Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 21.8 %

Procedure:
The O-alkylation procedure described for 190 was used. A round-bottom flask was charged with 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (0.882 g, 3 Mmol), K2CO3 (0.518 g, 3.75 mmol) and acetone (100 mL). To the above mixture ethyl 4-bromobutanoate (0.644 mL, 4.5 mmol) was added at room RT and the mixture was refluxed for 24 h. Regular work-up and purification by column chromatography afforded 0.400 g (33%) of the title compound 217 as a white solid and 0.560 g (36%) of dialkylated product. 0.125 g unreacted of SM was also recovered. 1H NMR (300 MHz, CDCl3): δ 7.06 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.17 (q, J=14.1 Hz, 6.9 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.34 (br s, 4H), 2.12 (quintet, J=13.2 Hz, J2=6.9 Hz, 2H), 1.59 (s, 8H), 1.28 (t, J=7.2 Hz, 3H). LCMS (ESI): m/z 407 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=1>CN(C)C=O.O>[Cl:1][C:2]1[N:6]([CH2:14][C:15]2[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Combine 2-chlorobenzimidazole (10.0 g, 66 mmol), and dimethylformamide (100 mL). Add portionwise sodium hydride (1.63 g, 68 mmol). After the evolution of gas ceases, add a solution of ethyl 2-chloromethyl-5-furoate (12.45 g, 0.66 mmol) in dimethylformamide (20 mL). After 18 hours, dilute the reaction mixture with water and extract four times with diethyl ether. Combine the organic layers and extract with water and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue eluting with 5% methanol/0.2% concentrated aqueous ammonia solution/dichloromethane to give 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([Sn](CCCC)(CCCC)C#C)[CH2:18]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:17]#[CH:18])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 120 °C
Yield: 69 %

Procedure:
To a solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 4.35 mmol) in dioxane (80 mL) were added tributyl(ethynyl)tin (1.4 mL, 4.78 mmol) and (Ph3P)4Pd (251.2 mg, 0.217 mmol) and the mixture was heated to 120° C. for 1.5 h. After cooling to r.t., the solvent was removed in vacuo and the residue was purified by two successive flash chromatographies (150 g silica gel, hexanes→DCM:hexanes (3:7 to 1:1) and then (50 g silica gel, hexanes→EtOAc:hexanes (1:9)) to provide the title compound (730 mg, 69%) as a beige-orange solid. API-ES: m/z 244 [M+H]+, rt 5.14 min.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.C[OH:25].[H-].[Na+].O>CS(C)=O.C(O)(=O)C>[O:13]=[C:12]1[C:6]2[CH:5]=[N:4][C:3](=[O:25])[NH:8][C:7]=2[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH3:23])[NH:11]1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.66 g) and methanol (0.26 g) were added to a stirring suspension of sodium hydride (0.38 g, 50% suspension in oil) in dry dimethylsulphoxide (15 ml). The mixture was stirred at ambient temperature for 1.5 hours and at 70°-80° C. for 18 hours. The cooled reaction mixture was poured into water (500 ml), then glacial acetic acid (0.46 ml) was added and the mixture was extracted with chloroform (20o ml and then 2×100 ml). The combined extracts were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure to yield a solid which was washed successively with ether and 40°-60° petroleum ether and recrystallised from dimethylformamide: water to yield a crude product (0.18 g). This together with another sample (0.24 g) similarly prepared was eluted from a silica column with chloroform and 10% methanol in chloroform. The combined fractions containing product were evaporated under reduced pressure and the residue recrystallised from dimethylformamide dilute hydrochloric acid and then from dimethylformamide to yield the title compound, 0.15 g, m.p. 271°-3° C. (decomposition).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH3:24])[CH:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]=2[O:11][CH2:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH3:24])[CH:16]=[C:17]([N:18]3[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)[C:12]=2[O:11][CH2:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(N2CCNCC2)c2c(c1)N(Cc1ccccc1)C(=O)CO2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2CCN(C)CC2)c2c(c1)N(Cc1ccccc1)C(=O)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Benzyl-6-methyl-8-piperazin-1-yl-4H-benzo[1,4]oxazin-3-one (140 mg, 0.42 mmol) in CH2Cl2 (5 ml) from Example 1 was added formaldehyde (37 wt % solution in water, 50 μl, 0.67 mmol) and NaBH(OAc)3. The solution was stirred with a magnetic stirrer at room temperature for 2 hours, and then partitioned between CH2Cl2 (20 ml) and saturated NaHCO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 (2×20 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo to give 4-Benzyl-6-methyl-8-(4-methyl-piperazin-1-yl)-4H-benzo[1,4]oxazin-3-one as yellow solid. (140 mg, 95%) MS: (M+H)+352.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]([F:16])([F:15])[CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([F:16])([F:15])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(F)(F)C(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C1CC(F)(F)C(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of the crude 4-(benzylamino)-3,3-difluoro-4-oxobutanoic acid in iPrOAc (40 mL), SOCl2 (2.04 mL, 27.9 mmol, 2 eq) was added at ambient temperature. The reaction solution was stirred at 55° C. for 4 hr. The reaction was cooled to 0-5° C. Half saturated brine (50 mL) was added slowly to quench the excess SOCl2. The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9, extracted two times with EtOAc. The combined organic layer was washed with brine (50 mL), the organic phase was dried over MgSO4, filtered and concentrated. The crude residue was diluted with CH2Cl2 and filtered to remove precipitate. The concentrated filtrate was purified by column chromatography and eluted with 2-20% EtOAc/Heptane to obtain the title compound as a clear oil (1.74 g, 65%)1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.43 (m, 5 H) 4.76 (s, 2 H) 3.18 (t, J=12.53 Hz, 2 H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:16])[C:13]=1[CH:14]=[O:15].[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[SH:22]>C1COCC1>[Cl:16][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([S:22][C:18]2[S:17][CH:21]=[CH:20][N:19]=2)[C:13]=1[CH2:14][OH:15]
Reactant: Sc1nccs1
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: OCc1c(Cl)cncc1Sc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (0.22 g, 0.68 mmol) was added to a solution of 3,5-dichloro-pyridine-4-carbaldehyde (0.10 g, 0.57 mmol) and thiazole-2-thiol (0.10 g, 0.85 mmol) in THF (10 mL). After stirring at room temperature overnight, the solvent was removed in vacuo and saturated aqueous NaCl solution (20 mL) and EA (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo and the residue was used in the following step without further purification. The aldehyde group in 3-chloro-5-(thiazol-2-ylsulfanyl)-pyridine-4-carbaldehyde was reduced as described for the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol to give [3-chloro-5-(thiazol-2-ylsulfanyl)-pyridin-4-yl]-methanol which was used in the following step without further purification. Conversion of [3-chloro-5-(thiazol-2-ylsulfanyl)-pyridin-4-yl]-methanol into 3-chloro-4-chloromethyl-5-(thiazol-2-ylsulfanyl)-pyridine according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine and subsequent reaction with 2-methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol according to the synthesis of 8-(3,5-dichloro-pyridin-4-ylmethoxy)-4-imidazol-1-yl-2-methylquinoline yielded the title compound as the TFA salt. MS (m/z): 480.2 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[OH:1][CH2:2][C:3]#[C:4][CH2:5][N:30]1[C:26](=[O:36])[C:27]2=[CH:35][CH:34]=[CH:33][CH:32]=[C:28]2[C:29]1=[O:31]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC#CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC#CCO
Yield: 53 %

Procedure:
1,4-Dihydroxy-2-butyne (430 mg, 5.0 mmol), triphenylphosphine (1.44 g, 5.5 mmol) and phthalimide (1.47 g, 10.0 mmol) were dissolved in 50 mL of dry THF. To this solution, with stirring under dry argon, was added diisopropyl azodicarboxylate (1.09 mL, 5.25 mmol) dropwise. After stirring at room temperature for 6 hours, the reaction mixture was evaporated in vacuo to remove the THF. The residue was dissolved in methylene chloride (25 mL) and ethyl acetate (25 mL), the insoluble phthalimide was filtered off and the filtrate was concentrated in vacuo. The residue was subjected to flash column chromatography (eluent, ethyl acetate -hexane, 1:1) to give 1-hydroxy-4-phthalimido-2-butyne (240) as a white solid (570 mg, 53%). 1H NMR (CDCl3) δ7.88 (2H, dd, J=5.7, 3.1 Hz), 7.74 (2H, dd, J=5.7, 3.1 Hz), 4.49 (2H, t, J=2.0 Hz), 4.24 (2H, dt, J=6.2, 2.0 Hz), 1.92 (1H, t, J=6.2 Hz).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1.CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (2.31 g, 15 mmol, Aldrich) in THF (40 mL) and DMF (10 mL) at rt was added 4-fluoroaniline (1.67 g, 15 mmol), and the reaction mixture was stirred for 2.5 h. To the 4-fluoroaniline intermediate formed via a Michael addition was added EDCI.HCl (3.85 g, 20 mmol) and DMAP (120 mg) at rt. The reaction mixture was stirred at rt overnight. To the reaction mixture were added 1 N aq. HCl (50 mL) and EtOAc (150 mL). The EtOAc layer was separated, and the aqueous layer was washed with EtOAc (150 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to obtain a semi-solid material (˜4.4 g). The crude product was dissolved in ether (100 mL) and methanol (15 mL), and the solid which formed after stirring was filtered off. The filtrate was concentrated in vacuo to afford the desired product (2.95 g, 80%) as a semi-solid, which was sufficiently pure to use in the next step without further purification. 1H NMR (DMSO-d6) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31].CCCCCC>ClCCl>[N+:30]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 8 h
Yield: 92088.6 %

Procedure:
Triethylamine (66.8 g, 0.66 mmol) was added to a solution of tert-butyl (N-2-aminoethyl)carbamate (55.0 g, 0.34 mmol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mmol) was slowly added. The reaction mixture exothermed. The reaction mixture was allowed to stir overnight. The resulting precipitate was isolated by filtration and rinsed with water to provide a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated to provide a yellow solid. The two batches of solid were combined, slurried with hexane, filtered and then dried to provide 101 g of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl }carbamate as a yellow solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:28]2[CH2:32][S:31][CH:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:29]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[C:48](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:11]([C:19]1[CH:20]=[C:21]([N:25]([CH3:48])[C:26]([CH:28]2[CH2:32][S:31][CH:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:29]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1C(C(=O)Nc2cccc(C(=O)c3ccccc3)c2)CSC1c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Lithium hexamethyl disilazide (0.6 mL, 1.0M in hexanes) was added at 0° C. under nitrogen to a solution of N-(3-benzoylphenyl) 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxamide prepared as described in example 2 (202 mg, 0.41 mmol), in dry THF (4 mL, 0.1 mL). The mixture was stirred for 20 min then methyl iodide (25 μL) was added and the mixture stirred for an additional 8 hours. The reaction mixture was partioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfated and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (12:3) to yield the desired product (0.53 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:26]1[CH2:25][CH:24]1[CH2:22][N:17]1[CH2:16][CH2:15][N:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
A solution of 4,4'-difluorobenzhydrylpiperazine (28.83 g, 100 mmol) in acetonitrile (250 mL) was added to an ice cold mixture of epibromohydrin (9.1 mL, 110 mmol) and anhydrous potassium carbonate (15.2 g, 110 mmol) in acetonitrile (150 mL) over a period of 40 min. The mixture was stirred at room temperature for 100 h, filtered and the solids were washed with methylene chloride. The combined filtrates were concentrated to dryness to give an oil which was eluted through a flash chromatographic silica gel column using 2-3% methanol/methylene chloride to give the title compound as glass, 23.98 (69.6%); 300 MHz 1H NMR (CDCl3):δ 7.4-6.9 (m, 8H). 4.22 (s. 1H). 3.09 (br m, 1H), 2.8-2.25 (m, 12H); MS 345 (MH+).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[N:20]=[C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)[O:18][N:17]=1>CN(C)C=O>[CH2:11]([N:14]([CH2:15][C:16]1[N:20]=[C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)[O:18][N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:12][CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccsc2C1=O
Reactant: CCCBr
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1noc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)n1
Reaction time: 1 h
Yield: 57.8 %

Procedure:
4 ml (23.4 mmol) of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of 1-bromopropane were added to a solution of 0.6 g (1.9 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, ethyl acetate/methanol 25:1). There were obtained 440 mg (57%) of 3-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.34 (silica gel, ethyl acetate/methanol 25:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=O)=[N:14]1.P(Cl)(Cl)(=O)[O:37][C:38]1[CH:43]=CC(Cl)=CC=1.[N+:48](C1N=CNN=1)([O-])=O>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[N:18]=[C:19]2[NH:48][CH2:43][CH2:38][OH:37])=[N:14]1
Reactant: Cn1cc(C#N)cc1-c1c2c(=O)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1cc(C#N)cc1-c1c2c(NCCO)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-cyclopropylmethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile (0.42 g) in pyridine (5 mL) were added 4-chlorophenyl phosphorodichloridate (0.5 mL) and 3-nitro-1,2,4 triazole (0.15 g). After heating (Tb=50° C.) for 3 h, the reaction was diluted with ethyl acetate. The organic solution was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (10 mL) and ethanolamine (1.0 mL). After 3 h, the reaction was concentrated. This residue was purified by flash chromatography using a FlashMaster™ yielding 0.22 g, ES (M+H)+=529.
Reaction SMILES: [SH:1][C:2]1[NH:3][N:4]=[N:5][CH:6]=1.[NH2:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1.Cl[C:15]1[C:16]2[N:24]=[C:23](Cl)[CH:22]=[CH:21][C:17]=2[N:18]=[CH:19][N:20]=1>>[N:5]1[CH:6]=[C:2]([S:1][C:23]2[CH:22]=[CH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:7][C:8]4[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=4)[C:16]=3[N:24]=2)[NH:3][N:4]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Sc1cnn[nH]1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Sc4cnn[nH]4)nc23)n1

Procedure:
The compound of Example 57 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 4-mercapto-3H-[1,2,3]triazole, 3-amino-1-methyl-1H-pyrazole and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:31]4[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)cc1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O-])(=O)C.[Na+].C[Si](C)(C)[O:16][C:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH:18]=1.O>C1COCC1.O.C(OCC)(=O)C>[Br:1][CH:18]1[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][C:17]1=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1C=C(O[Si](C)(C)C)CCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-bromosuccinimide (0.48 mmol) and sodium acetate (0.04 mmol) in THF/water (1:1, 5.2 ml) is cooled to 0° C. and trimethyl-(3-methyl-cyclohex-1-enyloxy)-silane (0.4 mmol, 80% pure) is added dropwise. The reaction mixture is heated to room temperature and stirring is continued overnight. After addition of water extraction is carried out with ethyl acetate. The title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating-off of the solvent in a vacuum (JOC 1997, 62, 19, 6692-6696).