Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)(=[O:3])[CH3:2].[CH3:11][O-:12].[Na+]>O>[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:12][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccncc1C(C)=O
Yield: 79.9 %

Procedure:
A solution of 3-acetyl-4-chloropyridine (0.75 g, 4.8 mmol) in sodium methoxide solution (0.5M in methanol, 10.6 ml, 5.3 mmol) was heated at reflux for 1 hour. After cooling water (10 ml) was added and the solvents evaporated. The residue was partitioned between dichloromethane (4×50 ml) and water (50 ml), the combined organic phases dried (MgSO4) and evaporated to afford the title compound (0.58 g, 80%) as a yellow solid. 1H NMR (360 MHz, CDCl3) δ 2.62 (3H, s), 3.98 (3H, s), 6.90 (1H, d, J=5.8 Hz), 8.57 (1H, d, J=5.7 Hz), 8.81 (1H, s).
Reaction SMILES: [Mg].II.[C:4]1([CH2:10][CH2:11][CH2:12]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-].C([O:17][P:18](Cl)[O:19]CC)C.C1(CCC[Mg]Br)C=CC=CC=1.Cl>C(OCC)C.O>[C:4]1([CH2:10][CH2:11][CH2:12][PH:18](=[O:17])[OH:19])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Br[Mg]CCCc1ccccc1
Agent: Cl
Agent: II
Solvent: CCOCC
Solvent: O
Product: O=[PH](O)CCCc1ccccc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
Magnesium turnings (2.44 g, 0.10 mol) in 20 mL of dry diethyl ether under an atmosphere of nitrogen was added several iodine crystals. Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 mL of diethyl ether was placed in a dropping funnel. Approximately 10 mL of the bromide solution was added to the magnesium turnings and stirring was initiated. After several minutes the iodine was consumed and additional phenylpropyl bromide was added while maintaining a temperature of 35° C. Once additional was complete (1.5 hours) the mixture was sealed and stored at 5° C. Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenylpropylmagnesium bromide (100 mL, 0.1 mol, 1.0 M solution of in Et2O) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and was stirred an additional 30 minutes. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. To the liquid was added 20 mL of water followed by 0.5ml of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 20 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. To the clear liquid was added sodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for 1 hour and then washed with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give 3-phenylpropylphosphinic acid (1,R=CH2CH2CH2Ph,R1=H)(9.8 g, 53%) as a clear and colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].[BH4-].[Na+]>>[CH2:16]([C:15]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][C:24]=2[CH:31]=1)([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH3:34])[CH:3]2[OH:33])=[C:10]([CH3:32])[CH:11]=1)[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Yield: 64 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (200 mg, 0.432 mmol) (Example 67) is reacted with sodium borohydride (36 mg, 0.864 mmol) in an analogous manner to Example 31 to yield (13 mg, 64% yield). MS (ES) m/e: 563.3 (M−1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:24][CH2:25][C:26](=[O:27])[C:9]2=3)=[CH:4][CH:3]=1.O.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[F:23][CH:21]([F:22])[C:17]1[CH:16]=[C:15]([N:11]2[C:10]3[CH2:24][CH2:25][C:26](=[O:27])[C:9]=3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=3)[NH:13][C:12]2=[O:14])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromophenyl)-1-(3-(difluoromethyl)-phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 6, 159 mg, 367 μmol), zinc cyanide (73 mg, 620 μmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. for 3 h and then cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The residue is purified by flash chromatography on silica (gradient cyclo-hexane/ethyl acetate 7:3 to ethyl acetate). Yield: 82 mg; ESI mass spectrum: [M+H]+=380; Retention time HPLC: 0.49 min (X012_S01).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:22]([NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)NCc1ccccc1
Yield: 90.9 %

Procedure:
To a solution of crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid (22.2 mg, 0.074 mmol) in anhydrous methylene chloride (0.50 mL) were added benzyl amine (9.7 mg, 0.091 mmmol) and 1-hydroxybenzotriazol monohydrate (11.1 mg, 0.082 mmol). To the reaction mixture stirred under ice-cold condition was added 1,3-dicyclohexylcarbodiimide (18.0 mg, 0.087 mmol), and the mixture was stirred for 0.5 hour. After removal of the ice bath, the mixture was stirred for 16 hours at room temperature, and then chloroform (20 mL) was added. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (2×3 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude oily material (47 . 7 mg). The crude oil was purified by column chromatography (silica gel 2g, about 15% ammonia/methanol-chloroform (1:100)) to obtain N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl amide (26.2 mg) as a colorless oily material [yield 90% from N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ether].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:27])([CH3:26])[CH2:19][C:20]#[C:21][Si](C)(C)C)[CH:14]=2)[N:9]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:8]1=[O:34].[F-].[Cs+]>CN(C=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:27])([CH3:26])[CH2:19][C:20]#[CH:21])[CH:14]=2)[N:9]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:8]1=[O:34]
Reactant: COc1ccc(Cn2c(=O)c3cc(C(C)(O)CC#C[Si](C)(C)C)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: C#CCC(C)(O)c1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 0.112 g of the compound obtained in Step 9.1, 0.031 g of caesium fluoride and 0.003 g of tetrabutylammonium fluoride in 5 ml of DMF is stirred overnight at room temperature. The resulting mixture is evaporated under reduced pressure. The residue is taken up in DCM. This solution is washed with water, and the organic phase is dried over MgSO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with EtOAc to give 0.084 g of the expected product.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[NH:14][C:10]=2[CH:9]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>N1C=CC=CC=1>[SH:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([NH:7][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
N,N-dimethylacetamide (250 ml) was added to 36.6 g of 5-amino-2-mercaptobenzimidazole and 17.1 ml of pyridine, and 34.4 g of phenyl chloroformate was added dropwise at room temperature. The mixture was stirred at room temperature for 1.5 hours, and 1.5 liters of ice water was added. As a result, crystals precipitated. The resulting crystals were collected by filtration and recrystallized from acetonitrile to give 47.7 g of 2-mercapto-5-phenoxycarbonylaminobenzimidazole.
Reaction SMILES: [C:1]([CH:4]([CH:10](C)[C:11](=O)[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>>[CH3:2][C:1]1[NH:23][C:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(C)=O)C(C)C(=O)c1ccsc1
Agent: CC(=O)[O-]
Product: CCOC(=O)c1cc(-c2ccsc2)[nH]c1C
Yield: 96.3 %

Procedure:
Using ethyl 2-acetyl-3-methyl-4-oxo-4-(3-thienyl)butanoate (1.86 g) and ammonium acetate (626 mg), a procedure as in Reference Example 14 was performed to give the title compound as a brown oil (yield 1.57 g, 91%).
Reaction SMILES: [OH-].[Na+].[Cl-].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:7])=[CH2:6].[CH3:15]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])=[CH2:6]
Reactant: CI
Reactant: C=C(C)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: C=C(C)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
A two-liter reaction flask was charged with 375 mls of water, 18.25 gms of sodium hydroxide, 125 mls of saturated sodium chloride, 50 gms of para-isopropenylphenol, 450 cc of methylene chloride, 7.5 gms of tetrabutylammoniumbromide, and 35 mls of methyl iodide. The reaction flask was flushed with nitrogen, and the mixture was stirred overnight. The phases were separated, and the aqueous phase was washed with methylene chloride. The combined organic layers were washed with 5% sodium hydroxide and saturated sodium chloride. The solution was dried over sodium sulfate. The methylene chloride was removed by distillation, and 400 mls of diethyl ether was added to precipitate the phase transfer catalyst. After filtration, the ether was stripped and the residue was distilled to give 25 gms of para-isopropenylanisole for a yield of 45%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)(O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH:10]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCC2(O)CCN(c3ccc(Cl)nn3)CC2)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(OCC2=CCN(c3ccc(Cl)nn3)CC2)cc1
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a stirred mixture of 7 parts of ethyl 4-[[1-(6-chloro-3-pyridazinyl)-4-hydroxy-4-piperidinyl]methoxy]benzoate and 150 parts of ethyl acetate were added dropwise 8.4 parts of thionyl chloride. Upon complete addition, stirring was continued first overnight at room temperature and then for 1 hour at 65° C. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with concentrated ammonium hydroxide and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1.8 parts (26.7%) of ethyl 4-[[1-(6-chloro-3-pyridazinyl)-1,2,3,6-tetrahydro-4-pyridinyl]methoxy]benzoate; mp. 161.7° C. (comp. 165).
Reaction SMILES: [C:1]1(/[C:7](/[CH3:14])=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:14]/[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(/CBr)c1ccccc1
Temperature: 75 °C

Procedure:
A mixture of 14 g (74 mmol) of ethyl (E)-3-phenylbut-2-enoate, 0.47 g of 2,2′-azobis(2-methylpropionitrile) and 330 ml of carbon tetrachloride is heated to 75° C. 19.8 g (111 mmol) of N-bromosuccinimide are added portionwise at this temperature. The mixture is then refluxed for five hours. The insoluble material is filtered off at 25° C. The filtrate is washed with water and dried over Na2SO4; the solvents are evaporated off (orange-coloured oil: 19.7 g; 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)C(N)=O)#[N:2].Cl.[CH3:13][OH:14].[CH3:15][OH:16]>>[C:1]([C:3]1[CH:4]=[CH:5][C:9]([C:13]([O:16][CH3:15])=[O:14])=[CH:10][CH:11]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1cccc(C(N)=O)c1
Agent: Cl
Product: COC(=O)c1ccc(C#N)cc1
Yield: 93 %

Procedure:
m-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and methanol (460.3 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 64° C. for 12 hours while a 20% hydrochloric acid/methanol solution (162.4 g) prepared in advance was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 74.9 g of methyl p-cyanobenzoate (yield 93%).
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:14]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[N:13][N:12]=[N:11]1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:8][C:7]([N:11]1[N:12]=[N:13][C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][CH:22]=2)=[N:10]1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Reactant: C=C(C)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)n1nnc(-c2ccc(C=O)cc2)n1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of 6.9 g (58 mmol) of 2-phenyl-propene (Fluka, Buchs, Switzerland) and 22 ml of toluene is added dropwise to 10 g (57 mmol) of 4-(tetrazol-5-yl)-benzaldehyde and 1 g (5.7 mmol) of methanesulfonic acid in 44 ml of boiling toluene and the mixture is then stirred under reflux conditions for 1 hour. The cooled reaction mixture is washed 2× with sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation to form the title compound: 1H-NMR (DMSO-d6) δ 10.09 (s, HCO), 8.29 and 8.08 (2d, J=8, each 2H), 7.33 and 7.17 (2m, 5H), 2.17 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]([CH3:25])[C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2NC(=O)CC3)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.25 h

Procedure:
A second intermediate compound, 1-Methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride, was produced as follows: To a solution of 4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 7.54 mmol) in THF (45 mL) cooled to −50° C. was added a solution of potassium t-butoxide, 1M in THF (8.3 mL, 8.30 mmol). After stirring for 15 minutes, methyl iodide (0.47 mL, 7.54 mmol) was added followed by stirring for 16 hours at 25° C. The mixture was evaporated and the residue was taken up into dichloromethane. The solution was washed consecutively with 1N citric acid, saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give a white foam, which was purified by chromatography on silica gel eluting with a gradient of dichloromethane and ethyl acetate. Evaporation of the appropriate fractions gave 4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH:32]OCC)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH:32][NH:14][C:13]1[N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(Cn2nccc2N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccc(OC)cc1)C(=O)OCC
Temperature: 120 °C
Yield: 53 %

Procedure:
2-(4-Methoxybenzyl)-2H-pyrazol-3-ylamine hydrochloride (5.582 g) was neutralized with a saturated sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. To the obtained yellow oil, 2-ethoxymethylenemalonic acid diethyl ester (3.89 mL, 0.7 equivalents) was added. The mixture was stirred at 120° C., and 2-ethoxymethylenemalonic acid diethyl ester (about 1 equivalent in total) was further added thereto while stirring at 120° C. to consume the raw material. The reaction solution was purified by silica-gel column chromatography (ethyl acetate/hexane=2/1 to 3/0) to give 2-{[2-(4-methoxybenzyl)-2H-pyrazol-3-ylamino]methylene}malonic acid diethyl ester (5.420 g, yield: 53%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([CH:27]([OH:31])[C:28](O)=[O:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:27]([OH:31])[C:28]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:29])=[CH:32][CH:33]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)C(O)c2ccc(Cl)cc2)ccc1OCCN1CCCC1
Temperature: 50 °C
Yield: 15.1 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (100 mg, 0.35 mmol), 4-chloromandelic acid (98 mg, 0.525 mmol), HATU (200 mg, 0.525 mmol) and triethylamine (0.5 mL) in DMF (6 mL) was heated at 50° C. overnight. The crude was purified by HPLC to provide the title compound as a semi-solid (24 mg, i 5%). 1H NMR (DMSO-d6, 400 MHz) δ 1.60-1.73 (m, 2H), 1.84-1.91 (m, 2H), 2.80-2.90 (m, 2H), 3.22-3.30 (m, 4H), 3.65 (s, 3H), 4.25 (t, J=5.05 Hz, 2H), 6.26 (d, J=1.77 Hz, 1H), 7.17 (d, J=9.09 Hz, 1H), 7.39-7.46 (m, 2H), 7.51-7.53 (m 3H), 7.67 (d, J=2.53 Hz, 1H), 7.80 (dd, J=2.78, 8.84 Hz, 1H), 9.50 (s br, 1H), 10.0 (s, 1H). Exact mass calculated for C24H27ClN4O3 454.2. found 455.4 (M+).
Reaction SMILES: [Cl: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]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH2:23][OH:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl: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]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH:23]=[O:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A suspension of 1.3 g of 6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol and 3.4 g of manganese dioxide in 200 ml of benzene is refluxed for 2 hours. The reaction mixture is then filtered and the filtrate concentrated by evaporation. The resulting foam is dissolved in a little ethyl acetate and the solution chromatographed on ca. 60 g of silica gel (Merck, 0.063 - 0.2 mm particle size) with ethyl acetate as the eluant. Fractions each of ca. 80 ml are collected. The fractions 4-8 are combined, concentrated by evaporation, and the residue crystallised from an ethyl acetate/ether/petroleum ether mixture to obtain 6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4] benzodiazepine-1-carboxaldehyde, M.P. 182°-189°.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:12]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][C:7]=2[S:6][C:5]=1[C:26]([O:28]CC)=[O:27]>O1CCOCC1.O>[NH2:3][C:4]1[C:12]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][C:7]=2[S:6][C:5]=1[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)O)c(N)c23)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Potassium hydroxide (20.0 g) was added to a solution of ethyl 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (example 31(e), 17.0 g) in a mixture of 1,4-dioxane (210 ml) and water (80 ml). After 16 h at 90° C., the mixture was cooled to 0° C. The resulting precipitate was filtered off, suspended in water (300 ml) and cooled to 0° C. The mixture was acidified to pH 3 by adding 2N aq. citric acid and stirred at 0° C. up to room temperature for 2 h. The resulting precipitate was filtered off, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(C2=CCNCC2)cc1
Reaction time: 8 h
Yield: 141.1 %

Procedure:
A solution of Example 6B (0.5 g, 1.8 mmol) in dichloromethane (5 mL) at room temperature was treated with 2M HCl in diethyl ether (5 mL), stirred overnight, and concentrated to provide the desired product (0.45 g, 95%). MS (ESI) m/e 178 (M+H)+.