Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])(=[O:8])=[O:7].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:10]=[C:9]([S:6]([Cl:5])(=[O:8])=[O:7])[CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Under a nitrogen atmosphere, aluminum chloride (7.5 g, 56.5 mmol) is slurried in dichloromethane (150 mL) then 3-chlorosulfonyl-benzoyl chloride (7.5 g, 31.4 mmol) is added and allowed to stir at ambient temperature for 10 minutes. Anisole (4.06 g, 37.65 mmol) is added. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a purple oil. Purification by silica gel chromatography (10% ethyl acetate in hexanes) yielded 4 g (41% yield) of the title compound as a yellow powder. 1H NMR (CDCl3): 8.5 (t, 1H, J=1.7 Hz), 8.25 (m, 1H), 8.1 (m, 1H), 7.7-7.9 (m, 3H), 7.0 (d, 2H, J=6.9 Hz), 3.9 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=1.[C:18]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])SC)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.C(N(CC)CC)C>[C:18]([O:22][C:23]([NH:25][C:26]([NH:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=1)=[O:31])=[N:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[CH:7][CH:8]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C)CCOc1ccc(CCCCN)cc1
Reactant: CSC(=NC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(CCCCN=C(NC(=O)OC(C)(C)C)NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
A suspension of compound 63 (0.22 g, 0.93 mmol) and 64 (0.33 g, 0.92 mmol) in THF/triethylamine (11 mL, 10/1) was stirred at room temperature for 48 h. After this time, a clear solution was formed. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 10:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) to provide the guanidine 65 (0.3 g, 60%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.19 (s, 6H), 2.58 (m, 4H), 3.99 (m, 2H), 6.83 (d, 2H), 7.12 (d, 2H), 7.40 (br s, 2H), 9.02 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[CH2:9]([O:11][C:12]#[CH:13])[CH3:10]>C(N(CC)CC)C>[CH2:12]([O:11][C:9]1[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[CH:10]=1)[CH3:13]
Reactant: C#COCC
Reactant: CCCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC1(C)C(=O)C=C1OCC
Yield: 77 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al [J. Org. Chem, 38, 1451-1455, (1973)]; to a solution of 2-methyl pentanoyl chloride (3.91 ml) and ethyl ethynylether (5 g, 40% solution in hexanes, 28.6 mmol) in ET2O (35 ml) at room temperature was added triethylamine (9.9 ml), with stirring. The reaction was warmed to 50° and stirred for 72 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a colourless oil (3.71 g, 17.9 mmol, 77%). δH (CDCl3, 300K), 4.84 (1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26 (3H, m), 0.91 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 178.1 (MH+).
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)C>[CH2:6]([C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To 3.00 g (42.80 mmol) of cyclobutanone in 143 mL of tetrahydrofuran at 0° C. was added 51.36 mL (51.36 mmol) of a 1 M solution of benzyl magnesium chloride in diethyl ether and the mixture was allowed to warm to RT and stirred for 20 h. The reaction was quenched with methanol, followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6.52 g (94%) of 1-benzylcyclobutanol. Then, 1.90 g (11.69 mmol) of the compound was dissolved in 12 mL of toluene and 2.00 g (11.69 mmol) of methyl(2S)-2-isocyanatohexanoate was added. The mixture was heated at 85° C. for 3 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:6) to give 2.44 g (63%) of methyl (2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate. Rf=0.30 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.48 (d, J=8 Hz, 1H), 7.29-7.13 (m, 5H), 4.02-3.94 (m, 1H), 3.64 (s, 3H), 3.16 (ABq, JAB=16 Hz, Δ84 AB=12 Hz, 2H), 2.22-2.02 (m, 4H), 1.82-1.44 (m, 4H), 1.36-1.18 (m, 4H), 0.86 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C(OCC)(=O)C>O1CCCC1>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: COC(=O)c1cncc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncc(C(=O)C=CN(C)C)c1

Procedure:
The mixture of methyl 5-acetyl-3-pyridinecarboxylate (3.0 g) and N,N-dimethylformamide dimethyl acetal (6.7 ml) in tetrahydrofuran (30 ml) was heated under reflux for 6 hours. To the mixture was added a mixture of ethyl acetate and tetrahydrofuran, and the mixture was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 5-(3-dimethylamino-1-oxo-2-propenyl)-3-pyridinecarboxylate (1.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([C:14]([O:16][CH3:17])=[O:15])=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:6]=1[C:22]([O:24][CH3:25])=[O:23])=[O:4].C(O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]>CO>[CH2:25]([O:24][C:22]([C:6]1[CH:5]([C:3]([O:2][CH2:1][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:4])[C:9]([C:10]([O:12][CH2:13][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:11])=[C:8]([C:14]([O:16][CH2:17][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:15])[C:7]=1[C:18]([O:20][CH2:21][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])=[O:19])=[O:23])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38]
Reactant: COC(=O)C1=C(C(=O)OC)C(C(=O)OC)C(C(=O)OC)=C1C(=O)OC
Reactant: CC(C)CCCCCCCCCCO
Solvent: CO
Product: CC(C)CCCCCCCCCCOC(=O)C1=C(C(=O)OCCCCCCCCCCC(C)C)C(C(=O)OCCCCCCCCCCC(C)C)C(C(=O)OCCCCCCCCCCC(C)C)=C1C(=O)OCCCCCCCCCCC(C)C
Yield: 100.2 %

Procedure:
7.13 g (20 mmol) of 1,2,3,4,5-pentamethoxycarbonylcyclopentadiene are treated with 20.0 g (100 mmol) of isotridecyl alcohol. 3.12 g (97.5% of the theoretical yield) of methanol are distilled off at 100° C. within 8 h, firstly at 1013 mbar, then at from 363 to 18 mbar. 24 g of 1,2,3,4,5-pentaisotridecyloxycarbonylcyclopentadiene are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12](O)=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:18].S(Cl)([Cl:21])=O>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([Cl:21])=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:18]
Reactant: O=S(Cl)Cl
Reactant: CN1C(=O)COc2c(C(=O)O)cc([N+](=O)[O-])cc21
Product: CN1C(=O)COc2c(C(=O)Cl)cc([N+](=O)[O-])cc21

Procedure:
To 99 g of 3,4-dihydro-4-methyl-6-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid is added portionwise 285 ml of thionyl chloride at room temperature, and the system heated with reflux for about an hour. After the resultant solution is dried under reduced pressure, to the residue is distilled off under reduced pressure. To the residue is added 200 ml of benzene to make the crystals finely particulate. After collecting by filtration, the crystals are washed with benzene and dried to give 103 g of 3,4-dihydro-4-methyl-6-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:13](=O)([O-])[O-].[Na+].[Na+].ICC.[OH-].[Na+].Cl>CC(N(C)C)=O>[CH2:10]([NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12])[CH3:13]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCI
Product: CCNC(=O)c1ccccc1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Dimethylacetamide (50 ml) and carsalam (10.00 g, 0.0613 mol) were placed into a round bottom flask fitted with nitrogen purge, cold water condenser and a magnetic stir bar. Sodium carbonate (6.50 g, 0.0613 mol) and iodoethane (4.38 ml, 0.0548 mol) were added and heating of the reaction mixture was started. Heating at 80° C. continued for 16 hours at which point heating was discontinued and the reaction mixture was allowed to cool to room temperature. The reaction mixture was then filtered through a sintered glass funnel and the filtrate was collected. Water was added to this filtrate until a white solid precipitated. The solid was isolated by filtration and placed in an Erlenmeyer flask with 2N aqueous sodium hydroxide solution (200 ml). This mixture was heated at reflux for approximately 1 hour and then stirred overnight at room temperature. This mixture was acidified with 2N aqueous hydrochloric acid and a yellow oil was noted to separate out. The reaction mixture was extracted two times with 200 ml portions of ethyl acetate. The combined ethyl acetate layers were washed two times with 200 ml portions of deionized water, dried with sodium sulfate and concentrated under vacuum. N-ethylsalicylamide was recovered as a yellow oil which, after drying overnight under vacuum, was isolated in a yield of 7.93 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O.C([N:31]=[C:32]=[S:33])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH2:9][C:10]#[CH:11])[CH:4]=3)[NH:1][C:32](=[S:33])[N:31]=2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Reaction time: 18 h

Procedure:
A solution of 0.5 g (1.71 mmol) (2-amino-5-prop-2-ynyloxy-phenyl)-(4-isopropyl-phenyl)-methanone and 0.23 ml (1.71 mmol) benzoyl isothiocyanate in 5 ml THF is stirred for 3 h at r.t. before 0.235 g potassium carbonate and 5 ml methanol are added. After stirring for 18 h, the reaction mixture is acidified with 0.1 M aqueous hydrochloric acid and extracted with dichloromethane. After evaporation of the organic phases, the residue is triturated with diethyl ether to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cn1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-2-methoxypyridine as a pink solid as described in Example 1. 1H NMR (CDCl3): 8.87 (d, J=2.1, 1H), 8.28 (d, J=3.0, 1H), 8.20-8.17 (m, 1H), 7.99-7.96 (m, 1H), 7.67 (s, 1H), 7.49 (d, J=8.7, 1H), 6.81 (d, J=8.7, 1H), 3.95 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[NH4+].[OH-]>C(O)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1ccccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1ccccc1[N+](=O)[O-]
Yield: 79 %

Procedure:
To a solution of 30 g (0.07 mol) of 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester in 72 ml of acetic acid, heated to reflux, 7.2 g (0.07 mol) of CrO3 were portionwise added. After the addition was complete, reflux was maintained for one additional hour. The reaction mixture was then slowly poured on ice-cooled aq NH4OH (150 ml). The mixture separated in two phases, and it was evacuated with CH2Cl2 (3×100 ml). The organic extract was dried with anh Na2SO4, and concentrated to dryness at reduced pressure. The resulting oil was crystallised in EtAcO-diethylether, yielding a white solid (mp 69-70° C., EtOH) with a yield of 79%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Fc1ccccc1CCl
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a suspension of Mg turnings (0.231 g, 9.51 mmol) in diethyl ether (1.5 mL) was added a solution of 2-fluorobenzyl chloride (1.25 g, 8.65 mmol) in diethyl ether (9 mL) dropwise to the refluxing reaction mixture. The mixture was stirred for 10 min, cooled to room temperature and added dropwise to a solution of diethyl oxalate (2.53 g, 17.29 mmol) in diethyl ether (17 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 1M aqueous hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The excess of diethyl oxalate was removed by bulb to bulb distillation at room temperature and the residue was purified by flash chromatography (SiO2, 15-20% ethyl acetate in petroleum ether) to give the resulting compound B4 as colorless oil in 70% yield which was used instantly in next step.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)CC)C.S=[C:21]1[CH2:25][S:24][C:23](=[O:26])[NH:22]1>C(O)C>[CH3:12][N:3]([CH3:2])[C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:6][C:21]1[CH2:25][S:24][C:23](=[O:26])[N:22]=1
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To a solution of the crude product containing N,N-dimethyl-L-leucinamide hydrochloride (11.7 g) obtained in B) and triethylamine (18.2 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (8.00 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the obtained solid was suspended in THF. The suspension was filtered through celite pad and silica gel pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (8.1 g).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][C:13]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=1.C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>C(Cl)Cl>[C:16]([C:14]1[N:15]=[C:11]([C:5]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])[O:12][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:40]([NH:39][CH3:38])=[O:41])[CH2:29][CH2:30]2)=[N:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Reactant: CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide dihydrochloride (0.060 g, 0.13 mmol) in DCM (3 mL) was added triethylamine (40 uL, 0.29 mmol) followed by methyl isocyanate (12 uL, 0.20 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC and then by SPE using a MP-TsOH resin (500 mg) cartridge to afford 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)-N-methylpiperazine-1-carboxamide (0.0057 g, 0.013 mmol, 10%) as a yellow solid. 1H NMR (DMSO) 2.58 (3H, d), 3.40 (4H, m), 3.61 (4H, m), 6.54 (1H, br. q), 6.99 (1H, d), 7.38 (2H, t), 7.65 (1H, br. s), 7.67 (1H, br. s), 7.72 (1H, m), 8.37 (1H, dd), 8.95 (1H, d). LCMS (2) Rt: 2.27 min; m/z (ES+) 443.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:29][C@@H:30]1[CH2:35][NH:34][CH2:33][C@H:32]([CH3:36])[N:31]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([N:31]1[C@H:32]([CH3:36])[CH2:33][N:34]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:28])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:35][C@@H:30]1[CH3:29])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: C[C@@H]1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)C[C@H](C)N1C(=O)OC(C)(C)C
Yield: 74.4 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (93 mg, 0.436 mmol) gave (2S,6R)-4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (170 mg, 74%) [following SiO2 chromatography, eluting with 0-10% MeOH)/dichloromethane]. MS (ESI) m/z 577.3 (M+H)+
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccc(-n2cccn2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 2.00 g (95.2%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 73.2 %

Procedure:
Using 0.19 g of 4-methylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.20 g of 2-(4-methylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (84)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1)[C:5](O)=[O:6].CC[N:41]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=2)(=[O:30])=[O:31])[CH:12]=1)[C:5]([NH2:41])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(=O)O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 3-fluoro-4-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzoic acid (500 mg, 0.936 mmol) in DMF (10 mL) was added EDC HCl (269 mg, 1.40 mmol) followed by HOBt and NH3 (284 mg, 1.87 mmol). The reaction was stirred at RT for 1 h, then quenched with ice cold water (20 mL) to get a precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give the crude product (250 mg). MS (ESI, pos. ion) m/z: 534.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](Cl)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([N:30]([CH2:31][CH2:32][OH:33])[CH3:29])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCO
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a liquid mixture of 150 mg of 3-(4-t-butylphenyl)-4-chlorocarbonyl-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one and 3 ml of tetrahydrofuran, 72 mg of N-methylethanolamine was added at room temperature, and the resulting mixture was stirred at the same temperature for another 1 hour and then concentrated under reduced pressure. After addition of 1N hydrochloric acid, the mixture was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized in ethyl acetate-hexane to give 110 mg of the title compound as colorless crystals.