Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:20]=[CH:19][C:13]([C:14](=[CH2:18])[C:15](N)=[O:16])=[CH:12][CH:11]=1.Cl.C(O)(=[O:24])C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:20]=[CH:19][C:13]([C:14](=[CH2:18])[C:15]([OH:24])=[O:16])=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: C=C(C(N)=O)c1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Product: C=C(C(=O)O)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
A mixture of 0.01 mole of p-(benzoxazol-2-yl)-atropamide, 15 ml. of acetic acid and 15 ml. of concentrated hydrochloric acid is heated on the steam-bath for 1 hour. Filtration of the reaction mixture into 200 ml. of cold water, followed by filtration of the resulting precipitate, gives p-(benzoxazol-2-yl)atropic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([OH:14])=O.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([N:30]=[N+:31]=[N-:32])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)/C=C/c1cc2ccccc2s1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of (2E)-3-(1-benzothien-2-yl)acrylic acid and Et3N (1.3 equiv) in acetone (0.22 M) at 0° C. was added isobutyl chloroformate (1.3 equiv). The mixture was stirred at 0° C. for 1 h. A solution of NaN3 (1.3 equiv) in H2O was added, the mixture was stirred at 0° C. for 0.5 h and then at room temperature for 0.5 h. The mixture was poured into H2O, stirred and filtered to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+].[F:38][C:39]([F:70])([F:69])[C:40]1[CH:41]=[C:42]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[CH2:43][N:44]([CH3:61])[C:45](=[O:60])[C:46]1[C:51]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])=[CH:50][C:49](I)=[N:48][CH:47]=1>CN(C)C=O.C(=O)(O)[O-].[Na+].[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:38][C:39]([F:70])([F:69])[C:40]1[CH:41]=[C:42]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[CH2:43][N:44]([CH3:61])[C:45]([C:46]1[C:51]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])=[CH:50][C:49]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[N:48][CH:47]=1)=[O:60]
Reactant: Cc1cc(I)ccn1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)ccn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A mixture of 300 mg (1.37 mmol) 4-iodo-2-methyl-pyridine, 383 mg (1.51 mmol) bis(pinacolato)diboron and 403 mg (4.11 mmol) potassium acetate in 8.5 ml N,N-dimethylformamide was deoxygenated by three freeze-thaw cycles. After addition of 112 mg (0.137 mmol) dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct the reaction mixture was stirred at 80° C. for 3 h. Cooling to room temperature was followed by addition of 4 ml of a 2 M aqueous solution of sodium carbonate, 396 mg (0.685 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 56 mg (0.068 mmol) dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct. The reaction mixture was reheated to 80° C. for 1.5 h. After cooling to room temperature the reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated. Drying in high vacuo at 50° C. and flash column chromatography gave 292 mg (78%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>>[CH2:16]([NH:18][C:19](=[O:20])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCN=C=O
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Product: CCNC(=O)OCCOc1ccc(SC(C)CC)cc1

Procedure:
Following the above procedure, 2-[4-(1-methylpropylthio)phenoxy]ethanol (2.16 g, 10.0 mmol) is reacted with ethyl isocyanate (1.5 ml, 18.0 mmol) to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylcarbamate (compound 39, Table A).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC(F)=CC=3)=NOC=2C)C=1)=O>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Agent: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)O)[nH]n1
Yield: 79.6 %

Procedure:
As described for example 10a, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (50 mg, 0.15 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester, was converted, to the title compound (38 mg, 79%) which was obtained as a white solid. MS: m/e=317.0 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[CH2:40][C:39]([CH3:46])([CH3:45])[CH:38]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.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.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[C:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[CH2:40][C:39]([CH3:46])([CH3:45])[CH:38]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)ccc2OS(=O)(=O)C(F)(F)F)CC1
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: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1(C)C=C(c2ccc(F)cc2C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a mixture of 4-(5-fluoro-2-trifluoromethanesulfonyloxyphenyl)piperidine-1-carboxylic acid t-butyl ester (523 mg, 1.22 mmol) produced in Example (106e), 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (387 mg, 1.46 mmol) produced in Example (4b) and 1,2-dimethoxyethane (10 mL) were added tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.06 mmol) and 2N aqueous solution of sodium carbonate (1.83 ml, 3.66 mmol), followed by stirring for 1 hour and 30 minutes at an external temperature of 90° C under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 245 mg of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:10]([CH3:16])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[C:13](=[O:14])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:17])[N:10]([CH3:16])[C:11]=1[CH3:15]
Reactant: BrBr
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-1,2,6-trimethylpyridin-4-one (0.5 g) in acetic acid (5 ml) was added dropwise a solution of bromine (0.1 ml) in acetic acid (1 ml). After 5 min the mixture was poured into water. The solid was filtered off, washed with water and recrytallised from ethanol (10 ml) to give the desired compound (0.25 g), m.p. 264°-266°, NMR δH (CDCl3) 7.3-7.4 (2H, m), 7.05-7.2 (2H, m), 6.95-7.12 (4H, m), 3.65 (3H, s), 2.7 (3H, s), 2.2. (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:22])[NH:15]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCO
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cccc3c2CC(=O)N3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3,4-dimethoxy-phenyl)-1H-indole (14.7 g, 58 mmol) in t-BuOH: ethanol: acetic acid (367 mL: 217 mL: 113 mL) was added pyridinium tribromide (55.68 g, 174 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (287 mL). Zinc dust (18.95 g, 290 mmol) was added to the reaction mixture portionwise. After stirring for one hour, water was added to the reaction. The unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (6×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated and triturated with ether to give 10.14 g (65%) of 4-(3,4-dimethoxy-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[S:34](=[O:36])(=[O:35])[N:33]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:32](=[O:41])[CH2:31]2)=[CH:26][CH:25]=1>O1CCCC1>[C:37]([N:33]1[C:32](=[O:41])[CH2:31][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7](=[O:8])[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:29][CH:28]=2)[S:34]1(=[O:36])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CBr)cc2)S1(=O)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)CC(c2ccc(CC(C(=O)c3ccccc3)c3ccccc3)cc2)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A solution of deoxybenzoin (62.6 mg, 0.32 mmol) in tetrahydrofuran (1.3 mL) was cooled to −78° C. and potassium tert-butoxide (0.15 mL, 0.15 mmol, 1.0 M in tetrahydrofuran) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and 4.19-A of Step 1 (115 mg, 0.32 mmol) in tetrahydrofuran (1.5 mL) was added dropwise. The reaction mixture was warmed to 25° C. and quenched with saturated ammonium chloride (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried with sodium sulfate, filtered, and concentrated to a crude yellow oil which was purified by flash column chromatography to yield the desired product (75 mg, 50%). LCMS found for C28H29NO4SNa (M+Na)+: m/z=498.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[O:15])=[CH:4][CH:3]=1.CN(C=O)C.Cl[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:37][C:32]1[N:31]=[C:30]([N:20]2[CH2:19][CH:18]3[CH:22]([CH2:23][N:16]([C:14]([C:9]4[N:10]=[C:11]([CH3:13])[S:12][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:15])[CH2:17]3)[CH2:21]2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: Cc1nc(C(=O)N2CC3CNCC3C2)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CC3CN(C(=O)c4nc(C)sc4-c4ccc(F)cc4)CC3C2)nc(C)n1
Temperature: 100 °C
Yield: 61.4 %

Procedure:
To a solution of Intermediate 48 (15.8 mg, 0.048 mmol) was added DMF (0.4 mL), 4-chloro-2,6-dimethylpyrimidine (8.2 mg, 0.057 mmol) and cesium carbonate (38.8 mg, 0.119 mmol). The mixture was heated to 100° C. for 18 hours, diluted with water and extract with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC to give the title compound (12.9 mg, 62%). MS (ESI): mass calculated for C23H24FN5OS, 437.5; m/z found [M+H]+438.2. 1H NMR (400 MHz, CDCl3): 7.51-7.41 (m, 2H), 7.06-6.95 (m, 2H), 6.29 (s, 1H), 3.892-3.76 (m, 2H), 3.73-3.51 (m, 3H), 3.44 (dd, J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5 Hz, 1H), 3.10 (dd, J=11.3, 5.3 Hz, 1H), 3.02-2.80 (m, 2H), 2.70 (s, 3H), 2.31 (d, J=20.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:6]2[C:2]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccsc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C
Yield: 69.5 %

Procedure:
Using tert-butyl {{5-bromo-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (0.60 g), 3-thienylboronic acid (0.35 g), tetrakis(triphenylphosphine)palladium (0.24 g) and sodium carbonate (0.43 g), a procedure as in Reference Example 56 was performed to give the title compound as a colorless solid (yield 0.42 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[C:11]([O-:13])=[O:12])=O)=[CH:4][CH:3]=1.[C:19](O)(=O)[CH3:20].N1CCCCC1.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]([C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH2:14][CH2:15][C:16](=[O:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(C(=O)[O-])C(=O)c1ccc(C)cc1
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(=O)C=C1c1ccc(C)cc1
Temperature: 25 °C
Yield: 587.5 %

Procedure:
A mixture of 2-((4-methylphenyl)carbonyl)-5-oxohexanoate(4.19 g, 15.2 mmol), acetic acid(137 mg, 2.28 mmol) and piperidine(129 mg, 1.52 mmol) in toluene(10 ml) was refluxed for 9 hr. After cooling down to room temperature, AcOEt was added to the reaction mixture and washed with dil. HCl, water and brine, dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 3.46 g of ethyl 2-(4-methylphenyl)-4-oxocyclohex-2-enecarboxylate(y=88.0%) as a brown oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.41(2H, d, J=8.2 Hz), 7.21(2H, d, J=8.2 Hz), 5.47(1H, s), 4.11(2H, q, J=7.0 Hz), 3.96(1H, dd, J=4.8 and 4.8 Hz), 2.55-2.65(1H, m), 2.40-2.55(3H, m), 2.38(3H, s), 1.14(3H, t, J=7.0 Hz).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:3]1([NH:2][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:17]=[CH:18][CH:19]=[N:20]1
Reactant: FC(F)(F)Oc1ccc(Br)nc1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(Nc2ccc(OC(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
A solution of N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 150 mg, 0.47 mmol), 2-bromo-5-(trifluoromethoxy)pyridine (CAS number 888327-36-4; 118 mg, 0.49 mmol), BINAP (29 mg, 0.047 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.34 mg, 0.023 mmol) and sodium tert-butoxide (63 mg, 0.65 mmol) in dry toluene (1.6 ml) was sealed, evacuated and purged with nitrogen. The reaction was heated at 140° C. for 17 hours and was then partitioned between ethyl acetate and water, washing with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-70% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([CH2:6][C:7](OCC)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[C:12]1([CH:20]=[C:18]([OH:19])[CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13]>>[OH:13][C:12]1[CH:20]=[C:18]([OH:19])[CH:17]=[C:15]2[C:14]=1[C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7](=[O:8])[O:16]2
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Oc1cc(O)cc(O)c1
Product: CCCc1cc(=O)oc2cc(O)cc(O)c12

Procedure:
condensing ethyl butyrylacetate and phloroglucinol in the presence of an acid catalyst to form 5,7-dihydroxy-4-propylcoumarin;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8](CC2C=CC(OC)=CC=2)[C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[NH:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(Cl)c2cc(F)cnc2[nH]c1=O
Yield: 98.7 %

Procedure:
A solution of 4-chloro-6-fluoro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (76) (6.0 g, 15.35 mmol) in neat TFA was refluxed for 3 h. The solution was cooled and the excess TFA was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were washed by water, and dried at room temperature to yield 4.1 g (98%) of 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (78) as white solids. MP: 217° C.; 1H-NM (DMSO-d6): 1.28 (t, J=7.2 Hz, 3H), 4.35 (q, J=7.2 Hz, 2H), 8.24 (dd, J=2.8, 8.0 Hz, 1H), 8.75 (d, J=2.8 Hz, 1H), 13.00 (s, 1H); EIMS: 271 (M+1).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=1)C>O.C(O)C>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:25])=[O:5])=[CH:9][CH:10]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.75 g of potassium hydroxide in 20 cc of water is added to 7 g of 4-(2-carboxybenzyl-thio)phenyl-acetic acid ethyl ester in 50 cc of ethanol, and the mixture is stirred at room temperature for 20 hours. The solution is then concentrated at reduced pressure, the residue is taken up in water and extracted with ether. The aqueous phase is subsequently acidified with 5 N hydrochloric acid and extracted with ethyl acetate. After washing the ethyl acetate extract with water and drying over sodium sulphate, the solvent is removed by distillation, whereby 4-(2-carboxy-benzyl-thio)phenyl-acetic acid is obtained as crystalline residue. M.P. 169° (from ethyl acetate/pentane).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[C:10]([CH3:13])[NH:9][C:8]=2[C:7](=[O:14])[NH:6][C:5]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CO>[CH2:16]([N:9]1[C:8]2[C:7](=[O:14])[NH:6][C:5](=[O:15])[N:4]([CH3:3])[C:12]=2[N:11]=[C:10]1[CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (400 mg) in water (5 ml) was added to a suspension of 3,8-dimethylxanthine (1.80 g) in methanol (10 ml) at 70° C. and stirred for 1 hour. Benzyl bromide (1.2 ml) was added and the mixture was stirred at 70-80° C. for 5 hours. After evaporation of the solvent under reduced pressure, the residue was suspended in saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate and concentrate. The product was purified by recrystallization from ethanol. Yield=1.06 g.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1.O>C(#N)C.C(Cl)(Cl)Cl>[OH:29][CH:26]1[CH2:27][CH2:28][N:24]([CH2:2][C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])[CH2:25]1
Reactant: OC1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CBr)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN2CCC(O)C2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.7 %

Procedure:
A suspension of (S)-3-(2-bromoacetyl)amino-1-(tert-butoxycarbonyl)pyrrolidine (671 mg) prepared in Example 113, Step A and potassium carbonate (604 mg) in acetonitrile (6 ml) was added with 3-pyrrolidinol (190 mg, Tokyo Kasei Kogyo), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was added with water and chloroform, and the organic layer was separated. Further, the aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (531 mg).