Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:1])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CNc1cccc2cccc(NC)c12
Reactant: CCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCC1N(C)c2cccc3cccc(c23)N1C

Procedure:
N,N'-dimethyl-1,8-naphthalene diamine was first prepared and condensed with tridecanal to give 2,3-dihydro-1,3-dimethyl-2-dodecylperimidine. The 2,3-dihydroperimidine was coupled with the his diazonium salt prepared in Example 12 to give the above blue dye.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:30])[CH2:25][C:26]([CH3:29])([NH2:28])[CH3:27].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:23][N:24]([CH3:30])[CH2:25][C:26]([NH:28][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:22])([CH3:29])[CH3:27]
Reactant: CN(C)CC(C)(C)N
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CN(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added N1,N1,2-trimethylpropane-1,2-diamine (100 mg, 0.86 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of methanol and THF (1:3, v/v) to give N-(1-(dimethylamino)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 16.5%) as a yellow solid. MS: (M+H)+=392; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.90 (brs, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 7.97 (s, 1 h), 7.45 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 2.74 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.P(Cl)(Cl)([Cl:24])=O>>[ClH:24].[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=1[N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCCN1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Product: Cl
Product: c1ccc2c(c1)Oc1ccccc1N2C1=NCCCC1

Procedure:
Reaction of phenoxazine, 2-piperidone, and phosphorus oxychloride according to the procedure of Example 1 provides 10-(3,4,5,6-TETRAHYDRO-2-PYRIDYL)PHENOXAZINE HYDROCHLORIDE, m.p. 218.5°-221° C. (corr.), in a 27% overall yield from absolute ethanol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Temperature: 95 °C
Yield: 75.6 %

Procedure:
A mixture of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) (1.0 g; 3.11 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (1.5 g; 3.57 mmol), tetrakis(triphenylphosphine)palladium (560 mg; 0.5 mmol), 1N sodium carbonate (8 mL), and 1,2-dimethoxyethane (40 mL) was heated at 95° C. in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×40 mL) and brine (1×40 mL), dried over solid sodium sulfate, and evaporated under reduced pressure. The resulting residue was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 1.2 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) as a light tan solid. MS 511.23 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2-fluoro-4-hydroxybenzoate (1.4685 g, manufactured by Changzhou Fine Chemical Corp.) and potassium carbonate (3.6917 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (21 mL; manufactured by Kanto Chemical Co., Inc.), added with benzyl bromide (1.22 mL; manufactured by Wako Pure Chemical Industries, Ltd.), and stirred at 50° C. overnight. After cooling to the room temperature, it was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=97:3→77:23) to obtain the title compound (2.2207 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].[K].Cl[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.C(O)C>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:7]=1
Reactant: NC(=S)c1cccs1
Reactant: CCOC(=O)CC(=O)Cl
Agent: [K]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2cccs2)s1
Reaction time: 20 h
Yield: 62.5 %

Procedure:
Acetic acid (3.78 ml) was added to a stirred mixture of 2-thiophenecarbothioamide (3.15 g), ethyl chloroformylacetate potassium salt (6.23 g) and ethanol (60 ml). Afte refluxing for 4 h, ethyl chloroformylacetate potassium salt (4.15 g) and acetic acid (2.52 ml) were added, and then the refluxing was continued for further 20 h. The reaction mixture was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to give an oil which was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v) the crystals of ethyl 2-(2-thienyl)-5-thiazolecarboxylate (3.29 g, 63%) were obtained. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 61-62° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:7][C:5]=2[N:6]=1
Reactant: ClCCCBr
Reactant: Cc1nc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cc(OCCCCl)ccc2s1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methyl-5-benzothiazolol (8 g, 48.4 mmol), 1-bromo-3-chloropropane (23 g, 146 mmol), and potassium carbonate (33.6 g, 240 mmol) in 50 ml of acetonitrile was stirred at 60° C. for 18 hr. The mixture was cooled, evaporated under reduced pressure, diluted with water and ethyl acetate. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum to give 2-methyl-5-(3-chloropropoxyl)-benzothiazole (IV) as a tan crystalline solid (10 g, 85%, mp 63-65° C., MS (CI) m+1=242).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][N:12]([CH3:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCCl.C(OCC)(=O)C>[C:5]([C:4]1[C:3]([F:10])=[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N:12]([CH3:11])[CH3:22])=[CH:21][CH:20]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1F
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN(C)c1ccc(C(=O)Nc2cccc(C#N)c2F)cc1
Temperature: 70 °C
Yield: 88.2 %

Procedure:
To a mixture of 3-amino-2-fluorobenzonitrile (2.24 g, 16.46 mmol) and 4-(dimethylamino)benzoyl chloride (3.46 g, 18.84 mmol) in 1,2-dichloroethane (50 mL) at rt was added pyridine (0.891 mL, 11.02 mmol). The resulting mixture was heated at 70° C. for 5 hr. On cooling to room temperature, the mixture was diluted with ethyl acetate (250 mL), washed with water (5×60 mL) and brine (60 mL), and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was subjected to ISCO (2×330 g silica gel, 25-50% ethyl acetate/hexane) to afford the desired product (4.11 g, 14.51 mmol, 88% yield) as a white solid.
Reaction SMILES: O1CCCC1.[CH2:6]([SH:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:18]([Cl:31])=[C:19]([CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[Cl:31][C:18]1[C:17]([CH2:16][S:8][CH2:6][CH3:7])=[C:26]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
To 100 ml of tetrahydrofuran, 1.3 g of ethanethiol and 1.5 g of potassium carbonate and then 4.4 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate were added, and the mixture was stirred for 1 day at room temperature. Then, the mixture was stirred further for 1 hour at a temperature of from 50° to 60° C. After cooling, chloroform was added thereto, and the mixture was washed with a dilute potassium carbonate aqueous solution. The chloroform layer was separated and dried. Then, the solvent was distilled off to obtain 4.1 g of methyl 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoate as an oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-cyano-3-fluorobenzyl)-5-(hydroxymethyl) imidazole, as described above in Step F, (2.31 g, 10.0 mmol) in 20 mL of DMSO at 0° C. was added triethylamine (5.6 mL, 40 mmol), then SO3-pyridine complex (3.89 g, 25 mmol). After 30 minutes, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a pale yellow powder.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].O.C1(C)C=CC=CC=1>CS(C)=O.[Cl-].[Na+].O>[O:11]([C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: COC(=O)c1csc(Br)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1csc(Oc2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of commercially available methyl 2-bromothiazole-4-carboxylate (1.000 g; 4.50 mmol) and sodium phenoxide (627 mg; 5.40 mmol) in anh. DMSO (20 ml) was heated to 80° C., under nitrogen, for 17 h. A second addition of sodium phenoxide (314 mg; 2.70 mmol) was performed, and the resulting mixture was further heated at 80° C. for 1 h. After cooling to rt, water (50 ml), brine (10 ml), and toluene (20 ml) were added. The separated aq. layer was further extracted with toluene (2×20 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded methyl 2-phenoxythiazole-4-carboxylate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 236.06 g/mol.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:12]=1[C:21]([O-:23])=O.[Si:24]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][NH2:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[Si:24]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][NH:35][C:21]([C:12]1[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:4]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:3]=1[F:2])=[O:23])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1c(C(=O)[O-])c(Nc2ccc(I)cc2F)c2cnccc21
Reactant: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](CONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid sodium salt (0.20 g, 0.46 mmol), O—[(S)-2-(tert-butyldimethylsilanyloxy)-propyl]-hydroxylamine (95 mg, 0.46 mmol), HOBT (69 mg, 0.51 mmol), EDCI (97 mg, 0.51 mmol) and DIPEA (0.08 ml, 0.46 mmol) were suspended in a mixture of THF (3 ml) and DMF (1 ml). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (20 ml) and washed with aqueous saturated sodium bicarbonate solution (20 ml). The aqueous layer was isolated and extracted with ethyl acetate (2×10 ml) and the combined organic layers dried, washed with brine and dried over magnesium sulfate before concentrating in vacuo. The crude residue was purified by flash chromatography (SiO2, gradient 1-3% methanol in dichloromethane) to yield the title compound as an off-white solid (171 mg, 62%). LCMS (method B): RT=3.00 min, M+H+=599.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[O:19][C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC.C([Li])CCC>[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3([C:7]3[CH:2]=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[CH:6]=3)[OH:34])[O:19][C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2(O)CCCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-bromoanisole (1.00 g) in tetrahydrofuran (4 ml), n-butyllithium hexane solution (1.56M, 3.4 ml) was added at −78° C. under a flow of nitrogen. After stirring for 0.5 hour, a solution of 2-[(4,5-diphenyloxazol-2-yl)methyl]cyclohexan-1-one (1.36 g) in tetrahydrofuran (3 ml) was added below −50° C. to the reaction mixture and stirred for 0.5 hour. After usual workup, the crude product was purified by column chromatography (silica gel 50 g, eluent; hexane/ethyl acetate=9 then 4) to give 2-[(4,5-diphenyloxazol-2-yl)methyl]-1-(3-methoxyphenyl)-1-cyclohexanol (1.01 g) as a foam.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH2:19]C=[CH:17][CH:16]=1.[CH2:20](O)C.[O-]CC.[Na+]>>[C:11]1([C:12]2[CH:13]=[CH:14][C:9](=[CH2:20])[C:1]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:17][CH:16]=[CH:15][CH:19]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCO
Reactant: C1=CCC=C1
Agent: CC[O-]
Agent: [Na+]
Product: C=C1C=CC(c2ccccc2)=C1c1ccccc1

Procedure:
About equal molar amounts of benzophenone and cyclopentadiene are reacted in an ethanol/sodium ethoxide solution according to the method suggested by Kice, JACS 80, 3796 (1958). The dark red crystals obtained are recrystallized from ethanol and dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(Cl)(Cl)Cl>O>[CH:18]1([C:21]([NH:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
A mixture comprising 5.0 g (32.6 mmol) of 2-amino-4-methyl-3-nitropyridine and 5.2 g of pyridine was heated at 110° C. in a nitrogen atmosphere. 3.8 g (36 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110° C. for 5 hours. The reaction mixture was brought to room temperature, followed by the addition of chloroform (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined and washed with water (20 ml) and a saturated aqueous solution (20 ml) of common salt, successively. The resultant organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 5.4 g of the title compound (yield 75%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:37]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:37][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:26][CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (220 mg) in N,N-dimethylformamide (5 mL) was added ammonium acetate (190 mg), and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio) to give a crude product. The obtained crude product was subjected to basic silica gel column chromatography, and the title compound (95 mg, yield 45%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 437 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (S)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]phenyl}-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (48%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:7]=2[CH:6]=1)=[O:4].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1NO.C(Cl)CCl.C1C=CC2[N:37]([OH:38])N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12](=[O:14])[NH:37][O:38][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(C(=O)O)cc2c1
Reactant: ONC1CCCCO1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2sc(C(=O)NOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester (191.3 mg, 0.81 mmol), O -(Tetrahydro-pyran-2-yl)-hydroxylamine (93 mg, 0.79 mmol), EDC (231 mg, 1.20 mmol), HOBt (107 mg, 0.79 mmol) and DIEA (0.30 mL, 2.2 mmol) in anhydrous THF (8 mL) was allowed to stir at rt for three days and then concentrated. To the residue was added MeOH (1 mL) and water (10 mL) and Et2O (5 mL). After stirring for 2 h, the solid formed was washed with water (2×3 mL) and Et2O (5 mL), and dried to give 2-(tetrahydro-pyran-2-yloxycarbamoyl)-benzo[b]thiophene-5-carboxylic acid methyl ester as a pale solid). MS (EI): cal'd 252.0 (M−THP+H+), exp 252.1 (M−THP+H+).