Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][C:16]=1[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl.O>[Cl:11][C:12]1[C:13]([CH:9]=[O:10])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][C:16]=1[CH3:17]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
POCl3 in 1,2-dichloroethane (14 mL) was slowly added to a solution of DMF (4.37 mL, 59.79 mmol) in 1,2-dichloroethane (10 mL). The reaction mixture was stirred for 15 min and then Intermediate 7 (2.04 g, 10.87 mmol) was added. The reaction mixture was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was treated with sodium acetate (10 g) in water (25 mL) and stirred for 1 h. The mixture was extracted with methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate) gave the desired compound (720 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I)[CH3:2].C([Sn](CC[CH2:44][CH3:45])(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.[I:46]I>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:45]=[CH:44]/[I:46])[CH3:2]
Reactant: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Reactant: CCOC(=O)CCCCOc1ccccc1I
Reactant: II
Product: CCOC(=O)CCCCOc1ccccc1/C=C/I
Yield: 57.5 %

Procedure:
Under the conditions of example 2D, 696 mg of 5-(2-iodophenoxy)-valeric acid ethyl ester and 3.2 g of (E)-1,2-bis-(tri-n-butylstannyl)-ethylene (50%) are reacted in the presence of 47 mg of tetrakis-(triphenylphosphine)palladium, treated with 1.02 g of iodine, worked up and chromatographed on silica gel with n-hexane/ethyl acetate-95/5. 430 mg of 5-[2-[(E)-2-iodovinyl]-phenoxy]-valeric acid ethyl ester is obtained as an oily crude product, which is used without further purification in the next stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45](=[O:53])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[NH2:52])=[N:42][CH:43]=1>C(Cl)Cl.CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:16]([C:17]([NH:52][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[C:45]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([Cl:37])=[CH:43][N:42]=2)=[O:53])=[O:19])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)O)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoic acid (507 mg, 2.05 mmol) was diluted with methylene chloride (20 mL). DMF (4 drops) and pyridine (0.2 mL, 2.47 mmol) were added, followed by oxalyl chloride (0.2 mL, 2.29 mmol). Vigorous bubbling occurred. After 1.5 hours, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (20 mL). N-(5-Chloropyridin-2-yl)-2-aminobenzamide (507 mg, 2.05 mmol) was added, followed by pyridine (0.2 mL, 2.47 mmol). After stirring overnight, the reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the desired product (992 mg, 1.74 mmol, 85%) as a white solid.
Reaction SMILES: [Cs+].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O-:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:33])=[O:32]>CO.CN(C=O)C>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:32])=[O:33])=[O:6]
Reactant: O=C([O-])c1c(Cl)cccc1Cl
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid cesium salt (prepared from 0.42 g of the acid and cesium carbonate (0.36 g) in methanol followed by removal of methanol and drying in vacuo) and 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) in DMF was allowed to react at 90°-100° C. for 2 hours, and then cooled. The mixture was diluted with ice/water, extracted with ether/ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography to afford 0.64 g (80%) of 2-(2,6-dichloro-phenylcarbonyloxymethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[C:19]([OH:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[OH:21].I[CH2:23][CH3:24]>O>[Br:8][C:9]1[C:10]([OH:21])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][C:19]=1[O:20][CH2:23][CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)c(Br)c(OCC)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil, 3.86 g) was added to a DMF (100 mL) solution of ethyl 4-bromo-3,5-dihydroxybenzoate (12.3 g), and the mixture was stirred at 00° C. for 30 minutes in a nitrogen atmosphere. Iodoethane (4.15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.87 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1c(CN(CCn2ccnc2)C2CCCc3cccnc32)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)CCCC2N(CCn1ccnc1)Cc1nc2ccccc2[nH]1
Yield: 91.5 %

Procedure:
A solution of 2-{[(2-imidazol-1-yl-ethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (21 mg, 0.044 mmol) in 3:1 TFA/CH2Cl2 (4 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was partitioned between CH2Cl2 (20 mL) and 1 N NaOH(aq) (10 mL), and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford COMPOUND 12 as a yellow foam (15 mg, 83%). 1H NMR (CDCl3) δ 1.73 (m, 2H), 1.99 (m, 1H), 2.20 (m, 1H), 2.69-2.88 (m, 2H), 2.92-3.08 (m, 2H), 3.82-3.98 (m, 2H), 4.04 (d, 1H, J=17 Hz), 4.09 (m, 1H), 4.19 (d, 1H, J=17 Hz), 6.70 (s, 1H), 6.93 (s, 1H), 7.18 (m, 3H), 7.42 (m, 2H), 7.57 (br s, 2H), 8.51 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 21.55, 25.06, 29.36, 46.03, 50.34, 52.23, 62.59, 119.32, 122.26, 122.82, 129.55, 134.97, 137.93, 147.26, 155.42, 156.77. ES-MS m/z 373 (M+H). Anal. Calcd. for C22H24N6.0.2CH2Cl2.0.8CH4O: C, 66.55; H, 6.70; N, 20.25. Found: C, 66.64; H, 6.40; N, 20.06.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2S[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])O.[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:47]([O-:50])(O)=[O:48].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:47](=[O:50])(=[O:48])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: O=S([O-])O
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (250 mg, 0.590 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (283 mg, 1.65 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfite solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 74 mg (yield: 28%) of the title compound. Amorphous powder.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.CN(C)N1C=CC=CC1.[CH2:27]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[CH:8][CH:9]=3)[N:17]=2)=[CH:42][CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: N/C(=N\O)c1ccc(Oc2cccnc2)cc1
Agent: CN(C)N1C=CC=CC1
Solvent: c1ccncc1
Product: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5cccnc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
(Z)-N′-Hydroxy-4-(pyridin-3-yloxy)benzamidine (206 mg, 89.9 μmol), N-dimethylaminopyridine (1.1 mg, 9.0 μmol) and 4-benzyloxybenzoyl chloride (28.8 mg, 116.8 μmol) were suspended in pyridine (5.0 mL) and the solution was refluxed for 45 hours. The reaction mixture was then cooled to room temperature, the solvent was removed under reduced pressure and the solid residue was purified by column chromatography (EtOAc/Hex 1:4) to give the product as a white solid (30 mg, 78%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.16 (2H, s), 7.11 (2H, d, J=6.0 Hz), 7.12 (2H, d, J=6.2 Hz), 7.33-7.37 (2H, m), 7.39-7.46 (5H, m), 8.15 (2H, d, J=7.6 Hz), 8.17 (2H, d, J=7.4 Hz), 8.45 (1H, d, J=4.6 Hz), 8.49 (1H, d, J=2.4 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 70.4 (CH2), 115.5 (CH), 117.2, 118.8 (CH), 123.0 (CH), 124.6, 126.8 (CH), 127.7 (CH), 128.5 (CH), 128.8, 128.9 (CH), 129.7 (CH), 130.3 (CH), 136.2, 141.9, 145.0, 159.1, 162.5, 168.3, 175.8. MS (FAB+): 422 (MH+). HRMS for C26H19N3O3 (MH+): calculated: 422.1505; found 422.1521.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)/[CH:14]=[CH:15]/[CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[F:45][C@H:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)[CH:14]=[CH:15][CH3:16])[C:10]([N:48]1[CH2:49][CH2:50][C@H:46]([F:45])[CH2:47]1)=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C/C=C/[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC=C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.11 g (5.49 mmol) of the acid from Step F dissolved in anhydrous dichloromethane (100 mL) was added EDC (1.34 g, 7.0 mmol), HOBT (0.95 g, 7.0 mmol), (3S)-3-fluoropyrrolidine hydrochloride (880 mg, 7.0 mmol) and N,N′-diisopropylethylamine (1.1 mL, 7.0 mmol). After stirring for 48 h at room temperature, the reaction mixture was concentrated and diluted with 100 mL of 10% aqueous hydrochloric acid. The resultant mixture was then extracted with three 150-mL portions of ethyl acetate, the organic phases combined and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude material as a viscous oil. The crude material was purified by flash chromatography on a Biotage® system (silica gel, 0 to 40% ethyl acetate/hexanes gradient) to give the title compound as a colorless solid. LC/MS 471.3 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(Cl)Cl>[CH2:17]([NH:20][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzoyl chloride (116 μL, 1 mmol) in 1 mL of dry CH2Cl2 was treated successively at 0° C. with triethylamine (167 μL, 1.2 mmol) and n-propylamine (124 μL, 1.5 mmol). The reaction was stirred at room temperature for two hours. The resulting reaction mixture was diluted with CH2Cl2 washed with 2M HCl, followed by saturated NaHCO3, then brine. The resulting solution was then dried over MgSO4. The residue was purified using SiO2 with CH2Cl2/Petroluem ether 95:5 to CH2Cl2 100%. A white solid was obtained (166 mg, quantitative yield). NMR 1H (ppm, CDCl3): 7.74 (d, J3=8.1 Hz, 2H), 7.41 (t. t., J3=7.2 Hz, J4=1.3 Hz, 1H), 7.33 (t. t., J3=7.6 Hz, J4=1.6 Hz, 2H), 5.23 (br. s., 1H), 3.36-3.30 (m, 2H), 1.57 (sext., J3=7.2 Hz, 2H), 0.90 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])CC2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.C(O)C>CN(C)C=O>[Si:18]([O:17][CH:14]1[N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1csc(N2CCC(O)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCC2O[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (1.00 g, 3.90 mmol) (obtained as described in Reference Example 13(2)) in dimethylformamide (50 ml) were added t-butyldimethylsilyl chloride (1.2 g, 7.96 mmol) and imidazole (0.6 g, 8.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes and then stirred for 18 hours. After checking the completion of the reaction, ethanol was added thereto in an ice bath, and the reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1) as the eluant to afford 4-t-butyidimethylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.38 g, yield 95%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[F:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](Cl)=[O:8]>C1COCC1>[CH2:1]([O:3][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([F:14])=[CH:13][C:5]=1[F:4])[CH3:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reaction time: 0.5 h

Procedure:
Ethanol (1.50 mL, 26.0 mmol) was added to a stirred mixture of 2,4-difluoro-5-nitro-benzoyl chloride (5.0 g, 22.6 mmol) and TEA (3.50 mL, 25.2 mmol) in 50 mL THF. After 30 min of stirring the precipitate was filtered and washed with THF. The filtrate was concentrated i.vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:34](Br)[CH3:35].O>CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[N:17]([CH2:34][CH3:35])[C:16]3=[O:21])=[CH:12][N:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)S1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)SC(=Cc2cn(-c3ccccc3)nc2-c2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
5-[3-(3,5-Difluoro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione (Compound No. 58, 0.10 g, 0.21 mmol) was dissolved in 1.0 mL of anhydrous dimethylformamide. Sodium carbonate (26.5 mg, 0.25 mmol) was added under nitrogen atmosphere and ethyl bromide (23.90 μL, 0.32 mmol) was added 10 minutes later. The mixture was stirred for 4 hours at room temperature. Water was added after the reaction was completed. The resultant solid was washed with water (10 mL×3 times). The solid was dried to obtain 85.3 mg (80%) of the target product.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[Br:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(16-bromohexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: C(N=[N+]=[N-])C1C=CC=CC=1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[N+:12]=[N-:13].[C:25]([C:27]1[S:28][C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:30]([CH3:32])[N:31]=1)#[CH:26]>>[CH3:32][C:30]1[N:31]=[C:27]([C:25]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH:26]=2)[S:28][C:29]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Agent: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1sc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)nc1C
Yield: 67 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with 1-(azidomethyl)-4-(trifluoromethyl)benzene to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 67% yield: 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.66-7.55 (m, 2H), 7.45-7.39 (m, 2H), 4.29 (q, J=7.1 Hz, 2H), 5.62 (s, 2H), 2.66 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); MS (ES+) m/z 397.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]=NC(C)(C)C)[CH:6]=1)=[O:4].[CH3:18][C:19]([CH3:22])([NH2:21])[CH3:20].[S:23](=[O:27])(=[O:26])([OH:25])[OH:24].[OH2:28]>CC(O)C>[S:23]([OH:27])([OH:26])(=[O:25])=[O:24].[CH3:18][C:19]([NH:21][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH:12]=[O:28])=[O:4])([CH3:22])[CH3:20].[CH3:18][C:19]([NH:21][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH:12]=[O:24])=[O:4])([CH3:22])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)N=Cc1cc(C(=O)CCl)ccc1O
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)NCC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (10g) is suspended in 2-propanol (60ml) under an inert atmosphere and cooled to 0°. To the stirring slurry is added 1,1-dimethylethanamine (13 ml) and the reaction mixture permitted to warm to room temperature and stir for 50 minutes. The solution is then treated with a mixture of concentrated sulfuric acid (3.5ml), 2-propanol (6.5ml) and deionized water (5ml). The reaction mixture is stirred for a further 18 hours whereupon the title compound (10.2g) is isolated by filtration and dried in vacuo at 50°.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[N:5][C:6]2[N:7]([N:10]=[CH:11][N:12]=2)[C:8]=1[NH2:9])#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:8]1[N:7]2[N:10]=[CH:11][N:12]=[C:6]2[N:5]=[C:4]([CH3:13])[C:3]=1[C:1]#[C:2][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: C#Cc1c(C)nc2ncnn2c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2c(C)nc3ncnn3c2N)cc1
Yield: 45.8 %

Procedure:
A mixture of Example 72B (17 mg, 0.1 mmol), methyl 2-(4-bromophenyl)-2-methylpropanoate (38 mg, 0.15 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol), and triethylamine (28 μL, 0.2 mmol) in acetonitrile (500 μL) was heated at 95° C. under nitrogen for 1 h. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with ethyl acetate) to provide the title compound as a white solid (16 mg, 45% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 3H), 7.64 (d, J=8.48 Hz, 2H), 7.36 (d, J=8.48 Hz, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 1.52 (s, 6H). MS (ESI) m/z 350 (M+H)+.