Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[N:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+].CO>O>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[N:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1nc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 263c (100 mg, 0.19 mmol), NaBH4 (30 mg, 0.78 mmol), and methanol (20 mL). The mixture was stirred at room temperature for 0.5 h. It was then diluted with water (30 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×30 mL) and the combined dichloromethane extract was dried and concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 263 as a white solid (67 mg, 68%). MS-ESI: [M+H]+ 517.3. 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.55 (d, J=4.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 7.56 (dd, J=1.0, 6.0 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 4.83 (t, J=5.5 Hz, 1H), 4.62-4.58 (m, 1H), 4.39-4.36 (m, 1H), 4.25-4.19 (m, 2H), 4.06-4.04 (m, 1H), 3.92-3.90 (m, 1H), 3.81 (s, 3H), 2.64-2.54 (m, 2H), 2.43-2.41 (m 2H), 1.78-1.76 (m, 2H), 1.69-1.67 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[O:8][C:9]4[C:14]([O:15][C:16]=3[C:17](=O)[NH:18][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[N:18]=[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]2=[C:7]2[C:16]=1[O:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:8]2
Reactant: O=c1[nH]c2ccccc2c2c1Oc1ccccc1O2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2c2c1Oc1ccccc1O2

Procedure:
Under an inert atmosphere, [5H]-7,12-dioxa-5-azabenz[a]anthracen-6-one is brought to reflux of phosphorus oxychloride for 6 hours. The solvent (phosphorus oxychloride) is then evaporated off under vacuum and the crude mixture is chromatographed by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH2:34]([NH2:36])[CH3:35]>C1(C)C=CC=CC=1>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:36][CH2:34][CH3:35])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCN
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)CC)c2oc1=O
Reaction time: 0.58 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in toluene (15 mL), added thionyl chloride (1.0 mL), was refluxed for 3 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in toluene (15 mL). The solvent was eliminated under reduced pressure. Dispersion in toluene and solvent elimination was repeated twice. The residue was dissolved toluene (10 mL) and added with stirring to a solution of the ethyl amine (0.06 g, 1.28 mmol). After 35 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (20 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-ethyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.34 g, 64% yield). White solid, m. p. 162-163° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 7.96 (d, J=8.2 Hz, 2H), 7.83-7.76 (m, 3H), 7.54 (d, J=15.7 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 3.57-3.39 (m, 3H), 2.45 (s, 3H), 1.80-1.73 (m, 2H), 1.34 (d, J=6.9 Hz, 3H), 1.28 (t, J=7.3 Hz, 3H). 0.91 (t, J=7.3 Hz, 3H): 13C NMR (CDCl3, 75 MHz): δ 189.6, 161.2, 161.1, 153.1, 148.5, 144.1, 142.3, 136.5, 135.4, 132.2, 131.4, 128.8, 127.1, 123.2, 119.1, 119.0, 122.8, 34.9, 33.7, 29.8, 21.8, 20.6, 14.8, 12.1; ESI-MS (m/z): 418(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([O:20]C(=O)C)=[CH:18][C:5]2[CH:6]=[C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[O:8][C:4]=2[C:3]=1[CH3:24].C(=O)(O)[O-].[Na+]>CO>[OH:20][C:19]1[C:2]([CH3:1])=[C:3]([CH3:24])[C:4]2[O:8][C:7]([C:9](=[O:17])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:6][C:5]=2[CH:18]=1
Reactant: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)cc2cc(C(=O)CN3CCOCC3)oc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of acetic acid 6,7-dimethyl-2-(2-morpholin4-yl-acetyl)-benzofuran-5-yl ester (23 mg), prepared as in Example 17, in MeOH (10 mL) was stirred while sodium bicarbonate (10 mg) was added. Then the mixture was stirred at RT overnight, followed by evaporation to dryness. The residue was purified by silica gel column, eluting with 5% MeOH in dichloromethane to give 11 mg of 1-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-2-morpholin-4-yl-ethanone as an oil. Conversion into HCl salt gave a yellow solid. 1H NMR (CD3OD, 300 MHz) δ: 7.60 (s, 1H), 7.20 (s, 1H), 3.78 (m, 6H), 2.64 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 187.98, 170.20, 153.31, 152.29, 146.58, 130.44, 124.53, 122.80, 114.36, 113.15, 64.69, 53.79, 21.28, 13.47, 12.86 ppm. M/S 290 (M+H+).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[F:18][C:19]1[C:20]([N+:28]([O-:30])=[O:29])=[C:21]([O:26][CH3:27])[CH:22]=[C:23](F)[CH:24]=1>CN1C(=O)CCC1>[F:18][C:19]1[CH:24]=[C:23]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:22]=[C:21]([O:26][CH3:27])[C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Di-t-butyl malonate(18 g) was added dropwise to a stirred suspension of sodium hydride[60% dispersion in mineral oil](3.3 g) in N-methyl pyrrolidinone(100 mL) under an atmosphere of argon and the mixture was stirred until effervescence ceased. 3,5 Difluoro-2-nitro-anisole(6.4 g) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature then partitioned between water and ether and then the ether extract was dried and evaporated to dryness. The residue was subjected to flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(5.5 g)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O.O>ClCCl>[NH2:24][C:25]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 46A (5.74 g, 20.0 mmol) in dichloromethane (40 mL) at 0° C. was treated with chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) and the mixture was stirred at 0° C. for 2 hours. Water (40 mL) was added to the cold reaction and the mixture was warmed to 25° C. and stirred for 2 hours. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:18]=[C:19]=[S:20])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][NH:24][C:19](=[S:20])[NH:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: NCCN
Reactant: Cc1ccc(N=C=S)c2c1N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: Cc1ccc(NC(=S)NCCN)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of 1-t-butoxycarbonyl-2,3-dihydro-4-isothiocyanato-7-methylindole (1.70 g; 5.86 mmol) in methylene chloride (10 mL) is slowly added to a solution of ethylenediamine (1.76 g, 29.3 mmol) in methylene chloride (10 mL). After 30 minutes, the solution is washed with four 50-mL portions of aqueous potassium carbonate, dried over anhydrous potassium carbonate, filtered and rotary evaporated to yield an off-white solid. The crude residue is purified via silica gel column chromatography using 10% methanol (ammonium hydroxide treated)/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 1.92 g of 4-[N'-(2-aminoethyl)thioureido]-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole as a white solid (94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7](I)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:32]=[CH:33][C:34]([C:7]3[C:6](=[O:19])[C:5]4[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=4)[O:9][C:8]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 48.8 %

Procedure:
7-Bromo-3-iodo-2-phenyl-chromen-4-one (320 mg, 0.75 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (295 mg, 0.8 mmol), tetrakis(triphenyphosphine)palladium (0) (87 mg, 0.075 mmol) and sodium carbonate (159 mg, 1.5 mmol) were suspended in DME (10 mL) and water (5 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated in a microwave at 125° C. for 15 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a pale yellow foam (200 mg, 49%). LCMS (Method A): RT=5.45 min, [M+H]+=546/548.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
3.8 g of N-aminomorpholine (36.9 mmol) and 5.1 ml of triethylamine (3.7 g, 36.9 mmol) were dissolved at room temperature in 40 ml of methylene chloride. Again at room temperature 4.8 ml of n-butanesulfonyl chloride (5.8 g, 36.9 mmol) were added dropwise to this solution over the course of one hour. After 20 h of stirring at room temperature the reaction mixture was extracted by shaking twice with 50 ml of water and the organic phase was dried over magnesium sulphate and concentrated. The 6.7 g of crude product obtained were recrystallized from 30 ml of tert-butyl methyl ether. The constitution of the target compound was verified by NMR spectroscopy.
Reaction SMILES: [BrH:1].[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]O)([CH3:4])[CH3:3]>C(Cl)Cl>[Br:1][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)c1ccccc1CO
Reactant: Br
Solvent: ClCCl
Product: CC(C)c1ccccc1CBr

Procedure:
Add 1.7M tert-BuLi (26 ml, 44 mmol) dropwise, at −78° C. under inert atmosphere, to a solution of 1-Iodo-2-iso-propylbenzene (5 g, 20.3 mmol) in 70 ml of dry THF and stir. After 10 min, add Paraformaldehyde (2 g, 66.7 mmol) in a single portion. Stir the reaction at this temperature for 15 min and then at room temperature for 2 h. Add a saturated aqueous solution of NH4Cl and extract with CH2Cl2 three times. Dry the combined organic extracts over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to afford pure (2-Isopropyl-phenyl)-methanol as pale purple oil. Add aqueous concentrated HBr (15 ml) to a solution of (2-Isopropyl-phenyl)-methanol (1,93 g, 12.85 mmol) in CH2Cl2(15 ml) and stir at room temperature. After 2 h. separate phases and wash the organic one with H2O; dry over Na2SO4 and evaporate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to obtain 1-Bromomethyl-2-isopropyl-benzene as very pale pink light oil. 1H-NMR (CDCl3, 200 MHz): δ 7.33-7.25 (m, 3H), 7.19-7.11 (m, 1H), 4.58 (s, 1H), 3.31 (sep, J=6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:11][CH2:10][CH:9]([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][CH:9]1[O:8][C:6]2[N:7]=[C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC1COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1COc2c(nc(-c3cnc(N)nc3)nc2N2CCOCC2)O1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-7-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (99 mg, 0.36 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (97 mg, 0.44 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol) and sodium carbonate (1.2 mL, 1.20 mmol, 1M aqueous solution) in acetonitrile (1.2 mL) was degassed then heated at 140° C. for 25 minutes using microwave irradiation. The reaction mixture was filtered, flushing with ethyl acetate. The filtrate phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM) then triturated with diethyl ether affording 103 as a white solid (12 mg, 11%). LCMS: RT=3.06 min, [M+H]+=331. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.01 (2H, s), 4.57-4.47 (1H, m), 4.36 (1H, dd, J=11.41, 2.34 Hz), 3.82 (1H, dd, J=11.43, 7.60 Hz), 3.77-3.61 (8H, m), 1.34 (3H, d, J=6.44 Hz)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1)[CH3:2].[C:22]([NH:30][NH2:31])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:30][N:31]=[C:11]3[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]=2[CH:21]=1)[CH3:2]
Reactant: NNC(=O)c1ccccc1
Reactant: CCc1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCO
Product: CCc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(-c3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-ethyl-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 8-ethyl-1-phenyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: FC1C=N[C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=NC=1.[F:22][C:23](F)([F:27])C(O)=O.C1(C)C=CC=CC=1>ClCCl>[F:22][CH:23]([F:27])[CH2:5][N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]1=[O:21]
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)N(CC(F)F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) in N,N-dimethylformamide (4 ml) at −35° C. under argon was added sodium hydride (80 mg, 1.998 mmol). The reaction mixture was warmed to 0° C. over 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg). LC/MS [M+H]+=265. (ii) 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.757 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene (×2) to give 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (0.757 mmol) which was used in the next step. LC/MS [M+H]+=209.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:18]=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Brc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
A suspension of 4-bromopyridine (13.7 g, 86.8 mmol) in 300 mL THF was purged with N2 and cooled to −78° C. under an atmosphere of dry N2. A solution of lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 43.4 mL, 86.8 mmol) was added over about 3 minutes. After 30 minutes, DMF (dimethylformamide) was added. The reaction mixture was maintained at −78° C. for 3 hours before allowing it to warm to ambient temperature overnight. The reaction mixture was quenched with saturated NH4Cl and concentrated under reduced pressure to remove most of the THF. The aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, evaporated, and chromatographed (150 g Analogix silica gel column eluting with a gradient of 100% heptane to 30% EtOAc/heptane over 45 minutes). Fractions containing the product were combined and evaporated to give 2.20 g (13.6%) of the title compound. MS m/z 186 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CCOC(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(NC3CCOCC3)CC2)cc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
19 g of 4-amino-1-benzylpiperidine are placed in 50 ml of 1,2-dichloroethane under dry nitrogen and 10 g of tetrahydropyran-4-one in 20 ml of 1,2-dichloro-ethane are added; after stirring for 10 minutes, 29.6 g of NaBH(OAc)3 are added and the mixture is then stirred for one day. 10% Na2CO3 solution and EtOAc are added to the reaction medium and the phases are then separated by settling. The organic phase is washed with 10% Na2CO3 solution and then with saturated NaCl solution, and then dried over MgSO4 and evaporated under vacuum. 23.4 g of the expected compound are obtained. m.p.=60° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:38][O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:38])=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:16][CH2:15]2)=[O:7])=[CH:32][CH:33]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1ccc2[nH]/c(=N\C(=O)c3ccc(F)cc3)n([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed and the residue was resuspended in ACN (2 mL), cooled to 0° C., and sodium methoxide (478 mg, 2.210 mmol) was added. The reaction was stirred overnight at RT. The solvent was removed on a rotovap, and the residue was partitioned between water and DCM. The aqueous layer was neutralized (pH approximately 8) with concentrated HCl and extracted with DCM. The combined organic layers were concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methoxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (45 mg, 43.6% yield). MS, m/z (C26H31FN4O3): calcd, 466.2. found, 466.8 [M+H].