Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25].[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1

Procedure:
Diethyl malonate (10.1 g; 60 mmole) was added to a solution of sodium metal (1.4 g; 60 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(2,4,6-trimethylphenyl)but-1-en-3-one (11.4 g; 61 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (7.3 g; 180 mmole in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-mesitylcyclohex-2-en-1-one, was obtained as a pale yellow solid (10.9 g; 77.4%), mp 165° C. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.0-4.1 (14H, m); 5.2 (1H, s); 6.8 (2H, s); 11.2 (1H, br.s.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:34](OCCCC)(=O)[CH:35]=[O:36].CC(O)=O>CCO>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]4[N:1]=[CH:34][C:35](=[O:36])[N:28]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[C:3]=4[N:4]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)CC1
Yield: 42.9 %

Procedure:
A mixture of 0.82 g (1.8 mmol) of 5-amino-2-[[4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]amino]-4-(cyclopentylamino)pyrimidine (from preparation 14A), 0.52 g (4 mmol) of butyl glyoxylate (F. J. Wolf, J. Weijlard, Org. Synth. Coll., 1963;4:124–125), and 0.5 mL HOAc in 15 mL of EtOH is heated under reflux for 14 hours, and the solvent is removed under vacuum. The residue is diluted with aqueous ammonia solution and extracted into EtOAc. Chromatography on silica, eluting with hexane/EtOAc (3:2) gave 0.38 g (43%) of the title compound (Compound 52): mp (MeOH) 215–217° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 60.2 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.54 mmol) in DCM (5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (121 mg, 0.896 mmol) and NH2OTHP (84 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (140 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][N:10](CC1C=CC=CC=1)[CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pd].O>[CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][NH:10][CH2:9]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN1CC2CCNCC2(Cc2ccccc2)C1=O
Yield: 77.8 %

Procedure:
To a solution of the compound of Example 200, Step D (0.034 g, 0.10 mmol) in acetic acid (18 mL) was added a slurry of palladium on carbon (10% by weight, 0.030 g) in H2O (2 mL). The reaction mixture was shaken under 50 psig hydrogen for 24 h, an additional aliquot of palladium on carbon (0.030 g) was introduced and the reaction was continued under 50 psig hydrogen for another 24 h. The reaction mixture was filtered through a bed of Celite® with the aid of MeOH, concentrated under vacuum, and the residue was partitioned between CH2Cl2 and H2O at pH 9. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the organic layers were combined and washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step E (0.019 g): +APcl MS (M+1)+ 245; 1H NMR (400 MHz, CDCl3) δ: 7.10-7.24 (arom, series of m, 5H), 3.21 (m, 1H), 2.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([OH:12])[O:5][C:6]2=[O:7].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([CH:4]=[O:12])=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:5][CH3:13])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(O)c2c(F)cccc21
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A stirred mixture containing 7.36 g 4-fluoro-3-hydroxyphthalide, 18.15 g potassium carbonate and 11 mL methyl iodide in 125 mL acetone is heated at reflux for two hours. After stirring overnight at room temperature, the mixture is filtered and concentrated. The residue is dispersed in 200 mL ether, filtered and the filtrate concentrated to give 7.6 g residue which is used directly without further purification. The nmr spectrum of this material is consistent with that expected for the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[CH:13][CH:14]=1
Reactant: OC1CNCc2occc21
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(OC2CNCc3occc32)cc1

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:3]=1.O.[NH2:24][NH2:25].Cl.O>C(O)C>[NH2:9][C:8]1[C:7]2[C:6]([Cl:10])=[N:5][C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:3][C:2]=2[NH:25][N:24]=1
Reactant: C[C@@H](NC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1)c1ccccc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound (R)-1-(4,6-dichloro-5-cyanopyridin-2-yl)-3-(1-phenylethyl)urea (0.10 g, 0.29 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (0.59 mL, 0.59 mmol, 1M solution in THF) and stirred at 80° C. for 2 h. After the precipitation of white solid, the reaction mixture was cooled to room temperature and a 2M solution of HCl in water (0.29 mL, 0.59 mmol) was added stirred at same temperature for 2 h. After confirming the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure to give crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.88 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.36-7.32 (m, 4H), 7.23 (d, J=8.00 Hz, 2H), 5.42 (s, 2H), 4.84-4.82 (m, 1H), 1.38 (d, J=8.00 Hz, 3H), MS ES calc'd. for C15H15ClN6O [M+H]+ 331. Found 331.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][N:20](C(OC(C)(C)C)=O)[CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(Br)cn1
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: C1COCCO1
Product: Fc1ccc(-c2cn[nH]c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) in dioxane (30 ml) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.671 g, 5.68 mmol), Na2CO3 (1.205 g, 11.36 mmol) and Pd(Ph3P)4 (0.657 g, 0.568 mmol). The reaction mixture was stirred at 100° C. under Ar atmosphere for overnight. The reaction was cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the title compound as white solid (0.5 g, 44.2% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1H), 8.29 (s, 1H), 8.2 (d, 1H), 8.18 (d, 1H), 7.99 (s, 1H), 7.18 (dd, 1H). LCMS (method B): [M+H]+=164, tR=1.73 min.
Reaction SMILES: [CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[C:8]([S:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[CH3:22].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][C:2]1[N:21]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[C:8]([S:10]([CH3:11])=[O:31])[CH:9]=[C:4]2[C:3]=1[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc2c(C)c(C)nc-2n(CC(=O)c2ccccc2)c1
Solvent: ClCCl
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(S(C)=O)cc-2c1C
Yield: 46 %

Procedure:
A solution of 2,3-dimethyl-5-methylthio-7-phenacylpyrrolo[2,3-b]pyridine (35 mg, 0.1 mmol) in 20 ml CH2Cl2 was cooled to -20° C. an treated with 71% m-CPBA (27 mg, 0.1 mmol) for 30 min. The volume was adjusted 50 ml with CH2Cl2 and the organic layer washed twice with 50 ml 5% Na2CO3 and once with 2M HCl (reextraction trice with 25 ml CH2Cl2). The organic layer was dried over MgSO4 and evaporated leaving 15 mg (41%) pure title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[C:8]4[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[C:31](Br)[CH:32]=5)[C:9]4=[C:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11]=3[C:12](=[O:15])[C:13]=2[CH:14]=1.C([Sn](CCCC)(CCCC)[C:54]1[S:55][CH:56]=[CH:57][CH:58]=1)CCC>C1(C)C=CC=CC=1.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>[S:55]1[CH:56]=[CH:57][CH:58]=[C:54]1[C:31]1[CH:30]=[CH:29][C:28]2[C:9]3[C:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:11]4[C:12](=[O:15])[C:13]5[C:5](=[CH:4][CH:3]=[C:2]([C:54]6[S:55][CH:56]=[CH:57][CH:58]=6)[CH:14]=5)[C:6]4=[C:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:8]=3[C:34](=[O:35])[C:33]=2[CH:32]=1
Reactant: CCCCCCCCCCCCc1c2c(=O)c3cc(Br)ccc3c2c(CCCCCCCCCCCC)c2c(=O)c3cc(Br)ccc3c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1c2c(=O)c3cc(-c4cccs4)ccc3c2c(CCCCCCCCCCCC)c2c(=O)c3cc(-c4cccs4)ccc3c12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Indenofluorenedione 5 (0.200 g, 0.257 mmol), 2-tributylstannylthiophene (0.231 g, 0.618 mmol), and Pd(PPh3)4 (20 mg) in anhydrous toluene (8.0 mL) were heated overnight at 110° C. under nitrogen. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by column chromatography on silica gel (CHCl3/hexanes (7:3)) to give 2,8-dithien-2-yl-5,11-didodecylindeno[1,2-b]fluorene-6,12-dione (5B) as a purple solid (121 mg, 60.0% yield). 1H NMR (CDCl3): δ 0.88-1.66 (m, 46H), 3.41 (b s, 4H), 7.11 (t, 2H), 7.39 (d, 2H, J=3.0 Hz), 7.62 (d, 2H, J=7.5 Hz), 7.74 (d, 2H, J=7.5 Hz), 7.88 (s, 2H) ppm; m.p: 205-206° C.; MS(MALDI-TOF) m/z (M+): 783.0; and Elemental Analysis: C, 79.60; H, 7.82.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=CC(C#N)=C[N:11]2[N:10]=[CH:9][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOC(C)=O>[NH2:6][C:7]1[C:5]2=[CH:1][C:2]([CH:3]=[O:4])=[CH:12][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: C1CCOC1
Reactant: N#Cc1cc2c(N)ncnn2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of THF (200 mL) was added 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 6.28 mmol). The solution was heated until all stalling material was in solution and was then cooled in an ice-water bath. 1M Diisobutylaluminum hydride in THF (50.3 mL, 50.3 mmol) was then added to the solution which was stirred for 1 h. EtOAc was added to the solution and it was then allowed to warm to it. Wet silica gel was carefully pipetted into the solution, and the reaction mixture was heated to 50° C. for 30 min, filtered through Celite, and washed with excess EtOAc. The solution was transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness yielding 0.92 g of yellow solid (5.69 mmol, yield 91%). 1H-NMR (DMSO-d6) 9.91 (s, 1H) 7.92 (d, J=1.7 Hz, 1H), 8.14 (d, J=35.3 Hz, 2H), 7.89 (s, 1H), 7.30 (d, J=1.8 Hz, 1H); MS [M+H]+=163.3; LCMS RT=1.07 min.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:13]([OH:15])[CH3:14]>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:15][CH2:13][CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(C#N)cc1
Yield: 94.9 %

Procedure:
p-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and ethanol (460.3 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 78° C. for 12 hours while a 20% hydrochloric acid/ethanol solution (162.4 g) prepared in advance was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 83.1 g of ethyl p-cyanobenzoate (yield 95%). Subsequently, the reaction mixture was concentrated under reduced pressure, and water was added thereto. The resultant mixture was dissolved through heating, and cooled for crystallization, to thereby obtain 74.7 g of ethyl p-cyanobenzoate having a purity of 99.5% (yield 85%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:29]O>>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH:21]=1
Reactant: CO
Reactant: O=C(NCc1cccc(C(=O)O)c1)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)c1cccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)c1

Procedure:
3-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid (200 mg, 0.54 mmol) was esterified with MeOH using Method B to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C1C=CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1L). The phases are separated and the aqueous phase is extracted with heptane (2×1L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ7.48 (dd, J=5.7, 2.4 Hz, 1H), 6.20 (d, J=5.7 Hz, 1H), 4.95-4.99 (m, 1H), 2.72 (dd, J=18.2, 6.0 Hz, 1H), 2.25 (dd, J=18.2, 2.3 Hz, 1H), 0.88 (s, 9H), 0.11 (s, 6H); 13C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57,100).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-heptylbenzene (0.82 ml, 4 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-heptylbenzoin was obtained as crystal (386.7 mg, 61.5% yield).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41].C([O-])(O)=O.[Na+]>ClCCl>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol, Eq: 1.00) in dichloromethane (500 μl) was added at room temperature N,N-diisopropylethylamine (31.6 mg, 42.7 μl, 245 μmol, Eq: 3) and 2,2,2-trifluoroethanesulfonyl chloride (22.3 mg mg, 122 μmol). The mixture was allowed to stir at room temperature over night. The crude reaction diluted with 5 mL sat NaHCO3 and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (16 mg, 41.1%), MS (ISP) m/z=478.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH2:39])=[CH:37][C:32]=2[O:31][CH2:30]1>>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH:39][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([CH:6]4[C:7]5=[N:8][CH:9]=[CH:10][CH:11]=[C:12]5[CH2:13][S:14][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]4=5)[CH2:16][CH2:17]3)=[N:22][C:23]#[N:24])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: CSC(=NC#N)N1CCC(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: NCc1ccc2c(c1)OCO2
Product: N#CN=C(NCc1ccc2c(c1)OCO2)N1CCC(C2c3ccc(Cl)cc3SCc3cccnc32)CC1

Procedure:
This compound could be prepared similarly from methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1 -piperidine-carboximidothioate and 1,3-benzodioxol-5-ylmethylamine.
Reaction SMILES: O.[N:2]1[C:9]([Cl:10])=[N:8][C:6](Cl)=[N:5][C:3]=1[Cl:4].[CH3:11][C:12]([NH2:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[OH-]>C1(C)C(C)=CC=CC=1>[Cl:10][C:9]1[N:2]=[C:3]([Cl:4])[N:5]=[C:6]([NH:19][C:12]([CH3:18])([CH3:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
Into a flask, 20 grams of water, 50.0 grams (0.271 mole) of cyanuric chloride and 125 grams of a mixed xylene were charged and 35.9 grams (0.278 mole) of 1,1,3,3-tetramethylbutylamine was slowly and dropwise added into the mixture while keeping the temperature at 8-10° C. Then, 55.5 grams of a 20% aqueous hydroxide solution was slowly and dropwise added into the mixture while keeping the temperature at 8-10C. After the reaction was complete, the oil (organic) and water phases were separated and the water phase was separated off to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(F)c(C#N)c(F)c1

Procedure:
Using 2,4,6-trifluorobenzonitrile (786 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 538 mg) by an operation similar to that in Example 3.