Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[C@H:6]([C:7]#[C:8][Si](C)(C)C)[NH:5][C:4]1=[O:13])[CH3:2].S(=O)(=O)(O)[OH:15].C(=O)(O)[O-].[Na+]>>[C:7]([C@@H:6]1[NH:5][C:4](=[O:13])[C@@H:3]1[CH2:1][CH3:2])(=[O:15])[CH3:8]
Reactant: CC[C@H]1C(=O)N[C@H]1C#C[Si](C)(C)C
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC[C@H]1C(=O)N[C@H]1C(C)=O

Procedure:
In a similar manner to that of Example 37, (3R,4R)-3-ethyl-4-trimethylsilylethynyl-2-azetidinone (0.18 g) is reacted with mercuric sulfate (0.05 g) and concentrated sulfuric acid (trace). To the reaction mixture is added sodium bicarbonate (0.1 g) and then evaporated under reduced pressure. The residue is extracted with a mixture of ethyl acetate (30 ml) and THF (30 ml), and then evaporated under reduced pressure. The residue is subjected to a column chromatography on silica gel (eluent: 50% ethyl acetate in hexane) to give (3R,4R)-4-acetyl-3-ethyl-2-azetidinone (0.08 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: c1c[nH]cn1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (85.0 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](N(OC)C)=[O:25])=[N:16]1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:24]([C:17]1[C:18](=[O:23])[C:19]([O:21][CH3:22])=[CH:20][N:15]([C:3]2[CH:4]=[C:5]([F:14])[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[F:1])[N:16]=1)(=[O:25])[CH3:30]
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (0.51 g, 1.2 mmol) in THF (40 mL) was added dropwise to MeMgBr (1.0 M in THF, 5.0 mL, 5.0 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with 1 M HCl aqueous solution (5.0 mL) at −78° C. The mixture warmed up to room temperature, diluted with AcOEt, and washed with brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (10/0 to 10/1) to give the title compound (340 mg, 75% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.91-3.21 (4H, m), 3.54-3.89 (7H, m), 7.19 (1H, dd, J=12.7, 7.7 Hz), 7.74 (1H, dd, J=12.8, 7.2 Hz), 8.46 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C(Cl)Cl>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Oc1ccccc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.05 g, 6.63 mmol), phenol (0.75 g, 7.95 mmol), triphenylphosphine (1.91 g, 7.29 mmol) in CH2Cl2 (20 mL) was added disopropyl azodicarboxylate (1.57 mL, 7.95 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was concentrated. The residue was flash chromatographed using 10:90 hexane-EtOAc to give 1.09 g of 8-phenoxy-1,4-dioxaspiro[4.5]decane. MS (EI) calcd: (M+H)+=235.1. Found: 235.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)=[N:7][CH:6]=[CH:5]2.[NH3:27]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH2:27])=[O:25])[CH2:14][CH2:13]1)=[N:7][CH:6]=[CH:5]2
Reactant: O=C1COC(=O)N1CCC1CCN(c2nccc3cc(F)ccc23)CC1
Reactant: N
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2nccc3cc(F)ccc23)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 0.597 g (1.67 mmol) of 3-{2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in Step 6.3, and 14.30 ml (100.20 mmol) of a solution (7M) of aqueous ammonia in methanol, and after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by recrystallization from diisopropyl ether, 0.168 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:27][C:25]([CH2:24][N:18]1[C:17](=[O:22])[CH:16]([CH2:15][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10](=[O:14])[N:11]3[CH3:13])[S:20][C:19]1=[O:21])=[O:26]
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)SC(Cc2ccc(OC)c3c2ccc(=O)n3C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
350 mg of 5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.156 ml of methyl bromoacetate and 0.25 g of potassium carbonate were added to the solution, followed by stirring at room temperature overnight. Water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography and recrystallized from methanol-acetone, giving 245 mg (57% yield) of 3-methoxycarbonylmethyl-5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as white crystals.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=O)[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:36]=1[OH:37])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=[C:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:36]=1[OH:37])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc(-c2csc(C=O)n2)cc(C(C)(C)C)c1O
Reactant: O=C1NCCC1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1cc(-c2csc(C=C3CCNC3=O)n2)cc(C(C)(C)C)c1O
Temperature: 70 °C

Procedure:
16.0 g (91 mmol) of 3-bromopyrrolidin-2-one were heated to boiling in 30 ml of acetic anhydride for 1 hour. After evaporating the reaction mixture t dryness under reduced pressure, the residue was dissolved in 50 ml of tetrahydrofuran and, after adding 26.2 g (0.1 mol) of triphenylphosphine, heated under reflux for 5 hours. It was then concentrated again, the residue was dissolved in 300 ml of ethanol and 24.7 g (78 mmol) of the aldehyde from Example 2 b1) and 27 ml (0.36 mol) of triethylamine were added. After heating the mixture at 70° C. for 2 hours, the yellow precipitate was filtered off and washed with ethanol. The crystal magma is dissolved in about 2 1 of chloroform, the solution is washed several times with saturated sodium chloride solution and dried over Na2SO4, and the chloroform phase is concentrated to a third. Yellow crystals deposit on allowing to stand for a relatively long time.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccc(C)c1
Yield: 70.2 %

Procedure:
3-Oxo-3-m-tolylpropionate ethyl ester (1 g, 4.84 mmol) was dissolved in benzene, and benzaldehyde (0.51 g, 4.84 mmol), acetic acid (0.15 g, 2.49 mmol) and piperidine (0.06 g, 0.8 mmol) were added thereto. The mixture was refluxed for 4 hours. After the reaction was completed, the organic layer extracted with ethyl acetate/saturated sodium chloride/sodium bicarbonate was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 2-(3-methylbenzoyl)-3-phenylacrylate ethyl ester (1 g, yield 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([O:28]CC2C=CC(OC)=CC=2)=[O:27])=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ICC1C=C(OCCOC(=O)[C@H](C(C)C)NC(OCC2C=CC=CC=2)=O)C=CC=1C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)c2ccc(OCCOC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)c(CI)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)benzoate (10.2 g, 19.04 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred 3 hours at room temperature. The solution was evaporated under reduced pressure and co-evaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 6.9 g=87%. The product may be activated and esterified direct to a drug or converted to iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid as described above, that is by treatment with a base, chloroiodomethane, separation and then treatment with NaI.
Reaction SMILES: [CH:1]1([N:7]([CH3:29])[C:8](=[O:28])[N:9]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)[CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([N:7]([CH3:29])[C:8](=[O:28])[N:9]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)[CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C=CCN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Yield: 69.6 %

Procedure:
6-[3-(3-Cyclohexyl-3-methyl-1-allylureido)propoxy]carbostyril (3.0 g) is dissolved in ethanol (90 ml), and thereto is added 10% palladium-carbon (0.3 g), and the mixture is subjected to catalytic hydrogenation under 1 atm of hydrogen gas at room temperature. After the reaction is complete, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1), and recrystallized from ethanol-diethyl ether to give 6-[3-(3-cyclohexyl-3-methyl-1-propylureido)propoxy]carbostyril (2.1 g) as colorless flakes.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>COCCOC>[F:21][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH3:22])=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][N:32]([CH2:31][CH2:30][O:29][CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)[CH:36]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Solvent: COCCOC
Product: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)c(F)cc21

Procedure:
6-Chloro-3-(6-fluoro-1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (Stage 281.2, 268 mg, 849 μmol) was introduced in a microwave reactor together with 1-[2-(tetrahydropyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 410 mg, 1.273 mmol) and DME (5 mL). The mixture was purged with Argon for 5 min. Tetrakis-(triphenylphosphine)-palladium (39.2 mg) and 2 M Na2CO3 (1.528 mL) were added and the mixture was flushed with argon before being sealed. The RM was submitted to microwave irradiation at 150° C. 30 min. The RM was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 45 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as an oil (tR 1.13 min (conditions 2), MH+=476)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][NH:22][C:23](=[O:34])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:16]1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][NH:22][C:23](=[O:34])[N:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:7])[CH2:16]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(F)cc1
Solvent: c1ccncc1
Product: CN(C(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)c1ccc(F)cc1
Temperature: 110 °C

Procedure:
4-Fluoro-N-methylaniline (0.007 ml) was added to a solution of Intermediate 10 (0.025 g) in anhydrous pyridine (1 ml). The mixture was heated at 110° C. in a thick walled glass vial (Reactivial) for 20 h. The mixture was evaporated to remove the pyridine, and partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The organic layer was washed with further sodium bicarbonate (10 ml×5), brine (10 ml), dried (MgSO4), concentrated in vacuo. The residue was purified by chromatography on silica gel (Trikonex flash tube 2002, 2 g), eluting with 70% ethyl acetate in cyclohexane to give the title compound as a pale yellow gum 0.014 g. LCMS (system A) Rt 2.52 min, Mass Spectrum m/z 426 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC1=NN=C(C=Cc2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 g (12.5 mmoles) of 1-(4-aminostyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (the compound of Example 68) are suspended in 20 ml of acetic anhydride. The suspension is stirred at room temperature for 1 hour. In the meantime the starting substance gets dissolved, the desired product begins to separate and the reaction mixture becomes thick. The separated product is filtered, washed three times with 25 ml each of diethyl ether and dried at a temperature between 80° C. and 100° C. Thus 4.0 g of the desired product are obtained. In order to purify the crude product it is boiled in 15 ml of 50% ethanol for 15 minutes, cooled, filtered, washed three times with 5 ml each of 50% ethanol and dried at a temperature between 80° C. and 100° C. Thus 3.87 g (85.6%) of the desired product are obtained. M.p.: 218-220° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1cccc2ccccc12
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)c1cccc2ccccc12

Procedure:
Combine 24.9 g (0.1 mol) of 2-bromo-1-(naphthalen-1-yl)ethanone and 24 g (0.37 mol) of sodium azide in 200 mL of 60% aqueous acetone. Heat the mixture at reflux for about 18 to 36 hr and follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction, distill off the acetone and add 25 mL of water. Extract the aqueous mixture with three 100 mL portions of diethyl ether. Dry the organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:21][CH:22]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(C2CC(c3csc(-c4ccncc4)n3)=NO2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]pyridine (i.e. the product of Example 13, Step A) (0.60 g, 1.95 mmol) in toluene (10 mL) was added benzyl bromide (0.670 g, 3.90 mmol), and the reaction mixture was heated to 100° C. for 12 h. Then the reaction mixture was cooled to room temperature. The solid that precipitated out was filtered and dried. The solid was dissolved in methanol (10 mL), and sodium borohydride (0.072 g, 1.95 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 h, diluted with water (50 mL), neutralized with 1.5 N aqueous hydrochloric acid solution, and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine (25 mL), and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography using 3% of methanol in chloroform as eluant to give 0.4 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[S:35])([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:35])([CH3:26])[CH3:25]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 45.4 %

Procedure:
To a stirred solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.10 g, 0.31 mmol) in tetrahydrofuran (5 mL) was added 1-isopropyl-2-isothiocyanatobenzene (0.10 g, 0.56 mmol). The solution was heated to reflux for 24 hours The solvent was removed under reduced pressure, then triturated with methanol to generate a white solid which was filtered and air-dried to provide the title compound (0.070 g, 45%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])(=O)/C=C\C([O-])=O.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc2cc(Cl)nc(N3CCSCC3)c2c1
Reactant: C1CNCCN1
Agent: O=C([O-])/C=C\C(=O)[O-]
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1ccc2cc(N3CCNCC3)nc(N3CCSCC3)c2c1
Yield: 85 %

Procedure:
1-Thiomorpholino-3-piperazino-7-chloro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3,7-dichloro-isoquinoline and piperazine by heating in diphenyl ether at 200°C. M.p. of its maleate: 188°-190°C (from ethanol); yield: 85% of theory.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:21])=[CH:22][CH:23]=3)=[CH:14][C:6]1=2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1)N1CCOCC1
Yield: 59 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (60 mg) was reacted with morpholine as in General Procedure 8 to give the title compound as a light yellow foam (59% yield). M.p. (foam), LCMS: m/z=451.21 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.444-3.48 (m, 2H), 3.62-3.66 (m, 2H), 3.64-3.76 (m, 8H), 4.50 (s, 2H), 5.00 (s, 1H), 6.75 (s, 1H), 6.84-7.15 (m, 3H) 7.43 (dd, J=8.3 Hz, 4H), 7.71 (d, J=1.8 Hz, 1H).