Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2CC(=NNC(=N)N)c3c(C)coc3C2)cc1
Yield: 72.2 %

Procedure:
A mixture of 3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml) and ethanol (30 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 33) (0.30 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield the 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid;
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=[C:3]1[CH2:16][C:17]#N.[CH2:19]([SH:21])[CH3:20].[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:16]([C:3]1[N:2]([CH3:1])[C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:17].[S:21]1[CH:19]=[CH:20][CH:26]=[C:22]1[CH2:23][C:24]([O-:8])=[O:25]
Reactant: CCS
Reactant: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Reactant: C1CCOC1
Product: CCc1ccc(C(=O)c2ccc(C)cc2)n1C
Product: O=C([O-])Cc1cccs1
Temperature: -20 °C
Yield: 42.5 %

Procedure:
To a dry 100 ml three-necked flask under nitrogen is added 1-methyl-5-(p-toluoyl)pyrrole-2-acetonitrile (4.0 g, 0.0168 mole) and 30 ml of dry THF. The solution is cooled to -20° C., ethyl mercaptan (1.38 ml, 0.0180 mole) is added and hydrogen chloride is then bubbled into the reaction mixture. When the reaction mixture is saturated with HCl the temperature is raised to and maintained at 0° C. for 2.5 hrs. The reaction mixture is poured into a three-necked, 300 ml round-bottom flask, 100 ml of toluene is added and steam blown into the organic layer until the red color disappears. The toluene layer is separated and the water layer washed twice with toluene. The toluene extracts are combined, washed with brine and dried over anhydrous MgSO4. The solvent is evaporated in vacuo to yield 4.27 g (84.4%) of crude product. One recrystallization from methanol yields 2.15 g (42.5%) of ethyl 1-methyl-5-(p-toluoyl)-pyrrole-2-thiolacetate, m.p. 74° -76° C.
Reaction SMILES: [CH2:1]([N:3]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=1)=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[N:32][CH:33]=1
Reactant: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 101.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(5-hydroxypyridine-2-carbonyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-dimethylacetamide (12 mg) following the synthetic method of Example 404 described below and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].[CH:33]12[O:39][CH:38]1[CH2:37][CH2:36][N:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]2>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:35]1[CH2:36][CH2:37][CH:38]([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:21]([O:23][CH3:24])=[O:22])[C@@H:10]([CH3:25])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH:33]([OH:39])[CH2:34]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4O)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (200 mg, 0.59 mmol) and N,N-dimethylformamide (10 mL). Sodium hydride (47 mg, 1.96 mmol) was added and the mixture stirred at room temperature for 30 minutes. tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (995 mg, 4.99 mmol) was added, and the resulting solution stirred overnight at 80° C. in an oil bath. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 mL), washed with water (3×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 78%) as yellow oil. MS (ESI, pos. ion) m/z 541 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:25][OH:26]>CCCCCCC.O>[Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH2:18][O:26][CH3:25])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Reactant: CO
Solvent: CCCCCCC
Solvent: O
Product: COCCS(=O)(=O)N1CCN(c2ccc(Cl)c(-c3ccccn3)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a 0° C. solution of 3-chloro-6-(4-(vinylsulfonyl)piperazin-1-yl)-2,2′-bipyridine (68 mg, 0.190 mL) in methanol (1.8 mL), Na metal (47.5 mg, 2.05 mmol) washed in heptane was added and stirred for 15 min at 0° C. The reaction mixture was heated to 50° C. and stirred for 2 h and was cooled to RT, diluted with H2O (20 mL), extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by column chromatography (30 to 75% ethyl acetate/heptane) to obtain pure product (29 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=4.80 Hz, 1 H) 7.92 (td, J=7.71, 1.77 Hz, 1 H) 7.75 (d, J=9.09 Hz, 1 H) 7.69 (d, J=7.83 Hz, 1 H) 7.44 (ddd, J=7.52, 4.86, 1.01 Hz, 1 H) 7.00 (d, J=8.84 Hz, 1 H) 3.57-3.70 (m, 8 H) 3.35 (t, J=5.94 Hz, 2 H) 3.30 (s, 3 H) 3.22-3.27 (m, 2 H). LCMS (M+H)+: 397.0.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][C:6](=[O:29])[C:7]([NH:25][C:26](=[O:28])[CH3:27])([CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:33]1[O:34][C:35]([CH3:37])([CH3:36])[C:31]([CH3:38])([CH3:30])[O:32]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of 2-acetylamino-2-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-hex-5-enoic acid, tert-butylamide (1.0 g, 2.38 mmol) in dichloromethane (10 mL) was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (48 mg, 3 mol %) and 1,2-bis(diphenylphosphino)ethane (57 mg, 6 mol %) under an atmosphere of nitrogen. The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (609 mg, 0.69 mL, 4.76 mmol) was added dropwise, and the reaction was then stirred overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10-40% ethyl acetate in heptane) gave the title compound as a white solid (1.07 g, 82%); 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=2 Hz, 1H), 7.35 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.96 (br s, NH, 1H), 6.53 (d, J=9.0 Hz, 1H), 5.78 (m, 1H), 5.46 (br s, NH, 1H), 4.36 (d, J=13 Hz, 1H), 4.12 (d, J=13 Hz, 1H), 2.83 (td, J1=13.5 Hz, J2=5 Hz, 1H), 2.72 (td, J1=12.5 Hz, J2=2 Hz, 2H), 2.42 (tt, J1=12 Hz, J2=3 Hz, 1H), 1.97 (s, 3H), 1.77 (m, 2H), 1.32-1.48 (m, 4H), 1.28 (s, 9H), 1.20 (s, 12H), 1.03-1.25 (m, 2H) and 0.72 (t, J=7.5 Hz, 2H); MS (+CI): m/z for C28H46BClN4O4: expected 548.3. found 549.3 (M+H)+, 571.3 (M+Na)+.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23])=[O:15].O>CS(C)=O>[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=2)=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23])=[O:15]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(CO)cc2)cc1C(N)=O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Nc1[nH]c(-c2ccc(C=O)cc2)cc1C(N)=O
Yield: 67 %

Procedure:
2-Iodoxybenzoic acid (150 mg, 0.53 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-hydroxymethylphenyl)pyrrole-3-carboxamide (Compound No. 13-1, 130 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. Water (15 mL) was added to the reaction solution, the precipitated solid was filtered off. The obtained solid was washed with 0.25N aqueous sodium hydroxide (2 mL) and water (2 mL), dried under reduced pressure to give the target compound (86 mg) as a yellow solid (Yield 67%).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH:12]1[C:13]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[CH:15]=[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]=1[F:18].[Na]>C1COCC1>[NH2:9][C:10](=[S:11])[N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[C:14]3[C:13]([C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]3[CH:33]3[CH2:34][CH2:35]3)=[CH:12][C:17]=2[F:18])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=C(N=C=S)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
[6R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR279## according to this invention, is made as follows. A solution of benzoyl isothiocyanate (0.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 9) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:19])[CH:11]=[CH:12]C1C=CC=CC=1.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.N1C=CC=CC=1>[F:9][C:6]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]2[C:5]=1[CH:12]=[CH:11][C:10](=[O:19])[NH:4]2
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1ccc2c(F)ccc(F)c2[nH]1
Yield: 20.7 %

Procedure:
10 g of 2,5-difluoroaniline and 6 g of pyridine in 350 ml of dichloromethane are mixed drop by drop at 0° C. with 12.9 g of cinnamic acid chloride and stirred until the conversion is completed at 0° C. The batch is added to 2N hydrochloric acid, and it is extracted with dichloromethane. It is washed with water, dried with sodium sulfate, and concentrated by evaporation in a vacuum. The solid that is obtained is mixed with 11.1 g of aluminum chloride and heated for 8 hours to 150° C. After chromatography on silica gel, 2.9 g of 5,8-difluoroquinolin-2(1H)-one is obtained. The latter is reacted in 100 ml of ethylene glycol in the presence of 780 mg of copper (II) oxide for 20 hours at 200° C. in an ammonia atmosphere at 60 bar. After chromatography on silica gel, in this case, 5-amino-8-fluoroquinolin-2(1H)-one is obtained as fraction A and 2,5-diamino-8-fluoroquinoline is obtained as fraction B.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:10][CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[N:6]=[CH:5][N:4]([CH2:10][CH2:11][O:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1
Reactant: Brc1cnc[nH]1
Reactant: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 5-bromo-1H-imidazole as prepared in part A (2.2 g, 15 mmol) in DMF (22 mL) at 0° C. was added NaH (658 mg, 60% dispersion, 2.42 mmol) in small portions. The resulting solution was allowed to warm to r.t. and then stirred for 1 hr. The solution was cooled to 0° C. and 1,1′,1″-[(2-bromoethoxy)methanetriyl]tribenzene (5.5 g, 15 mmol) in DMF (10 mL) was added drop-wise. The resulting solution was allowed to warm to r.t. where stirring continued until the reaction was judged complete by TLC (16 hr). The suspension was diluted with water and extracted with DCM (2×50 mL). The organics were dried (MgSO4), filtered, and concentrated to a solid that was recrystallized (EtOAc/Hex) to give 4.47 g of the title compound (69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:15].COS(OC)(=O)=O>C1COCC1>[CH3:15][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[O:10][C:9]1=[O:11]
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1c(=O)oc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.7 g of 6-bromo-oxazolo[4,5-b]-pyridin-2(3H)-one (0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)2 (0.024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 20 ml of sat. ammonium chloride and extracted with 3×80 ml ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.[OH-].[Na+].Cl.[CH2:30]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:31]1[CH:39]=[CH:38][C:37]2[O:36][CH2:35][O:34][C:33]=2[CH:32]=1>C(O)C.CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][C:22]([N:43]2[CH2:44][CH2:45][N:40]([CH2:30][C:31]3[CH:39]=[CH:38][C:37]4[O:36][CH2:35][O:34][C:33]=4[CH:32]=3)[CH2:41][CH2:42]2)=[O:23])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCOC(=O)CCc1ccc(N(C)c2ccc([N+](=O)[O-])cn2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CCC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1N(C)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-{3-methoxy-4-[methyl-(5-nitropyridin-2-yl)amino]phenyl}propionate (3.85 g, 11 mmol) in ethanol (80 mL) was added 2 N aqueous sodium hydroxide (6.4 mL, 13 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. To the resulting reaction solution was added 6 N hydrochloric acid (2.2 mL, 13 mmol), and the solvent was removed under reduced pressure. To the residue were added THF (80 mL) and N,N′-carbonyldiimidazole (2.08 g, 13 mmol), and the resulting solution was stirred at room temperature for 3 hours. To the resulting reaction solution were added 1-piperonylpiperazine (2.60 g, 12 mmol) and DMF (40 mL), and stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 4.59 g of the title compound.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1>>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:13]=[CH:12][S:11][N+:10]=1[CH3:6]
Reactant: COS(=O)(=O)F
Reactant: COc1ccsn1
Product: COc1ccs[n+]1C
Product: O=S(=O)([O-])F
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Methyl fluorosulfonate (6 ml) was added dropwise to 5.4 g (0.046 mol) of 3-methoxyisothiazole (exothermic reaction). After stirring for 30 min., the resulting solid was washed with ether to yield 9.3 g (89%) of 3-methoxy-2-methylisothiazolium fluorosulfonate, mp 120°-123° C.
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2cccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 70.0 mg (0.17 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thienyl)-2-naphthalenyl)ethynyl]benzoate (Compound 33a) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.27 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.23 (1H, t, J=4.9 Hz), 7.14 (2H, m), 7.38-7.56 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:17](=O)([O:20]C)[O:18][CH3:19].S([O-])(O)(=O)=O.[Na+]>O1CCOCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14](=[O:16])[CH2:15][C:17]([O:18][CH3:19])=[O:20])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: COC(=O)OC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CCC1
Yield: 83.4 %

Procedure:
Sodium hydride (1.86 g of a 60% dispersion in mineral oil, 46.5 mmol) was added to a solution of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (4.18 g, 20.0 mmol) and of dimethyl carbonate (8.4 mL, 99.6 mmol) in of dioxane (20 mL). After the reaction mixture had been refluxed for 4 h, it was chilled in an ice-water bath and treated drop wise with 1 M aqueous sodium hydrogen sulfate solution (50 mL). The mixture containing now a thick precipitate was then partitioned between diethyl ether and water. The organic phase was washed with sat. sodium hydrogen carbonate solution and with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-10% ethyl acetate as eluent to afford the title compound (4.45 g, 79%) as pale-yellow oil.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:12])=[O:11]>O>[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:11])=[O:12]
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1
Reaction time: 0.25 h

Procedure:
A mixture of selenium dioxide (11.1 g.), dioxane (250 ml.) and water (5 ml. was stirred for 15 minutes at 110° to 115° C. to give yellow solution. Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate (26.4 g) was added thereto with stirring at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled to precipitate yellow crystals. The crystals were collected by filtration, washed with dioxane and ether and dried to give ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (23.5 g.).