Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH3:32])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]=1[C:9]([OH:11])=[O:10])([CH3:3])=[CH2:2].C1CCN2C(=NCCC2)CC1.[C:44]1([C:50](Cl)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl[CH2:65][C:66]1[O:67][C:68](=[O:72])[O:69][C:70]=1[CH3:71]>CC(C)=O>[C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH3:32])[N:7]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:26]=[N:27][N:28]([C:50]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:29]=3)=[CH:17][CH:18]=2)[C:8]=1[C:9]([O:11][CH2:65][C:66]1[O:67][C:68](=[O:72])[O:69][C:70]=1[CH3:71])=[O:10])([CH3:3])=[CH2:2]
Reactant: Cc1oc(=O)oc1CCl
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)O
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)c1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1C(=O)OCc1oc(=O)oc1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 128.8 %

Procedure:
4-Isopropenyl-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid [olmesartan dehydrate, compound 34b described in J. Med. Chem., 39, 323-338 (1996)] (139.36 g), acetone (1022.3 ml), 1,8-diazabicyclo[5,4,0]-7-undecene [DBU] (154.3 g) and triphenylmethyl chloride [TPC] (109.6 g) were mixed and the mixture was stirred at 48 to 52° C. for 5 hours. The reaction mixture was cooled to 20° C. and 4-chloromethyl-5-methyl-1,3-dioxol-2-one [DMDO-Cl] (99.1 g) was added, and the reaction mixture was stirred at 48 to 52° C. for 2.5 hours and then at 55 to 58° C. for 1.5 hours. 1,8-Diazabicyclo[5,4,0]-7-undecene [DBU] (45.4 g) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one [DMDO-Cl] (49.5 g) were added to the reaction mixture and the reaction mixture was stirred at 56 to 57° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (3000 ml) and water (1000 ml) and extracted 4 times. The obtained organic layer was concentrated under reduced pressure to obtain 327.83 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-isopropenyl-2-propyl-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate [crude trityl olmesartan medoxomil dehydrate] as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNC(=O)Oc2ccccc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.050 g, 0.130 mmol), phenyl chloroformate (0.020 mL, 0.59 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.574 mmol) in CH2Cl2 (10 mL) was stirred at room temperature, then concentrated to dryness. The crude product was purified using preparative reverse-phase HPLC to provide 7-chloro-4-oxo-3-(phenoxycarbonylamino-methyl)-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester. MS calcd. for C25H20ClN2O5 [(M+H)+] 463.1, obsd. 462.9.
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24](O)=[O:25])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:25])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Reactant: NCCCO
Product: O=C(NCCCO)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 496) and 3-amino-propan-1-ol.
Reaction SMILES: [C:1]1([P:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=[O:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1>[C:1]1([P:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[CH:11]([OH:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1P(=O)(c1ccccc1)c1ccccc1)c1ccccc1P(=O)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OC(c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Yield: 36 %

Procedure:
Into 10 ml of toluene was dissolved 252 mg (0.36 mmol) of 2,2′-bis{diphenylphosphinyl}benzophenone, and further 2.0 ml (14.4 mmol) of triethylamine was added thereto. The resultant solution was cooled to 0° C. Thereto was added 360 μl (3.6 mmol) of trichlorosilane, and then the resultant solution was stirred for 30 minutes while the temperature thereof was kept at 0° C. Thereafter, the temperature thereof was slowly raised to a temperature at which the solution was allowed to be refluxed. The solution was then refluxed for 4 hours. The reaction mixture was cooled, and thereto was added dropwise 10 ml of 25% aqueous sodium hydroxide slowly. The aqueous phase was extracted with 10 ml of methylene chloride. The organic phases were combined, and the resultant was washed with 1N hydrochloric acid two times and then dried over magnesium sulfate. The resultant was concentrated under reduced pressure to distill off the solvent, and then purified by column chromatography on silica gel (ethyl acetate:hexane=1:6 to give 47.7 mg (yield: 20%) of the title compound in the form of a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].[Br-]>>[C:25]1([C:7]2[C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][C:9]=3[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.091 g, 88%) from (1,3-diphenyl-dibenzofuran-2-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp>120° C. (decomp.); 1H NMR (DMSO-d6) δ 3.66 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.09–7.15 (m, 1H), 7.33–7.39 (m, 1H), 7.39–7.47 (m, 3H), 7.48–7.56 (m, 5H), 7.68 (d, J=8.1 Hz, 1H), 7.70–7.74 (m, 3H); IR (KBr) 3420, 3070, 2950, 2910, 1730, 1610, 1500, 1465, 1455, 1405, 1330, 1310, 1240, 1220, 1175, 1155, 1070, 750, and 700 cm−1; mass spectrum [EI], m/z 394 (M)+; Anal. Calcd. for C26H18O4.1.25H2O: C, 74.90; H, 4.96; N, 0.00. Found: C, 75.07; H, 4.89; N, 0.06.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 98.9 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.70, g 1.81 mmol) in dry MeOH (15 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.90 mL, 18.10 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 minutes or until the solution became clear. The reaction was cooled and filtered trough Celite, washed with MeOH (20 mL), and the solvent evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a brownish solid (0.64 g, quantitative). 1H-NMR (CDCl3) δ 1.12 (t, 3H, J=6.8 Hz), 1.45 (s, 9H), 1.53-1.69 (m, 3H), 1.71-1.79 (m 1H), 1.82-1.92 (m, 1H), 2.07-2.17 (m, 2H), 3.06-3.24 (m, 2H), 3.43-3.56 (m, 1H), 4.43 (s, 1H), 6.64 (dd, 1H, J=2.1, 8.4 Hz), 6.89 (d, 1H, J=2.1 Hz), 7.15 (d, 1H, J=8.4 Hz), 7.26 (s, 1H), 7.33 (s, 1H), 7.82 (s, 1H); EI-MS (m/z, %) 357 (M+, 70), 212 (100).
Reaction SMILES: [NH2:1][NH2:2].C1(C)C=CC(S([O:12][CH2:13][C@H:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15](OC)=O)(=O)=O)=CC=1>C(Cl)Cl>[C:23]([O:22][C:20]([NH:19][CH:14]1[CH2:15][NH:2][NH:1][C:13]1=[O:12])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: NN
Reactant: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CNNC1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Under a nitrogen atmosphere, dry methylene chloride (50 ml) was cooled in an ice bath and anhydrous hydrazine (97%, 11.0 g, 333 mmole) was added. The ice bath was removed and the solution was stirred until it warmed to room temperature. At this time a solution of methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate (20.0 g, 53.6 mmole) in dry methylene chloride (50 ml) was gradually added. The reaction solution was stirred under nitrogen at room temperature for 5 hours. The solution was then concentrated under reduced pressure and the concentrate was taken up in saturated aqueous sodium bicarbonate solution. The aqueous solution was continuously extracted for 14 hours with methylene chloride (700 ml). The methylene chloride solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield approximately 5.15 g, 48% of 4-(R,S)-(t-butoxycarbonylamino)-3-oxo-1,2-diazolidine: n.m.r. (CDCl3, 90 MHz): δ7.04 (m, 1), 5.12 (m, 1), 4,28 (m, 1, C-4 proton), 3.94 (m, 1, C-5 proton), 3.20 (m, 1, C-5 proton), 1.45 (s, 9, t-butyl protons); i.r. (CHCl3): 3430, 3250, 3019, 2983, 1702, 1545, 1503, 1370, 1297, 1241, 1215, 1165 cm-1 ; f.d.m.s.: M+ =201;
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[OH:6].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>O1CCOCC1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH:5]([OH:6])[CH2:4][NH:3][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:1])=[CH:8][CH:9]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCC(O)c1ccc(O)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCC(O)c1ccc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (79.1 ml, 79.1 mmol) solution was added to a solution of 5 g (26.4 mmol) of 4-(2-amino-1-hydroxyethyl)phenol in dioxane (50 ml), and the mixture was stirred at room temperature for 5 min. 2-Nitrobenzenesulfonyl chloride (14.6 g, 65.9 mmol) was added to this solution, and the mixture was stirred at room temperature for 17 hr. Dioxane as the solvent was removed under the reduced pressure, and the residue was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 13.3 g (yield 97%) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([N:24]([C:32]4[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[CH2:10][CH2:9][C:8](=[O:11])[NH:7][CH2:6][CH2:5]1.Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][O:3][C:4]1([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([N:24]([C:32]4[N:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[CH:34][N:33]=4)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[CH2:10][CH2:9][C:8](=[O:11])[NH:7][CH2:6][CH2:5]1
Reactant: Cc1cc(-c2cnc(C3(O)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Temperature: 125 °C
Yield: 46.1 %

Procedure:
A flame dried microwave vessel was charged with a solution of sodium hydride (4.26 mg, 0.106 mmol, 2.0 equiv) in anhydrous DMF (1 ml). tert-butyl {3-[2-(4-hydroxy-7-oxoazepan-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (30 mg, 0.05 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (19.1 mg, 0.08 mmol, 1.5 equiv) were added, causing an exotherm and color change from tan to dark orange. This mixture was heated at 125° C. for 30 min. The resulting mixture of products was purified via reverse-phase HPLC (acetonitrile/water gradient with 0.05% TFA present), to afford tert-butyl (3-{2-[4-(2-hydroxyethoxy)-7-oxoazepan-4-yl]-1,3-thiazol-5-yl}-5-methylphenyl)[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (14 mg, 33%), as an orange oil. MS ESI: [M+H]+ m/z 7222
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[C:7]([F:16])[C:8](=[O:15])[N:9]3CC(=C)C=1[C:10]=23.S([O-])([O-])=O.[Na+].[Na+].[C:23]([OH:27])([CH3:26])([CH3:25])[CH3:24].[OH2:28]>>[F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[C:7]([F:16])[C:8](=[O:15])[N:9]3[CH2:25][C:23]([OH:27])([CH2:26][OH:28])[C:24]=1[C:10]=23
Reactant: CC(C)(C)O
Reactant: C=C1Cn2c(=O)c(F)cc3ncc(F)c1c32
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=c1c(F)cc2ncc(F)c3c2n1CC3(O)CO
Yield: 82 %

Procedure:
A solution of 3,8-difluoro-4-methylidene-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (219 mg, 1 mmol) in tert-butanol/water (10 ml/10 ml) was treated with AD mix alpha/beta (0.75 g/0.75 g). After 6 hours the reaction mixture was treated with saturated sodium sulphite solution (10 ml). After 10 minutes the mixture was extracted with 20% methanol in dichloromethane (3×200 ml). The aqueous phase was concentrated (to ca 20 ml) and further extracted with 20% methanol in dichloromethane (3×200 ml). The organic extracts were dried and evaporated affording a white solid (206 mg, 82%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([CH:27]([OH:37])[C:28]2[N:29]=[N:30][N:31]([CH2:33][C:34]([O-:36])=O)[CH:32]=2)[CH:24]=[CH:23][CH:22]=1)=[O:3].[K+].C1C=CC2N(O)N=[N:45]C=2C=1.C(Cl)CCl.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:45][C:34](=[O:36])[CH2:33][N:31]1[CH:32]=[C:28]([CH:27]([OH:37])[C:25]2[N:26]=[C:21]([NH:20][C:5]3[S:6][C:7]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=4[F:19])=[CH:8][C:4]=3[C:2]([NH2:1])=[O:3])[CH:22]=[CH:23][CH:24]=2)[N:29]=[N:30]1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)c4cn(CC(=O)[O-])nn4)n3)s2)c(F)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)c4cn(CC(N)=O)nn4)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium{4-[[6-({3-(aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl](hydroxy)methyl]-1H-1,2,3-triazol-1-yl}acetate (96 mg, 0.17 mmol), HOBT (52 mg, 0.34 mmol), EDC (65 mg, 0.34 mmol), and NH4Cl (46 mg, 0.85 mmol) were combined in DMF (3.0 mL), and DIEA (89 μL, 0.51 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by reverse phase HPLC (10-70% MeCN/water w/0.025% TFA). The isolated product was of insufficient purity, so flash chromatography (dry load, 0-10% MeOH/EtOAc) was performed to afford the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([OH:18])[O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:39][CH2:40][CH2:41][CH2:42]O>ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([O:18][CH2:42][CH2:41][CH2:40][Br:39])[O:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: OCCCBr
Reactant: COc1cc(C2CCC(O)O2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCC(OCCCBr)O2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Compound 105 (1.0 g, 3.94 mmol) was dissolved in 4 mL dichloromethane. Triethylamine (597 mg, 5.90 mmol) was added to this solution. The reaction mixture was cooled with an ice bath and trifluoroacetic anhydride (1.24 g, 5.90 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and then 3-bromopropanol (1.84 g, 13.27 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 4:1 hexane/ethyl acetate) (128: 430 mg and its cis isomer 250 mg; total yield 46%). 1H NMR (CDCl3): 128 (trans): 1.77(m,1H); 1.98(m,1H); 2.15(m,2H); 2.20(m,1H); 2.40(m,1H); 3.53(t,2H); 3.60(m,1H); 3.83(s,3H); 3.87(m,1H); 3.89(s,6H); 5.01(t,1H); 5.35(dd,1H); 6.57(s,2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(CO[Si](C)(C)C(C)(C)C)cc3ccoc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(CO)cc3ccoc23)CC1
Yield: 89.6 %

Procedure:
A mixture of 0.42 gm 1-(5-(tert-butyldimethylsilyloxymethyl)benzofur-7-yl)-4-tert-butoxycarbonylpiperazine and excess tetrabutylammonium fluoride was stirred in tetrahydrofuran for 30 minutes. The reaction mixture was then diluted with ethyl acetate and washed three times with dilute aqueous sodium bicarbonate. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5:2 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.28 gm (89%) 1-(5-(hydroxymethyl)benzofur-7-yl)-4-tert-butoxycarbonylpiperazine. This material was dissolved in trifluoroacetic acid and the resulting solution stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 10% methanol and a trace of ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 1-(5-hydroxymethyl)benzofur-7-yl)piperazine. This compound was treated with hydrogen chloride to provide the title compound as a white solid.
Reaction SMILES: OC([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([OH:14])=[CH:11][CH:10]=[CH:9]2)C.F[C:16](F)(F)[C:17](O)=O.[C:22]([O:25][CH2:26]C)(=O)C.O>O1CCCC1.N1C=CC=CC=1>[CH2:16]([C:5]1[CH:4]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[O:14][CH2:26][O:25][CH3:22])=[CH:7][CH:6]=1)[CH3:17]
Reactant: CC(O)c1cccc2cccc(O)c12
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc2cccc(OCOC)c2c1
Reaction time: 6 h

Procedure:
270 g of 8-(1-hydroxyethyl)-1-naphthol was dissolved in 500 ml of tetrahydrofuran and 170 ml of pyridine, followed by dropping 357 g of anhydrous trifluoroacetic acid under ice-cooling conditions in 45 minutes. The reaction solution was agitated under ice-cooling conditions for 0.5 hours, after which 2 liters of ethyl acetate was added. After washing with a saturated saline solution, 1N hydrochloric acid, a saturated saline solution and a sodium hydrogencarbonate saturated aqueous solution in this order, the reaction solution was dried with anhydrous magnesium sulfate. Insoluble matters were removed by filtration and 3.75 liters of tetrahydrofuran was added to the resultant filtrate. 3.75 g of 10% palladium-carbon (water content:50%) was further added, followed by violent agitation in an atmosphere of hydrogen at 1 atm., for 6 hours. After removal of the palladium-carbon by filtration, the filtrate was concentrated to half in volume. The resultant residue was added under agitation to a saturated sodium hydrogencarbonate aqueous solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant residue was dissolved in 1 liter of N,N-dimethylformamide. 69 g of 60% sodium hydride was gently added to the solution under ice-cooling conditions, followed by agitation for further 20 minutes. 160 g of chloromethyl methyl ether was dropped in the resultant reaction solution so that the inner temperature did not exceed 20 C. After further agitation at room temperature for 30 minutes, the reaction solution was poured into iced water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off, followed by purification by silica gel column chromatography (hexane), thereby obtaining 259 g of the captioned compound as a light yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.N1C=CC=CC=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>N1CCCCC1.O>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][N:6]=1
Reactant: Cc1ncc(C=O)s1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: Cc1ncc(C=CC(=O)O)s1
Yield: 72 %

Procedure:
A mixture of 29 g of 2-methyl-5-thiazolecarboxaldehyde, 30 ml of pyridine, 29 g of malonic acid and 30 drops of piperidine was heated at 100°-100°C for 5 hours and was then returned to room temperature and poured into 500 ml of water. The pH of the solution was adjusted to 3 by addition of N sulfuric acid and the mixture was vacuum filtered. The recovered precipitate was dried to obtain 27.8 g of 3-(2-methyl-5-thiazolyl)-2-propenoic acid which was crystallized from 800 ml of ethanol containing 10% ethanol to obtain 23.8 of the said product melting at 204°C.