Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17]>CN(C=O)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][N:3]3[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]3[CH3:1])[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Cc1c[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N2CCN(c3ccc(Cl)cc3)CC2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-dimethylimidazole (0.633 g, 0.7 mmol) was taken up in dry DMF (15 ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added and the reaction mixture was stirred at room temperature for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration gave material that was purified on a silica gel column (CHCl3/MeOH): 1H NMR (300 MHz, CDCl3): δ 7.25 (d, 2H), 6.80 (d, 2H), 6.53 (s, 1H), 4.62 (s, 2H), 3.78 (br, 2H), 3.59 (br, 2H), 3.21 (br, 4H), 2.31 (s, 3H), 2.17 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19].O>N1C=CC=CC=1>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)=[O:22]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Amino-6-chloropyridazine (516 mg) was dissolved in pyridine (26 mL), and to the solution were sequentially added triethylamine (665 mL) and methyl chlorooxoacetate (441 μL) under ice cooling, followed by stirring at room temperature for 14 hours. Water was added to the reaction mixture to partition the mixture, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (748 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[H]1[BH2][H][BH2]1.C1COCC1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A cold (0° C.) solution of 4-(3-bromophenyl)butyric acid (2.85 g, 11.7 mmol) in THF was treated slowly with a solution of B2H6-THF (35 mL), stirred at room temperature for 18 hours, poured into ice/water, basified with 2.5 N NaOH to pH=11 and extracted with CH2Cl2. The extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by column chromatography using hexanes/CH2Cl2/MeOH (4/4.5/0.5) as the eluting solvent afforded 4-(3-bromophenyl)butan-1-ol as a colorless oil (1.9 g, 70% yield. m/e (M)+ 228; 1H NMR (400 MHZ, DMSO-d6) δ ppm, 1.3-1.4 (m, 2 H) 1.5-1.6 (m, 2 H), 2.55-2.59 (m, 2 H), 3.3-3.38 (m, 2H), 4.3 (t, J=7.5, 1H), 7.2-7.2 (m, 1 H), 7.3 (t, J=7.5 Hz, 1 H), 7.4-7.4 (m, 1 H), 7.4-7.4 (m, 1 H).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:23]\[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=2)/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(/C=C2\NC(=O)CN(C(C)=O)C2=O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (10.0 g, 50 mmol), prepared by the published procedure mentioned in Example 3, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120° C. After 21/2 h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.CCN(C(C)C)C(C)C.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[OH:39]>CC(N(C)C)=O.CCOC(C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:32][C@@H:33]4[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]4[OH:39])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.3 g, 3.96 mmol) from Step 5 of this Example in DMA (6 mL) were added DIEA (511 mg, 3.96 mmol) and (1R,2R)-2-aminocyclohexanol (1.36 g, 11.9 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. for 6 h. After cooling to rt, the mixture was diluted with 120 mL of EtOAc and washed with 120 mL of water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of acetone-EtOAc (1:12, v/v) as eluent to give (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as an off white solid (864 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.17-7.35 (m, 3H), 5.49 (s, 2H), 4.73 (d, J=5.3 Hz, 1H), 3.52 (d, J=8.5 Hz, 1H), 3.32 (br s, 1H), 1.76-2.12 (m, 2H), 1.61 (br s, 2H), 1.07-1.38 (m, 4H). LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1(=[O:26])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([OH:15])=[O:14])[C:10](=[O:21])[C:9]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:8]12.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:10]1(=[O:21])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([O:15][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])[C:7](=[O:26])[C:8]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:9]12
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of cesium carbonate (3.819 g, 11.7 mmol.) and (S)-2-phthalimido-6-hydroxyhexanoic acid (6.00 g, 21.6 mmol.) in dimethylformamide (60 ml.) was treated with benzyl bromide (3.30 ml., 4.75 g., 27.7 mmol.). After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic extract was washed with water (twice) and brine, then dried (sodium sulfate), filtered and stripped to give an oil. The oil was flash chromatographed (Merck silica gel, 6/4-ethyl acetate/hexane) to give essentially pure product as a solid. Recrystallization from ethyl acetate/hexane gave 7.173 g. (1st crop) and 394 mg. (2nd crop) for a total of 7.567 g. of pure title product; m.p. 106°-108.5° C.; [α]D =-27.5° (c=1.5, methanol). TLC (75/25 ethyl acetate/hexanes) Rf =0.43.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[P:16]([O-:23])(OCC)OCC.Cl>O1CCCC1.C1(C)C=CC=CC=1.O>[C:5]1([CH3:6])[CH:13]=[CH:14][C:9]([PH:16](=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:10][CH:11]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1ccc(Br)cc1
Reactant: BrCCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc([PH](=O)c2ccc(C)cc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
In a stream of nitrogen, a solution of magnesium (58.41 g, 3.48 equivalents), a slight amount of iodine and 1,2-dibromoethane in tetrahydrofuran (400 mL) was stirred at room temperature for 1 hour. After addition of a solution of p-bromotoluene (411.11 g, 3.48 equivalents) in tetrahydrofuran (2000 mL) at 22° C., the mixture was stirred at 40° C. for 1 hour. Then, after addition of a solution of diethyl phosphite (94.76 g, 0.69 mol) in tetrahydrofuran (160 mL) at 20° C., the mixture was stirred at 24° C. for 30 minutes. 6M-HCl (320 mL) was added thereto at 4° C., followed by further addition of water (320 mL) and toluene (1000 mL), and the resulting mixture was stirred at a room temperature for 30 minutes. The reaction mixture was separated into layers, and the organic layer was successively washed with water (320 mL), an aqueous 5% NaHCO3 solution (320 mL) and an aqueous 5% NaCl solution (320 mL). The organic layer was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from n-hexane and dried (under reduced pressure at 40° C.) to obtain the titled compound (87.12 g, white powder). The yield was 54.8%.
Reaction SMILES: N1C=CC=NC=1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[C:20]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:19][N:18]=[C:17]([CH2:26][NH:27][CH2:28][CH2:29][NH:30]C(=O)C(F)(F)F)[N:16]=1.[OH-].[K+].O>CO>[NH2:30][CH2:29][CH2:28][NH:27][CH2:26][C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[Cl:7])[C:20]([C:21]2[NH:25][CH:24]=[CH:23][N:22]=2)=[CH:19][N:18]=1
Reactant: O=C(NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1cncnc1
Solvent: CO
Product: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The aforementioned pyrimidine, N-(2-{[4-(2,4-dichlorophenyl)-5-imidazolyl-pyrimidin-2-yl]methylamino}ethyl)-2,2,2-trifluoroacetamide (114 mg, 0.25 mmol) was dissolved in 2 mL methanol and potassium hydroxide (40 mg, 1 mmol) added. This suspension was stirred at room temperature for 1 hour. Water was added, and the solution extracted with methylene chloride. The aqueous layer was thoroughly extracted with methylene chloride and the organic layers washed with brine, dried and concentrated to give the deprotected primary amine, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine, in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Fc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)ccc1C(F)(F)F
Yield: 63.3 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl -acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 63%). MS (ISP) 427.0 [(M+H)+]; mp 162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-].[ClH:10]>>[Cl:10][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=1
Reactant: Cl
Reactant: Cc1cccc(C)[n+]1[O-]
Product: Cc1cc(Cl)cc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of concentrated HCl (10 ml) at 10° C. was added 2,6-dimethylpyridine N-oxide (3.0 g, 24.3 mmol) and the resulting white slurry was stirred at room temperature for 3 hours. The product was filtered and washed with iPrOH (2×10 ml) and dried at reduced pressure. The resulting solid was dissolved in POCl3 (10 ml) and heated at reflux for 8 hours then cooled to 0° C. The reaction was quenched carefully with saturated K2CO3 (40 ml) and extracted with dichloromethane (2×50 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was dissolved in ethanol (20 ml) and NEt3 (5 ml) and heated at reflux for 24 hours then cooled to room temperature and concentrated at reduced pressure. Water (5 ml) was added to the residue the aqueous mixture was extracted with chloroform (2×10 ml). The organics were combined and washed with brine (10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound as brown solid (1.0 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:37]=[CH:36][C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Clc1ncc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ncc6ccccc6n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-quinazoline following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 50° C. LC (method 3): tR=0.53 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)C>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:21][CH:20]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Yield: 69.1 %

Procedure:
Treatment of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.567 g) with methanesulphonyl chloride (0.263 g) in pyridine (18 ml) according to the method of Example 1 gave the title compound, (0.50 g), m.p. 214°-215° (from ethanol).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:32]1[CH2:33][CH2:34][N:29]([CH2:24][C:23]2[CH:22]=[C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccc(CN3CCOCC3)c1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.11 mmol), morpholine (28 mg, 0.33 mmol) and acetic acid (33 mg, 0.55 mmol) in methanol (50 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (31 mg, yield 66%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.23-2.24 (m, 4H), 3.32-3.43 (q, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.19 (m, 6H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 1H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 439(M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH:25]=O)[NH:22][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1cc(C=O)[nH]n1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C)n[nH]1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 3-methyl-1H-pyrazole-5-carbaldehyde 93 (70.8 mg, 0.404 mmol). PTSA (153.8 mg, 0.808 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 94 and was purified through flash chromatography by using 100-200 mesh silica gel eluting at 2% MeOH in DCM to afford yellow coloured solid compound (E)-6-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methylene)-5-morpholino-2, 3-dihydro-1H-inden-1-one 94.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].[N+:23]([CH3:26])([O-])=O.Cl>O1CCCC1.C(O)C.[C].[Pd]>[NH2:23][CH2:26][C:16]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([OH:17])[C:15]([F:22])([F:21])[F:14]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1
Reactant: C[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Product: NCC(O)(c1ccc(F)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
n-Butyllithium (2.66 M solution in hexane, 12.4 mL, 33.0 mmol) was added dropwise to 1-bromo-4-fluorobenzene (5.25 g, 30.0 mmol) in tetrahydrofuran (50 mL) cooled to −78° C., and the reaction mixture was stirred at −78° C. for 30 minutes, mixed with ethyl 2,2,2-trifluoroacetate (4.64 mL, 45 mmol) at −78° C. and then stirred for another 30 minutes while the temperature was gradually raised to room temperature. The reaction mixture was stirred with nitromethane (3.25 mL, 60 mmol) at room temperature for 30 minutes. The resulting reaction mixture was added to 1 M hydrochloric acid (50 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v/)) to give a colorless oil. The colorless oil was dissolved in ethanol (25 mL) and stirred with 10% palladium-carbon (1 g) at room temperature for one day under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (4.52 g, yield 68% (three steps)).
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:19]([CH3:29])[CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C@H:19]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:22](=[O:24])[NH:21][CH2:20]1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (4.9 g, 12 mmol) was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (18.3 mL) at 0° C. After removal of the ice bath, the solution was stirred for 30 min, and evaporated under reduced pressure. The residue was dissolved in methanol (40 mL), then after addition of saturated sodium bicarbonate solution (90 mL) the mixture was stirred for 20 h at room temperature. Water (100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography on silica gel with hexane/ethyl acetate (1:1) yielded the title compound as a white solid (2.9 g, 90%). M.p.: 201–204° C., EI-MS: m/e=268.2 (M+), αD20=+7.5
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17]#[N:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17](=[S:1])[NH2:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12
Reactant: S
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 70 h
Yield: 67 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 5.0 g (0.020 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark brown solution was left to stand for 70 hrs., then degassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was chromatographed over silica gel with ethyl acetate as the eluent, stirred vigorously in ether for 16 hrs. and subsequently filtered off under suction. There were obtained 3.8 g (67%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo-[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 227°-230° and [α]D20 =-473.7° (DMF, c=1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
An ice-cooled solution of 4-bromophenol (69.2 g) and cinnamoyl chloride (66.8 g) in dichloromethane (150 ml) was treated with triethylamine (40.6 g). After stirring for 18 hrs at room temperature the mixture was washed with water (250 ml), 1 M aqueous HCl, and dried over anhydrous sodium sulphate. Evaporation in vacuum left solid 3-phenylacrylic acid 4-bromophenyl ester (121.0 g, 99.8% yield), m.p. 113.3° C., tlc: (1) 0.83. NMR (CDCl3) 116.85, 118.87, 123.49, 128.38, 129.06, 130.90, 132.49, 134.02, 147.07, 149.84, 165.06.