Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[N:19]=[CH:18][C:17]3[C:12](=[C:13]([F:24])[CH:14]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)[C:11]2=[O:25])[C:7]=1[CH:8]=[O:9].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][C@@H:50]3[CH3:59])=[CH:45][N:44]=2)[C:28]1=[O:60].CC([O-])=O.[K+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([F:24])[CH:14]=1)[C:11](=[O:25])[N:10]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:54][CH2:53][N:52]([CH:55]6[CH2:56][O:57][CH2:58]6)[CH2:51][C@@H:50]5[CH3:59])=[CH:45][N:44]=4)[C:28](=[O:60])[N:27]([CH3:26])[CH:32]=3)[C:7]=1[CH:8]=[O:9])[N:19]=[CH:18]2)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cncc(Br)c3C=O)ncc2c1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cncc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 110 °C
Yield: 48.3 %

Procedure:
A 25 mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 109a (118 mg, 0.29 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 105f (140 mg, 0.29 mmol), Pd(dppf)Cl2 (24.8 mg, 0.03 mmol), KOAc (58.9 mg, 0.60 mmol), K3PO4.3H2O (159.8 mg, 0.60 mmol), acetonitrile (6 mL) and water (3 d). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. The reaction mixture was then cooled to room temperature, filtered and the filtrate was evaporated in vacuo. The residue was purified by prep-TLC developing with dichloromethane/methanol (20:1, UV) to afford 109b (95 mg, 36%) as a red solid. MS: [M+H]+ 679
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]2[NH:33][C:32]3[CH2:37][CH2:38][N:39]([CH3:41])[CH2:40][C:31]=3[C:30]=2[CH:29]=1>[Cu]I.CN(C=O)C>[Cl:27][C:28]1[CH:36]=[CH:35][C:34]2[N:33](/[CH:2]=[C:3](\[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)/[CH3:4])[C:32]3[CH2:37][CH2:38][N:39]([CH3:41])[CH2:40][C:31]=3[C:30]=2[CH:29]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4-(1-Bromoprop-1-en-2-yl)pyridine (346 mg, 1.75 mmol) was adsorbed in potassium phosphate (617 mg, 2.9 mmol) and DMF (5 mL) was added followed by copper (I) iodide (27 mg, 0.145 mmol) and L-proline (33 mg, 0.29 mmol). 8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (321 mg, 1.45 mmol) was added to the reaction mixture and nitrogen gas purged for 2 min. The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was cooled to RT and water (20 mL) was added. The compound was extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL) and compound was purified through silica gel (100-200 mesh) using 0-5% MeOH:DCM as eluent and further purified through reverse phase HPLC. Yield: 46 mg. 1H NMR (DMSO, D1-HCl salt) δ (ppm): 8.60 (d, 2H), 7.55 (s, 1H), 7.50 (d, 2H), 7.30 (s, 1H), 7.12 (d, 1H), 7.02 (d, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.60 (m, 1H), 3.38 (m, 1H), 2.85 (m, 2H), 2.80 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[C:4]=2[O:3]1.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CC3CCC4(CC3)OCCO4)c2O1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Cc2cccc(CC3CCC(=O)CC3)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 5.4 grams (0.018 mole) of 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 100 mL of acetic acid, yielding 4-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)cyclohexanone.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F-].[Cs+].[F:14][C:15]([F:37])([F:36])[C:16]([N:18]([C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:17].FC(F)(F)C([O-])=O>CN(C)C(=O)C.O>[F:37][C:15]([F:14])([F:36])[C:16]([N:18]([CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:17]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2CCC(CCN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
Methyl 6-bromonicotinate, 13 (0.476 g, 2.206 mmol) and CsF (2.68 g, 17.64 mmol) were added to a stirred solution of 2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide, trifluoroacetate (1 g, 2.206 mmol) in N,N-dimethylacetamide (10 mL) in a Microwave vial. The reaction vessel was sealed and heated in CEM Discover to 100° C. for 45 min under microwave conditions. Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with water (2×30 mL), brine (1×50 mL), filtered and dried over Na2SO4 and concentrated under reduced pressure to afford crude product The crude product was purified by column chromatography using 100-200 mesh silica gel, by eluting with 30% ethyl acetate in pet-ether to afford methyl 6-(4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidin-1-yl)nicotinate (500 mg, 27.3% yield) as yellow gum. LCMS (ES) m/e 476.14 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]([CH2:2][NH:1][C:25]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[O:31])=[N:7][N:6]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC1=NN=C(CNC(=O)C=CC(=O)O)C1=NNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
5-Aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg, 0.25 mmole) was dissolved in 3 mL of anhydrous DMF. To this solution was added triethylamine (0.51 mmole, 52 mg) and then a solution of maleic anhydride (30.2 mg, 0.31 mmole) in 1 mL of DMF. The reaction mixture was stirred at ambient temperature for 30 minutes and then worked up by the addition of saline and ethyl acetate. The mixture was acidified with 1 mL of 1.5 M HCl. The aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with saline three times and dried over anhydrous MgSO4. The solution was then filtered, concentrated and purified by preparative TLC (CH2Cl2:MeOH:trace acetic acid=6:1) to yield 58 mg of the title compound as a yellow powder. MS (m/z, ES−): 331 (M−1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) □δ 11.90 (br s, 1H), 7.35-7.70 (m, 3H), 7.30 (br s, 2H), 6.12 (d, 1H), 5.70 (d, 1H), 4.52 (s, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=1[Cl:24])[NH:6][C:7](=[O:19])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:24][C:23]1[CH:22]=[C:21]([Cl:25])[CH:20]=[C:5]2[C:4]=1[C:3]([OH:2])=[C:8]([S:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1)[C:7](=[O:19])[NH:6]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)CSCCCc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(O)c1SCCCc1cncnc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2.2 g (5.31 mmol) of 4,6-dichloro-N-[3-(pyrimidin-5-yl)-propylthio]acetyl-anthranilic acid methyl ester are placed in 25 ml of tetrahydrofuran at 0° under nitrogen. 10.62 ml of a 1-molar tetrahydrofuran solution of sodium bis-trimethylsilylamide are added dropwise thereto. The mixture is then stirred for 2 hours at 0°. The reaction mixture is poured into 50 ml of 2N hydrochloric acid/ice and filtered. The residue is taken up in a small amount of ethyl acetate, and hexane is added until precipitation begins. The precipitate formed is filtered off with suction, washed with hexane and dried. 1.75 g (86.2% of theory) of 5,7-dichloro-4-hydroxy-3-[3-(pyrimidin-5-yl)propylthio)-2-(1H)-quinolone are obtained in the form of red crystals having a melting point of 252°-254°.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.N>P(Cl)(Cl)(Cl)=O>[C:9]1([C:7]2([C:6]3[CH:15]=[CH:16][C:3]([N:2]([CH3:17])[CH3:1])=[CH:4][CH:5]=3)[C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][CH:19]=3)[O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Reactant: Oc1ccccc1-c1cc2ccccc2[nH]1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C2(c3ccccc3)Oc3ccccc3-c3[nH]c4ccccc4c32)cc1
Yield: 80.2 %

Procedure:
11.26 g of 4-dimethylaminobenzophenone and 10.5 g of 2-(2'-hydroxyphenyl)-indole are stirred in 50 ml of phosphorus oxychloride for 4 hours under reflux. The reaction mixture is poured onto ice and rendered alkaline with ammonia and the resulting precipitate is then filtered off. Repeated dissolving of the residue in methanol with the addition of a little 37% strength hydrochloric acid and precipitating with ammonia and water gives a slightly impure product, which is purified through a column, packed with 80 g of silica gel/ethyl acetate. Crystallisation from ethyl acetate/ethanol gives 16.7 g of 6-phenyl-6-(4-dimethylaminophenyl)-6H-chromeno[4,3-b]-indole of the formula ##STR17## in the form of yellowish crystals with a melting point of 229°-231° C. On silton clay, this colour-forming agent develops a blue colour with a λ max of 600 nm.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH3:11][Li].O>CCOCC>[CH2:1]([C:3]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: CCC(CC)=C1C=CC=C1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCC(C)(CC)C1=CC=CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 8.00 g (59.6 mmol) of 6,6-diethylfulvene in 35 ml of ether, 60.0 ml (68.4 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (92° C./40 mmHg) to obtain 5.50 g (36.6 mmol) of a light yellow liquid (yield: 61%). The analyzed values are given below.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[C:16]=1[F:23]>O1CCCC1>[F:22][C:17]1[C:16]([F:23])=[C:15]([CH3:14])[CH:20]=[CH:19][C:18]=1[CH2:21][N:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[NH2:12]
Reactant: Cc1ccc(CBr)c(F)c1F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN(N)c2ccc(F)cc2)c(F)c1F
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.64 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-2,3-difluoro-4-methylbenzene (598 mg, 2.72 mmol; Aldrich) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 250 (M+H−NH3)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (0.25 g), 2-(tert-butoxycarbonylamino)ethanol (0.33 g) and triphenylphosphine (0.59 g) in tetra hydrofuran (2 mL) was added diethyl azodicarboxylate (40% toluene solution, 1.34 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-3/1) to give 4-[2-(tert-butoxycarbonylamino)ethoxy]benzaldehyde (0.41 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.
Reaction SMILES: C(O)(=O)C.[C:5](#[N:9])[CH2:6][C:7]#[N:8].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[C:10]1(=[C:6]([C:5]#[N:9])[C:7]#[N:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#CCC#N
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#CC(C#N)=C1CCCCC1
Temperature: 25 °C

Procedure:
Acetic acid was added at room temperature to a stirring mixture of malononitrile (2.65 mL, 42.1 mmol), cyclohexanone (5.03 g, 51.3 mmol) and NH4OAc (6.49 g, 84 mmol) in toluene (200 mL). The resulting mixture was heated at reflux under a Dean-Stark trap for 2 hours (6 mL water collected), then cooled to room temperature. The mixture was concentrated under vacuum, and the residue was distilled under vacuum (air bath 110-130° C./˜10 mm) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.61-1.74 (m, 2H), 1.81 (ddt, J=6.5, 6.2, 5.8 Hz, 4H), 2.66 (dd, J=6.5, 6.2 Hz, 4H).
Reaction SMILES: [CH:1]([C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=O.[CH3:15][O:16][C:17]([CH2:19]P(=O)(OCC)OCC)=[O:18]>>[CH3:15][O:16][C:17](/[CH:19]=[CH:1]/[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:18]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C=O)CCCCn1ccnc1
Product: COC(=O)/C=C/C(C)(C)CCCCn1ccnc1

Procedure:
By the proceeding as described in Example 1 but utilizing 1-(5-formyl-5-methylhexyl)imidazole and diethyl methoxycarbonylmethylphosphonate, there was obtained the title compound having the following physical characteristic in 66% yields:
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:8][C:7]2[CH:9]=[CH:10][C:4]([Cl:3])=[CH:5][C:6]=2[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:23][CH:22]=1
Reactant: COc1ccc(CO)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a slurry of 4-Chloro-2-trifluoroacetylaniline, hydrochloride hydrate (40.0 kg, 144 mol) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to pH 7.0. After removing the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was heated to reflux and the water/toluene azeotrope (30 L) distilled. The solution was cooled to room temperature and washed with saturated brine (80 kg). The organic solution was concentrated in vacuo to a volume of 35-40 L, then diluted with THF (52 kg). The weight percent of the title compound in toluene/THF was calculated by HPLC to be 43%. The yield based on HPLC weight % analysis was 47.7 kg (96%). An analytical sample was obtained by removing the solvent in vacuo and recrystallizing from heptane: mp 82-84° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (s,1H), 7.74 (d, J=2 Hz, 1H), 7.35 (dd, J=2, 9 Hz), 7.24 (d, J=8 Hz, 2H), 6.91 (d, J=8 Hz, 2H), 6.75 (d, J=9 Hz, 1H), 4.43 (d, J=6 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 119.9,117.0, 114.5, 114.4, 111.3, 55.3, 46.6.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(Cl)([Cl:24])=O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:24])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1C2=O
Product: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride is obtained by heating 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionic acid (28 g.) in thionyl chloride (280 cc.) for one hour. After cooling, the thionyl chloride is evaporated at 60°C. under reduced pressure (20 mm.Hg). 2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (28.8 g.) is thus obtained in the form of an oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Na].[CH2:8]1[O:27][C:11]([CH:15]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17][C:16]2=[O:26])(OCC)[O:10][CH2:9]1.Cl>CO.C(OCC)(=O)C>[CH2:8]1[O:27][C:11]([CH:15]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17][C:16]2=[O:26])([NH:2][OH:3])[O:10][CH2:9]1
Reactant: CCOC1(C2CCN(C(=O)OC)CCC2=O)OCCO1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N1CCC(=O)C(C2(NO)OCCO2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of hydroxylamine hydrochloride (11.6 g; 0.17 mol) in methanol (80 mL) was added at 40° C. and with stirring a solution of sodium methoxide in methanol (80 mL) prepared from 7.7 g (0.33 mol) of sodium. To this solution was added at 0° C. a solution of crude (V) (31.6 g; ca. 0.11 mol) in methanol (40 mL). This mixture was left at 25° C. with stirring for 24 h, and after cooling to 0° C. and with continued stirring, pH of the solution was adjusted to ca. 3 by addition of a solution of hydrogen chloride in ethyl acetate (2.5 M). The filtered and evaporated reaction mixture was extracted with ethyl acetate, and after filtration and addition of light petroleum (50 mL) compound (IV) crystallized. The yield of (IV) was 12.0 g (39%), M.p. 152.0-154.0° C. Anal. C11H18N2O6.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:43])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[N:37]3)[CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Cl:27][C:25]1[CH:26]=[C:21]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)[C:22]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:43])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[N:37]3)[CH2:30][CH2:29]2)=[N:23][CH:24]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3NC(=O)c3ccc(S(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 4-methanesulfonyl-benzoic acid (0.030 g, (0.150 mmol) in methylene chloride (2 mL) is added oxalyl chloride (0.017 mL, 0.200 mmol) followed by 1 drop of N,N-dimethylformamide. Vigourous bubbling is observed and the reaction mixture is stirred at room temperature for 2 h. The mixture is concentrated under a stream of nitrogen. The residue is dissolved in methylene chloride (2 mL) and 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.040 g, 0.110 mmol) is added followed by (0.040 mL, 0.220 mmol) N,N-diisopropylethylamine (0.040 mL, 0.220 mmol). The mixture is stirred at room temperature for 3 days then concentrated under a stream of nitrogen. The residue is dissolved in dimethylsulfoxide and purified by reverse phase preparative HPLC to provide, after removal of the eluent, 0.022 g of N-(5-Chloro-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-pyridin-3-yl)-4-methanesulfonyl-benzamide as a white solid in 36% yield. MS; MH+=531.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CC(C)=O>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: COc1ccc(CCl)cc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C#N)c(F)c2)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
4-Methoxybenzyl chloride (5.0 g) and potassium carbonate (8.3 g) were added to an acetone (0.5 L) solution of 2-fluoro-4-hydroxybenzonitrile (4.1 g), and stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (7.2 g).