Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(C2C=CC=CC=2)=CC(N)=CC=1C1C=CC=CC=1.CC1C=C(C)C=C(C)C=1N=C(C1C=CC=C(C(=O)C)N=1)C.[CH3:42][C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[C:44]=1[N:51]=[C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([C:60](=[N:62][C:63]2[CH:68]=[C:67]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:66]([O:75]CCC)=[C:65]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[CH:64]=2)[CH3:61])[N:55]=1)[CH3:53]>C1(C)C=CC=CC=1>[CH3:42][C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[C:44]=1[N:51]=[C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([C:60](=[N:62][C:63]2[CH:68]=[C:67]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:66]([OH:75])=[C:65]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[CH:64]=2)[CH3:61])[N:55]=1)[CH3:53]
Reactant: CCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1-c1ccccc1
Agent: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Agent: Nc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
The title compound was prepared by condensation of 4-hydroxy-3,5-diphenylaniline with 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine, prepared according to the method disclosed in WO02/28805, in toluene, using 4 Å molecular sieves, similarly to the above-described preparation of 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-[1-(4-propoxy-3,5-diphenylphenylimino)ethyl]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[S:56]1[C:60]2[CH:61]=[CH:62][C:63]([NH2:65])=[CH:64][C:59]=2[N:58]=[CH:57]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClC(Cl)C>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:21]([NH:65][C:63]4[CH:62]=[CH:61][C:60]5[S:56][CH:57]=[N:58][C:59]=5[CH:64]=4)=[N:20][CH:19]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH3:24])[CH:17]=3)[N:10]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc2scnc2c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCNCC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (3.65 g, 5.55 mmol) and trifluoroacetic acid (6.41 mL, 83 mmol) in dichloroethane (30 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was added to a round bottom flask and concentrated in vacuo. The crude residue was diluted with THF (10 mL), then benzo[d]thiazol-5-amine (0.539 g, 3.59 mmol) was added to the reaction mixture with stirring. The mixture was chilled to 0° C. in an ice bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 5.74 mL, 5.74 mmol) was added slowly via syringe into the mixture. After the addition, the ice bath was removed and the mixture allowed to stir under inert atmosphere for 1 h. The reaction mixture was diluted with sat. sodium bicarbonate (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with a 20% mixture of 10:1 methanol and ammonium hydroxide/dichloromethane to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.651 g, 0.946 mmol, 66.0% yield) as a tan oil. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H) 8.96 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 8.12 (d, J=1.76 Hz, 1H) 7.78 (td, J=8.12, 2.35 Hz, 1H) 7.60 (dd, J=8.61, 1.96 Hz, 1H) 7.14-7.28 (m, 4H) 6.80-6.91 (m, 4H) 4.76-4.91 (m, 4H) 3.72-3.82 (m, 6H) 3.37-3.51 (m, 1H) 2.86 (dt, J=12.67, 4.72 Hz, 4H) 2.40-2.55 (m, 4H) 2.62 (s, 3H) 2.32-2.40 (m, 1H). m/z (ESI, +ve ion) 688.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccnc2)c1C

Procedure:
3-Aminopyridine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents were removed under vacuum. The named product was purified over silica gel and analyzed by 1H-NMR (CDCl3, ppm): 1.35 t (3H), 2.40 s (3H), 4.3 q (2H), 6.78 s (1H), 7.03-7.39 m (7H), 8.4 sd (1H), and about 8.6 dd (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:13][Mg+].[Br-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:12])[CH3:13])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C[Mg+]
Reactant: O=Cc1cc(Cl)cc2c1OCO2
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(Cl)cc2c1OCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chlorobenzo[d][1,3]dioxole-4-carbaldehyde (147.0 mg, 0.79 mmol) was dissolved in 6 mL of diethyl ether and cooled to 0° C. MeMgBr (0.60 mL, 1.99 mmol) was added to the solution and the ice bath was removed. The reaction was allowed to stir at rt for 10 min and at reflux for 30 min. The reaction was cooled to 0° C. and 10 mL of sat NH4Cl were added to quench the reaction. The diethyl ether layer was separated and washed with water (10 mL×2). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to collect the desired product (155.0 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 6.90 (d, 1H), 6.75 (d, 1H), 6.01 (d, 2H), 4.96 (m, 1H), 1.50 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1CCC=CC1.C(O)C.Cl>[Pd].O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1CC=CCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2 was charged 4-tert-butyl-2,6-dinitroanisole (620 g, 2.439 mol), IMS (4774 mL) and 10% Pd/C (31.8 g). The reaction mixture was heated to reflux (78° C.) and 4-methyl-1-cyclohexene (500 mL, 4.159 mol) was added dropwise over 4.5 h. The reaction was stirred at reflux overnight, whereupon HPLC analysis indicated 72.13% product and 27.17% starting material. Further 4-methyl-1-cyclohexene (160 mL, 1.331 mol) was added dropwise over 3 h and the reaction was stirred at reflux for 72 h. HPLC analysis indicated 92.72% product and 0% starting material. The reaction was cooled to room temperature and the catalyst was removed via vacuum filtration and washed with IMS (500 mL). The solvents were concentrated to ca. 1200 mL to give a ratio of 1:4.45 product:ethanol (target 1:5). 2 M HCl (124 mL) was charged dropwise to the remainder while maintaining the temperature below 23° C. Water (3100 mL) was charged and the resulting suspension was stirred at room temperature for 1.5 h. The solid was collected via vacuum filtration and washed with water (2×1000 mL). The resulting orange needles were dried, under vacuum, at 40° C. overnight. Yield=475.2 g (86.9%). Purity >97% by 1H NMR. HPLC purity 98.8%. KF 0.36%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH:29]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH3:34]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-Bromopyridine-2-carbaldehyde (502 mg, 2.70 mmol) was added to a solution of ethyl (triphenyl-λ5-phosphanylidene)acetate (1570 mg, 4.51 mmol) in DMF (5.00 mL) and the reaction mixture was stirred at room temperature for 40 minutes. The mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. A mixture of hexane:ethyl acetate (2:1) was added to the crude residue and the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (4% ethyl acetate in hexanes) to afford ethyl-3-(5-bromopyridin-2-yl)prop-2-enoate MS APCI calc'd for C10H11BrNO2 [M+H]+ 256 and 258. found 256 and 258.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][NH2:18].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][N:18]=[C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 288 h
Yield: 90 %

Procedure:
A solution of 52.5 g of titanium tetrachloride in 300 ml of anhydrous benzene is added slowly, under nitrogen, to a stirred, cooled (ice-bath) mixture of 100 g of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, 103 g of methylamine and 1200 ml of anhydrous benzene. After stirring at room temperature for 12 days the mixture is cooled, treated with concentrated aqueous sodium bicarbonate solution and filtered through Celite. The layers of the filtrate are separated, and the benzene layer is dried with magnesium sulfate. Removal of the solvent and crystallization of the residue from 200 ml of hexane gives 95.6 g (88% yield) of N-methyl-10,11-dihydro5H-dibenzo[a,d]cyclohepten-5-imine, mp 89°-90°. An analytical sample (hexane) also had mp 89°-90°. Nmr spectrum (in CDCl3): multiplets at τ 2.3-3.2 (8H) and 6.8-7.2 (4H) and singlet at 6.7 (3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:23])[C:20](=[O:21])[CH2:19][C:18](=[O:22])[CH2:17][O:16]1.C(N(CC)CC)C.CC(C)(O)C#N>[Cl-]>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:19]1[C:18](=[O:22])[CH2:17][O:16][C:15]([CH3:23])([CH3:14])[C:20]1=[O:21])=[O:7])([O-:3])=[O:2]
Reactant: CC1(C)OCC(=O)CC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC1(C)OCC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and 2,2-dimethyl-2H-pyran-3,5-(4H,6H)-dione (1.4 g, 10 mmol) were dissolved in 150 milliliters (ml) chloride. Triethylamine (3 ml, 22 mmol) was added and the resulting solution stirred at room temperature for fifteen minutes. The solution was washed with dilute hydrochloric acid, 5% potassium carbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was dissolved in 10 ml acetonitrile. Triethylamine (3 ml, 22 mmol) and acetone cyanohydrin (0.2 g) were added and the mixture stirred at room temperature for 2 hours. After dilution with ether, the solution was washed with dilute hydrochloric acid and extracted with 5% potassium carbonate. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum, yielding 1.4 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CCCCC1n1ccc(Cl)c(C#N)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCC1n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 86.1 %

Procedure:
To a solution of 4-chloro-1-(2-methylcyclohexyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (1.14 g) in N,N-dimethylformamide (9.0 mL) was added N-bromosuccinimide (993 mg) at room temperature. The reaction mixture was heated at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.29 g).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]([S:11][CH3:12])=[NH:10])=[O:7])[CH:5]=[CH:4]N=[CH:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21]C(CN)=[CH:17][CH:16]=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:4]([CH2:5][N:1]2[CH:2]=[N:10][C:9]([S:11][CH3:12])=[N:8][C:6]2=[O:7])=[CH:17][CH:16]=1
Reactant: CSC(=N)NC(=O)n1ccnc1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(SC)nc2=O)cc1
Yield: 53.9 %

Procedure:
A tetrahydrofuran solution (5.0 mL) of methyl 1H-imidazole-1-carbonylcarbamimidothioate (921 mg, 5.00 mmol) synthesized in Reference Synthesis Example 289 was refluxed and a tetrahydrofuran solution (5.0 mL) of 4-methoxybenzylamine (343 mg, 2.50 mmol) was added dropwise to the refluxed solution, followed by refluxing the resultant mixture for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a compound. The obtained compound was used to obtain the title compound (355 mg, two step yield 48%) by synthesis in a similar manner to Reference Synthesis Example 291.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([O:30]C)=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1.COC1C=CC2C=C(C)SC=2C=1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Agent: COc1ccc2cc(C)sc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a solution of methyl 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 1:1b (258 mg, 0.535 mmole) in a mixture of THF/MeOH/H2O (3:2:1, 6 ml) was added LiOH.H2O (224 mg, 5.35 mmole). The reaction was stirred 24 hours at ambient temperature. The mixture was diluted with H2O (10 ml) and acidified to pH 1 with 1 M HCl. The precipitate was collected by vacuum filtration, rinsed with MeOH, and dried at 50° C. under vacuum to afford 116 mg (45%) of a pale brown solid. 1H NMR (DMSO-d6) δ8.58 (1H, d, J=5.4 Hz), 8.44 (1H, d, J=8.9 Hz), 8.07 (1H, s), 8.00 (1H, d, J=24 Hz), 7.39 (1H, dd, J=2.4, 8.9 Hz), 6.78 (1H, d, J=5.4 Hz), 4.10-3.81 (3H, m), 3.69-3.54 (4H. m), 3.27, 3.24 (3H, s), 2.81 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29](Br)=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]2=[O:15])=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Oc1ncccc1OCc1ccccc1
Product: Cc1nc(-n2cccc(OCc3ccccc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 7 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3-(benzyloxy)pyridin-2-ol in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 7% yield: mp 198-201° C.; 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J=6.0, 3.0 Hz, 1H), 7.46-7.29 (m, 10H), 6.73 (d, J=6.0 Hz, 1H), 6.32 (t, J=6.0 Hz, 1H), 6.13 (br, 1H), 5.15 (s, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.9, 162.1, 152.1, 148.9, 137.7, 135.5, 128.8, 128.7, 128.3, 127.8, 127.7, 127.3, 122.9, 114.8, 106.7, 106.7, 96.8, 71.1, 44.1, 17.3; MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [Br: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]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([OH:25])=O)=[C:11]2[CH2:10][N:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:32]([NH2:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br: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]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([NH:34][CH2:32][CH3:33])=[O:25])=[C:11]2[CH2:10][N:9]=1
Reactant: CCN
Reactant: O=C(O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.4 g (1 mmol) of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 50 mL of methylene chloride and 0.3 g (1.44 mmol) of phosphorus pentachloride was stirred at room temperature for 2.5 hours. Ethylamine was introduced until the reaction mixture was basic. It was layered with 10% aqueous sodium carbonate solution and the two phases were stirred for 15 minutes The organic layer was separated, dried and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 0.37 g of product having the above formula. For analysis it was recrystallized from ethanol to leave colorless crystals with m.p. 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=O)=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1.[C:16](Cl)(=[O:20])[C:17](Cl)=O.C[N:23]([CH3:26])C=O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:23][CH2:26][C@:16]3([OH:20])[CH2:17][CH2:6][CH2:7][C@H:8]([CH3:12])[CH2:9]3)=[O:14])=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2,6-dichloro-quinoline-5-carboxylic acid (2.40 g) (WO2004/106305, Example 76, step b) in dichloromethane (100 ml) was added oxalyl chloride (3.15 g, 2.16 ml) and a drop of N,N-dimethylformamide. The reaction was stirred at room temperature for 2 hours before the volatiles were removed in vacuo and the residue diluted in dichloromethane (100 ml). To this solution were added (1S,3S)-1-(aminomethyl)-3-methylcyclohexanol.HCl (1.78 g) and diisopropylethylamine (6.70 ml) and the reaction stirred for 20 hours before washing with water. The organic layer was dried (MgSO4), filtered and the volatiles were evaporated to provide a crude solid. The material was recrystallised from toluene to provide the subtitle compound as a beige solid (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].Cl>O>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: N#Cc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 200 °C
Yield: 32.1 %

Procedure:
A mixture of (2-amino-5-chlorophenyl)(phenyl)methanone (1 g, 4.32 mmol, Eq: 1.00), ethyl 2-cyanoacetate (2.44 g, 2.3 ml, 21.6 mmol, Eq: 5) and cerium (III) chloride heptahydrate (322 mg, 863 μmol, Eq: 0.2) was heated to 200° C. for 30 min in a microwave. Then water was added and the mixture was acidified to pH 2-3 with 0.1N HCl. The mixture was then extracted with ethyl acetate (3×) and the combined extracts were washed with water and brine, dried with Na2SO4, filtered and evaporated. The remaining residue was triturated with a mixture of DCM (5 ml) and heptane (2 ml) for 2 h. Filtration yielded the title compound (389 mg, light yellow solid). MS (ESI): 281.1 (M+H)+.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]#N)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[K+].C(O)CO.C.[OH2:26]>>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([OH:26])=[O:19])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: N#CC1(c2ccc(C(=O)c3cccs3)cc2)CC1
Reactant: O
Agent: [K+]
Solvent: OCCO
Product: O=C(c1ccc(C2(C(=O)O)CC2)cc1)c1cccs1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
A mixture of 10 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarbonitrile, 3.92 parts of potassium hydroxide, 35 parts of ethylene glycol and 3.5 parts of water is stirred for 48 hours while heating at 140° C. The reaction mixture is poured onto water, stirred with activated charcoal and filtered over hyflo. The filtrate is acidified with hydrochloric acid and the product is extracted with ether. The latter is washed with water, dried, filtered and evaporated. The solid residue is crystallized from acetonitrile, yielding 6.1 parts of 1-[p-(2-thenoyl)phenyl]cyclopropanecarboxylic acid; m.p. 165.9° C (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1)[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11]2=[O:16])=[CH:27][CH:28]=1)[CH3:18]
Reactant: CCOC(=O)CCc1ccc(CCl)cc1
Reactant: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1

Procedure:
3-(4-Nitrophenyl)-1H-pyridin-2-one (P3, 200 mg, 0.93 mmol), 3-(4-chloromethyl-phenyl)propionic acid ethyl ester (P6, 270 mg, 1.20 mmol) and cesium carbonate (900 mg, 2.78 mmol) were stirred for 18 hours in dimethyl formamide (5 mL) at room temperature. The reaction mixture was filtered through celite (Diatomaceous Earth), concentrated and the crude mixture was purified by chromatography on silica gel (50% v/v ethyl acetate in petroleum ether) to afford the title compound as a solid.