Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C1C=CN=CC=1)C.ClCCl>[C:10]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 28.1 g (212 mmol) of 2,2-dimethyl-1,3-dioxolane-4-methanol and 44 g (361 mmol) of DMAP in 1 L of dichloromethane was added 36 mL (382 mmol) of acetic anhydride dropwise. The resulting mixture was stirred at rt for 0.5 h. The reaction mixture was then quenched with NH4Cl (aq), the organic layer separated and washed with saturated NaHCO3. The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to give an oil which was used without further purification. 1H NMR (500 MHz, acetone-d6): δ 4.30-4.25 (m, 1H), 4.09-4.01 (m, 1H), 3.72 (dd, 1H), 2.01 (s, 3H), 1.33 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[C:7](N)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.N([O-])=O.[Na+].[I-:17].[K+]>O>[I:17][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][S:1](=[O:12])(=[O:11])[C:5]=2[CH:6]=1
Reactant: Nc1ccc2c(c1)S(=O)(=O)CC2
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)CCc2ccc(I)cc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of 2,3-dihydro-1-benzothiophen-6-amine 1,1-dioxide (1.1 g) 2M hydrochloric acid (14 ml) was cooled in an ice-bath. Sodium nitrite (355 mg) in water (5 ml) was added dropwise and the mixture was stirred for 15 min before aqueous potassium iodide (830 mg) was added. The mixture was stirred overnight, before it was heated to 65° C. for 0.5 h. The mixture was cooled to 20° C. and extracted into ethyl acetate. The organic solution was washed with aqueous sodium metabisulfite solution, brine, dried and purified on two SPE silica cartridges (10 g) eluting with dichloromethane, diethyl ether and ethyl acetate. The dichloromethane fractions were combined and evaporated to give the title compound (550 mg) LCMS RT=2.65 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.[NH4+].O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:34])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 90.2 %

Procedure:
To an ice-cooled and stirred mixture of (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (80 mg) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole ammonium salt (53 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (72 mg, 91%) as colorless crystals. MS 460 (MH+). mp 169-170° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: O=C1CCCCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added mesitaldehyde (10.0 g, 67.6 mmol), 25 mL (0.242 mol) of cyclohexanone and 100 mg of benzoyl peroxide. Oxygen was bubbled in at fast rate while the stirred solution was maintained at 85°. After 24 hour an additional 50 mg of benzoyl peroxide was added and the reaction was continued at 90° for an additional 5 hr. After 29 hr total time the solution was mixed with 150 mL of water and 150 mL of methylene chloride; 20% aqueous potassium hydroxide was added dropwise until a pH of 8 was reached. The aqueous layer was separated and acidified with concentrated hydrochloric acid, after which the precipitated product was collected, washed with water and air dried to give 9.74 g (88% yield) of white mesitoic acid: mp 153°-155°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:27][N:28]1[C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]([CH3:36])=[N:29]1>C1COCC1.CCN(CC)CC>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:33]([C:32]5[N:28]([CH3:27])[N:29]=[C:30]([CH3:36])[CH:31]=5)=[O:34])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(-n3ccc(C)c(N4CCc5nc(N)ncc5C4)c3=O)cc2)n(C)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-(4-aminophenyl)-4-methylpyridin-2(1H)-one (26 mg, 0.078 mmol) in 3 mL of THF (3 mL) and NEt3 (3 mL) was treated with 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (16 mg, 0.105 mmol). The reaction was heated to 40° C. and allowed to stir for 5 h. The reaction was cooled and then extracted with EtOAc (3×˜10 mL) and water (˜10 mL). The combined organic layers were then washed with ˜20 mL of NaHCO3(aq). The organic layers were then dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was purified over silica (EtOAc/Hexanes gradient). Following concentration of the appropriate fractions the title compound was isolated as a grey solid (25 mg, 76%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.78(m, 1H), 7.45-7.52 (m, 2H), 7.44 (m, 1H), 7.24-7.32 (m, 2H), 6.65 (m, 1H), 6.28 (s, 2H), 6.17 (m, 1H), 3.96 (br. s, H), 3.29 (s, 2H), 2.66 (t, J=5.3 Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2)#[CH:2].[Cl:11][C:12]1[N:17]=[C:16](I)[C:15]([OH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]2[CH:2]=[C:1]([C:3]34[CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][CH2:4]4)[O:19][C:15]2=[CH:14][CH:13]=1
Reactant: C#CC12CCCN1CCC2
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Clc1ccc2oc(C34CCCN3CCC4)cc2n1
Yield: 77 %

Procedure:
7a-Ethynyl-hexahydro-1H-pyrrolizine from Example 15b (225 mg, 1.66 mol, 6-chloro-2-iodo-3-pyridinol (509 mg, 2.0 mmol), copper(I) iodide (60 mg, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (58 mg, 0.08 mmol) and triethylamine (0.280 mL, 2.0 mmol) were combined in a similar fashion as that described in Example 15c. The crude product was chromatographed (silica gel; CHCl3 /MeOH, 97.5:2.5) to afford a waxy tan solid (335 mg, 77%): 1H NMR (CDCl3, 300 MHz) δ 1.88-1.97 (m, 6H), 2.21-2.33 (m, 2H), 2.67-2.79 (m, 2H), 3.19-3.26 (m, 2H), 6.70 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H); MS (CI/NH3) m/z: 263 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[C:34]1([S:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.5 mmol of benzenesulfonyl chloride in 6 ml of DMF were added. The reaction solution was then stirred at RT for a further 12 h. The crude product was purified using chromatographic methods.
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)=[C:14]([O:29][CH3:30])[CH:13]=2)(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)=[C:14]([O:29][CH3:30])[CH:13]=1
Reactant: COc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1ccc2cc(O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(O)ccc1-c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-(6-hydroxy-2-naphthyl)-3-methoxyphenyl 4-methylbenzenesulfonate (1.74 g, 4.05 mmol), potassium hydroxide (5 g), water (85 mL), and ethanol (85 mL) was stirred at 90° C. for 2 hr. The reaction was cooled to room temperature and concentrated to 50% volume, neutralized with acetic acid, and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column (25% ethyl acetate—hexanes) yielded 1.01 g (94%) of the title compound as a tan solid. A sample was further purified by preparative reverse phase HPLC to yield a tan solid: mp 152-154° C.;
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH3:4][S:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([S:3][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([S:5]([CH3:4])(=[O:7])=[O:6])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of ethanethiol (0.3 mL, 4.9 mmol) and 4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21° C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, the reaction mixture was poured into water and then filtered off to provide the 1-ethylsulfanylmethyl-4-methanesulfonyl-benzene compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[N:13]([CH2:30][CH2:31][CH3:32])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:1]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3 (2H)-dione (7.21 g, 16.9 mmol) and hydrazine hydrate (4.22 g, 84.3 mmol) in ethanol (400 mL) was heated at reflux for 2 hours. The resulting solution was allowed to cool to room temperature, filtered, and concentrated under reduced pressure to yield 3.52 g of 1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellow solid, mp 137-139° C.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]2[N:12]=[C:11]([SH:13])[NH:10][C:9]=2[CH:14]=1)=[O:4].[ClH:17].[Cl:18][CH2:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[ClH:18].[ClH:17].[NH2:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH2:19][S:13][C:11]1[NH:10][C:9]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([O:15][CH3:16])=[CH:7][C:8]=2[N:12]=1
Reactant: COC(=O)c1cc2[nH]c(S)nc2cc1OC
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: COC(=O)c1cc2[nH]c(SCc3ccccc3N)nc2cc1OC

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at -40° C., was slowly added 22.3 g (0.10 mole) of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mMol) of the diamine and 7.08 g (49.2 mMol) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mMol) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mMol)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Anal. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; Cl, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; Cl, 16.77.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:21][CH2:15][C:16]2[O:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccco1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccco1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
10 g of 2-amino-3-cyano-4-chloroquinoline is heated with 19 g of furfurylamine at 120° C. for 3 hours. The reaction mixture is cooled to 25° C. and mixed 6 times with 50 ml of water. The crystals are filtered off and dried. The resulting product is recrystallized from 60 ml of N,N-dimethylformamide, to obtain 5.8 g of the title compound, m.p.: 206° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:37]([NH:36][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:38])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1

Procedure:
A mixture of Example L (0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2Cl2 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea. mp: 194-196; 1H NMR (200 MHz, DMSO-d6): δ 9.07 (1H, s), 8.45 (s, 1H), 8.06-7.93 (m, 3H), 7.69-7.44 (m, 7H), 7.33-7.29 (d, 6.9 Hz, 1H), 6.44 (s, 1H), 3.85 (m, 2H), 3.54-3.45 (m, 8H), 1.31 (s, 9H); MS:
Reaction SMILES: [O-][C:2]#[N:3].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(=O)=O.O>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][C:2]#[N:3]
Reactant: N#C[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 9.89 gm of sodium cyanate in 35 ml of dimethylsulfoxide (hereinafter abbreviated as DMSO) was added dropwise a solution of 31.2 gm of the compound prepared in (4) above in 70 ml of DMSO. The mixture was stirred for 12 hours at room temperature. After the addition of 500 ml of water, the mixture was extracted twice with 200 ml of ether. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 15.4 gm of the title compound.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCC(O)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Ammonium chloride (1.2 g) and iron powder (6.3 g) were added to a mixed solvent of water (16 ml) and ethanol (48 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-hydroxypiperidino)benzonitrile (10 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (4.5 g), melting point: 144–145° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:33](COCC[Si](C)(C)C)[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30](=O)[CH3:31])C(=O)OC(C)(C)C)[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)OCC[O:3]1.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[CH3:31][C:30]1[N:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([C:2](=[O:3])[CH3:1])=[CH:12][CH:11]=4)[NH:33][C:16]=3[N:17]=[CH:18][C:19]2=[N:21][CH:29]=1
Reactant: CC(=O)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)c1ccc(-c2cc3c(ncc4ncc(C)n43)[nH]2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-oxopropyl)carbamate (0.425 g, 0.729 mmol) was stirred in TFA (4.0 mL, 52 mmol). To the mixture was added TFAA (4 mL, 28.3 mmol) and the reaction stirred for about 20 h at rt. The solvents were removed under vacuum and 1,4-dioxane (12 mL) was added along with concentrated NH4OH (8 mL). The mixture was stirred for about 3 h. The resulting solid was collected by vacuum filtration washed with water and dried under vacuum at about 50° C. in the presence of P2O5 to a constant weight give 1-(4-(8-methyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.121 g, 57%): LC/MS (Table 2, Method h) Rt=1.06 min.; MS m/z: 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[C:17](OC(=O)C)(=[O:19])C.O>C(O)=O>[CH:17]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1)=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Solvent: O=CO
Solvent: O
Product: O=CNC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (1.907 g) was dissolved in formic acid (20 ml). The solution was stirred at 60° and acetic anhydride (2.4 ml) was added dropwise. The mixture was heated for 1 hour at 60° and then poured into water and stirred to decompose the residual excess anhydride. 3-Formamido-1-(3-trifluoromethylphenyl)-2-pyrazoline resulted as a crystalline solid m.p. 128°-129°. This compound was then used to prepare the compound of Example 1, as hereinbefore described.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:7][C:6]1=O.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28]N>>[CH2:18]([C:5]1([CH2:4][C:3]([OH:2])=[O:20])[C:6]2[NH:28][C:23]3[C:24](=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[C:7]=2[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10]1)[CH3:19]
Reactant: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Reactant: Cc1ccccc1NN
Product: C=CCCCCC1CCC(CC)(CC(=O)O)c2[nH]c3c(C)cccc3c21

Procedure:
The title compound was prepared from 1-ethyl-4-(5-hexenyl)-2-oxocyclohexaneacetic acid methyl ester (isomer A) and 2-methylphenylhydrazine as described in Example 1, m.p. 110°-111° C.