH:24])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: Cc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 125 mL round-bottomed flask equipped with N2 inlet were added 1.78 g (11.4 mmol) 1-bromo-4-methylnaphthalene and 20 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 5.49 mL (13.7 mmol) of a 2.5M solution of n-butyl lithium in hexane was added over 5 minutes, and the reaction stirred at −70° C. for 10 minutes. The solution was then treated with 2.34 mL (13.7 mmol) triethyl borate, stirred 5 minutes at −70° C., then warmed to room temperature and stirred 40 hours. The reaction was quenched with aqueous ammonium chloride solution, poured into 0.5 N hydrochloric acid, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to a white solid after trituration with hexane, mp 224-228° C., 1.9 g (90%).
Reaction SMILES: [H-].[Na+:2].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4].[CH:9](OCC)=[O:10]>C(OC(C)C)(C)C>[CH2:7]([O:6][C:3]([CH:4]=[CH:9][O-:10])=[O:5])[CH3:8].[Na+:2]
Reactant: CCOC(C)=O
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C=C[O-]
Temperature: 45 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil) (269 g, 16.7 mol) in isopropyl ether (12 L) was slowly added ethyl acetate (1280 g, 14.2 mol) at such a rate as to maintain an internal temperature of 45° C. Ethyl formate (2232 g, 30.13 mol) then added dropwise at 42° C. and stirred at ambient temperature for 18 h. The mixture was filtered and washed with ethyl ether (2×300 mL), with hexanes (500 mL) and the solid was dried to give sodium 2-ethoxycarbonyl ethenolate as a white solid (1930 g, 99%); 1H NMR (DMSO-d6, 300 MHz) δ1.03 (t.3H), 3.86 (q, 2H), 4.08(d, 1H), 8.03 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[H-].[Na+]>CN(C)C=O.Cl.O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.33 g) and 4-tertbutylbenzenesulfonamide (1.96 g) in dimethylformamide (20 ml) is added sodium hydride (60% dispersion-type, 714 mg). The mixture is stirred at room temperature for two hours, and the reaction solution is diluted with 10% hydrochloric acid and water. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate to give 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (2.02 g).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][CH2:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]3=[O:54])=[CH:44][CH:43]=2)[CH:41]=1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:35][CH2:36][C:37]2[N:38]=[CH:39][N:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]4=[O:54])=[CH:46][CH:47]=3)[CH:41]=2)=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)O)s1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NCc2cn(-c3ccc(-n4ccccc4=O)cc3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-ethynyl-thiophene-2-carboxylic acid (83 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (4 mL), HATU (228 mg, 0.60 mmol) was added. After being stirred at room temperature for 30 min, a solution of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (145 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature overnight. It was then purified by HPLC to give the title compound (65 mg). MS 401 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH2:16]>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1.[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][OH:16].[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: N[C@@H](CO)C(=O)O
Product: c1ccc2[nH]ccc2c1

Procedure:
Active carbon and water were added to a reacton fluid containing L-tryptophan obtained by condensing indole with L-serine in an aqueous medium in the presence of tryptophan synthase as an enzyme prepared by culturing Escherichia coli, followed by making the pH of the mixture 4 with sulfuric acid, heating at 95°~100° C. for one hour to convert the fungus body into flocs, and thereafter removing the fungus body adsorbed onto the active carbon, as it was, by filtration. The aqueous solution (2,580 g; the total mol equivalent of amino acids and cations, 1.9) obtained by the above pretreatment and containing L-tryptophan (3.8%, 0.19 M), indole (0.1%), L-serine (0.2%, 0.02 M), ammonium ion (0.8%, 0.44 M) and sodium ion (0.2%, 0.09 M) was passed through a column filled with 1 liter of Lewatit SP-112 (tradename of product manufactured by Bayer Company; exchange capacity, 1.9 mol/l) subjected to conditioning regeneration, from the upper part of the column, at a SV of 5. The flowing down fluid after completion of the passage was subjected to to detection of L-tryptophan according to a high speed liquid chromatography. It was not detected.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: BrCCCOc1ccc(I)cc1
Reactant: Oc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-bromopropoxy)-4-iodobenzene (277 mg) in dimethylformamide (3 ml), 115 mg of phenol and 49 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH2:48][C:49]1[CH:55]=CC(N)=[CH:51][CH:50]=1)[CH3:47].N[C:57]1C=CC=C[CH:58]=1>>[CH:6]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:51]=[CH:50][C:49]([CH2:48][N:46]([CH3:47])[CH3:45])=[CH:55][CH:30]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:8]([CH2:57][CH2:58]1)[CH2:9][O:12][CH2:5]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: Nc1ccccc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(CN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-((dimethylamino)methyl)aniline as the aniline component. (23%, MS=527.2 (M+H))
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:27]([NH2:29])=[NH:28])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>CO.O>[NH:26]([O:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][C:4]([OH:30])=[O:3])[CH:14]=[CH:15]2)[C:27]([NH2:29])=[NH:28]
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC(=N)N)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NOCCOc1ccc2c(ccn2C(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
3-(5-{2-[guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid ethyl ester (0.30 gg, 0.71 mmol) was dissolved in 70% methanol/water (4 mL) and lithium hydroxide monohydratate (0.70 g, 4.67 mmol) was added. The reaction was stirred for 16 h at room temperature under an argon atmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) and the solvent was evaporated under vacuum. The crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (80% yield). 1H NMR (CD3OD-d4) δ 7.34 (d, 1H, J=3.2 Hz), 7.06-7.15 (m, 6H), 6.97 (d, 1H, J=2.3 Hz), 6.65 (dd, 1H, J=2.5, 9.0 Hz), 6.31 (d, 1H, J=3.2 Hz), 5.93 (t, 1H, J=7.0 Hz), 4.01 (m, 4H), 3.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][N:3]=1.S(C)C.C1COCC1>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][NH:8][C:9]=2[CH:10]=1
Reactant: Clc1cc2[nH]ccc2cn1
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: Clc1cc2c(cn1)CCN2
Temperature: 25 °C
Yield: 41.1 %

Procedure:
Under nitrogen, 6-chloro-5-aza indole (500 mg, 3.29 mmol) was dissolved in 2.0 M BH3.SMe2 in THF (6.6 mL, 13.16 mmol) and heated gently to 68° C. for 2 h. After cooling to ambient temperature, MeOH (6.0 mL) was added slowly over 20 min. Once bubbling had stopped, the reaction was heated to 68° C. for 30 min, then cooled to ambient temperature and concentrated in vacuo. Chromatography on silica gel (gradient elution, 0-60% EtOAc/petrol), gave the title compound (209 mg, 41%) as colourless oil. 1H NMR (CDCl3): 7.86 (1H, s), 6.43 (1H, s), 4.33 (1H, s), 3.80-3.65 (2H, m), 3.05 (2H, t).
Reaction SMILES: [NH2-].[Na+].[CH3:3][CH:4]([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:9][O:10][CH:11]([CH3:16])[C:12](OC)=[O:13].O>C(O)(=O)C>[CH3:9][O:10][CH:11]([C:12](=[O:13])[CH2:6][C:5](=[O:7])[CH:4]([CH3:8])[CH3:3])[CH3:16]
Reactant: COC(=O)C(C)OC
Reactant: CC(=O)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(C)C(=O)CC(=O)C(C)C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 5.15 g (132 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 12.0 g (139.3-mmol) of 3-methyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 5.65 g (47.8 mmol) of methyl 2-methoxy-propionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (41° C., 27 Pa) to give 4.25 g (yield: 52%) of 2-methoxy-6-methyl-3,5-heptanedione as colorless liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[H][H].Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:14][N:13]=1>CN(C)C=O.CCCCCC>[CH3:3][C:4]1[CH:8]=[CH:7][N:6]([C:12]2[N:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH2:28][N:27]4[CH:35]=[CH:36][CH:37]=[C:26]4[CH2:25]3)=[O:23])=[CH:14][N:13]=2)[N:5]=1
Reactant: [H][H]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccn(-c2ncc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)n2)n1
Temperature: 110 °C
Yield: 49.4 %

Procedure:
To 60% sodium hydride in oil (0.15 g, degreased with hexane) in dimethylformamide (25 ml) was added 3-methylpyrazole (0.25 g). When the hydrogen evolution subsided, (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g) was added. The reaction mixture was heated for 18 hours in a sand bath (internal temperature 110° C.). The mixture was then poured onto ice and further diluted with a saturated saline solution. The precipitate was filtered, redissolved in dichloromethane and dried over anhydrous sodium sulfate. Purification was aided by filtration through a short column of hydrous sodium magnesium silicate and further elution with several volumes of dichloromethane. The combined eluate was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the solid was collected by filtration to yield the title compound (0.54 g) as colorless crystals, m.p. 202-204° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C:16](=[O:17])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:54][Mg+].[Br-]>C1COCC1>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C@:16]([OH:17])([CH3:54])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:35])([CH3:34])[CH3:36])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@]1(NC(=O)N(C)C)[C@@H](NC(=O)OCc2ccccc2)[C@H]2O[C@@]2(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@]1(C)O
Temperature: 0 °C

Procedure:
A flame-dried 25-mL round-bottomed flask was charged with ketone 12 (1.7 g, 2.3 mmol, 1.0 equiv) and THF (23 mL). The solution was cooled to 0° C. and MeMgBr (3M in THF, 7.6 mL, 22.9 mmol, 10.0 equiv) was added dropwise. The reaction was stirred at 0° C. until TLC analysis indicated complete ketone consumption, typically 2 h. Saturated NH4Cl(aq.) (20 mL) was carefully added dropwise and the resulting mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (90:10 to 70:30 hexanes:EtOAc) to afford carbinol 13 as a clear, viscous oil with >10:1 diastereoselection (1.3 g, 75%). The enantiomeric ratio was assayed at this intermediate and was found to be 95:5. This composition was determined by SFC analysis (Chiralcel, OD, 4.0% MeOH, 1.5 mL/min, 150 bar, 210 urn; tR-minor 34.4 min, tR-major 37.6 min). Analytical data: [α]D19 +7.2 (c=0.70, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.2 Hz, 2H), 7.45-7.30 (m, 12H), 5.55 (br s, 1H), 5.21 (d, J=12.6 Hz, 1H), 5.17 (br s, 1H), 5.07 (d, J=12.0 Hz, 1H), 4.77 (br s, 1H), 4.64 (dd, J=8.4, 3.6 Hz, 1H), 4.21 (d, J=12.6 Hz, 1H), 4.12 (d, J=12.6 Hz, 1H), 3.90 (s, 1H), 2.75 (s, 6H), 1.30 (s, 3H), 1.25 (d, J=6.0 Hz, 3H), 1.07 (s, 9H), 0.97 (s, 9H), 0.11 (s, 3H), −0.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 158.8, 156.5, 136.3, 135.6, 135.5, 134.7, 133.3, 132.9, 129.6, 129.4, 128.4, 128.2, 128.1, 127.7, 127.6, 127.6, 67.1, 66.8, 62.1, 58.3, 36.1, 26.7, 26.5, 25.7, 23.8, 19.6, 19.2, 17.8, −4.2, −5.5; LRMS (ESI+) Calcd. for C42H61N3O7Si2+H, 776.41. Found, 776.36. IR (thin film, cm−1) 3430, 2429, 2359, 1716, 1635, 1506, 1456, 1112, 831, 700; TLC (90:10 hexanes/EtOAc): Rf=0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N:19][CH:20]=2)[N:15]=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][C:24]1[C:23]2[C:14]([NH:13][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:5][C:4]=3[Cl:12])=[N:15][C:16]3[C:21]([C:22]=2[C:27](=[O:28])[NH:26][CH:25]=1)=[CH:20][N:19]=[CH:18][CH:17]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Solvent: CN(C)C=O
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]cc(Br)c23)c(Cl)c1
Reaction time: 1.5 h

Procedure:
To a solution of 6-{[2,6-dichloro-4-(1-hydroxy-1-methylethyl)phenyl]amino}pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 146, Step 1) (86, 0.21 mmol) in DMF (4 mL) at 0° C. was added NBS (44 mg, 0.25 mmol) and the reaction mixture was stirred for 1.5 hr. The solution was quenched with 10% sodium thiosulfate and saturated NaHCO3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (100% CH2Cl2 to 65% CH2Cl2/35% MeOH) afforded the desired product.