Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[C:14]([OH:16])=O)[C:5](=[O:7])[CH3:6])([CH3:3])[CH3:2].C[O-].[Na+]>O1CCOCC1>[OH:16][C:14]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:7])[CH:6]=1
Reactant: CC(=O)N(C1=C(C(=O)O)CCCC1)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1c2c(c(O)cc1=O)CCCC2

Procedure:
Cyclisation of a 60:40 mixture of the ethyl and methyl esters of 2-(N-isopropyl-acetamido)cyclohex-1-ene-1-carboxylic acid (14.16 g; 0.057 mole) with sodium methoxide (3.5 g; 0.064 mole) in dry dioxan (100 ml) over 6 hrs. at 100° C gave the title compound and after work-up as in Example 8. It had m.p. (EtOH) 304° - 307° C (d).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:12][C@H:5]2[CH2:6][N:7]([C:9]([NH2:11])=[O:10])[CH2:8][C@@:4]2([C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=3)[CH2:16]2)=[O:14])[CH2:3]1.[CH3:29][O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:29][O:30][C@H:31]1[C@@H:36]([NH:1][C@@H:2]2[CH2:12][C@H:5]3[CH2:6][N:7]([C:9]([NH2:11])=[O:10])[CH2:8][C@@:4]3([C:13]([N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=4)[CH2:16]3)=[O:14])[CH2:3]2)[CH2:35][CH2:34][O:33][CH2:32]1
Reactant: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(C(N)=O)C[C@@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step B (316 mg, 0.62 mmol), 3-methoxydihydro-2H-pyran-4(3H)-one (242 mg, 1.86 mmol), 4 Å molecular sieves (0.3 g) and TEA (0.259 mL, 1.86 mmol) in DCM (8 mL) was stirred at rt for 2 h, followed by addition of sodium triacetoxyborohydride (263 mg, 1.24 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched by the addition of saturated NaHCO3 aqueous solution, extracted with DCM, and dried over Na2SO4. After removal of the solvent, the residue was purified by column chromatography (eluent: EtOAc to 15% 7N NH3 in methanol in EtOAc) to give the product as a white foam. 1H-NMR (400 MHz, CDCl3): δ 1.76 (br. s., 1H), 1.89-2.41 (m, 4H), 2.53 (br. s., 1H), 2.85-2.99 (m, 2H), 3.06-4.02 (m, 18H), 4.12 (q, J=7.1 Hz, 1H), 4.69 (br. s., 2H), 5.17-5.31 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.34-7.49 (m, 2H); LC/MS: C25H33F3N4O4: m/z 511.0 (M+H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#N.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2nnc(N)s2)c1
Temperature: 0 °C

Procedure:
Thiosemicarbazide (455.69 mg; 5.00 mmol; 1.00 eq.) and 3-aminobenzonitrile (590.69 mg; 5.00 mmol; 1.00 eq.) are heated in TFA (2.50 ml) at 60° C. for 4 h00. The mixture become a thick yellowish solution. The reaction mixture is poured into ice-water (15 mL) and neutralized with saturated NaHCO3 aqueous solution. The resulting precipitate is filtered, affording 5-(3-aminophenyl)-1,3,4-thiadiazol-2-amine as white-off solid (291.00 mg; 30.27%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[CH3:27][CH2:28][N:29](C(C)C)C(C)C.C(N)C>S(Cl)(Cl)=O.C1COCC1.C(OCC)(=O)C>[CH2:28]([NH:29][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:16][N:15]=[CH:14]3)[CH:4]=1)[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (100 mg, 286 μmol) was dissolved in thionyl chloride (5.7 mL) and heated to 65° C. for 1 h before being concentrated in vacuo. The concentrate was dissolved in THF (5.7 mL), and DIPEA (150 μL, 859 μmol) and ethylamine—2 M in THF (0.71 mL) were added at 0° C. The reaction mixture was warmed to RT and stirred for 3 h, then diluted with 50 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give a crude residue, which was purified by chromatography to afford the title compound. MS (ES+): 377(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CO.[OH-].[Na+].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)Cc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Temperature: 25 °C

Procedure:
To a flask charged with methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 5 mmol) was added MeOH (1.5 mL), H2O (0.5 mL), followed by NaOH (2 mL, 6 M, 12 mmol) to generate a yellow solution, which was capped and maintained at rt for 18 h. The solution was acidified with conc. HCl to pH=3 and poured into CH2Cl2. The layers were separated and the organic layer was extracted with CH2Cl2 (2×10 mL), followed by EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to produce a colorless solid, which was of sufficient purity for use in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:8]1([O:13][CH2:14][C:15](Cl)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:13][CH2:14][C:15]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCOCC1
Reactant: O=C(Cl)COC1CCCC1
Product: O=C1CCOCC1C(=O)COC1CCCC1
Yield: 37.5 %

Procedure:
3-(2-(cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)-one (280 mg, 21.5%) was synthesised from dihydro-2H-pyran-4(3H)-one (0.462 ml, 5.00 mmol) and (2-(cyclopentyloxy)acetyl chloride (3.3 mmol) by the general procedure for the preparation of diketones.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([C:18]2[CH2:19][CH2:20]S[CH2:22][CH:23]=2)=[CH:4][N:3]=1.OO[S:26]([O-:28])=O.[K+]>CC(C)=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([C:18]2[CH2:19][CH2:20][S:26](=[O:28])[CH2:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: O=S([O-])OO
Reactant: Nc1ncc(C2=CCSCC2)cc1-c1ccc(C(=O)[O-])c(F)c1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CCS(=O)CC3)cnc2N)cc1F
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A 0° C. solution of 4-(2-amino-5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate in acetone (20 mL) was treated with a solution of oxone (227 mg, 0.369 mmol) in water (5 mL). After 20 min, the reaction was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (50 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered and concentrated to provide tert-butyl 4-(2-amino-5-(1-oxido-3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate (220 mg, 74% yield). LCMS (m/z): 403.5 (MH+), 0.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[OH-].[K+].CCOCC>[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:6]=[C:5]2[CH3:11]
Reactant: Fc1ccc(Br)cc1
Reactant: Cc1c[nH]c2ccc(Br)cc12
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cn(-c2ccc(F)cc2)c2ccc(Br)cc12
Yield: 12.3 %

Procedure:
To 4.2 g (20 mmol) 5-Bromo-3-methyl-1H-indole [prepared according to Noland, Wayland E.; Reich, Charles. Synthesis and reactions of 5-bromoskatole and 5-bromo-1,3-dimethylindole. J. Org. Chem. (1967), 32(3), 828-32.] in 22 ml (0.2 mol) 1-bromo-4-fluorobenzene were added 5.6 g (0.1 mol) powdered potassium hydroxide and 1.14 g (60 mmol) CuI as powder. The suspension was heated to reflux for 0.5 h. At RT, ether and water were added, the phases were separated and the aqueous phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with hexane yielded 750 mg 5-Bromo-1-(4-fluoro-phenyl)-3-methyl-1H-indole as colorless solid, mp 97-98° C., MS: 303(M, 1Br).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:8])[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(=O)[nH]cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Fluorocytosine (500 mg) and potassium carbonate (803 mg) were suspended in N,N-dimethylfoiliamide (5 mL) and ethyl bromoacetate (430 μl) was added to the suspension. The mixture was stirred at 100° C. overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=99:1 to 92:9) to give 329 mg (39% yield) of the desired product as a white amorphous.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: Cc1c(F)c(F)cc(C(=O)Cl)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.7 %

Procedure:
To a mixture of magnesium turnings (0.69 g) and absolute ethanol (4.7 ml) was added carbon tetrachloride (0.4 ml). To the stirring suspension was added a solution of diethyl malonate (4.41 g) and absolute ethanol (4.7 ml) in anhydrous toluene (19.2 ml) dropwise during 10 minutes at 15° to 50° C. After the mixture was stirred at 50° to 60° C. for 2 hours, to the mixture was added a solution of 2,4,5-trifluoro-3-methylbenzoyl chloride (4.51 g) in anhydrous toluene (6.4 ml) dropwise at -16° to -13° C. during 10 minutes. The reacting mixture was stirred at -20° C. for 1 hour, and then warmed gradually to room temperature during 1.5 hours with stirring. To this solution was added ice water (25 ml) containing concentrated sulfuric acid (0.8 ml), extracted with toluene. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride and concentrated under reduced pressure to give the title compound (8.10 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[O:6].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)C(CCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:18]
Reactant: Cc1cccnc1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1CCl

Procedure:
A solution of 24 g (0.17 mol) of 2-chloromethyl-3-methylpyridine in 200 ml of methylene chloride ls treated while cooling with ice with a solution of 44 g (0.25 mol) of m-chloroperbenzoic acid in 200 ml of methylene chloride. The reaction mixture is heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2-chloromethyl-3-methyl-pyridine 1-oxide obtained is processed directly.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[C:13]([NH:15][C:16]1[C:17]([CH3:32])=[N:18][C:19]([O:22][CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=1)=[O:14])=[O:10])([CH3:7])[CH:3]=[N:4][O:5][CH3:6].BrN1C(=O)CCC1=O.[I:45]N1C(=O)CCC1=O>>[CH3:7][C:2]([NH:8][C:9]([C:11]1[C:36]([I:45])=[CH:35][CH:34]=[CH:33][C:12]=1[C:13]([NH:15][C:16]1[C:17]([CH3:32])=[N:18][C:19]([O:22][CH:23]([C:28]([F:31])([F:29])[F:30])[C:24]([F:26])([F:27])[F:25])=[CH:20][CH:21]=1)=[O:14])=[O:10])([CH3:1])[CH:3]=[N:4][O:5][CH3:6]
Reactant: O=C1CCC(=O)N1I
Reactant: CON=CC(C)(C)NC(=O)c1ccccc1C(=O)Nc1ccc(OC(C(F)(F)F)C(F)(F)F)nc1C
Agent: O=C1CCC(=O)N1Br
Product: CON=CC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(OC(C(F)(F)F)C(F)(F)F)nc1C
Yield: 83 %

Procedure:
2-(1,1-Dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-N-(6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-2-methylpyridin-3-yl)benzamide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-iodosuccinimide, to obtain 2-(1,1-dimethyl-2-(N-methoxyimino)ethylaminocarbonyl)-N-(6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-2-methylpyridin-3-yl)-3-iodobenzamide (yield 83%, melting point 220° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:20]=3[N:16]2[CH2:15][CH:14]([OH:30])[CH2:13][CH2:12]1.CI.[C:33](OCC)(=O)C>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:17]2=[N:18][C:19]3[C:20](=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[N:16]2[CH2:15][CH:14]([O:30][CH3:33])[CH2:13][CH2:12]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(O)CCN3c1ccc(Cl)cc1Cl
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCN(CC)c1cccc2nc3n(c12)CC(OC)CCN3c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60%, 5.7 mg, 0.14 mmol) in tetrahydrofuran (1 mL) was added a solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-4-ol (40.0 mg, 0.0954 mmol) in tetrahydrofuran (1 mL) at 0° C. After 30 min, methyl iodide (0.0178 mL, 0.286 mmol) was added to the reaction mixture at 0° C. and the resultant mixture was stirred at 40° C. for 2 hr. Ethyl acetate was added and the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (39.5 mg, 0.0911 mmol, 95%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:12]=3O[C:10](=O)[C:9]=2[C:23]#[N:24])[CH2:4][CH2:3]1.[H-].[Na+]>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH2:16][CH2:15][C:14]4[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[C:21]3[C:13]4[C:14]([CH2:18][C:10]=3[C:9]=2[C:23]#[N:24])=[CH:15][CH:16]=[CH:17][CH:12]=4)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2c3c(oc(=O)c2C#N)-c2ccccc2CC3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CCN(c2c(C#N)c3c(c4c2CCc2ccccc2-4)-c2ccccc2C3)CC1

Procedure:
A mixture of 4-(4-methylpiperidin-1-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile (320 mg), indanone-2 (132 mg) and NaH (36 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 152-154° C.; IR (KBr) 2212 cm−1 (CN); MS (ESI) 391 (M+11).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[N:23](S(C)(=O)=O)[CH2:24][N:25]=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4].[CH3:32][C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:40][C@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:32])[N:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4]
Reactant: C[C@H](N)c1ccccc1
Reactant: COC(=O)C1CCCn2c(C3=CC=NCN3S(C)(=O)=O)c(-c3ccc(F)cc3)c(=O)n21
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCn2c(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Temperature: 100 °C
Yield: 66 %

Procedure:
To a solution of 2-(4fluorophenyl)-1-(3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6, 7, 8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 21, (0.10 g, 0.22 mmol) in toluene (1.4 mL) is added (S)-(−)-α-methylbenzylamine (1.4 mL, 1.12 mmol). The reaction solution is heated to 100° C. for 4 hours after which the reaction is cooled and diluted with 1 N HCl. The resulting solution is extracted with ethyl acetate (3×25 mL), the organic layers are combined, dried, and concentrated in vacuo to afford 0.071 g (66% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.22 (ddd, J=11.4, 5.1, 2.1 Hz, 1 H), 7.22-7.37 (m, 7 H), 6.97 (dt, J=8.7, 2.1 Hz, 2 H), 6.41 (ddd, J=15.6, 5.1, 2.1 Hz, 1H), 5.72-5.83 (m, 1 H), 5.2 (br s, 2 H), 5.52-5.62 (m, 1 H), 3.77 (s, 3 H), 3.47 (d, J=2.7 Hz, 1 H), 2.47-2.51 (m, 2 H), 200 (br s, 1 H), 1.41 (d, J=6.6 Hz, 3 H); APCI/MS: 487 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].[OH-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:41])=[O:40]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2cc(Cl)ccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 177.6 %

Procedure:
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.050 g of triethylamine and 0.083 g of 2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromethane is stirred at room temperature for 1 hour and then 4 mg of 4-(N,N-dimethylamino)pyridine is added. After another hour, 93 mg of 2,5-dichlorobenzenesulfonyl chloride is added along with 50 mg of triethylamine. The mixture is stirred at room temperature for 2 days and 1 N NaOH added. The mixture is extracted with ethyl acetate and the extract washed with 50% ammonium chloride solution, brine and dried (Na2SO4). The solvent is removed to give 0.30 g of solid. Trituration with ether-hexane gives 0.26 g of solid. This solid is dissolved in a mixture of 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of 1 N NaOH and the mixture stirred for 18 hours at room temperature. The organic solvents are removed and the mixture extracted with ether acetate. The extract is washed with NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue (0.16 g) triturated with ether to give 0.14 g of yellow solid.