Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31](CNN)[CH:30]=1>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([O:27][CH3:26])=[O:38])[CH:30]=2)[C:12]=1[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)cc1
Reactant: COC(=O)c1cccc(CNN)c1
Agent: Cl
Product: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2N)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #50, replacing 4-Hydrazinomethyl-benzoic acid methyl ester hydrochloride with 3-Hydrazinomethyl-benzoic acid methyl ester hydrochloride (Intermediate #53)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.Cl.[CH3:15]O>O1CCOCC1>[CH3:15][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: CO
Reactant: COc1ccc(Br)cc1CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
5-Bromo-2-methoxyphenylacetic acid (0.900 g, 3.67 mmol) in MeOH (20 mL) was treated with 4N HCl in 1,4-dioxane (4 mL) and stirred at 80° C. for 6 hours. The mixture was concentrated to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(Cl)CCl.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH2:3]1
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexane carboxylic acid (1.5 g, 10.6 mmol) in CH2Cl2 (35 mL) were added DMAP (0.129 g, 1.06 mmol), EDC (4.05 g, 21.1 mmol), and BnOH (1.2 mL, 11.6 mmol). The reaction was maintained at ambient temperature for 1 h. The reaction was further diluted with CH2Cl2, and then washed with saturated aqueous NaHCO3, followed by brine. The organic layer was separated, dried with MgSO4, filtered, and concentrated. The resulting crude product was used in the next step without further purification. LCMS: calculated for C14H16O3 232.28, observed m/e 233.1 (M+H)+ 255.0 (M+Na) (Rt 1.74/4 min).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:13])[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1)=[CH2:2]>CCO.[Pd]>[CH2:1]([C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:13])[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc2c(c1)NC(=O)CCC2=O
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 70 °C
Yield: 90.8 %

Procedure:
To a solution of 8-vinyl-3,4-dihydro-1H-1-benzazepine-2,5-dione (2.6 g, 13 mmol) in EtOH (160 mL) was added 10% (w/w) palladium on carbon (260 mg). The reaction mixture was allowed to stir under an atmosphere of H2 (5 bar) at 70° C. until reaction was complete. The reaction mixture was filtered over Celite® and the filtrate was concentrated to give 8-ethyl-3,4-dihydro-1H-1-benzazepine-2,5-dione (2.4 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17]O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.O=S(Cl)[Cl:25]>>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][Cl:25])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCO)cc3)nc12
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCCl)cc3)nc12

Procedure:
2-[4-(6-Chloro-7-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)phenoxy]ethanol (0.26 g, 0.8 mmol) was dissolved in SOCl2 (10 ml). The reaction mixture was refluxed for 3 h, after which the excess SOCl2 was removed by evaporation. Repetitive co-evaporation with toluene yielded pure title compound (0.275 g, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[I-].[K+].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:42])=[C:28]([CH:41]=1)[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:42][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:28]([CH:41]=1)[CH2:29][N:30]1[C:31](=[O:40])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]1=[O:39]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Yield: 63.3 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.75 g, 2.50 mmol) in dry dimethylformamide (25 mL) was added potassium iodide (0.40 g, 2.39 mmol), 2-(5-chloro-2-hydroxy-benzyl)-isoindole-1,3-dione (0.80 g, 2.76 mmol) and potassium carbonate (0.70 g, 5.10 mmol). The resulting mixture was heated to 70° C. for 23 hours. The reaction was cooled to ambient temperature, diluted with water and extracted with 1:1 diethyl ether/hexanes (3×). The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.87 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:19][NH:20][CH2:21][CH:22]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[OH:23]>>[OH:23][CH:22]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:21][N:20]([CH3:19])[C:5](=[O:7])[C:4]1[C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: CNCC(O)C1COC(C)(C)O1
Reactant: O=C(O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F
Product: CN(CC(O)C1COC(C)(C)O1)C(=O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F

Procedure:
Analogously to Example 22(a), 4.31 g (15 mmol) of 3-fluoro-6-(trifluoromethylsulfamoyl)-benzoic acid is reacted with 3.22 g (20 mmol) of 2-methylamino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethanol and the crude product is purified by chromatography on silica gel with ethyl acetate/hexane. 4.93 g=76.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[N:19]1([C:28](Cl)=O)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1>C1(C)C=CC=CC=1>[N:19]1([C:28]2[O:9][C:8](=[O:10])[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:11]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[N:20]1
Reactant: O=C(Cl)n1nnc2ccccc21
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(-n3nnc4ccccc43)oc(=O)c12
Reaction time: 12 h
Yield: 22.6 %

Procedure:
A solution of 960 mg of 6-methyl anthranilic acid in 30 ml of dry toluene containing 1.77 ml of dry triethylamine, which had been stirred for 30 minutes, was added to a solution of 2.1 gm of 1-benzotriazole carboxylic acid chloride in 30 ml toluene over a period of 30 minutes, and stirred for 12 hours. The resulting precipitate was filtered. The filtrate was reduced to one-half of its initial volume, and the resulting solids isolated by filtration. The combined residues were washed with water, dried under high vacuum and recrystallized from chloroform, giving 400 mg of 2-(1-benzotriazolyl)-5-methyl-4H-3,1-benzoxazin-4-one, m.p. 214°-215° C. (decomp.).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccsc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccsc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-thiopheneboronic acid. The title compound was obtained in 5% yield as a yellow oil. MS (m/e): 488.5 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15].Cl.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[ClH:17].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl 1-methylimidazol-2-yl sulphide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(1-methylimidazol-2-ylthio)anilino]-6,7-dimethoxyquinazoline dihydrochloride salt in 71% yield, m.p. 244°-246° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[F:14][C:15]([F:21])([F:20])[S:16](Cl)(=[O:18])=[O:17]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][S:16]([C:15]([F:21])([F:20])[F:14])(=[O:18])=[O:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1CCc2c(Cl)cc(Cl)c(O)c21
Solvent: CN(C)C=O
Product: O=C1CCc2c(Cl)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c21
Temperature: 0 °C

Procedure:
4,6-Dichloro-7-hydroxyindan-1-one (21.71 g., 0.1 mole) was dissolved in DMF (80 ml) in a dry apparatus under nitrogen. Trifluormethanesulfonylchloride (21.60 g., 0.128 mole) was added with stirring, slowly, dropwise over a 20 minute period with occasional cooling to keep the internal temperature below 30° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes, then poured into ice-water with swirling. The green crystals were collected, washed with water, sucked dry, then dried in a vacuum oven at 50° C. to give 32.7 g. of the title compound mp 96°-100° C. Recrystallization from hexanes gave 22.4 g., mp 96°-98° C. A sublimed sample had mp 90°-96° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[CH:6][CH:5]=2.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cc1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2[nH]1
Yield: 39 %

Procedure:
The title compound is prepared from 2-methyl-1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 39% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:21]=[C:20]([C:22]#[N:23])[O:19][CH:18]=1.[H-].[Na+].CO.C(Cl)Cl>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:21]=[C:20]([C:22]#[N:23])[O:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1cc(CBr)co1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2coc(C#N)c2)C1=O
Yield: 200 %

Procedure:
A solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (0.78 g, 3.9 mmol) in 40 mL of THF:DMF (5:1) is treated with 3-bromomethylfuran-5-carbonitrile (0.78 g, 3.9 mmol) and sodium hydride (60%) (0.10 g, 4.2 mmol) as described in EXAMPLE 122, Part F. After addition, the solution is allowed to warm to ambient temperatures. Standard workup folowed by chromatography (5-10% MeOH/CH2Cl2) affords [1-(2-cyanofuran-4-ylmethyl)-2-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (1.05 g, 7.8 mmol) as a white solid. This material is treated with trimethylsilyliodide (0.844 g, 4.22 mmol) and free based with Amberlite (OH) resin to yield the title compound (0.926 g, 4.51 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1Cl

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.116 g, 25% yield). MS: m/z 469.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]1=[S:16].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23].Br>CS(C)=O.CCCCCC>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12](=[O:15])[C:13](=[O:14])[N:9]([CH3:8])[C:10]1=[S:16]
Reactant: CN1C(=O)C(=O)NC1=S
Reactant: BrCCCCCBr
Agent: Br
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=O)N(CCCCCBr)C1=S
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Triethylamine (84 ml, 0.60 mole) was added dropwise over a period of 6 hours to a stirred solution of 1-methyl-2-thioxo-4,5-imidazolidinedione (88 g, 0.61 mole) and 1,5-dibromopentane (264 g, 1.20 mole) in dimethylsulphoxide (650 ml) at room temperature. The mixture was allowed to stand overnight and then poured into ice water (3 liters) containing concentrated hydrobromic acid (1 ml). The mixture was extracted with chloroform and the extracts were washed with water, dried over magnesium sulphate and evaporated to give an oil which was treated with hexane to give yellow crystals of 1-(5-bromopentyl)-3-methyl-2-thioxo-4,5-imidazolidinedione (82.3 g), m.p. 48°-50°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[CH3:20]O.S(=O)(=O)(O)O>O>[CH3:20][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[S:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: CO
Reactant: Cc1ccc(Sc2ccc(C)cc2CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cc(C)ccc1Sc1ccc(C)cc1

Procedure:
47 g. of crude 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid are dissolved in 170 ml. of methanol. 19 Ml. of concentrated sulfuric acid are added dropwise with stirring and the mixture is subsequently heated at reflux for 3.5 hours. After cooling, the mixture is diluted with water and extracted several times with benzene. The benzene extracts are washed with water, sodium bicarbonate solution and again with water. After evaporation of the solvent, there remains a residue which is chromatographed on 400 g. of silica gel. By elution with benzene, there is obtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid methyl ester, which ester is dissolved in 73 ml. of methanol, treated with 18.8 g. of potassium hydroxide and 73 ml. of water and subsequently heated at reflux for 1 hour. Thereafter, the methanol is removed in vacuo and the residue acidified with hydrochloric acid. The mixture is extracted with benzene, the benzene extract washed with water and concentrated in vacuo. The residue is crystallized from cyclohexane, and there is obtained 5-methyl-2-(4-methylthio-phenoxy)-phenylacetic acid having a melting point of 81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]1[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][C@@H:15]2[CH3:24])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 2.12 g, 0.02 mol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.0 g, 0.02 mol) in dichloromethane (200 mL) was added HOBt (1.77 g, 0.02 mol) and N-methyl morpholine (3.8 mL, 0.03 mol) and then the mixture was stirred for 1 h at room temperature. EDC HCl (3.98 g, 0.0208 mol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was added to 2N hydrochloric acid (200 mL). The organic layer was washed with sodium bicarbonate (200 mL), water (250 mL), and brine. The organic layer was dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to get methyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.3 g (72%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].[NH:26]([CH2:28][C:29]1[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=1)[NH2:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]2[N:26]([CH2:28][C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)[N:27]=[C:18]([CH3:19])[CH:17]=2)[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:9])=[O:10]
Reactant: Cn1cncc1CNN
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1cncn1C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with 5-(hydrazinylmethyl)-1-methyl-1H-imidazole (CAS Reg. No. 887592-51-0) to give the title compound as yellow oil. MS (ESI): m/z=478.1 [M+H]
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:24])[NH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=4)=[N:13]3)=[C:8]([CH2:25][CH3:26])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10](=[O:24])[C:9]3=[C:8]([CH2:25][CH3:26])[N:7]=[C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:14]3[N:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Agent: [Pd]
Solvent: CO
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12

Procedure:
1.8 g (5.1 mmol) 7-cyclopentyl-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 21A) are dissolved in 100 ml methanol, and 200 mg palladium (10% on charcoal) are added. The mixture is exposed to an hydrogen atmosphere until no more hydrogen is absorbed. Then the palladium/charcoal is removed by filtration and the filtrate is evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](N3C=NC=N3)=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2].O.NN>CC#N.CCO>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)cnc2=O)C[C@@H]1N=[N+]=[N-]

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(1,2,4-triazol-1-yl)-2-(1H)-pyrimidinone (0.5 g, 1.4 mMol) was dissolved in CH3CN (10 mL) and treated with 85% hydrazine hydrate (0.105 g, 2.1 mMol) for 30 minutes at ambient temperature, analogous to the procedure described in (1). The solvents were evaporated in vacuo and the residue chromatographed on silica gel with 9:1 CHCl3 /MeOH (v/v) as the eluting solvent. Collection and evaporation of appropriate fractions yielded a solid. The solid was dissolved in EtOH (50 mL) containing Ag2O (0.35 g, 1.5 mMol, 1.5 eq) and refluxed for 90 minutes. Filtration of the hot suspension through a bed of celite followed by removal of solvents in vacuo gave a solid. The solid was chromatographed on silica gel and eluted with 20:1 CHCl3 /MeOH (v/v). Combination and evaporation of appropriate fractions gave the title compound as a golden oil: UV (nm): at pH 1λmax =327 (ε=6900), λmin =254 (ε=700); at pH 13λmax =322 (ε=17200), λmin =247 (ε=600); 1H NMR: (DMSO-d6) δ8.46(d, J=3.13 Hz, 1H, H4), 7.92(d, J=3.90 Hz, 1H, H6), 6.03(dd, J=5.28 Hz, 6.64 Hz, 1H, H1 ') 4.46-4.03(m, 4H, H3 ', H4 'H5 '), 2.71-2.32(m, 2H, H2 '), 2.05, 2.04(2s, 6H, 5-CH3, acetyl).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([N:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]6)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)n1
Reactant: C1CNCCN1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)c1
Yield: 31 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 111 was obtained as an off-white solid (41.7 mg, 31%). 1H NMR (400 MHz, DMSO) δ 9.33-9.28 (s, 1H), 9.06-8.99 (d, J=2.5 Hz, 2H), 8.66-8.61 (s, 1H), 8.50-8.45 (d, J=2.1 Hz, 1H), 8.09-8.03 (t, J=2.0 Hz, 1H), 7.81-7.73 (t, J=8.1 Hz, 1H), 7.29-7.20 (d, J=7.7 Hz, 1H), 6.85-6.76 (d, J=8.5 Hz, 1H), 3.65-3.56 (m, 4H), 2.94-2.84 (m, 4H), 2.13-2.04 (m, 1H), 1.12-1.04 (m, 2H), 0.88-0.81 (m, 2H); MS (ESI) m/z: 398.2 [M+H]+