Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14]1>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[ClH:1].[CH:13]1([N:16]2[CH2:21][CH2:20][N:19]([C:2]3[S:3][C:4]4[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1
Reactant: C1CN(C2CC2)CCN1
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Product: Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A mixture of 2-chloro-6-methoxybenzothiazole (0.20 g, 1.0 mmol) and 1-cyclopropyl-piperazine (0.25 g, 2.0 mmol) was stirred at 120° C. overnight. The reaction mixture was allowed to cool and dissolved in a mixture of ethyl acetate a NaHCO3 solution. The phases were separated and the organic phase was washed with water (3×) and then extracted with 0.25 M hydrochloric acid (20 mL). The acidic aqueous extract was concentrated and re-evaporated with ethanol. The residue was crystallized from a mixture of ethanol and ethyl acetate to give 60 mg (18%) of 2-(4-cyclopropylpiperazin-1-yl)-6-methoxybenzothiazole, hydrochloride.
Reaction SMILES: [C:1](=[O:36])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:11]2[C:6]1=[C:7]([OH:35])[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=2)[NH2:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[C:4]([O:35][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:36])[NH2:2])[C:17]1([O:19][C:17](=[O:18])[CH3:16])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:3])[CH3:5]
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 194.1 %

Procedure:
11-Benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (15 mg) was dissolved in a mixture of pyridine (1.0 ml) and acetic anhydride (0.5 ml). The solution was stirred for 1 day at room temperature. To the solution was added 4-dimethylaminopyridine (catalytic amount) and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated in vacuo, and the residue was subjected to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 11-benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (17 mg).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14]N.NCC1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>O1CCCC1>[NH2:28][C:27]1[CH:29]=[CH:30][C:11]([CH2:12][NH:8][C:1]([NH:3][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:2])=[CH:25][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NN
Reactant: NCc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (1.783 g, 11.00 mmol) in anhydrous tetrahydrofuran (7 ml) was added tert-butyl carbazate (1.322 g, 10.00 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 4-(aminomethyl)aniline (1.228 g, 10.05 mmol) in anhydrous tetrahydrofuran (3 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under to reduced pressure, and ethyl acetate (50 ml) and water (50 ml) were added to the residue. The mixture was stirred, stood still and partitioned. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 90 g, ethyl acetate:hexane=7:3→8:2→9:1) to give tert-butyl 2-[(4-aminobenzyl)carbamoyl]hydrazinecarboxylate (2.180 g, 7.778 mmol, yield 77.8%) as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.N1C=CN=C1.[C:11]([O:15][C:16](=[O:27])[NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24](=O)[NH2:25])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:15][C:16](=[O:27])[NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[N:25])[CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(N)=O)C1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCCC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a mixture of phosphorus oxychloride (4.60 g, 30.0 mmol) and imidazole (1.22 g, 18.0 mmol) in pyridine (40 mL) cooled in an ice-methanol bath was slowly added (3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.45 g, 6.00 mmol). The reaction was stirred for 3 hours, allowing to warm to room temperature. The suspension was filtered, the filtrate evaporated and the solids combined before partitioning between aq. NH4Cl (30 mL) and EtOAc (3×30 mL). The combined organic layers were dried (MgSO4) and evaporated to give 930 mg (69%) of (3-cyano-cyclohexyl)-carbamic acid tert-butyl ester as a gum, which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ: 4.53-4.29 (m, 1H), 3.50-3.33 (m, 1H), 2.58-2.44 (m, 1H), 2.42-2.33 (m, 1H), 2.09-1.99 (m, 1H), 1.99-1.77 (m, 3 h), 1.44 (s, 9H), 1.39-1.30 (m, 2H), 1.18-1.02 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:29])=O.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>C1(C)C=CC=CC=1>[ClH:29].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:36][C:35]1[CH:37]=[CH:38][CH:39]=[C:33]([Cl:32])[C:34]=1[F:40])(=[O:3])[CH3:2]
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC(C)=O
Product: Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
6-Acetoxy-7-methoxyquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 21.4 kg, 89.3 mol) was suspended in toluene (150 kg). To this was added N-ethyldiisopropylamine (13.3 kg, 103 mol). The brown suspension was heated to 70° C. then phosphorus oxychloride (36.0 kg, 228 mol) was charged. The reaction mixture was stirred at 70° C. for 5 hours. Further toluene (84.0 kg) was added followed by 3-chloro-2-fluoroaniline (14.88 kg, 102 mol). The reaction mixture was stirred at 70° C. for 2 hours during which time a solid precipitated. The suspension was cooled to 25° C. and held at this temperature for 93 hours. The reaction mixture was filtered and the filter cake washed with toluene (2×55.5 kg). The cake was further washed with a mixture of ethanol (24.5 kg) and water (32.0 kg) twice, then ethanol (50.5 kg) twice and the solid then dried under vacuum to give the title product as a beige solid (33.4 kg, 78%); 1H NMR: 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s, 1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H); Mass Spectrum: 362.4, 364.4.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@@H:9]2[C:14]([OH:16])=O)[CH:2]=[CH2:3].[CH3:18][O:19][C:20]1[CH:45]=[CH:44][C:23]([CH2:24][O:25][C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:30][N:29]=[C:28]([CH2:42][NH2:43])[CH:27]=2)=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]([NH:43][CH2:42][C:28]1[CH:27]=[C:26]([O:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:45][CH:44]=2)[C:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:30][N:29]=1)=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Reactant: COc1ccc(COc2cnc(CN)cc2OCc2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)NCc1cc(OCc2ccc(OC)cc2)c(OCc2ccc(OC)cc2)cn1
Yield: 36.1 %

Procedure:
To a solution of (R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 32, 0.469 g, 1.97 mmol) in DMF (10 mL) at room temperature was added (4,5-bis(4-methoxybenzyloxy)pyridin-2-yl)methanamine (Intermediate 65, 0.824 g, 2.17 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.497 g, 3.94 mmol) and N,N-diisopropylethylamine (1.372 mL, 7.87 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, and 1/1 brine/water twice. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the title compound as a light pink foam (0.427 g, 36%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][Cl:23])([O-:18])=[O:17]>>[Cl-:23].[CH3:15][N+:2]([CH3:1])([CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCCNC(=O)c1ccccc1
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Product: COc1ccc(C[N+](C)(C)CCCNC(=O)c2ccccc2)cc1[N+](=O)[O-]
Product: [Cl-]

Procedure:
Proceeding in a manner similar to that described above in 1a, and using N-(3-dimethylaminopropyl)benzamide, and 3-nitro-4-methoxybenzyl chloride, there was obtained N,N-dimethyl-N-(3-nitro-4-methoxybenzyl)-N-3-benzamidopropylammonium chloride, as an off white solid which melted at 133°-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.B([C:18]1[CH:19]=[C:20]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:26]1[CH:25]=[C:24]3[C:37]([CH3:45])([CH3:44])[C:38]4[C:43]([C:23]3=[CH:22][C:21]2=1)=[CH:42][CH:41]=[CH:40][CH:39]=4)(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O1CCOCC1.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.O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:18]2[CH:19]=[C:20]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]2[CH:25]=[C:24]4[C:37]([CH3:45])([CH3:44])[C:38]5[C:43]([C:23]4=[CH:22][C:21]3=2)=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:3]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(B(O)O)ccc4n(-c4ccccc4)c3cc21
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccc6[nH]c7ccccc7c6c5)ccc4n(-c4ccccc4)c3cc21

Procedure:
14.07 g (57.18 mmol) of 3-bromo-9H-carbazole 22, 25.37 g (62.90 mmol) of compound 13 and 6.75 g of sodium carbonate are suspended in 1800 ml of dioxane, 1800 ml of toluene and 750 ml of water. 3.38 g (2.93 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. The yield is 19.5 g (65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]#[C:13][CH2:14][OH:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+:17].[ClH:18]>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]#[C:13][CH2:14][OH:15])[CH:9]=1.[Cl-:18].[Li+:17]
Reactant: Cl
Reactant: COC(=O)c1ncc(C#CCO)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(C#CCO)cnc1C(=O)O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 3-amino-5-(3-hydroxy-prop-1-ynyl)-pyridine-2-carboxylic acid methyl ester (297 mg, 1.44 mmol) in THF (10 ml) was added 1N lithium hydroxide and the mixture was vigorously stirred at room temperature for 4.5 h. To the mixture was added 4N HCl (0.47 ml, 1.87 mmol), after dilution with toluene the solvent was evaporated, the residue was suspended in toluene and evaporated (twice). The residue was suspended in TBME/hexane, filtered and the solid dried under reduced pressure at 50° C. to provide the title compound together with lithium chloride as a brown solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:26]([CH2:28][CH3:29])[CH3:27])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:28]([N:26]([CH3:27])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[C:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:29]
Reactant: CCOC(=O)C1(NC(=O)c2c(C)cc(C)nc2N(C)CC)Cc2ccccc2C1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCN(C)c1nc(C)cc(C)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(ethyl-methyl-amino)-4,6-dimethyl-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (348, 260 mg, 0.66 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (70 mg, 1.66 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 38 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.18 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CO.C(Cl)Cl>[O:11]=[C:10]1[C:4]2[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)C(=O)CCCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 128A (1.63 g, 9.30 mmol) and K2CO3 (2.57 g, 18.60 mmol) in MeOH (10 ml) under nitrogen atmosphere was cooled to 0° C. The mixture was treated with benzyl chloroformate (1.726 ml, 12.09 mmol), raised to room temperature and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.75-1.90 (m, 4H), 2.67-2.75 (m, 2H), 2.84-2.92 (m, 2H), 4.70 (d, J=5.76 Hz, 2H), 6.72 (s, 1H), 7.16 (d, J=8.14 Hz, 1H), 7.36-7.39 (m, 5H), 7.49 (d, J=2.71 Hz, 1H), 7.70 (d, J=7.12 Hz, 1H). MS (M+NH4)+ m/z 327.
Reaction SMILES: CO.[H-].[Na+].[CH3:5][SH:6].Cl[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:19]2[NH:20][C:21](=[O:28])[C:22]([CH:25]([CH3:27])[CH3:26])([CH3:24])[N:23]=2)[N:10]=1>C(O)(=O)C>[CH:25]([C:22]1([CH3:24])[C:21](=[O:28])[NH:20][C:19]([C:11]2[N:10]=[C:9]([CH2:8][S:6][CH3:5])[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[N:23]1)([CH3:27])[CH3:26]
Reactant: CS
Reactant: COC(=O)c1ccc(CCl)nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CSC)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 mL of absolute methanol, stirred at -10° under nitrogen, is added in portions 0.9 g of 50% sodium hydride (oil dispersion). A stream of methyl mercaptan is then added to the solution until a pH of 10 is achieved. To this solution is added 3 g of methyl 6-chloromethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate, and stirring is continued at -10° for 1 hour. The reaction is then allowed to warm to room temperature over 1 hour, and is then acidified with glacial acetic acid to pH 4. The mixture is concentrated in vacuo, and the residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue is dissolved in absolute methanol, washed with hexanes, and concentrated in vacuo to afford the desired product. Recrystallization from methylene chloride-hexane affords a solid, mp 113.5°-115° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[OH-:17].[K+].[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[CH3:20].Cl>C(O)C>[C:22]1([C:19]2[CH:20]=[C:7]([C:8]([OH:17])=[O:13])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=3)[N:9]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [OH-]
Reactant: CC(=O)c1ccccc1
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12
Yield: 86.5 %

Procedure:
Commercially available 5-trifluoromethoxyisatin (5.66 g, 24.5 mmol) was added in small portions to an ethanol (75 mL) solution of potassium hydroxide (85%, 3.60 g, 54.5 mmol) under ice cooling. To the mixture, acetophenone (3.00 mL, 25.7 mmol) was further added, and then, the mixture was heated to reflux for 1 hour. After the reaction solution was concentrated, water was added to the residue, and then concentrated hydrochloric acid (4.47 mL, 53.6 mmol) was added thereto. The deposited crystal was collected by filtration, washed with water, and dried. The crude crystal was dissolved in a saturated aqueous solution of sodium bicarbonate and washed with diisopropyl ether, and then, concentrated hydrochloric acid was added until a crystal was deposited. The deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound (7.06 g, 21.2 mmol) as an ocherous powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:16][O-:17].[Li+].S(=O)(=O)(O)O>CC1CCCC(C)C1=O>[CH3:16][O:17][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: C[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC1CCCC(C)C1=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a stirred solution of 3,5-dinitrobenzoic acid (2.0 g, 9.42 mmol) in 2,6-dimethylcyclohexanone (20.0 ml) was added lithium methoxide (1.43 g, 37.8 mol). The resulting mixture was stirred at room temperature for 20 hours and poured into cold diluted sulfuric acid aqueous solution. The mixture was extracted with diethylether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.31 g, yield: 70.25%, reddish brown solid).
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[CH3:6][C:7](=[O:10])[C:8]#[CH:9].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([C:7](=[O:10])[CH3:6])[O:4][N:3]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.1 %

Procedure:
A mixture of dibromoformaldoxime(which was obtained in Example 116) (32.5 g, 160.2 mmol), 3-butyn-one (13.41 g, 197 mmol), potassium carbonate (11 g, 80.1 mmol), and methylene chloride (300 mL) was stirred at ambient temperature for 20 hours. The slurry was then treated with aqueous hydrochloric acid (2N, 200 mL) and extracted with methylene chloride. The combined organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl acetate/hexanes 5/95) gave a white solid (16.76 g, 56% yield); 1H NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 6.97 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:27][N:2]([CH3:1])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][N:17]([C:29]3[C:30]4[C:37]([CH3:38])=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3c[nH]cn3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(Cc4c[nH]cn4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 42 %

Procedure:
3-(4-((1H-imidazol-4-yl)methyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (10 mg, 0.027 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (5 mg, 0.03 mmol), and N,N-diisopropylethylamine (23 μL, 0.135 mmol) were combined in isopropanol (0.5 mL). The resulting mixture was heated at 100° C. in a sealed pressure tube for 24 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by prep HPLC (10-95% MeOH:H2O with 0.1% HCOOH), then treated with AcOH in H2O and lyophilized to give the title compound (5.7 mg, 42%) as the acetate salt.
Reaction SMILES: [CH3:1][N:2]([C:4](/[CH:6]=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:3].[Br:14]Br.C(N(CC)CC)C>ClCCl.CCOCC>[CH3:1][N:2]([C:4](/[C:6](/[Br:14])=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:3]
Reactant: CN(C)C(=O)/C=C/C1CCCCC1
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)C(=O)/C(Br)=C/C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To an ice cold solution of 1.18 g (6.51 mmol) of 1-cyclohexyl-3-dimethylamino-propenone in 8 mL of dichloromethane was added dropwise 1.04 g (6.51 mmol) of bromine via an addition funnel. The reaction mixture was stirred at 0□C. for 0.5 h and then 0.9 mL (6.51 mmol) of triethylamine in 10 mL of ether was added dropwise. The mixture was stirred at 0□C. for 1 h and allowed to warm up to rt. A light yellow solid precipitated from the solution, and it was separated by filtration. The filtrate was then concentrated to give 1.69 g of 2-bromo-1-cyclohexyl-3-dimethylamino-propenone as a brown solid as indicated by 1H NMR. The product was used in the next reaction without any further purification.