Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[N:21]([CH2:22][C:23]2[S:27][C:26]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:25]=3[CH:24]=2)[C:11]2=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]2[CH:9]=1)=[O:7])C.Cl>O.C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:25]2[CH:24]=[C:23]([CH2:22][N:21]3[C:11]4=[CH:12][N:13]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=[C:10]4[CH:9]=[C:8]3[C:6]([OH:7])=[O:5])[S:27][C:26]=2[CH:28]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc2ccc(Cl)cc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1cc2cc(C(=O)O)n(Cc3cc4ccc(Cl)cc4s3)c2cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8 mL of a 1M LiOH solution in water were added to solution of 890 mg (2 mmol) 1-(6-Chloro-benzo[b]thiophen-2-ylmethyl)-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 30 mL THF and 15 mL MeOH and the mixture was stirred for 1 h at 50° C. 16 mL of 1N HCl were added, the organic solvent removed in vacuo and the residue extracted with ethyl acetate. The organic phase was dried over MgSO4. After filtration the solvent was evaporated yielding the desired product. Yield: 810 mg.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:10][S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Br:25]Br>C1COCC1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[N:10][S:11][C:12]=1[Br:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)c1csnc1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8 (3.50 g) in THF (60 ml) is cooled to −78° C. under N2 followed by drop wise addition of BuLi (8.0 ml, 1.6M in hexane). After complete addition stirring is continued at −78° C. for 15 min. Bromine (1.2 ml) is now added drop wise and stirring is continued at −78° C. for 15 min, after which the cooling bath is removed. The mixture is allowed to warm to room temp. TLC shows a good conversion into a slightly faster moving spot (Hep/EA, 9/1). 1N HCl (50 ml) is added and the THF is removed in vacuo. Water (100 ml), containing some sodium thiosulfate, is added and the product is extracted with EtOAc (150 ml). The organic layer is washed with sat. NaHCO3, brine, dried and concentrated. The orange/red oily residue is purified by flash column chromatography (˜50 g silica, 5% diisopropyl ether in heptane) yielding 3.1 g of 9 as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[CH3:29][O:30][C:31]1[C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[NH2:1][C:2]1[C:3]([C:34]2[CH:35]=[C:36]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:31]([O:30][CH3:29])=[N:32][CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(Br)c3c(=O)n2-c2ccccc2)cc1NS(C)(=O)=O
Yield: 10 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.16 mmol) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (80 mg, 0.24 mmol) were stirred at 80° C. following the experimental procedure described in Example 3. 10 mg (3% yield) of the title compound were obtained as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([F:21])=[CH:18][C:17]=3[F:22])[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethyl-pyridine-4-carbaldehyde (0.99 g, 7.32 mmol) and 2-amino-4,6-difluorobenzamide (1.26 g, 7.32 mmol) in N,N-dimethyl acetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.59 g, 8.78 mmol) and p-toluenesulfonic acid (0.21 g, 1.09 mmol). The reaction mixture was stirred at 115° C. for 16 hours under nitrogen. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (50 mL) was added, the precipitated solid was filtered, washed with water, and dried under vacuum, to give 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a yellow solid. Yield: 0.63 g (30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 ml dichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 25 ml dichloromethane. To this mixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.95 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless solid (4.5 g, 45% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.34 (s, 1H), 7.75 (dd, J=9.4, 3.1 Hz, 1H), 7.42 (m, 2H), 7.12 (m, 3H), 7.05 (dd, J=9.0, 4.5 Hz, 1H), 4.47 (s, 2H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[BrH:20]>O.C(O)C>[Br:20][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)c1cc(N)cc2ccccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Br)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.34 g (62.9 mmol) of sodium nitrite in 40 mL of water was added dropwise to a 0° C. solution of 11.5 g (57.2 mmol) of the above methyl 3-amino-1-naphthoate in 300 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid while maintaining an internal reaction temperature below 10° C. After complete addition of the aqueous solution the resulting dark red reaction mixture was stirred at 0° C. for an additional 30 min. The cooled (0° C.) reaction mixture was then added over 20 min. to a suspension of 8.21 g (57.2 mmol) of cuprous bromide in 60 mL of ethanol and 60 mL of 48% aqueous hydrobromic acid heated to 95° C. After stirring for 30 min. the reaction mixture was cooled to 0° C. and carefully partitioned between ethyl ether (250 mL) and water (600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl ether (2×300 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel eluting with 30% dichloromethane in hexanes and the filtrate concentrated in vacuo. Flash chromatography on a Biotage® purification apparatus (silica gel, 7% dichloromethane/hexanes) yielded the title compound as a colorless solid. 1H NMR (DMSO-d6): δ 8.67 (d, J=8.4 Hz, 1 H), 8.50 (s, 1 H), 8.15 (s, 1H), 8.02 (d, J=8.0 Hz, 1 H), 7.68-7.71 (m, 1 H), 7.63-7.66 (t, J=7.6 Hz, 1 H), 3.94 (s, 3 H). LC/MS 265.0 (M+1) and 267.0 (M+3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:50][CH2:51][C@@:52]([OH:59])([C:55]([F:58])([F:57])[F:56])[CH2:53][OH:54]>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:50][CH2:51][C@:52]([OH:59])([CH2:53][OH:54])[C:55]([F:58])([F:57])[F:56])=[O:16]
Reactant: NC[C@](O)(CO)C(F)(F)F
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1c(C(=O)NC[C@](O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.4 %

Procedure:
5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (104 mg) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (0.33 ml) was added followed by the addition of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (196 mg). The reaction was stirred at room temperature, under nitrogen, for 20 minutes. (S)-2-(Aminomethyl)-3,3,3-trifluoro-1,2-propanediol (90 mg) in dry dimethylformamide (2 ml) was added and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml) and the separated aqueous phase was re-extracted with ethyl acetate (50 ml). The combined organics were washed with water, 1M hydrochloric acid, 10% lithium chloride solution (2 times), bicarbonate and brine. The organics were dried using a hydrophobic frit and evaporated to give a pale yellow oil (200 mg). This was dissolved in dichloromethane (ca. 5 ml) and left to stand at room temperature for 4 hours wherein a precipitate formed. The precipitate was filtered and washed with a small amount of dichloromethane to give the title compound as a white solid (93 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:8][C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)#[N:2].Cl>[Pd].C(O)C>[NH2:2][CH2:1][C:3]1[N:4]([CH2:8][C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: N#Cc1nccn1Cc1ccoc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1nccn1Cc1ccoc1

Procedure:
Place 4.0 g (0.021 mol) 2-cyano-1-(3-furylmethyl)-1H-imidazole, 20 ml ethanolic HCl, 20 ml ethanol and 1 g 10% Pd/C in a Parr hydrogenator with an initial pressure of 52 psi. After 18 hours remove the reaction mixture from the Parr hydrogenator, add 20 ml H2O, remove the catalyst by filtration, concentrate the filtrate to obtain an off-white solid which is recrystallized from ethanol containing a little concentrated HCl to give the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:5]([C:6]([NH:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=O)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:1][C:2]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:5]([CH2:6][NH:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nccn1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A suspension of 200 mg of 1-(4-hydroxy-3,5-di-tert.-butylbenzoylamino)-2-methyl-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is treated under an inert gas with 1.2 ml of a 2N borane-dimethyl sulfide complex solution in toluene. The mixture is then heated at reflux for 4 hours, left to cool to 0°, treated with methanolic hydrochloric acid (5 ml of methanol and 0.5 ml of conc. HCl), and again heated at reflux for 1 hour and evaporated in a vacuum. The residue is taken up in 4 ml of water and saturated sodium bicarbonate solution is added until the pH amounts to 8-9. The mixture is extracted three times with 5 ml of methylene chloride each time and, after drying, the combined methylene chloride phases are evaporated. The residue is recrystallized from cyclohexane and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-methylimidazole of m.p. 180°.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33]CC)=[O:32])C1C=CC=CC=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([N:10]1[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([OH:33])=[O:32])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(OCc3ccc4ccccc4n3)cc2n1Cc1ccccc1
Reactant: BrCc1ccccc1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared using analogous conditions described in Example 64 using ethyl 3-(1-benzyl-6-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate and (bromomethyl)benzene in Step A. MS (ESI): mass calcd. for C29H27N3O3, 465.21; m/z found, 466.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.13-7.94 (m, 2H), 7.80-7.65 (m, 2H), 7.63-7.47 (m, 2H), 7.34-7.04 (m, 4H), 6.99-6.73 (m, 4H), 5.21 (s, 4H), 3.03 (s, 2H), 1.14 (s, 6H).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4C)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1.[H-].[Na+].[CH:47]1C=CC(CBr)=CC=1>CO>[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:39]=[CH:40][CH:41]=[C:42]([CH3:47])[CH:43]=4)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1ccccc1C
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1cccc(C)c1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Hydrogen chloride was bubbled through 29 (2.00 g, 6.16 mmol) in anhydrous MeOH (44.0 mL) for 3 minutes at room temperature, then the solution was stirred at 50° C. for 5 minutes. The solvent was concentrated and the residue placed under high vacuum for 6 hours to ensure complete removal of MeOH. The yellow residue was dissolved in anhydrous dimethylformamide (44.0 mL) and cooled to 0° C., then NaH (997 mg, 24.93 mmol) was added. After 15 minutes, BnBr (1.20 mL, 1.73 g, 10.09 mmol) was added and the reaction was warmed to room temperature over 18 hours. Reaction contents were partitioned between saturated aqueous NaHCO3 (500 mL) and EtOAc (500 mL), then extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 9:1 Hexanes:EtOAc) to give 30 as a light orange solid containing greater than 80% 3-bromo isomer (1.70 g, 88%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:16].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](=[NH:29])OCC>C(O)C>[ClH:16].[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: Nc1ncccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1ccccc1
Yield: 16.3 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (4.0 g, 20 mmol) and ethyl 2-methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 1 hour. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol 10:1). The product was obtained as a white crystalline solid (1.2 g), m.p. 119°-120° C.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=CNNc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
68.2 g of 1-formyl-2-(4-aminophenyl)hydrazine and 60 ml of triethylamine were dissolved in 500 ml of acetonitrile. To the resulting solution, 70 g of 3-nitrobenzoyl chloride was added dropwise with stirring while keeping the solution temperature at less than 50° C., by which crystals precipitated. After being heated to 60° C. for a further 2 hours, it was cooled and poured into water. Crystals were filtered off and recrystallized from ethanol to obtain 72.8 g of 1-formyl-2-(4-(3-nitrobenzamido)phenyl)hydrazine. Yield: 54%. Melting point: 185°-187° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=4[Cl:28])[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:6][C:5]=1[F:29].[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:28][C:21]1[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[CH2:19][N:16]1[C:14]2=[N:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=3)=[CH:11][CH:12]=[C:13]2[N:18]=[N:17]1
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4c(F)ccc(F)c4Cl)c3n2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4c(F)ccc(F)c4Cl)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.5 %

Procedure:
To a solution of Example 17 (0.300 g, 0.725 mmol) in methanol (1 ml), THF (2 ml), sodium hydroxide (0.150 g, 3.75 mmol) in water (1 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.120 g, 41%). M.P.: 211-213° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.65 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.02 (m, 2H), 7.83 (t. J=7.4 Hz, 1H). 7.60 (dt, J=9.1, 4.8 Hz, 1H), 7.46 (dt, J=9.0, 4.0 Hz, 1H), 6.11 (s, 2H), MS (m/z): 418.70 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([Cl:23])=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cc2nnc(Cl)c3ccccc23)cc1

Procedure:
To 4-(4-methoxybenzyl)phthalazin-1(2H)-one (1.18 g, 4.43 mmol) was added phosphorus oxychloride (4.13 ml, 44.3 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 15 hours. The reaction was concentrated in vacuo, diluted with methylene chloride and ice water, then quenched with solid sodium bicarbonate until pH was basic and gas evolution ceased. The layers were separated and the organic layers were dried over sodium sulfate, filtered through a pad of silica gel using EtOAc and concentrated to yield 1-(4-methoxybenzyl)-4-chlorophthalazine as a light orange solid. MS m/z=285 [M+1]+. Calc'd for C16H13ClN2O: 284.75.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:26][CH2:27][CH3:28])=[C:11]([C:13]2[NH:14][C:15](=[O:25])[C:16]3[CH:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:17]=3[N:18]=2)[CH:12]=1.[C:29](=[O:31])=[O:30].[Cl-].[NH4+]>C1COCC1>[CH2:27]([O:26][C:10]1[CH:9]=[CH:8][C:7]([C:29]([OH:31])=[O:30])=[CH:12][C:11]=1[C:13]1[NH:14][C:15](=[O:25])[C:16]2[CH:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:17]=2[N:18]=1)[CH3:28]
Reactant: O=C=O
Reactant: CCCn1ncc2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)O)ccc3OCC)nc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
n-Butyllithium (2.5 M solution in hexane, 2.0 ml, 0.005 mol) was added dropwise to a stirred solution of 6-(5-bromo-2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one (0.755 g, 0.002 mol) in dry THF (20 ml) at −78° C. under a dry nitrogen atmosphere. The bright yellow solution was stirred for 1 hour at −78° C., then excess crushed solid carbon dioxide was added and the resulting solution was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (3 ml) was then added and the solvents removed by evaporation under vacuum. The residue was partitioned between saturated aqueous sodium carbonate solution (30 ml) and dichloromethane (30 ml), the organic phase was removed and the aqueous phase extracted with further dichloromethane (3×30 ml). The aqueous phase was then acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (5×40 ml). The combined ethyl acetate extracts were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a white solid. Crystallisation from ethyl acetate-methanol gave the title compound as a white powder (0.130 g, 19%), m.p. 277-279° C. Found: C,59.64; H,5.19; N,16.39. C17H18N4O4 requires C,59.64; H,5.23; N,16.37%.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:24]
Reactant: CCNCc1ccc2ccccc2n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: CCN(Cc1ccc2ccccc2n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-2-ylmethyl-amine
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[N:9](CC2C=CC(OC)=CC=2)[C:8]([CH3:20])([CH3:19])[CH2:7][C:6](=[O:21])[CH2:5]1)[CH3:3].C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[OH:1][C@H:2]([C@H:4]1[NH:9][C:8]([CH3:20])([CH3:19])[CH2:7][C:6](=[O:21])[CH2:5]1)[CH3:3]
Reactant: COc1ccc(CN2[C@H]([C@H](C)O)CC(=O)CC2(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](O)[C@@H]1CC(=O)CC(C)(C)N1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of (S)-6-((S)-1-hydroxyethyl)-1-(4-methoxybenzyl)-2,2-dimethylpiperidin-4-one (0.28 g, 0.96 mmol) in MeOH (40 mL) was added acetic acid (0.055 mL, 0.96 mmol) and palladium hydroxide (0.13 g, 0.96 mmol). After degassing, the mixture was stirred overnight under hydrogen. The mixture was filtered through the celite, washed with MeOH (20 mL), and concentrated in vacuo to give 0.11 g (67%) of (S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-one which was used in the next step without purification.