Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1Cl)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1[O:18][C:8]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=1[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1CCOP1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP2OCCN2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A 500 ml, three neck flask equipped with a thermometer, an addition funnel and a condenser topped with a nitrogen sweep is charged with 4.4 g (0.11 mol) of sodium hydride. The sodium hydride is washed with two 20 ml portions of hexane and finally suspended in 45 ml of tetrahydrofuran (THF). To the resultant suspension is added dropwise a solution of 22.04 g (0.10 mol) of 2,6-di-tert-butyl-4-methylphenol in 150 ml of THF at such a rate to keep the reaction temperature between 20°-30° C. The resulting yellow solution is warmed to approximately 40° C. for 1 hour and then cooled in an ice bath. A solution of 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 150 ml of THF is added and stirring continued for 16 hours at room temperature. The resulting cloudy mixture is filtered and the solvent evaporated under reduced pressure. The residue is treated with 200 ml of toluene and the resultant suspension filtered. The filtrate is concentrated in vacuo to yield a thick syrup. Triturating with methanol gives 24.5 g (67.0%) of colorless solid: mp 105°-107° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[C:29]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]=1[O:42][CH3:43])[C:36](O)=[O:37])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:41]=1[O:42][CH3:43])[C:36]([N:26]1[CH2:27][CH2:28][C@@H:24]([N:2]([CH3:1])[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:25]1)=[O:37])([CH3:47])([CH3:46])[CH3:45]
Reactant: CN(C(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCNC1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc(C(=O)N2CC[C@@H](N(C)C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (R)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid methyl-pyrrolidin-3-yl-amide (0.78 g, 2.02 mmol) in dry CH2Cl2 (30 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.53 g, 2.02 mmol) under nitrogen. To the reaction was added EDC (0.77 g, 4.04 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 1.1 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([CH3:13])=[CH2:12])[N:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH:16][Si](C)(C)C)=[N-]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([CH3:13])=[CH2:12])[N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: C=C(C)c1cc(C(=O)O)cc(Cl)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: C=C(C)c1cc(C(=O)OC)cc(Cl)n1

Procedure:
To a solution of 2-chloro-6-isopropenylisonicotinic acid (0.25 g, 1.27 mmol) in dichloromethane (4.7 mL) and methanol (1.6 mL) was added (diazomethyl)(trimethyl)silane (0.63 mL, 1.27 mmol). After the addition, the mixture was concentrated and carried onto the next step. MS 212.0 (M+1).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][C@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@H:23]4[CH3:22])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.8 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (R)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.297 g, 91.0% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)#[N:2].CN(C=O)C.S(Cl)([Cl:20])=O>>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:20])=[O:9])=[CH:6][CH:5]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: N#CCc1ccc(C(=O)Cl)cc1

Procedure:
A solution of 4-cyanomethylbenzoic acid (10.0 g, 62.2 mmol) in thionyl chloride (65 mL) containing DMF (1 mL) was refluxed for three hours, cooled, concentrated, dissolved in hot EtOAc, treated with activated charcoal, filtered through Celite, and concentrated to yield 4-cyanomethylbenzoyl chloride. 4-Cyanomethylbenzoyl chloride was converted to the title compound following the procedure described in step A of Example 82 with the following modifications: 1) 1-(4-cyanomethylphenyl)-2-phenylethanone was chromatographed on silica gel using 2:3 EtOAc/hexane; 2) purification of N-[1-(4-cyanomethylphenyl)-2-phenylethyl]formamide entailed treatment with activated charcoal in EtOAc followed by recrystallization from EtOAc/hexane; and 3) the title compound was chromatographed on silica gel eluting with 10% acetone/EtOAc.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-fluorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.82-6.67 (m, 4H), 6.44 (q, J=7.7, 7.1 Hz, 4H), 6.33 (d, J=8.3 Hz, 1H), 5.09 (s, 1H), 3.44 (dd, J=10.9, 4.2 Hz, 1H), 3.32 (dd, J=11.2, 4.7 Hz, 1H); ESIMS m/z 502 ([M+H]+).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]3[NH:31][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([O:28]CC)=[O:27])[CH2:21]5)=[CH:18][CH:19]=[C:14]4[N:13]=3)[CH2:11][CH2:10]2)[CH:8]=1>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]3[NH:31][C:15]4=[N:16][C:17]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([OH:28])=[O:27])[CH2:21]5)=[CH:18][CH:19]=[C:14]4[N:13]=3)[CH2:10][CH2:11]2)[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
Lithium hydroxide (27.6 mg, 1.1 mmol) was added to a solution of (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (300 mg, 0.77 mmol) in tetrahydrofuran/water (1:1, 6 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was dissolved in water and the pH was adjusted to 6 using aqueous hydrogen chloride (1N). The mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 mg). MS (ES+APCI) (M+H) 387.1; LCMS retention time 3.432 min (Method S1).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>O>[CH3:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]1
Reactant: CN(C)C=O
Reactant: c1ccc(CN(CCc2c[nH]c3ccccc23)Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(CCN(Cc2ccccc2)Cc2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
N,N-dibenzyl-tryptamine (1.72 g) was added to an anhydrous DMF solution containing 0.24 g of NaH (60% nujol) and the mixture was stirred for 15 minutes. Methyl iodide (0.31 ml) was added and the mixture was stirred for one hour. Water was added and the solvent was evaporated off. The residue to which water was added was extracted with IPE, the extract was washed with water and the brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel. Eluates with ethyl acetate/hexane (1/9) afforded 1.58 g of the oily title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C([O-])(=O)C.[NH4+]>CC(O)C>[C:11]([C:10](=[CH:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:14])[CH3:8])(=[O:13])[CH3:12]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccco1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccco1)C(C)=O
Yield: 61 %

Procedure:
A solution containing 2.9g of furfural, 5.0 g of 2,4-pentanedione and 1 g of ammonium acetate in 25ml of 2-propanol was refluxed for 3 h. The solvent was evaporated in vacuo and the residue was purified by using column chromatography. Yellowish oil, yield 61%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Using 1-iodo-4-nitro-benzene (500 mg) instead of 1-bromo-3-nitro-benzene, and 3-(4-methyl-piperazin-1-yl)-propylamine (379 mg) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (432 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][C:33]#[N:34]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:32][C:33]#[N:34])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: N#CCBr
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(N2CCN(CC#N)CC2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (550 mg), potassium carbonate (302 mg), dimethylformamide (7 ml) and bromoacetonitrile (0.12 ml) were combined and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off, and the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (480 mg) as colorless crystals (78%).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH2:13][CH:12]2[C:18](Cl)=[O:19])[CH:9]=[CH2:10]>>[CH2:1]([NH:7][C:18]([CH:12]1[CH2:13][CH:14]2[CH2:17][C:11]1([CH2:8][CH:9]=[CH2:10])[CH:16]=[CH:15]2)=[O:19])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Reactant: NCc1ccco1
Product: C=CCC12C=CC(CC1C(=O)NCc1ccco1)C2

Procedure:
21.4 g of furfurylamine and 39.3 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are reacted in accordance with process A, affording 38.1 g (73.8% of theory) of a reddish brown liquid resin; η25 =1287.2 m Pas.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Mg].[C:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:1]([O:35][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1Br
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Octadecyloxytriphenylmethane (C18 Tr-OH) was prepared in a Grignard procedure starting from octadecyloxyphenyl bromide and magnesium in dry THF. Benzophenone was added to the metalorganic compound and the product was hydrolyzed with 2 M HCl. The worked-up reaction mixture was dried, evaporated, and the pure product crystallized from toluene. The trityl alcohol was converted to the trityl chloride by treatment with an excess of acetylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.[Cl-].[NH4+]>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH2:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 258 g 4,4'-dimethoxybenzophenone in 3000 ml warm toluene was added to 1600 ml 1.4M methylmagnesium bromide under nitrogen with stirring, over a one-hour period. The reaction temperature was kept below 40° C. After addition was complete, stirring was continued for one hour at 30°-40° C. and two hours at 50° C. The mixture was cooled to room temperature and poured into a stirred mixture of 400 ml acetic acid and 624 g ammonium chloride in 7200 ml deionized water. After gas evolution and exotherm had subsided, the organic (toluene) phase was separated and the aqueous phase was washed with 2×600 ml toluene. The combined toluene phases were washed with 1×2400 ml water, then placed in a flask and treated with a solution of 1470 ml deionized water and 1470 ml acetic acid at 50° C. for three hours to effect dehydration of the intermediate hydroxy compound. On cooling, the phases were separated and the toluene phase was washed with 2×1000 ml deionized water, then dried over magnesium sulfate. Filtration and removal of toluene gave a slightly wet cake which was triturated with 1400 ml diethyl ether, filtered and dried to give 222 g 1,1-di(p-methoxyphenyl)-ethene, m.p. 141°-143° C. whose structure was also confirmed by NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1([C@H:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:12](=[O:23])[C@H:11]2[F:24])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([C:6]1([C@H:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:23])[C@H:11]2[F:24])[CH2:7][CH2:8][CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](c1ccccc1)N1C[C@H](C2(C(=O)O)CCC2)[C@H](F)C1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
cis 4-(1-Ethoxycarbonylcyclobutyl)-3-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (optical isomer B; 1.79 g, 5.37 mmol) was dissolved in methanol (10 ml) and a 1 N aqueous solution of sodium hydroxide was added dropwise thereinto. The liquid reaction mixture was stirred at 40° C. for 18 hours and then methanol was evaporated under reduced pressure. Water (50 ml) was added to the residue followed by washing with chloroform (100 ml). The aqueous layer thus separated was acidified by dropping 1 N hydrochloric acid thereinto and then extracted with chloroform (100 ml×2). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound in a quantitative amount as a crude product.
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1.O>CN1C(=O)CCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH2:5][C:4]([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][N:31]=3)[CH2:35][CH2:36]2)=[O:25])=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Reactant: COc1ccnc(N2CCNCC2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccnc(N2CCN(C(=O)Cc3nc(-c4ccc(F)cc4)cn3-c3ccc(F)cc3)CC2)c1
Yield: 31 %

Procedure:
70 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester, 58 mg 1-(4-methoxy-pyridin-2-yl)-piperazine and 0.05 mLN,N-diisopropylethylamine in 2 mL NMP was stirred 50 min. at 180° C. under microwave condition. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by HPLC (column: Waters Symmetry 50×140 mm 7 μm, mobile layer: water+0.3% HCOOH/methanol 10% until 90% in 14 min) to give 31 mg desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7]([C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:8][NH:9][C:10]=2[CH:11]=1.[CH3:22][N:23]1[CH2:28][CH2:27]N[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:1]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:7]([C:12](=[O:21])[N:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:14]=4)=[CH:8][NH:9][C:10]=3[CH:11]=2)[CH2:25][CH2:24]1
Reactant: Nc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3c4nn(-c5ccccc5)c(=O)c-4c[nH]c3c2)CC1

Procedure:
The title compound was prepared following the procedure in Step 5 using 13a and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.44 (3H, s), 2.74 (4H, brm), 3.44 (4H, brm), 7.03 (1H, d, J=2.20 Hz), 7.27 (1H, ddd, J=7.41, 1.64, 1.10 Hz), 7.35 (1H, dd, J=9.07, 2.47 Hz), 7.65 (2H, m), 7.99 (2H, m), 8.17 (1H, d, J=9.07 Hz), 8.53 (1H, s). m/z 360.4 (MH+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5]1.Br[CH2:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)[CH:24]=[C:25]([CH3:27])[CH:26]=2)=[CH:19][N:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:25]1[CH:26]=[C:21]([C:18]2[S:17][C:16]([CH2:15][C:8]3([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][C:4]3=[O:3])=[N:20][CH:19]=2)[CH:22]=[C:23]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[CH:31][N:30]=2)[CH:24]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Reactant: CCOC(=O)C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCNC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=O)[CH2:17][CH2:16]1.O>O1CCOCC1>[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=[S:2])[CH2:17][CH2:16]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(C(F)F)c(C(=S)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Temperature: 100 °C

Procedure:
A solution of 140 mg (0.31 mmol) of phosphorus pentasulfide and 500 mg (1.26 mmol) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[2-(trimethylsilyl)benzyl]-1H-pyrazole-4-carboxamide in 20 ml of dioxane was heated at 100° C. for 2.5 hours. 2 ml of water were then added and the reaction mixture was heated at 100° C. for another 1 hour.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccncc2)ns1
Temperature: 25 °C
Yield: 6 %

Procedure:
To a solution of pyridine-4-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to give 150 mg (5.98%) of the desired product as a solid.