Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH:7][CH:8]=[O:9])=[CH:5][CH:4]=[C:3](I)[CH:2]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:50])[CH2:42][C:43]([CH3:49])([CH3:48])[C:44]([O:46][CH3:47])=[O:45])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.CN(C)C=O>[CH:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:35]2[CH:36]=[CH:37][C:38]([C:41](=[O:50])[CH2:42][C:43]([CH3:48])([CH3:49])[C:44]([O:46][CH3:47])=[O:45])=[CH:39][CH:40]=2)=[CH:2][CH:1]=1)=[O:9]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Reactant: O=CNc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(NC=O)cc2)cc1
Temperature: 80 °C

Procedure:
To a 2-L three-necked round-bottomed flask, were charged 4-iodoformanilide (30.0 g, 121 mmol, 1.0 eq), bis(pinacolato)diboron (30.8 g, 121 mmol, 1.0 eq), palladium acetate (0.82 g, 3.6 mmol, 3 mol %), potassium acetate (35.70 g, 364.3 mmol), and 500 mL N,N-dimethylformamide. The mixture was degassed by gently bubbling argon through the solution for 30 minutes at rt. The mixture was then heated at 80° C. under argon until the reaction was complete (2-3 hours). After the mixture was cooled to rt, methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (36.3 g, 121 mmol), cesium carbonate (59.4 g, 182 mmol), and palladium tetrakistriphenylphosphine (4.2 g, 3.6 mmol, 3 mol %) were added. The reaction mixture was then heated at 80° C. overnight under argon. The mixture was cooled to rt, and slowly diluted with water (1.5 L), which caused solid material to precipitate. The solids were removed by filtration, and washed with 500 mL water. Then the solids were dissolved in 500 mL methylene chloride, and black particles were removed by passing the solution through a pad of Celite®. The filtrate was washed with 150 mL water (2×). After the solution was dried over sodium sulfate, the solution was concentrated under reduced pressure to afford a dark, brown residue. The residue was stirred in ethyl acetate (200 mL) and hexane (200 mL) for 1 h. After filtration and drying, methyl 4-[4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate was obtained as a yellow solid (28.0 g, 68%). 1H NMR (CDCl3) δ 8.42 (d, J=2 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.62 (m, 6H), 3.70 (s, 3H), 3.33 (s, 2H), 1.35 (s, 6H) and 40% tautomer; ESI-MS m/z 340.1 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20](N4CCN(C(=O)C)CC4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.NC1C=CC([C:37]([OH:39])=[O:38])=CC=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:37]([OH:39])=[O:38])=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: NCC1CCN(c2nc(Nc3ccc(C(=O)O)cc3)ncc2F)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 4-aminobenzoic acid. MS 346.2 (M+H); UV 215.8, 275.8, 292.8 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:10]1[N:11]=[C:12]([CH:14]2[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]2)[O:13][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCC(c2ncc(Sc3ccc(Cl)cc3)o2)CC1
Solvent: ClCCl
Product: COC(=O)C1CCC(c2nc(Br)c(Sc3ccc(Cl)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of methyl 4-{5-[(4-chlorophenyl)sulfanyl]-1,3-oxazol-2-yl}cyclohexanecarboxylate (3.762 g, 10.69 mmol) in DCM (107 ml) was added NBS (2.093 g, 11.76 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 330 g, 0 to 25% EtOAc in hexane), to give methyl 4-{4-bromo-5-[(4-chlorophenyl)sulfanyl]-1,3-oxazol-2-yl}cyclohexanecarboxylate (3.5 g), as a ca. 2:1 mixture of trans/cis isomers. LCMS: M+H 430.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].N[C@H:33](C1C=CC=CC=1)CCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.C(Cl)(=O)CC>>[CH3:23][CH:22]([CH3:24])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][C@@H:5]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:4][C:1](=[O:3])[CH2:2][CH3:33])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Agent: CCC(=O)Cl
Product: CCC(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Yield: 97 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[(3S)-3-(acetylamino)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide, N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and propionyl chloride (3.80 mg, 0.0420 mmol) provided 2-methyl-N-(3-{1-[(3S)-3-phenyl-3-(propionylamino)propyl]-4-piperidinyl}phenyl)propanamide (12 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.59 (s, 1H), 7.40–7.20 (m, 7H), 6.96 (s, 1H), 5.19–5.12 (m, 1H), 3.18 (d, 1H, J=12.0 Hz), 2.99 (d, 1H, J=10.4 Hz), 2.93–2.86 (m, 1H), 2.61–2.40 (m, 3H), 2.38–2.23 (m, 3H), 2.19–1.75 (m, 8H), 1.25 (d, 6H, J=6.9 Hz), 1.22–1.08 (m, 3H); ESMS m/e: 436.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cccnc3F)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(-c3cccnc3F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: BrCC1C=CC=CC=1[C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2.[Br-].C([N+]1C=CC(C2C=C[NH+]=CC=2)=CC=1)CCC.[Br-]>C(#N)C>[CH:11]1[C:10]2[C:15](=[N:16][C:17]3[C:22]([CH:9]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1-c1c2ccccc2nc2ccccc12
Agent: CCCC[n+]1ccc(-c2cc[nH+]cc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: c1ccc2nc3ccccc3cc2c1
Yield: 35 %

Procedure:
A solution of 9-(2-bromomethylphenyl)acridine (1-5 mmol) and 1-butyl-4,4′-bipyridinium bromide (1-5 mmol) in the ratio of 1:1 in dry acetonitrile (30-120 mL) was stirred at 50° C. for 15h. The precipitated solid thus obtained was filtered, washed with dry acetonitrile and dichloromethane to remove any unreacted starting materials. The solid was further purified by soxhlet extraction with dichloromethane to give compound of formula 1c (wherein n=1, R=—MV2+—(CH2)3—CH3, X=Br and acridine is at the ortho position) in 35-55% yield and the product was further purified by recrystallization from ethyl acetate. Similarly, the reaction of 9-(4-bromomethyl phenyl)acridine (1-5 mmol) and 1-butyl-4,4′-bipyridinium bromide (1-5 mmol) in the ratio of 1:1 in dry acetonitrile (30-120 mL) gave compound of formula 1c (wherein n=1, R=—MV2−—(CH)3—CH3, X=Br and acridine is at the para position) in 55-70% yield and the product was further purified by recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:33][C:34]1([NH:38][CH3:39])[CH2:37][NH:36][CH2:35]1>>[CH2:18]([N:8]1[C:7]2[N:6]=[C:5]3[CH:20]=[C:21]([N:36]4[CH2:37][C:34]([CH3:33])([NH:38][CH3:39])[CH2:35]4)[C:2]([F:1])=[CH:3][C:4]3=[CH:13][C:12]=2[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]1)[CH3:19]
Reactant: CNC1(C)CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(NC)C4)cc3nc21
Yield: 61.4 %

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b]-[1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. 1.18 g of 1-ethyl-7-fluoro-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 338° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[CH:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: OCc1cccc2cc[nH]c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Indole-7 carboxyldehyde (I-1). Ethyl Indole-7 m carboxylate was prepared according to literature procedure {Batcho B. and Leimgruber, K., Org. Syn. Vol IIV, page 34-40). To a solution of methyl 7-indolecarboxylate (13 g, 74.2 mmol) in 250 ml of anhydrous THF was added LiAlH4 (10.9 g, 0.288 mol) in portions, and reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the excess hydride was quenched by addition of water (12 mL), 15% NaOH (12 mL) and water (26 mL). The solids were removed by filtration through a pad of Celite and filtrate was evaporated in vacuo to yield (1H-indol-7-yl)-methanol (10.7 g, 98%). 1HNMR (CDCl3). To a solution of the alcohol, (1H-indol-7-yl)-methanol (8.0 g, 54.3 mmol) in 400 mL of methylene chloride was added activated manganese (IV) oxide (85%, 41.0 g, 0.40 mol), and stirred at ambient temperature for 72 h. After additional of 200 mL of methylene chloride and 400 mL of methanol to the reaction mixture, the whole mixture was filtered through a pad of silica gel to remove solid materials. The filtrate was concentrated to afford a crude product, which was purified by a column chromatography on silica gel to yield 1H-indole-7-carbaldehyde, I-1 (6.55 g, 83%). 1HNMR (CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].N[C:29]1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2[CH:30]=1.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:29][CH3:30])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1cc2nc(-n3cc(C(=O)OCC)cn3)n(COCCOC)c2cc1Cl
Temperature: 23 °C
Reaction time: 7.5 h

Procedure:
To a slurry of 4 Å molecular sieves (1.2 g) and 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol), and ethanol (3 mL) was added acetaldehyde (0.500 mL, 8.91 mmol) at 0° C. in a sealable microwave tube. The tube was sealed and the reaction mixture was allowed to warm to 23° C. over 16 h. The reaction mixture was heated at 60° C. for 1 h. The molecular sieves were removed from the resulting solution by filtration and the filtrate was concentrated under reduced pressure. Sodium triacetoxy borohydride (0.242 g, 1.14 mmol), THF (3 mL), and glacial acetic acid (0.04 mL) were added to the residue and the resulting suspension was stirred for 7.5 h at 23° C. The reaction mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate and EtOAc (35 mL). The aqueous layer was further extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.169 g, 47% crude yield). This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C19H24ClN5O4, 421.2; m/z found, 422.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[OH:37])[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(O)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 71.5 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(4-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (2 g; 4.07 mmol), 4-(3-chloropropyl)morpholine (1.66 g; 2.5 equiv.) and caesium carbonate (8.3 g; 6.25 equiv) in DMF was heated at 90° C. overnight then evaporated. The residue was dissolved in EtOAc, washed with brine, dried (MgSO4) and evaporated. Purification of the crude material using a Biotage SP4 (40S, 40 ml/min), using gradient elution form 0% to 10% MeOH/EtOAc gave 1.8 g of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone as a pale yellow gum. MS: [M+H]+ 619.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:14])O[C:8](C)(C)[O:9][C:10]=1[CH3:11])[CH:2]([CH3:4])[CH3:3].C=[N:16][C:17]([CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH3:18]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[C:6](=[O:14])[N:16]([C:17]([CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:18])[CH2:8][O:9][C:10]=1[CH3:11])[CH:2]([CH3:3])[CH3:4]
Reactant: CC1=C(CC(C)C)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1cccc(Cl)c1
Solvent: Cc1ccccc1C
Product: CC1=C(CC(C)C)C(=O)N(C(C)(C)c2cccc(Cl)c2)CO1
Yield: 54.3 %

Procedure:
Xylene (1 ml) was added to a mixture of 5-isobutyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.59 g) and N-methylene-1-methyl-1-(3-chlorophenyl)ethylamine (0.55 g), and the resulting mixture was heated at reflux for 60 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.52 g).
Reaction SMILES: CCC([O-])(C)C.[K+].[N:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=O)=[N:10][CH:9]=1.Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C1(C)C=CC=CC=1.O>[O:16]=[C:14]([C:11]1[CH:12]=[CH:13][N:8]=[CH:9][N:10]=1)[CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1ccncn1
Reactant: CCOC(C)=O
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccncn1
Yield: 76 %

Procedure:
To a 25% solution (5.31 g, 10.52 mmol) of potassium tert-amylate in toluene was added dropwise a solution of ethyl pyrimidine-4-carboxylate (1.00 g, 6.57 mmol) and ethyl acetate (1.09 mL, 11.1 mmol) in toluene (2.4 ml) at room temperature. Disappearance of the ethyl ester was confirmed by HPLC analysis, water (5 mL), ethyl acetate (5 mL) and concentrated hydrochloric acid (0.45 mL) were added, and the mixture was extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (0.97 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC#Cc1cc(Br)cnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
5-Bromo-3-prop-1-ynyl-pyridin-2-ylamine (91 g, 431 mmol) was treated with a 1M solution of potassium tert-butoxide in tert-butanol (700 mL) and the reaction mixture was heated at 85 OC for 1 hour. The mixture was then allowed to cool to ambient temperature and poured onto a 1:1 mixture of water/ice (ca. 1 L). The resultant precipitate was collected by filtration, washed with water and left to air dry. The resultant solid was dissolved in dichloromethane, dried (Na2SO4) and evaporated then triturated with diethyl ether to afford the title compound as a brown solid (88.7 g, 97%). 1H NMR (400 MHz, CDCl3): 10.21 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 6.13 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH:6]1[C:5]2[C:10](=[CH:1][C:2]3[C:3]([CH:4]=2)=[CH:3][CH:2]=[CH:1][CH:10]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 60 °C
Yield: 456.3 %

Procedure:
The resultant compound was dissolved in toluene (1 L) under a nitrogen atmosphere, and 2-naphthalenyl boronic acid (51.6 g, 0.3 mol), tetrakistriphenylphosphine palladium (9.3 g, 8.1 mmol), sodium carbonate (31.4 g, 0.3 mol), and water (300 ml) were added thereto. The reaction mixture was stirred under reflux for three hours. The reaction solution was cooled to about 60° C., filtered on silica gel, and extracted with toluene. The extracted solution was concentrated to remove an organic solvent, and methanol was added thereto. The resultant solid was filtered. The resultant yellowish brown matter was dissolved in methylene chloride, and methanol was dropwise added thereto to give an anthracene derivative (Cpd 1, 122 g, yield 85%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]([CH3:26])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:24]O)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]([CH3:26])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH2:24][C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)=N1
Yield: 51 %

Procedure:
A solution of 14.0 g (0.0356 mol) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-3-hydroxy-propionate in 250 ml of tetrahydrofuran was treated while gassing with argon with 9.3 g (0.0392 mol) of methoxycarbonylsulphamoyl-triethylammonium hydroxide internal salt (Burgess reagent) according to the method described in Tetr. Letters 1992, 33, 907. The mixture was boiled at reflux for 31/2 hrs. and completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted and chromatographed over silica gel with ethyl acetate/ethanol 19:1 as the eluent. There were obtained 6.80 g (51%) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate as white crystals; m.p. 216-218°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16]C(C2OC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(OCCN1CCN(C(=O)c2ccco2)CC1)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccco1)N1CCN(CCO)CC1
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a solution of 3.7 g of 1-(2-furanylcarbonyl)-4-(2-(2-furanylcarbonyloxy)ethyl)piperazine in 30 ml of methanol, 12.5 ml of a 3% aqueous solution of sodium hydroxide was added at room temperature. The resulting mixture was stirred for 40 minutes. After distilling off the methanol under reduced pressure, the residue was taken up in chloroform and then washed once with a saturated aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of chloroform and methanol) to give 2.3 g of an oily substance (yield: 82%).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][CH:18]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(I)C.[Na+].[Cl-]>CCCCCC.O1CCCC1>[CH2:1]([CH:20]1[S:19][CH:18]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:17]([CH2:16][CH2:15][N:14]([CH3:29])[CH3:13])[C:21]1=[O:22])[CH3:2]
Reactant: CN(C)CCN1C(=O)CSC1c1cccnc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCI
Solvent: CCCCCC
Product: CCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
n-Butyllithium solution (5 ml, 8 mmol) in hexane was added dropwise to a solution of diisopropylamine (1.42 ml, 7.96 mmol) in dry tetrahydrofuran at -30° to -40° C. The mixture was kept between those temperatures for 1 hour and then cooled to -78° C. Thereto was added dropwise a solution of 3-(2-dimethylaminoethyl)-2-(3-pyridyl)thiazolidin-4-one (2 g, 7.96 mmol) in dry tetrahydrofuran (10 ml). This reaction mixture was kept at that temperature for 1 hour. Then, ethyl iodide (1.24 g, 7.96 mmol) was added, and this reaction mixture was slowly warmed up to room temperature and maintained there for 30 minutes. The resulting mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography, giving 5-ethyl-3-(2-dimethylaminoethyl)-2-(3-pyridyl)thiazolidin-4-one (1.84 g, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH2:11])[CH:3]=1.[C:12]([CH2:14][C:15](Cl)=[O:16])#[N:13]>C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH:3]=1
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Solvent: c1ccccc1
Product: N#CCC(=O)Nc1cc(N)ccc1[N+](=O)[O-]

Procedure:
9.04 gm (0.059 mol) of 1,3-diamino-4-nitrobenzene, 5.69 gm (0.054 mol) of cyanoacetyl chloride were boiled in 100 ml of benzene for 4 hours at reflux. The precipitation of the reaction product occurred during the reaction and was completed by concentration of the reaction solution. The separated precipitate was purified by recrystallization from acetic acid. On the basis of the analysis data and IR- and NRM-measurements the product has the formula: 1-amino-3-cyanoacetylamino-4-nitrobenzene and a melting point of 218°-220°C.