Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([C@H:8]2[CH2:12][CH:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][Cl:56].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:56][CH2:55][C@@H:54]([OH:57])[CH2:53][NH:52][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:9]3[CH2:10][CH:11]([OH:13])[CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[OH:26])=[N:15][C:16]=12)=[O:24]
Reactant: NC[C@H](O)CCl
Reactant: O=C(O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3O)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3O)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation D; 0.0339 g, 0.0946 mmol) and HATU (0.0540 g, 0.142 mmol) in DMF (0.5 mL) at 0° C. was added (S)-1-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0155 g, 0.142 mmol; prepared according to the method described in Org. Process Res. Dev. 2003, vol. 7, p. 533) and N,N-diisopropylethylamine (0.0494 mL, 0.284 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH/DCM to afford N-((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (as a mixture of cis and trans isomers, 0.0407 g, 82.2% yield, 86% purity). LC/MS (ES+APCI) m/z=448.1 (M−H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][N:17]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:13]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.9 g, 34.3 mmol) and (4-methoxy-benzylamino)acetic acid ethyl ester (7.70 g, 34.5 mmol) in DMF (200 mL) was treated with triethylamine (10.0 mL, 71.2 mmol). After stirring at room temperature overnight, the cloudy mixture was diluted with H2O (400 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (13.0 g, 93%) as a yellow syrup: MS (ESI) m/e 408 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH:1]1([CH2:7][C:8]([NH:59][C:57]2[S:56][C:46]3[C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CC3CCCCC3)nc12

Procedure:
From cyclohexylacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 391 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[C:3]([F:19])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC1(C)OB(c2cc(Cl)c(F)c(Cl)c2F)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 70 °C
Yield: 59.7 %

Procedure:
A mixture of 2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.34 g, 23.75 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5.82 g, 33.25 mmol), Cs2CO3 (15.5 g, 47.5 mmol) and Pd(PPh3)2Cl2 (400 mg) in THF (30 mL) and water (15 mL) was heated at 70° C. in a sealed tube for 4 h under argon. The mixture was cooled to rt and partitioned between EA and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel eluted with hexanes to give crude compound of 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.93 g) as a colorless oil. It was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). The reaction was cooled to about −78° C., and a 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. The reaction was stirred at about −78° C. for about 1 hour, and then benzyl bromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about 30 minutes more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 31 g of crude product. Purification by silica gel chromatography using 10-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (20.33 g, 82%): +APcI MS (M−55)+ 413, (M−99)+ 369; 1H NMR=400 MHz (CDCl3) δ: 7.37 (arom, m, 5H), 7.22 (arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH:17]([O:21]CC)OCC)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[NH2:25][C:26]1[C:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:34][C:33]2[C:32]3[CH:43]=[CH:44][C:45]([OH:47])=[CH:46][C:31]=3[CH:30]=[CH:29][C:28]=2[N:27]=1.Cl>C(O)C.O>[CH:40]1[CH:39]=[CH:38][C:37]([CH2:36][C:35]2[NH:34][C:33]3[C:32]4[CH:43]=[CH:44][C:45]([OH:47])=[CH:46][C:31]=4[CH:30]=[CH:29][C:28]=3[N:27]3[C:26]=2[N:25]=[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]3=[O:21])=[CH:42][CH:41]=1
Reactant: Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Reactant: CCOC(OCC)C(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c3c4ccc(O)cc4ccc3n1-2
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-(4-(tert-butyldimethylsilyloxy)phenyl)-1,1-diethoxypropan-2-one (15) (101 mg, 286 μmol) in ethanol (2 mL) and water (0.4 mL) was added 3-amino-2-benzylbenzo[f]quinoxalin-8-ol (14) (55.5 mg, 184 μmol). After cooling to 0° C., to the mixture was further added conc. hydrochloric acid (0.20 mL). The mixture was heated to 80° C. and stirred overnight (18 hours). After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1→1/2→ethyl acetate alone) in an argon flow to give v-coelenterazine (2, v-CTZ) (10.9 mg, 24.4 μmol, 13.2%) as ocherous powders. TLC Rf=0.50 (n-hexane/ethyl acetate=1/1); 1H NMR (500 MHz, CD3OD) δ 4.08 (s, 2H), 4.51 (s, 2H), 6.69-6.72 (AA′BB′, 2H), 7.17-7.24 (m, 5H), 7.29 (t, 2H, J=7.5 Hz), 7.43 (d, 2H, J=7.5 Hz), 7.63 (d, 1H, J=8.5 Hz), 8.40 (br, 1H), 9.26 (br, 1H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:21])([CH3:20])[N:4]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)=O.CC(C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:7]2[O:6][C:5]([CH3:21])([CH3:20])[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]2[CH2:2][F:1])=[CH:13][CH:12]=1)#[CH:15]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [F-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a THF (20 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-((trimethylsilyl)ethynyl)phenyl)oxazolidine-3-carboxylate (1.65 g, 4.1 mmol) that had been cooled to −78° C. (dry ice/acetone) is added tetra-n-butyl-ammonium fluoride (5 ml of 1M solution in tetrahydrofuran, 5 mmol). The reaction is stirred at −78° C. for 1 hour. The reaction mixture is quenched (while at −78° C.) by the addition of saturated aqueous ammonium chloride solution (2 ml). The reaction mixture is warmed to room temperature and diluted with ethyl acetate (50 ml). The organic phase is washed with water (3×25 ml), dried over sodium sulfate and the volatiles removed by evaporation to give the title product (1.35 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](F)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Tl].[C:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1>CCOCC>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([CH:26]3[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:25]3=[O:32])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)F
Agent: [Tl]
Solvent: CCOCC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)C1C(=O)CCCC1=O

Procedure:
2-[4-(4-Trifluoromethylphenoxy)phenoxy]propionic acid fluoride (0.10 mol) is added to a solution of the thallium salt of cyclohexane-1,3-dione in ether (200 ml) over a period of 30 minutes. The mixture is filtered and the filtrate is concentrated to give 2-[[2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]]cyclohexane-1,3-dione (V; Y is H, Z is CF3, R1 is CH3 and n is two).
Reaction SMILES: BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:22][C:23]1[C:24]([C:39]([NH:41][NH2:42])=[O:40])=[N:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:31][CH2:30]2)=[CH:27][N:28]=1.[Br:43][CH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=O)=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CC#N.C(OCC)(=O)C>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]2)=[N:25][C:24]=1[C:39]1[O:40][C:49]([C:48]2[CH:52]=[CH:53][C:45]([CH2:44][Br:43])=[CH:46][CH:47]=2)=[N:42][N:41]=1
Reactant: CCC(=O)N1CCC(c2cnc(N)c(C(=O)NN)n2)CC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reaction time: 1 h

Procedure:
Dibromo(triphenyl)phosphorane (682 mg, 1.6 mmol) was added to a suspension of 3-amino-6-(1-propanoyl-4-piperidyl)pyrazine-2-carbohydrazide (105 mg, 0.36 mmol) and 4-(bromomethyl)benzoic acid (77 mg, 0.36 mmol) in MeCN (2 mL) at room temperature and the resulting solution was stirred for 1 h under an atmosphere of nitrogen. DIPEA (278.5 mg, 375.3 μL, 2.155 mmol) was added dropwise and the solution was stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, concentrated in vacuo to obtain 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-1-piperidyl]propan-1-one, which was taken to the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1C(CO)=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1C(CO)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 55.3 %

Procedure:
A suspension of 10% palladium carbon (16 g) in acetic acid (50 ml) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (9.0 g) in ethanol (300 ml.), and the mixture was subjected to catalytic reduction at 65° C. in the presence of hydrogen at 20 atm. for 9 hours. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (150 ml.) and adjusted to pH 7.5 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with petroleum ether and collected by filtration to give t-butyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (5.0 g.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:21])[CH:12]=[C:13]([SH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C(N(CC)CC)C.O.II>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:20]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(C=C(S)c1ccccc1)Nc1ccc(C(=O)O)cc1
Agent: II
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(-n2sc(-c3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
Compound of Formula (I) in which R1, R2, R4 and R5 =H, Ar1 =Ar2 =phenyl and R3 =4-CO2H A mixture of 1.449 g (0.005 mole) N-(4-carboxyphenyl)-3-mercapto-3-phenylpropenamide (A. Yokoyama, K. Ashida and H. Tanaka, Chem. Pharm. Bull. 12 (6), 690-5 (1964)), 3 mL (excess) triethylamine, 100 mL water and 100 mL ethanol was stirred at room temperature. Added, portionwise, was 1.269 g (0.005 mole) iodine and the mixture stirred at room temperature for 3 hrs. The solution was filtered and the filtrate was acidified to pH 1 with concentrated hydrochloric acid. The resulting solid was filtered and recrystallized twice from ethanol/water to provide 0.350 g (1.180 mmol, 23%) N-(4-carboxyphenyl)-5-phenyl-4-isothiazolin-3-one as a white powder, mp=238°-240° C. NMR (CDCl3 /TMS): 6.6 (S, 1H), 7.5-7.6 (m, 5H), 7.9 (d, 2H), 8.2 (d, 2H). IR (Nujol): 3481, 1698, 1619. High resolution mass spectrum: Calculated; 298.053790. Measured; 298.053472. Anal. calcd. for C16H11NO3S: C 64.65, H 3.70, N 4.71, S 10.77; Found C 64.52, H 3.64, N 4.59, S 10.75.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]([C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH2:35])=[CH:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:23]>>[NH2:35][CH2:34][CH2:33][C:28]1[C:27]2[C:31](=[CH:32][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=2)[NH:30][C:29]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4](=[O:13])[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: O=Cc1ccccc1
Reactant: CCc1ccc2c(CCN)c[nH]c2c1
Product: CCc1ccc2c(CCN)c(C(C3=C(O)C(c4ccccc4)CC3=O)c3ccccc3)[nH]c2c1

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and 2-(6-ethyl-1H-indol-3-yl)-ethylamine (Lit. 8) to give the title compound as a pale brown solid. MS: 451.0 ([M+H]+).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]3[CH2:36][CH2:35][CH:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]3)[CH:26]=2)=[O:23])=[CH:17][C:16]=1[O:41][CH3:42]>O1CCCC1>[C:37]([CH:34]1[CH2:33][CH2:32][CH:31]([C:27]2[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][CH:1]=[O:2])=[C:16]([O:41][CH3:42])[CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)([CH3:38])([CH3:39])[CH3:40]
Reactant: O=CO
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCN
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1OCCNC=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Formic acid (30 mg) is slowly added to acetic anhydride (75 mg), and the mixture is heated with stirring at 60° C. for 2 hours. To the mixture is added dry tetrahydrofuran (0.2 ml), and further added 4-(2-aminoethoxy)-N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-3-methoxyphenylacetamide (100 mg) obtained in Example 62 at −20° C. The mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Ethyl 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.49 g, 4.3 mmol) in abs ethanol (20 ml) was treated with 1N NaOH (6 ml). The reaction mixture was stirred at room temperature for 2 hours and then acidified with 1 M HCl. The resulting white solid was filtered, washed with cold water and dried under vacuum to provide the title compound.
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2(CC(O)=O)[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[NH:15]2)[CH:9]=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[N:22]([CH2:6][C:5]([CH:39]3[CH2:40][N:35]([CH3:34])[CH2:36][CH2:37][NH:38]3)=[O:4])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CC1(c2cc(Cl)ccn2)Nc2cccnc2N1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCNC(C(=O)Cn2c(-c3cc(Cl)ccn3)nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A solution of ethyl chloroformate (0.66 g, 0.0061 mole) in 20 ml of methylene chloride was added slowly to a solution of 2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine acetic acid (1.75 g, 0.006 mole) and triethylamine (0.68 g, 0.0067 mole) in 75 ml of methylene chloride. After the solution was allowed to stir at room temperature for 2 hrs, a solution of N-methylpiperazine (0.61 g, 0.0061 mole) in methylene chloride was added slowly at room temperature and allowed to stir overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between dilute hydrochloric acid and diethyl ether. The aqueous layer was separated and extracted with diethyl ester (2×) and methylene chloride (3×). The aqueous layer was neutralized (pH 7) and refrigerated. The small amount of precipitate was removed by filtration. The aqueous filtrate was basified and extracted with methylene chloride (3×). The methylene chloride extracts were combined and evaporated to a gum. The gummy residue was purified by alumina column chromatography (Brockman activity 1, 80-200 mesh, 40 g) by elution with 20% acetone/80% benzene. The appropriate fractions (TLC) were combined and evaporated. The residue was crystallized from acetone/petroleum ether (bp 50°-110° C.). The crystalline solid was collected, washed with petroleum ether and isopropyl ether, and dried under high vacuum at room temperature to give 0.54 g (24%) of title compound, mp 174°-75° C.
Reaction SMILES: COC(C1C=C(OC)C=C2OC(C)CC=12)=O.[CH3:17][O:18][C:19](=[O:31])[C:20]1[CH:25]=[C:24]([OH:26])[C:23]([CH2:27][CH:28]=[CH2:29])=[C:22]([OH:30])[CH:21]=1>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH3:17][O:18][C:19]([C:20]1[CH:25]=[C:24]([OH:26])[C:23]2[CH2:27][CH:28]([CH3:29])[O:30][C:22]=2[CH:21]=1)=[O:31]
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1O
Agent: [Zr+4]
Agent: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: [Cl-]
Product: COC(=O)c1cc(O)c2c(c1)OC(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1d, from zirconium(IV) chloride and 4-allyl-3,5-dihydroxy-benzoic acid methyl ester (10b) (85 mg, 0.41 mmol). Purification by flash column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (58 mg, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.21 (m, 2 H) 5.76 (s, 1 H) 4.42-4.51 (m, 1 H) 3.91 (s, 3 H) 3.11-3.21 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:11][O:12][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([O:15][CH3:14])[N:7]=1
Reactant: C[O-]
Reactant: CO
Reactant: O=Cc1ncc(Cl)nc1Cl
Agent: [Na+]
Product: COc1cnc(C=O)c(OC)n1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dichloro-pyrazine-2-carbaldehyde (150 mg, 0.85 mmol) in methanol (5 mL) is added sodium methoxide (25% w/w in MeOH, 458 mg, 2.1 mmol). After the mixture is stirred at room temperature over night, the reaction is quenched with saturated NH4Cl (1 mL) and solvent removed in vacuo until dryness. DCM (20 mL) is added, and the solution is dried and solvent removed to give 140 mg of 3,5-dimethoxy-pyrazine-2-carbaldehyde as an oil.