Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[OH:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10]>C1C=CC=CC=1>[OH:3][CH2:4][C:5]1[S:6][C:7]([I:1])=[CH:8][C:9]=1[CH3:10]
Reactant: II
Reactant: Cc1ccsc1CO
Solvent: c1ccccc1
Product: Cc1cc(I)sc1CO

Procedure:
6.58 G. (33 mmol) of mercuric oxide and 7.62 g. (30 mmol) of iodine were added alternately in small amounts to a vigorously stirred solution of 3.84 g. (30 mmol) of 2-hydroxymethyl-3-methylthiophene in 30 ml. of benzene. The reaction was kept at room temperature by cooling with an ice bath. The orange mercuric iodide which precipitated was filtered and washed well with benzene. The combined organic solutions were washed with sodium thiosulfate and saturated sodium chloride solution, dried and evaporated to yield crude 2-hydroxymethyl-3-methyl-5-iodothiophene as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=O)[CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccn2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccn1)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-chloro2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-chloro-6-(2-pyridyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([N:13]1[C:14]2[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:7][CH:8]=[CH:9][C:10]=2[NH:11][C:12]1=[O:15])[CH:26]=[CH2:25]
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 30.4 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added sodium hydride (60% dispersion in mineral oil, 4.80 g, 120 mmol) portionwise at 0° C. After stirring for 30 min, allyl bromide (10.4 mL, 120 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and 4N hydrogen chloride solution in ethyl acetate (300 mL) was added. After stirring for 70 hr, the mixture was concentrated in vacuo to give a solid which was washed with n-hexane to afford the title compound (22.2 g, 90.6 mmol, 91%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]([CH2:23][CH3:24])([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:17]([CH3:22])[CH:16]=3)([CH2:13][CH3:14])[CH2:23][CH3:24])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
2-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzooxazole-6-carboxylic acid methyl ester (1.20 g, 3.38 mmol) in acetone (40 mL) is treated with 1-bromopinacolone (0.73 g, 4.06 mmol) and K2CO3 (0.93 g, 6.76 mmol). The suspension is stirred at RT for 4 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified using silica gel column chromatography (15% EtOAc/Hex) to give the title compound as a pale yellow oil (1.50 g, 98%). H-NMR (ppm, CDCl3) δ: 8.14 (1H, d, J=2.4 Hz), 8.07 (1H, dd, J=1.2, 8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.05 (1H, d, J=1.6 Hz), 7.00 (1H, dd, J=2.4, 8.4 Hz), 6.56 (1H, d, J=8.4 Hz), 4.87 (2H, s), 3.96 (3H, s), 2.40 (2H, q, J=7.5 Hz), 2.30 (2. H, q, J=7.5 Hz), 2.28 (3H, s), 1.27 (9H, s), 0.77 (6H, t, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][C@H:15]2[CH2:16][CH2:17][C@H:18]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:19][CH2:20]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (5.6 g, 26.7 mmol) in methanol (50 mL), acetic acid (1.2 g, 20.57 mmol) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (1.6 g, 26.74 mmol) was added at 0° C. and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography twice eluting with ethyl acetate:hexane to afford (4 g, 44%) of less polar cis isomer and (3 g, 33%) of the pure more polar trans isomer.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cc1ccccc1
Reaction time: 0.05 h
Yield: 34.9 %

Procedure:
40% Methanolic Triton B (0.12 mL, 0.26 mM) was added to a solution of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (701 mg, 0.17 mM) in 10 mL DMF at 25° C. After 3 minutes, methyl bromoacetate (55 mg, 0.34 mM) was added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed with 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (73%) of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.4-7.00 (m, 14H), 6.65 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.4 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.95 (s, 2H), 4.2 (s, 2H), and 3.80 (s, 3H). IR (KBr, cm−1) 3414, 3186, 1759, 1625, 1583, 1500, 1452, 1424, 1340, 1325, 1213, 1199, and 1108. MS (ES) m/e 477, 479.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:4].C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:16][O:15][C:13]([CH:12]([CH:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:14]
Reactant: COC(=O)CC(CC(=O)OC)CC(=O)OC
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CC(CC(=O)OC)C(CC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To 5 ml of a tetrahydrofuran solution containing 600 mg of dimethyl 3-methoxycarbonylmethylglutarate, 1.36 ml of a 1.5M lithium diisopropylamide cyclohexane solution and 0.54 ml of hexamethylphosphoramide were dropwise added at -78° C. under a nitrogen atmosphere, followed by stirring at the same temperature for 1.5 hours. Then, a tetrahydrofuran solution containing 620 mg of benzyl bromoacetate was added thereto, followed by further stirring for one hour. The reaction solution was warmed to room temperature over a period of one hour and then stirred at the same temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid column chromatography (hexane/ethyl acetate=3/1) to obtain 555 mg of the above-identified compound as colorless oily substance.
Reaction SMILES: [CH2:1]1[O:21][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.C(O)C.C(OCC)(=O)C>[H][H]>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[O:21][CH2:1]1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(C2=CCC3(CC2)OCCO3)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)Oc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 99.9 %

Procedure:
A mixture of (4-trifluoromethoxyphenyl)cyclohexen-4-one ethyleneketal (43.3 g, 0.144 mol), ethanol (200 ml), ethyl acetate (50 ml) and Pa-C (2 g) was stirred at room temperature for 10 hours in hydrogen atmosphere (at that time, hydrogen (3.59 l) was consumed), filtering off the catalyst from the reaction solution, distilling off the solvent under reduced pressure, to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone ethyleneketal (43.5 g) (m.p. 41.2° C.), adding thereto formic acid (250 ml), heating the mixture under reflux for 2.5 hours, feeding the reaction substance into water, extracting with a mixed solvent of toluene (400 ml) with ethyl acetate (100 ml), twice washing the resulting orgnaic layer with water, drying over anhydrous MgSO4, filtering off anhydrous MgSO4, distilling off the solvent under reduced pressure and subjecting the resulting residue to column chromatography (silica gel, eluent: toluene), to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone (20.7 g). Yield: 47%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][SH:8].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][S:21][CH2:12][CH3:13]
Reactant: Cn1cccc1CS
Reactant: CCN1C(=O)c2ccccc2C1=S
Product: CCSSCc1cccn1C

Procedure:
Starting from 1-methyl-2-mercaptomethyl-pyrrole and N-ethylthiophthalimide there is obtained (1-methyl-2-pyrrolyl)methyl-ethyl-disulphide.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20](O)=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][OH:40]>C(Cl)(Cl)Cl.O>[CH3:23][C:9]1[N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=2)=[O:7])[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[C:10]=1[CH2:19][C:20]([NH:39][OH:40])=[O:21]
Reactant: NO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)NO)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 88.4 %

Procedure:
In a four-necked flask equipped with a mechanical stirrer, a dropping funnel, a cooler with CaCl2 tube and thermometer, there was poured a solution of 230 g (0.637 mole) of 1-(4-chloro-benzoyl)-5-methoxy-2-methyl-3-indolyl-acetic acid and 88.2 ml (0.637 mole) of triethylamine in 400 ml of chloroform. This solution was added dropwise with stirring to a solution of 60.7 ml (0.637 mole) of ethyl chlorocarbonate, keeping the temperature low by an external cooling of ice and water. The formed triethylamine hydrochloride was removed by filtration, then the chloroform solution was added at room temperature to 21.12 g (0.64 mole) of hydroxylamine. After stirring for some hours, the formed precipitate was recovered by filtration, washed with chloroform, dried and subsequently washed several times with water in order to remove the inorganic residues. After drying in oven, 210 g (yield 91% by weight) of pure oxamethacin were obtained. M.p. 181°-83° C.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[C@@H:22]([OH:33])[C@@H:21]1[OH:34])(=[O:17])[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][CH3:16].CN(C)C=O.[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:64](O)=[O:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:54])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.O1CCOCC1>[C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH:30][C:64](=[O:65])[C@H:56]([CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[NH:55][C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[CH2:48][NH:47][C:45]([O:44][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:46])=[N:28][C:26]2=[O:27])[C@@H:22]([OH:33])[C@@H:21]1[OH:34])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)[C@H](Cc3ccccc3)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)nc2=O)[C@@H](O)[C@@H]1O
Temperature: 5 °C
Reaction time: 96 h

Procedure:
A solution consisting of 4.82 g. (0.01 mole) 1-(5'-O-palmitoyl-β-D-arabinofuranosyl)cytosine and a solvent mixture consisting of equal parts dimethylformamide and dioxane was obtained by warming slightly. This solution was cooled to 5° C. and 3.8 g. (0.01 mole) N-[N-[N-(tertbutoxycarbonyl)glycyl]glycyl]-L-phenylalanine was added, followed by 2.47 g. (0.012 mole) dicyclohexylcarbodiimide. This reaction mixture was stirred continuously for 4 days while the temperature was maintained at 5° C. The reaction mixture was then filtered in order to remove the dicyclohexylurea that had formed. The solvents were removed from the filtrate by evaporation under reduced pressure. The residual oil thus obtained was dissolved in 25 ml. diethyl ether, and the ether solution was set aside in a refrigerator for about 16 hrs. Some solids that separated were removed by filtering, and the filtrate was concentrated to a glass by removing the ether by evaporation. The glassy residue was dissolved in 50 ml. of a solvent system consisting of 72 parts methyl ethyl ketone, 20 parts acetone, and 8 parts water, and the solution was poured onto a column of silica gel 45 mm. × 115 cm. amounting to 800 g. which had been equilibrated with this same solvent. The chromatogram was developed with about 100 ml. of the solvent mixture, and then 10 ml. fractions were collected. After combining fractions 75 through 105, and concentrating the solution by evaporation of the solvents under reduced pressure, the concentrate was lyophilized. There was thus obtained 4.0 g. of 1-(5'-O-palmitoyl-β-D-arabinofuranosyl)-N4 -[N-[N-[N-(tert-butoxycarbonyl)glycyl]glycyl]-L-phenylalanyl]cytosine having optical rotation [α]D25 = +46° (c 1.1 in methanol)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>C(OCC)(=O)C>[CH3:22][O:21][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COc1cc(Nc2ncnc(Cl)n2)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc(Oc3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Yield: 33 %

Procedure:
This compound was prepared from (4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxybenzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 33% yield.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:14])[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:16]>CN(C)C=O>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][NH:17][C:15]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:4]=1[F:1])=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[O:16])[CH3:22]
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1F
Temperature: 200 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
Potassium fluoride (674 mg, 11.6 mmol) was dried under vacuum and stirring, at 200° C. for 3 h. After cooling to room temperature, a solution of compound 95 (1.00 g, 2.32 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added. The mixture was then heated at 130° C., under argon, for 2 h. After cooling to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 96 (0.50 g, 1.20 mmol) as a yellow solid. Yield 52%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.46; mp 88-90° C.; IR (KBr) ν 1105, 1342, 1518, 1656, 2830, 2966, 3405 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.07 (t, 6H, J=7.1 Hz), 2.59 (q, 4H, J=7.1 Hz), 2.69 (t, 2H, J=5.9 Hz), 3.57 (q, 2H, J=5.9 Hz), 7.58 (se, 1H), 7.86 (d, 1H, J=9.0 Hz), 8.06 (dd, 1H, J=1.8, 9.0 Hz), 8.54 (d, 1H, J=1.8 Hz), 9.44 (d, 1H, 4JH-F=10.6 Hz); MS m/z 415 (M+, 1), 299 (3), 145 (1), 118 (3), 86 (100), 58 (9).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Si:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)c2cccnc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)c2cccnc12

Procedure:
A mixture of Example 201A (10.40 g, 38.4 mmol), tert-butyldimethylsilyl chloride (6.07 g, 40.3 mmol), and imidazole (5.49 g, 80.6 mmol) in DMF (75 mL) at room temperature was stirred for 16 hours, treated with water (300 mL), and extracted with diethyl ether (3×400 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH:1]1([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:23][C:24]([NH2:26])=[S:25].O.[OH-].[Na+]>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.C1COCC1.C(OCC)(=O)C>[NH2:26][C:24]1[S:25][C:18]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:13][CH2:12]3)=[CH:21][CH:20]=2)=[N:19][N:23]=1
Reactant: N#Cc1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1nnc(-c2ccc(N3CCC(OC4CCCCC4)CC3)cc2)s1
Reaction time: 7 h
Yield: 71.8 %

Procedure:
A solution of 4-(4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g), thiosemicarbazide (0.91 g) in toluene (20 ml) and trifluroacetic acid (10 ml) was stirred at 60-65° C. with stirring for 7 hours. After cooling, the reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml) and adjusted to pH 10 with 1N-sodium hydroxide. The mixture was dissolved in a mixture of THF (50 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitate was washed diisopropyl ether and dried in vacuo to give 2-amino-5-[4-[4-(cyclohexyloxy)piperidin-1-yl]phenyl]-1,3,4-thiadiazole (1.72 g).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:18])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(NC2CCCC2)c1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 4.69 mmol) in acetonitrile (10 mL), cesium carbonate (3 g, 9.2 mmol) and methyl iodide (3.38 g, 23.3 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered and the residue was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to afford methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1.1 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:22]([O:32][CH2:33][CH3:34])=[N:21]4)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([O:32][CH2:33][CH3:34])=[N:21]4)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
After a mixture of ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (605 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (534 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 160–161° C.