Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 42.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (190 mg), 163 mg of 6-methoxy-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 140 mg of the title compound (43%) as a brown solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:23]=[CH:22][C:9]([C:10](=[O:21])[CH2:11][N:12](CC2C=CC=CC=2)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]>C(O)C.[Pd]>[OH:21][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=1)[CH2:11][NH:12][CH3:13]
Reactant: CN(CC(=O)c1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
N-(4-Methanesulphonamidophenacyl)-N-methyl-benzylamine (14.5 g) in ethanol (300 ml) containing 10% palladium on charcoal (2.0 g) was stirred under a hydrogen atmosphere (50 psi) at room temperature for 18 hours. Further catalyst (1.0 g) was added and hydrogenation was continued for a further 18 hours. The reaction was filtered and evaporated to afford an oil which was chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)], eluting with methylene chloride containing methanol (0% up to 20%) to give, after collection and evaporation of appropriate fractions, the title compound as a solid, yield 5 g. [Washing the column with methylene chloride:methanol:acetic acid (80:20:0.25) gave a further 4 g of the product as the acetate salt].
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
2.96 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 100 ml of ethanol and added at room temperature to 100 mg of 10% palladium-on-charcoal. The mixture was shaken at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was then removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution. There were obtained 2.44 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 114-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.[N:11](=[C:13]([C:19](=O)[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:12].[ClH:22].COC1C=CC(C2OC(C)=C(C)[N+]=2[O-])=CC=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:19]([CH3:20])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N+:11]=2[O-:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: COc1ccc(C=O)cc1
Agent: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Agent: Cl
Product: CCOC(=O)c1c(C)oc(-c2ccc(OC)cc2)[n+]1[O-]
Yield: 67 %

Procedure:
2-(4-Methoxyphenyl)-4-carbethoxy-5-methyloxazole N-oxide hydrochloride was prepared in 67% yield from anisaldehyde and ethyl 2-oximino-3-oxobutanoate according to the procedure of Example 89, part (a). The crude product was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]([OH:25])=O)=[CH:18][CH:17]=[CH:16]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[NH2:41])=[O:33])=[CH:30][CH:29]=1>>[NH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][C:32]([C:31]1[CH:42]=[CH:43][C:28]([CH2:27][NH:26][C:23]([C:19]2[C:20]3[C:15](=[CH:14][C:13]([O:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[O:25])=[CH:29][CH:30]=1)=[O:33]
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)c2cccc3cc(Oc4ccnc5cc(Cl)ccc45)ccc23)cc1
Yield: 74 %

Procedure:
The title compound (42.4 mg, 74% yield) was prepared as a brown solid from 6-(7-chloroquinolin-4-yloxy)-1-naphthoic acid (35.0 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.64 (d, J=5.8 Hz, 2H, —CH2), 4.87 (s, 2H, benzene-NH2), 6.60 (t, J=7.0 Hz, 1H, Ar—H), 6.75-6.79 (m, 2H, Ar—H), 6.97 (t, J=7.5 Hz, 1H, Ar—H), 7.18 (d, J=7.7 Hz, 1H, Ar—H), 7.53-7.59 (m, 3H, Ar—H), 7.66 (t, J=8.0 Hz, 1H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.92 (d, J=2.0 Hz, 1H, Ar—H), 7.99 (d, J=7.9 Hz, 2H, Ar—H), 8.06 (d, J=8.2 Hz, 1H, Ar—H), 8.13 (s, 1H, Ar—H), 8.39-8.42 (m, 2H, Ar—H), 8.75 (d, J=5.1 Hz, 1H, Ar—H), 9.22 (t, J=5.6 Hz, 1H, —CONH), 9.62 (s, 1H, benzene-NH). LC-MS (m/z) 573 (M+1).
Reaction SMILES: [Na].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[C:11](=[O:22])[CH:10]1[CH2:23][CH2:24][S:25][CH3:26])=[O:8])([CH3:5])([CH3:4])[CH3:3]>COCCOCCOC.N>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:22])[CH:10]1[CH2:23][CH2:24][S:25][CH3:26])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CSCCC1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: N
Agent: [Na]
Solvent: COCCOCCOC
Product: CSCCC1C(=O)NCCN1C(=O)OC(C)(C)C

Procedure:
Sodium metal (1.3 g., 0.057 mole) is added to a stirred solution of 4-t-butoxycarbonyl-3-[2-(methylthio)ethyl]-1-(phenylmethyl)-2-piperazinone (XVI, Example 42, 3.71 g., 0.01 mole) in diglyme (100 ml.) and ammonia (500 ml.) at -60°. The solution is allowed to reflux for 2 hours, the ammonia is allowed to evaporate and the diglyme is removed at 20°-25° under reduced pressure. The residue is partitioned between diethylether and water. Evaporation of the diethylether gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].[CH:17]([Mg]Br)([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Br
Reactant: COc1cc2c(cc1Br)C(=O)CCC2(C)C
Product: COc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 68 %

Procedure:
Following General Procedure A, 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 92, 1.0 g, 3.5 mmol) was reacted with i-PrMgBr to afford 0.74 g (68%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)(=[O:25])=[O:24])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Product: NS(=O)(=O)c1cc(Cl)ccc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 49% yield, starting from 2-amino-5-chlorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH:12][C:11]=2[CH:24]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[NH:12][C:11]=2[CH:24]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)NCc1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc(CNC(=O)OC(C)(C)C)[nH]c2c1
Reaction time: 1 h

Procedure:
To tert-butyl ((6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (G5, 82 mg) and potassium carbonate (99 mg), methanol (1 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 80 to 30% hexane in ethyl acetate) to obtain tert-butyl ((6-ethynyl-1H-benzo[d]imidazol-2-yl)methyl)carbamate (G6, 62 mg).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[O:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(O)(C(F)(F)F)=O>[CH3:20][C:18](=[CH2:19])[CH2:17][O:16][CH:4]1[C:3](=[O:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1
Reactant: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 68.1 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 4,4-dimethoxy-3-[(2-methyl-2-propen-1-yl) oxy]piperidine-1-carboxylate obtained in Example (117a) (4.8 g, 18.7 mmol), a water/TFA mixed solution (1/1, 20 mL) and di-tert-butyl dicarbonate (4.8 g, 22 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 3.43 g of the title compound as a light brown oily substance (84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)CCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([O:19][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC

Procedure:
The ester can be prepared by acid catalysed esterification of 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoic acid with/in 1-hexanol. Isocratic HPLC method 2 (8.57 min.): 92.2%.
Reaction SMILES: [O:1]=[S:2]1(=[O:10])[CH2:6][CH2:5][CH:4]([C:7](O)=[O:8])[CH2:3]1>O1CCCC1>[O:1]=[S:2]1(=[O:10])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1
Reactant: O=C(O)C1CCS(=O)(=O)C1
Solvent: C1CCOC1
Product: O=S1(=O)CCC(CO)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dioxo-tetrahydrothiophene-3-carboxylic acid (300 mg) is dissolved in dry tetrahydrofuran (10 mL). The reaction mixture is cooled to 0° C. and borane tetrahydrofuran complex (2 mL) is added dropwise. After stirring for 1 hour at 0° C., the mixture is concentrated under vacuum, partitioned between dichloromethane and water. The organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 250 mg.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30]Br>C(#N)C>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][N:11]1[C:10](=[O:13])[NH:9][C:8](=[O:14])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12]1
Reactant: O=c1[nH]nc(-c2ccccc2)c(=O)[nH]1
Reactant: Fc1cccc(F)c1CBr
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: O=c1[nH]c(=O)n(Cc2c(F)cccc2F)nc1-c1ccccc1
Temperature: 80 °C
Yield: 88.1 %

Procedure:
To a stirring suspension of 6-phenyl-1,2,4-triazine-3,5-(2H,4H)-dione (6.00 g, 31.7 mmol) in dry acetonitrile (50 mL) under nitrogen was added bis(trimethylsilyl)acetamide (15.7 mL, 63.4 mmol). The resulting yellow solution was heated at 80° C. for 3 hours. The solution was cooled and 2,6-difluorobenzyl bromide (8.20 g, 39.6 mmol) was added in one portion. The mixture was heated at 80° C. under nitrogen for an additional 15 hours. The resulting solution was cooled to room temperature, quenched with methanol (20 mL), and diluted with dichloromethane (175 mL). The mixture was washed with water (75 mL) and brine (70 mL), and dried over magnesium sulfate. Evaporation gave a tan solid that was triturated with cold diethyl ether (5×5 mL). After drying in vacuo, the compound was isolated as a flocculent, off-white solid (8.80 g, 88%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[OH-].[Ca+2].[OH-]>O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
Decarboxylation of 3,4,5,6-tetrafluorophthalic acid was carried out by following the procedure of Example 1, except that 238 g (1.00 mole) of 3,4,5,6-tetrafluorophthalic acid, 13.8 g (0.140 mole) of sulfuric acid, 5.5 g (0.042 mole) of ammonium sulfate, 22.2 g (0.30 mole) of calcium hydroxide, and 480 g of water were used [pH 1.89 at 70° C. at the time of charging]. This example was found to have produced 2,3,4,5-tetrafluorobenzoic acid in a yield of 95.4 mole %.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#CCNC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (44.9 mg, 0.65 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([O:11]CC3C=CC=CC=3)=[O:10])[CH2:6][CH2:5]2)[NH:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]2)[NH:3]1
Reactant: O=C1NCCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCC2(CC[C@@H](C(=O)O)C2)N1
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of (2R)-benzyl 7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylate (from step E, 20 mg, 0.069 mmol) in methanol (2 mL) was added palladium (Pd/C, 10% wt., 7.38 mg, 6.94 mmol). The resulting mixture was stirred under a hydrogen balloon for 30 min. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to yield (2R)-7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylic acid (10 mg, 0.050 mmol, 72.7% yield) as an oil. It was used as such for the next step without further purification. MS m/z 199 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:28])[N:11]([CH2:17][C:18]([O:20]CC3C=CC=CC=3)=[O:19])[C:12]([CH3:16])=[C:13]([Cl:15])[N:14]=2)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:28])[N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:12]([CH3:16])=[C:13]([Cl:15])[N:14]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2nc(Cl)c(C)n(CC(=O)O)c2=O)cc1
Reaction time: 16 h

Procedure:
A solution of the benzyl ester 18-4 (1.06 g, 2.48 mmol) in toluene (60 mL) was degassed with argon and then 150 mg 10% palladium on carbon was added. The mixture was stirred under an atmosphere of hydrogen gas for 16 h. The solution was filtered through celite and the solvent evaporated to give the title compound 18-5 as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NCC(=O)c1ccco1)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccco1
Yield: 64.9 %

Procedure:
24.0 g of N-(4-fluorobenzoyl)-(2-furylcarbonyl)methylamine, 4.7 g of 61% sodium hydride and 18.4 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 21.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 64.8%
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:17]([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])=[CH:16][C:15]([C:23]2[C:24](=[O:34])[N:25]([CH3:33])[C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[C:14]([F:35])[CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Cl:11][C:12]1[C:17]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:16][C:15]([C:23]2[C:24](=[O:34])[N:25]([CH3:33])[C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[C:14]([F:35])[CH:13]=1
Reactant: CCCC(O)c1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
0.21 g (1.64 mmol) of oxalyl chloride was dissolved in 10 ml of dichloromethane and cooled to −65° C. In a nitrogen atmosphere, 0.17 g (2.18 mmol) of dimethylsulfoxide was slowly dropwise added thereto, followed by stirring for 15 minutes. Then, 0.31 g (0.82 mmol) of 3-[4-chloro-2-fluoro-5-(1-hydroxybutyl)phenyl]-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of dichloromethane and dropwise added thereto, followed by stirring for 1 hour. Further, 0.42 g (4.1 mmol) of triethylamine was dropwise added thereto, followed by heating to room temperature. An aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.29 g (yield: 94%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2>C(O)C>[N:29]1[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:7][C:6]=3[CH:19]=2)=[C:22]2[C:26]([N:25]=[CH:24][NH:23]2)=[N:27][CH:28]=1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Product: O=C(Nc1nc2cc(Nc3ncnc4nc[nH]c34)ccc2s1)c1ccccc1

Procedure:
N-[5-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80° C. for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (68 mg, 0.174 mmol, 94%). LC/ESI-MS: m/z=388 [M+H]+; m/z=386 [M−H]−; Rt=3.13 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[ClH:11].[CH3:12]O>>[ClH:11].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: NC1CCC(C(=O)O)CC1
Agent: Cl
Product: COC(=O)C1CCC(N)CC1

Procedure:
To 5.109 g (35.680 mM) of 4-aminocyclohexane-carboxylic acid was added 50 ml of 10% HCl/methanol and the mixture was refluxed overnight. The solvent was then distilled off under reduced pressure and the residue was crystallized from methanol-diethyl ether to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:9](=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].C1COCC1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCCN2CCCN1CCCC1
Temperature: 0 °C
Yield: 56.6 %

Procedure:
A solution of 6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.648 mmol) in borane tetrahydrofuran complex, 1 M in THF (16.500 mL, 16.50 mmol) was stirred overnight at 60° C. The reaction mixture was then cooled to 0° C., and quenched with methanol. The resulting solution was concentrated, and the residue was stirred in refluxing methanol and 1N HCl for 1 h. The mixture was then neutralized with 1N sodium hydroxide, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated then chromatographed on silica gel using ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane as eluent to give the desired 6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (270 mg, 0.933 mmol, 56.6% yield). 1H NMR (DMSO-d6) δ 7.87 (dd, J=9.3, 2.7 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H), 6.70 (d, J=9.3 Hz, 1H), 3.46-3.38 (m, 4H), 2.74 (t, J=6 Hz, 2H), 2.43-2.38 (m, 6H), 1.86-1.82 (m, 2H), 1.74-1.67 (m, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[N+:21]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:21][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([OH:14])=[O:13]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NC1CCCCC1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NC1CCCCC1

Procedure:
By substituting 4-cyclohexylamino-3-nitro-5-sulphamyl-benzoic acid (15 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 233° C (decomp.)