Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[N:5]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(N=C=O)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
A 200-mL three-neck flask fitted with a dry ice condenser and magnetic stirrer was charged with a solution of 20% phosgene in toluene solution (2.0 mL) and dioxane (80 mL). To this mixture was added 7-amino-4-methyl-2H-chromen-2-one (2.00 g, 11.4 mmol). The mixture was stirred at 100° C. for 12 h. The initial yellow colour disappeared and a white solid precipitated. An additional 20% phosgene in toluene solution (7.0 mL) was added and the mixture heated for an additional 5 h, at which time the solution cleared. Excess phosgene and traces of HCl was removed by bubbling nitrogen gas through the solution. The cloudy solution was filtered to remove unreacted 7-amino-4-methyl-2H-chromen-2-one and concentrated to give 76 (0.5 g, 25%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=7.50 (1H, d, J=7.40 Hz, ArH), 7.46 (2H, s, ArH), 6.20 (1H, s, ArH), 2.35 (3H, s, CH3): ir (CH2CL2) 2314 (N═C═O), 1726 and 1615 cm−1.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
Triethylamine (0.94 mL, 6.71 mmol) was added to a stirred reaction mixture of N-tert-butoxycarbonyl piperazine (0.50 g, 2.68 mmol) in tetrahydrofuran (6 mL) at 0° C., then the reaction mixture was stirred at room temperature for 15 minutes. A solution of 4-bromo-benzenesulfonyl chloride (0.686 g, 2.68 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture and stirring continued for another 2 hours. Tetrahydrofuran was evaporated off under reduced pressure, then the reaction mixture was diluted with ethyl acetate (20 mL). The inorganic materials were filtered off through a celite bed. The filtrate was washed with 2 N aqueous HCl (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.00 g (92%) of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid, which was used in the next step without further purification. MS cald. for C15H21BrN2O4S [(M+NH4)+] 422, obsd. 422.1.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].C[Li].O>C(OCC)C>[C:11]1([S:8]([O:7][CH2:6][CH2:5][C:3]2[CH2:4][CH:2]=2)(=[O:10])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(OCCC1(Br)CC1(Br)Br)c1ccccc1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(OCCC1=CC1)c1ccccc1
Temperature: -78 °C
Yield: 70 %

Procedure:
A solution of 0.745 g (0.00150 mol) of 1,1,2-tribromo-2-(2-benzenesulfonyloxyethyl)-cyclopropane in 4 ml of diethyl ether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling to −78° C. in a dry ice/acetone bath, 23.45 ml (0.00450 mol) of 1.4 M methyl lithium in diethyl ether was added slowly via syringe. After 15 minutes warmed to 0° C. in an ice water bath then returned to −78° C. for about 30 minutes before 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield >0.155 g of 70% pure 2-(2-benzenesulfonyloxyethyl)-cyclopropene contaminated with 30% 1-(2-hydroxethyl)cyclopropene as an oil.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:37])[CH2:20][NH:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)[C:9]2[S:13][C:12]([O:14]C(C)C)=[N:11][C:10]=2[CH:18]=1)(C)(C)C.Cl.[OH-].[Na+]>C(O)(C)C.O>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([NH:21][CH2:20][C@@H:19]([C:8]2[C:9]3[S:13][C:12](=[O:14])[NH:11][C:10]=3[CH:18]=[C:6]([OH:5])[CH:7]=2)[OH:37])([CH3:35])[CH3:36])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(OC(C)(C)C)cc3nc(OC(C)C)sc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(O)cc3[nH]c(=O)sc23)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To (R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol (7.5 g) in isopropanol (30 ml) and water (25 ml) was added 1M HCl aqueous solution (43 ml). The reaction mixture was then heated to 60° C. and stirred for 2.5 h. The mixture was cooled to 50° C., and then 2M NaOH aqueous solution (18 ml) was added slowly to adjust pH between 8.2-8.4. The reaction mixture was then cooled to 30° C., followed by extraction with TBME (first time with 40 ml, the second time with 25 ml). Two organic layers were combined and washed with water (38 ml for two times) before drying with anhydrous Na2SO4. After filtration, the filtrate was concentrated, and then dissolved in MeCN (145 ml). The solution was treated with active carbon (0.6 g) and heated to 60° C. After a second filtration, the cake was washed with MeCN (10 ml for two times), the filtrate was crystallized at 60° C. to gain (R)-7-(2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)-1-hydroxyethyl)-5-hydroxybenzo[d]thiazol-2(3H)-one (3.8 g). e.e.=97.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[C:34]([S:37][CH3:38])[CH:33]=4)[NH:1][C:39]3=[O:40])[CH2:14][CH2:13]2)=[CH:23][CH:24]=1
Reactant: CSc1ccc(N)c(C(=O)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Yield: 85 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-5-(methylthio)benzamide, 1.78 parts of 1,1'-carbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.2 parts (85%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-2,4(1H,3H)-quinazolinedione; mp. 238° C. (compound 126).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)c(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzylbromide (2.9 ml) was added to the mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (5.0 g) and potassium t-butoxide (2.7 g) in N,N-dimethylformamide (40 ml) under ice-cooling and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration. The residue was crystallized from the mixture of toluene and diisopropyl ether and collected by filtration to give methyl 4-benzyloxy3-(pyrrol-1-yl)benzoate (4.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O.C(Cl)Cl>CN(C)C=O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccn1
Reaction time: 5 h

Procedure:
2-pyrazine carboxylic acid, 104.3 gm, and 105.9 gm thionyl chloride were added to 800 ml methylene chloride and 5 ml dimethylformamide. The system was heated to reflux, at which point gas evolution took place. The system was stirred at reflux until gas evolution ceased, after about 5 hours, to give the 2-pyrazine carboxylic acid chloride. The solution was cooled to room temperature and transferred to a dropping funnel for use in Step (b) without further isolation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
A solution of 2-fluorophenylamine (1.47 g, 13.19 mmol) in anhydrous THF (20 mL) was cooled to −70° C. To this was added dropwise 1M LiHMDS in THF (25.14 mL, 25.14 mmol) over 10 minutes to afford a dark yellow solution. A solution of 2,4-difluoronitrobenzene (2.00 g, 12.57 mmol) in anhydrous THF (10 mL) was added dropwise to the yellow solution, to afford a purple solution. The was stirred at −70° C. for 15 minutes, before being allowed to reach RT. It was then quenched with saturated aqueous NH4Cl solution (25 mL) and extracted into EtOAc (3×50 mL). The combined organic fractions were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo to afford an orange solid. This was purified by column chromatography (silica gel, gradient 0-100% DCM in cyclohexane) to afford the title compound as a yellow solid (3.04 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 9.36 (1H, s), 8.20 (1H, dd, J=9.45, 5.94 Hz), 7.34-7.26 (1H, m), 7.24-7.10 (3H, m), 6.56 (1H, dt, J=11.09, 2.07 Hz), 6.45 (1H, ddd, J=9.44, 7.13, 2.63 Hz)
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:7]=1)=O.[OH-].[Li+]>C1COCC1.O>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
A solution of 2,2,2-trifluoro-N-(3-{3-[2-(3-fluoro-phenylamino)-pyrimidin-4-yl]-pyrazolo[1,5-a]pyridin-2-yl}-phenyl)-acetamide (2.15 g, 4.4 mmol) and lithium hydroxide (277 mg, 6.6 mmol) in THF (44 mL) and water (10 mL) was stirred for 16 h. The reaction was extracted with DCM. The combined organic phases were dried over MgSO4 and purified through silica gel to give the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO): δ 9.75 (s, 1H), 8.78 (d, J=6.8 Hz, 1H), 8.52 (d, J=9.2 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.80 (d, J=12.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.29-7.23 (m, 1H), 7.12-7.06 (m, 2H), 6.77 (s, 1H), 6.71 (dt, J=8.4 and 2.4 Hz, 1H), 6.66-6.62 (m, 2H), 6.54 (d, J=5.6 Hz, 1H), 5.21 (s, 2H) ppm. HRMS calculated C23H17FN6 [M+H]+ 397.1577 found 397.1558.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.C(O)C.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1
Reactant: COC(=O)CC1CCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CC1CCCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
(3-Oxo-cyclohexyl)-acetic acid methyl ester (240 mg, 1.39 mmol) was dissolved in 5 ml THF and 5 ml ethanol and cooled to 0-5° C. Sodium borohydride (79 mg, 2.09 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO3-solution and extracted three times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (240 mg, 100%) was obtained as a light yellow oil and used without any further purification for the next step.
Reaction SMILES: [C:1]([CH2:9]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([OH:34])[C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:14]=1[N+:31]([O-:33])=[O:32]>>[CH3:11][N:12]([O:34][CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:14]=1[N+:31]([O-:33])=[O:32]
Reactant: O=C(CBr)c1ccccc1
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CN(OCC(=O)c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 14, benzoylmethyl bromide is reacted with N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine to give N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]benzoylmethoxyamine (IVA; R3 is H, n is one, and R4 is phenyl).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[SH:9][C:10]1[CH:19]=[C:18]([CH3:20])[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([S:9][C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH:7]=1
Reactant: Cc1cc(S)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Sc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
820 mg (5.50 mmol) 4,6-dichloropyrimidine, 1.00 g (5.50 mmol) 6-mercapto-4-methyl-3H-benzoxazol-2-one and 5.00 mL (29.1 mmol) DIPEA were combined in 20 mL DCM and stirred overnight at 40° C. The reaction mixture was evaporated down, the residue was taken up in EtOAc and combined with sodium hydrogen carbonate solution. The precipitate formed was suction filtered, washed with copious amounts of water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:23][C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@H]1CCCc2ccccc21
Product: O=[N+]([O-])c1cc(CN[C@H]2CCCc3ccccc32)ccc1Cl

Procedure:
4-Chloro-3-nitrobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:25]2[CH:26]=[C:14]([Cl:13])[C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])=[CH:23][C:24]=2[F:28])[CH:7]=1
Reactant: O=C(c1cc(F)c(F)cc1Cl)N1CCCC1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2cc(Cl)c(C(=O)N3CCCC3)cc2F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17](O)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(C(=O)O)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Reactant: CN1CCNCC1
Product: Cc1cc2cc(C(=O)N3CCN(C)CC3)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Yield: 57 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 57%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=O)[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Li].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CCN1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a stirring suspension of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-1-acetylpiperidine (0.11 mmol,41.4 mg) in THF (1.0 mL) was added lithium alumininum hydride (0.14 mmol, 0.14 mL of a 1M solution in THF) and the reaction stirred at room temperature for 2 h. The reaction was then quenched with water (0.1 mL), diluted with ethyl acetate (25 mL), the suspension filtered, the filtrates dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give 25 mg of the title compound as a white powder. mp=242°-244° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl>CN(C)C=O>[CH2:1]([NH:3][CH2:4][CH2:5][O:6][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCNCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
2-(Ethylamino)-ethanol (2.5 g, 24.2 mmol) (Aldrich) was added to a cooled (−5° C.) mixture of sodium hydride (50%, 580 mg, 24.2 mmol) in dimethyl-formamide (100 mL) and stirred for 10 minutes at 0° C., 30 minutes at room temperature, then 30 minutes at 45° C. After cooling to −1° C., 1-fluoro-4-nitrobenzene (4.1 g, 29 mmol) (Aldrich) was added and the mixture was stirred 20 minutes at −100° C. and for 90 minutes at room temperature. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid and the mixture extracted with ether (4×50 mL). The aqueous layer was adjusted to pH 9 with 3N sodium hydroxide and extracted with ethyl acetate (5×50 mL), dried (Na2SO4), concentrated in vacuo, and dried under high vacuum at 40° C. to give 2.2 g (41%) ethyl-[2-(4-nitro-phenoxy)-ethyl]-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23](C(Cl)(Cl)Cl)[N:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)[C:21]=2[CH:36]=1>CN(C)C=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[N:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)[C:21]=2[CH:36]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
A mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (800 mg, 6.05 mmol), cesium carbonate (1.7 g, 5.22 mmol) and 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12 hr at room temperature. The reaction mixture was quenched with 20 mL of water and the precipitate was collected by filtration. The solid was dried in a vacuum oven to afford 385 mg (75%) of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.40 (d, J=5.2 Hz, 2H), 7.40 (s, 2H), 7.21 (d, J=6.0 Hz, 1H), 5.28 (s, 2H), 4.77-4.60 (m, 3H), 4.22-4.20 (m, 1H), 3.96-3.92 (m, 1H), 1.49 (s, 3H), 1.42 (s, 3H); LC-MS: m/z=+420 (M+H)+.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23]
Reactant: CN(CCCn1c2c(c(=O)[nH]c1=O)CCCC2)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCn1c2c(c(=O)[nH]c1=O)CCCC2
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of 4.29 g (13.11 mmol) of 1-{3-[benzyl(methyl)amino]propyl}-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione in a mixture of 50 ml of methanol and 10 ml of tetrahydrofuran is admixed with 5.6 mg of 10% palladium-on-carbon. Over a period of 45 minutes, three portions of in total 8.61 g (136.6 mmol) of ammonium formate are then added. After the addition has ended, the mixture is heated at reflux for 1.5 hours. After cooling, the mixture if filtered through a little kieselguhr and the solvent is removed under reduced pressure. This gives 2.24 g (9.44 mmol, 72% yield) of the product as a colourless solid.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:37][C:38]2[CH:43]=[N:42][NH:41][C:40](=[O:44])[CH:39]=2)=[N:34][CH:35]=1>>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:41]2[C:40](=[O:44])[CH:39]=[C:38]([O:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=3)[CH:43]=[N:42]2)=[C:19]([CH3:26])[CH:20]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: COc1ccc(COc2cn[nH]c(=O)c2)nc1
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Yield: 70 %

Procedure:
2-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9b) instead of 4-benzyloxy-1H-pyridin-2-one.