Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1>C(OC(=O)C)(=O)C>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[C:12]1([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18]1
Reactant: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3cccn3-c3ccccc3)OC(=O)c3ccccc32)c(N(C)C)c1
Yield: 59.7 %

Procedure:
A mixture of 2.91 g (0.01 mole) of 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid prepared in part A above, 2.34 g (0.017 mole) of 84.6 percent active N,N,N',N'-tetramethyl-m-phenylenediamine in 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C to obtain 2.61 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-phenyl-2-pyrrolyl)phthalide (Formula IV: R°=R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R7 =C6H5), a peach-colored powder melting at 193°-194° C. The infrared spectrum showed a maximum at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed an immediate orange-red-colored image.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[H][H].[ClH:12]>O.[Pt]=O>[ClH:12].[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: OCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: OCCC1CCNCC1

Procedure:
2-(4-pyridyl)ethanol (70. g, 0.57 M) and platinum oxide (2 g) in water (600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at the pressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidine hydrochloride in quantitative yield. Treatment of 4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12 M) with phosphorus tribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration with diethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidine hydrogen bromide (20.76 g, 77% yield). The solution of the 4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085 M) in tetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. To this solution was added formic acetic anhydride (12.7 ml) at 0° C., followed by the addition of triethylamine (25 ml) with vigorously stirring. The reaction mixture was stirred overnight. After the reaction, it was filtered and the filtrate was stripped in vacuo to dryness and water (100 ml) was then added to the residue and the mixture was extracted with diethyl ether (3×100 ml). Removal of the solvent and purification on silica gel columns, eluted with ethyl acetate-hexane (9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde (12.06 g, 66% yield).
Reaction SMILES: COC1C=C2C(=CC=1OC)C(=O)CCC2.[N:16]1C=CC=CC=1.[N+:22]([C:25]1[CH:47]=[CH:46][C:28]([CH2:29][O:30]/[N:31]=[C:32]2\[CH2:33][CH2:34][CH2:35][C:36]3[C:41]\2=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)=[CH:27][CH:26]=1)([O-])=[O:23].C(OCC)(=O)C.CCCCCC>C(O)C>[N:22]1[O:23][N:16]=[C:47]2[CH:46]=[C:28]([CH2:29][O:30]/[N:31]=[C:32]3\[CH2:33][CH2:34][CH2:35][C:36]4[C:41]\3=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=4)[CH:27]=[CH:26][C:25]=12
Reactant: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Reactant: c1ccncc1
Agent: COc1cc2c(cc1OC)C(=O)CCC2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)/C(=N/OCc1ccc3nonc3c1)CCC2
Yield: 88 %

Procedure:
6,7-Dimethoxy-1-tetralone (40 mg, 0.19 mmol) was subjected to reaction with 0-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)hydroxylamine hydrochloride (41 mg, 0.20 mmol) in ethanol (2 mL) and pyridine (0.2 mL, 2.58 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded the title compound as white crystals (60 mg, 88%), m.p. 139-140° C., Rf 0.4.
Reaction SMILES: CC1C=C(C2C=CC(C)=CC=2)SC=1C(O)=O.C=O.S(Cl)(Cl)=O.Cl[CH2:24][CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[S:28][C:27]=1[C:38](Cl)=[O:39].[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:52][CH2:51][C@@H:50]([N:53]([CH3:55])[CH3:54])[CH2:49]2)=[CH:44][CH:43]=1>>[CH3:54][N:53]([CH3:55])[C@@H:50]1[CH2:51][CH2:52][N:48]([C:45]2[CH:46]=[CH:47][C:42]([N:41]3[CH2:24][CH2:25][C:26]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[S:28][C:27]=4[C:38]3=[O:39])=[CH:43][CH:44]=2)[CH2:49]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: Cc1ccc(-c2cc(CCCl)c(C(=O)Cl)s2)cc1
Agent: C=O
Agent: Cc1ccc(-c2cc(C)c(C(=O)O)s2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(N4CC[C@@H](N(C)C)C4)cc2)CC3)cc1

Procedure:
Firstly 3-methyl-5-p-tolylthiophene-2-carboxylic acid was reacted with paraformaldehyde by method C1, and then the product was treated with thionyl chloride by method B. The resulting 3-(2-chloroethyl)-5-p-tolylthiophene-2-carbonyl chloride was finally reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A. The product with the molecular weight of 431.60 (C26H29N3OS) was obtained in this way; MS (ESI): 432 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(I)cc2)c1Br
Yield: 65 %

Procedure:
4-Iodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-iodobenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 166°-173° C., yield 65%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]=1.C(OCC)(=O)C>O>[ClH:9].[ClH:9].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[C:12]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: Clc1nc(NCc2ccccc2)c2ncn(C3CCOC3)c2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cl
Product: NC1CCC(Nc2nc(NCc3ccccc3)c3ncn(C4CCOC4)c3n2)CC1
Reaction time: 5 h
Yield: 101.2 %

Procedure:
656 mg of trans-1,4-diaminocyclohexane and 133 mg of the product obtained in Stage 2 above are mixed together and the reaction medium is taken to a temperature of 130 to 150° C. for approximately 5 hours then left overnight at ambient temperature. Then the reaction medium is taken up in 10 ml of water and 20 ml of ethyl acetate and left to settle, followed by re-extracting with 2×5 ml of ethyl acetate, washing with 10 ml of water and 10 ml of saturated aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2, 1.5 ml of hydrochloric acid at 1.4 N in ethanol is added and the reaction medium is left to crystallize. After diluting with 2 ml of ethyl acetate and leaving for one hour at ambient temperature, separation is carried out, followed by washing with 5 ml of ethyl acetate and drying at a temperature of approximately 50° C. In this way 98 mg of expected product is obtained in the form of white/cream crystals.
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[CH2:11]([C@H:19]1[CH2:21][O:20]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[C:13]1([CH2:12][CH2:11][C@H:19]([OH:20])[CH:21]=[CH2:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]CCCC
Reactant: c1ccc(CC[C@H]2CO2)cc1
Agent: C[S+](C)C
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@@H](O)CCc1ccccc1
Temperature: -20 °C
Yield: 66.2 %

Procedure:
A modified procedure of Falck was used (Alcaraz, L. et al., Tetrahedron Letters 1994, 35, 5449). A suspension of trimethylsulfonium iodide (18.2 g, 89.1 mmol) in anhydrous THF (220 ml) was stirred and cooled to −20° C. 1.6 M n-BuLi (55.7 ml, 89.1 mmol) was added slowly and the reaction stirred at −20° C. for 1 h. A solution of epoxide 63 (4.40 g, 29.7 mmol) in anhydrous THF (50.0 ml) was added slowly. The reaction was stirred at −20° C. for 1 h and then allowed to warm to r.t. slowly. The reaction mixture was poured into water (200 ml) and extracted with Et2O (1×200 ml, 1×100 ml). The combined organic phases were washed with saturated NaCl solution (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by column chromatography (130 g silica), eluting with petrol/EtOAc (9:1), to give partially purified material. This was re-purified by column chromatography (50 g silica), eluting with petrol/EtOAc (9:1), to give allylic alcohol 66 (3.19 g, 66%) as a pale yellow liquid. The analytical data matched that described for the racemic material above.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:31])([F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN(C=O)C.O>[Cl:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][N:67]([C:27](=[O:29])[CH2:26][NH:25][C:23]([C:20]2[CH:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:10])([F:31])[F:30])[NH:22][N:21]=2)=[O:24])[CH2:66][CH2:65]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reaction time: 0.03 h
Yield: 44.1 %

Procedure:
DIPEA (137 mg, 1.06 mmol) was added to a stirred solution {[5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (95 mg, 0.3 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (2′-trifluoromethyl)acetophenone) in DMF (2.0 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI.HCl (67 mg, 0.35 mmol). After 2 minutes of stirring, (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (75 mg, 0.3 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated under reduced pressure. The residue was purified washing with diethyl ether to afford 67 mg (43.5% Yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 506.12, 97.9%, 1H NMR (300 MHz, DMSO-d6): δ13.2 (d, 1H), 8.2 (m, 1H), 7.5 (m, 5H), 7.2 (m, 2H), 6.85 (m, 1H), 6.5 (m, 2H), 4.8 (m, 1H), 4.3 (m, 1H), 4.1 (d, 2H), 4.0 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.3 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](OC)=[O:23])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])[CH3:2].Cl>O1CCCC1.[OH-].[Li+].O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH2:17][C:18](=[C:22]=[O:23])[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(C1=CC=CC(=C=O)C1)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 326 %

Procedure:
A mixture of 2-(3-methoxycarbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.16 g, 1 mmol) in tetrahydrofuran (40 mL), 2M lithium hydroxide in water (20 mL) was stirred for 48 h at 25° C. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution, diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.1 g, 98%) as a white solid: LC/MS m/e calcd for C21H23NO4 (M+H)+: 354.42, observed: 354.0.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=C=S.[CH2:15]([NH2:18])[CH2:16][NH2:17].[CH2:19](Cl)Cl>CO>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][N:17]1[CH2:16][CH2:15][N:18]=[CH:19]1
Reactant: ClCCl
Reactant: NCCN
Reactant: Cc1cc2nc[nH]c2c(C)c1N=C=S
Solvent: CO
Product: Cc1cc2nc[nH]c2c(C)c1NN1C=NCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4,6-dimethyl-5-isothiocyanatobenzimidazole (250 mg, 1.23 mmol) in methylene chloride (5 mL) is added dropwise to a solution of ethylenediamine (370 mg, 6.2 mmol) in methylene chloride (5 mL). The resulting solution is stirred at room temperature for 15 minutes then rotary evaporated. The residue is dissolved in methanol (10 mL) and to this solution is added mercuric acetate (390 mg, 1.23 mmol). The resulting reaction mixture is stirred at room temperature for 1 hour, filtered through a pad of silica gel and rotary evaporated. The residue is purified by chromatography on silica gel (70:30:0.5 methylene chloride:methanol:ammonium hydroxide) to afford 4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:5]([I:10])=[C:6]([NH2:9])[C:7]=1[I:8].[CH3:18][C:19]1([CH3:27])[O:23][CH:22]([C:24](Cl)=[O:25])[CH2:21][O:20]1>>[CH3:18][C:19]1([CH3:27])[O:23][CH:22]([C:24]([NH:9][C:6]2[C:5]([I:10])=[C:4]([CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:3]([I:17])=[C:2]([NH:1][C:24]([CH:22]3[CH2:21][O:20][C:19]([CH3:27])([CH3:18])[O:23]3)=[O:25])[C:7]=2[I:8])=[O:25])[CH2:21][O:20]1
Reactant: CC1(C)OCC(C(=O)Cl)O1
Reactant: CC(=O)OCCc1c(I)c(N)c(I)c(N)c1I
Product: CC(=O)OCCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(NC(=O)C2COC(C)(C)O2)c1I
Yield: 47 %

Procedure:
3,5-Diamino-2,4,6-triiodo-(2-acetoxyethyl)benzene was acylated with 2,2-dimethyl-1,3-dioxolane-4-carboxylic chloride (prepared in situ) according to the procedure in Example 29a. After work up, the product was purified by preparative HPLC and isolated in 47% yield.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CC1C=CC(S(O[CH2:30][CH2:31][CH:32]2[CH2:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[N:46]4[C:42]([S:43][C:44]([CH2:47][O:48][CH3:49])=[N:45]4)=[N:41][C:40]=3[Cl:50])[CH2:33]2)(=O)=O)=CC=1.O>C1COCC1>[Cl:50][C:40]1[N:41]=[C:42]2[N:46]([C:39]=1[CH2:38][N:34]1[CH2:33][CH:32]([CH2:31][CH2:30][F:1])[CH2:36][C:35]1=[O:37])[N:45]=[C:44]([CH2:47][O:48][CH3:49])[S:43]2
Reactant: [F-]
Reactant: COCc1nn2c(CN3CC(CCOS(=O)(=O)c4ccc(C)cc4)CC3=O)c(Cl)nc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn2c(CN3CC(CCF)CC3=O)c(Cl)nc2s1
Yield: 22 %

Procedure:
A 1M solution of tetrabutylammonium fluoride in THF solution (4 ml) is added to 2-(1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-5-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate a39 (308 mg, 0.617 mmol, 1 eq). The resulting solution is irradiated in a microwave apparatus (Biotage) at 100° C. for 1 h. Water (10 ml) is added to the reaction mixture, and the crude compound is extracted by ethyl acetate (4×10 ml). The cumulated organic layer are washed successively by a saturated NH4Cl aqueous solution (2×10 ml), water (2×10 ml), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by flash chromatography over silicagel (eluent: CH2Cl2/MeOH 99:1) to afford 47 mg of pure 1-{[6-chloro-2-(methoxymethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2-fluoroethyl)pyrrolidin-2-one 28.
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH3:22])[CH2:20][O:19]1.Cl>CN(C)C=O.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]([OH:19])([CH:21]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)[CH3:22])[CH2:20][SH:1]
Reactant: COC(=O)CCS
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(CS)c1ccc(F)cc1F
Reaction time: 0.08 h

Procedure:
Methyl 3-mercaptopropionate (0.88 ml) was added to N,N-dimethylformamide (14 ml) containing 60% sodium hydride in oil (0.32 g) under ice-cooling. After 5 minutes, a solution of 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.67 g) in N,N-dimethylformamide (3.5 ml) was added over 5 minutes with ice-cooling. After 15 minutes, the reaction mixture was poured into water (150 ml), neutralized with hydrochloric acid and extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 ml× 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×10 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether was added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of low polarity; compound 116, diastereomer B). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give 0.21 g of compound 116. The mother liquor of the above crude crystals was further subjected to silica gel chromatography (2 cm×12 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether and hexane were added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of high polarity; compound 115, diastereomer A). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give crystals of compound 115 (0.11 g). Compound 115 (diastereomer A) m.p. 112°-117° C. (colorless prism)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:21][C:19]1[N:20]=[C:13]2[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=[CH:15][N:14]2[CH:18]=1
Reactant: Cc1cn2cccc(Br)c2n1
Reactant: OB(O)c1ccc(O)cc1
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: COCCOC
Solvent: O
Product: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Yield: 25.7 %

Procedure:
A mixture of 4-hydroxyphenylboronic acid (1.1 g), 8-bromo-2-methylimidazo[1,2-a]pyridine (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.28 g), sodium carbonate (3.0 g), DME (35 ml) and water (7 ml) was heated under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (0.46 g).
Reaction SMILES: [CH:1]1([C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)([OH:12])[CH2:5][CH2:6][N:7](C)[C:8](=O)C)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]1([C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)([OH:12])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:2][CH2:3]1
Reactant: CC(=O)N(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNCCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 0 °C

Procedure:
A mixture of 5 g. (0.016 mole) of 1-cyclopropyl-3-(N-methylacetamido)-1-(3-trifluoromethylphenyl)-1-propanol, 2.9 g. (0.024 mole) of potassium tertiary butoxide and 25 ml. of dimethyl sulfoxide was warmed on a steam bath for 45 minutes. The mixture was cooled, poured into ice water and extracted with benzene. The benzene extract was dried over magnesium sulfate and concentrated to an oil which was distilled at 108° C./0.15 mm. The yield was 2.6 g. (59%).
Reaction SMILES: [C:1]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)c1cccc2ccccc12
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: BrC(c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.5 %

Procedure:
To a solution of 32.3 g (138 mmol) of 7 in 150 mL of dry diethyl ether, 24.8 g (8.62 mL, 91.6 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 37.7 g (92%) of 8.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:29]4[O:28][C:27]([C:30]([NH2:32])=O)=[CH:26][C:25](=[O:33])[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:29]4[O:28][C:27]([C:30]#[N:32])=[CH:26][C:25](=[O:33])[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Yield: 97 %

Procedure:
Following the process described in example 2 (point D), by reacting 8-[(E)-2-[4-(4-phenylbutoxy)phenyl]-ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide with phosphorous oxychloride in DMF for 0.5 h at 0° C., the title compound was prepared (97% yield).