Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O>>[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35][N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: O=Cc1ncc[nH]1
Product: COc1ccc(N2CCN(Cc3ncc[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 27 %

Procedure:
Prepared using the same procedure described in Example 75 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and 1H-imidazole-2-carbaldehyde to afford the title compound as a yellow solid (39 mg, 27%). LC/MS (Method B) 2.85 min, [M+1]+ 482.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[NH:15]C(=O)N[C:12]3=[O:17])=[CH:7][C:5]=2[N:6]=1.[OH2:18]>>[NH2:15][CH:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH:7]=1)[C:12]([OH:17])=[O:18]
Reactant: Nc1nc2cc(C3NC(=O)NC3=O)ccc2s1
Reactant: O
Product: Nc1nc2cc(C(N)C(=O)O)ccc2s1

Procedure:
23.6 g (0.095 mol) of 5-(2-aminobenzothiazol-5-yl)-2,4-imidazolidinedione are cleaved with 22.7 g (0.95 mol) of LiOH--dissolved in 1,000 m of water--in analogy to Example 1d.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:13]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23]>C(O)(=O)C.Cl.O>[F:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][N:13]=[C:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NNc1ccc(C(F)(F)F)cc1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)aniline (1.0 g, 5.58 mmol) in 8 mL of acetic acid and 1.3 mL of concentrated hydrochloride solution, sodium nitrite (462 mg, 6.69 mmol) in 2.1 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture were added sodium acetate (1.37 g, 16.8 mmol, 3.0 equiv.) and acetylacetone (726 mg, 7.26 mmol, 1.3 equiv.) The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1/1) and hexane, and dried to give the title compound (720 mg, yield 44%): 1H NMR (400 MHz, CDCl3): δ ppm 2.51 (s, 31-0, 2.63 (s, 3H), 7.42-7.50 (m, 2H), 7.86 (t, J=8.0 Hz, 1H), 14.56 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:22][CH:11]2[CH2:12][O:13][C:14]3[C:19]([C:10]2([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][CH2:8]1)=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:10]23[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH2:4][NH2:1])[CH2:22][CH:11]2[CH2:12][O:13][C:14]2[C:19]3=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A solution of 8-(2-azido-ethoxy)-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (110 mg, 0.242 mmol) in 4:1 THF/H2O (5 mL) was treated with Ph3P (127 mg, 0.484 mmol) and the reaction was heated to 60° C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to remove the THF. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Flash chromatography (10% MeOH/CH2Cl2) provided the title compound (52 mg, 52%): 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.43 (m, 1H), 5.22 (dd, J=10.9, 2.9 Hz, 1H), 4.11 (d, J=11.7 Hz, 1H), 3.51 (m, 1H), 3.41 (m, 2H), 2.98 (m, 1H), 2.88 (br s, 2H), 2.39 (m, 2H), 1.94 (m, 2H), 1.49 (m, 3H), 1.13 (m, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]([Mg]Br)=[CH2:18].[Cl-].[NH4+].C(OCC)C>C1COCC1.O>[CH:17]([C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[CH2:18]
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC1(O)c2ccccc2CCc2ccccc21

Procedure:
A solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (9.4 g, 0.045 mol) in dry THF (100 ml) was placed under an atmosphere of nitrogen. A solution of vinylmagnesium bromide in THF (100 ml, 0.5 M) was added in such a rate to keep the reaction temperature at 30°-35° C. When addition was complete the mixture was heated at 50°-60° C. for 1.5 h. The reaction mixture was cooled on an ice-bath and a solution of ammonium chloride (10 g) in water (50 ml) was carefully added. Diethyl ether (100 ml) was added and the phases were separated. The aqueous phase was extracted with diethyl ether (100 ml) and the combined organic phases were dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue which was re-evaporated twice with dichloromethane to give 11.8 g of crude 5-ethenyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [CH3:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[O:4][CH2:3]1.[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:15](O)C>>[CH:9]1([NH:14][CH2:3][C:2]([OH:4])([CH3:1])[C:5]([O:7][CH2:8][CH3:15])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCC1
Reactant: CCO
Reactant: COC(=O)C1(C)CO1
Product: CCOC(=O)C(C)(O)CNC1CCCC1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-methylglycidate (3.18 g, 27 mmol) and cyclopentylamine (4 mL, 41 mmol) in ethanol (50 mL) was heated at 80° C. for 3 d. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (3.9 g, 60%). [M+H] calc'd for C11H21NO3, 216. found 216.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([Si](C)(C)C)#[N:12].[CH3:17][NH2:18]>CCO.[I-].[Zn+2].[I-]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:12][CH3:11])[C:17]#[N:18])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)C#N
Reactant: CN
Agent: [I-]
Agent: [Zn+2]
Solvent: CCO
Product: CNC(C#N)c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyanotrimethylsilane is cooled in an ice bath, 10 mg of zinc iodide are added and the mixture is stirred for 30 minutes at RT. 20 ml of a 33% solution of methylamine in EtOH are then added and the mixture is heated at 40° C. for 2 hours. The solvent is concentrated under vacuum, the residue is extracted with ether and the organic phase is dried over MgSO4 and filtered. A saturated solution of gaseous HCl in ether is added to the filtrate until the pH is 1, and acetone is then added until the product precipitates. The precipitate formed is wrung, washed with ether and dried to give 12.8 g of the expected product. M.p.=172° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.OO.[F:31][C:32]([F:40])([F:39])C([OH:38])C(F)(F)F>>[F:31][C:32]([F:40])([F:39])[C:23]([OH:25])=[O:24].[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:38]
Reactant: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: OO
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3)nc2)CC1
Product: O=C(O)C(F)(F)F
Yield: 99 %

Procedure:
The title compound (370 mg, 99%) was prepared as an off-white solid from 1-methylethyl 4-[({6-[4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 173, Step 1, 360 mg, 0.9 mmol), 30% H2O2 (aq) (0.612 mL, 5.4 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (3 mL) in a manner similar to Example 171, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.50 (d, 1H, J=2.7 Hz), 8.05 (d, 2H, J=8.4 Hz), 7.78-7.71 (m, 3H), 7.45 (dd, 1H, Ja=8.7 Hz, Jb=2.5 Hz), 4.91 (septet, 1H, J=6.2 Hz), 4.21 (bs, 2H), 3.93 (d, 2H, J=6.3 Hz), 2.84-2.72 (m, 5H), 2.09-1.96 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.20 (m, 8H); LRMS (ESI), m/z 417 (M+H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]=1[CH3:13])=[C:2]=[S:3].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C1(C)C=CC=CC=1>[NH2:16][CH2:15][CH2:14][NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]=1[CH3:13]
Reactant: Cc1c(N=C=S)ccc2ocnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)ccc2ocnc12
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 5-isothiocyanato-4-methylbenzoxazole (0.68 g, 3.58 mmol) in toluene (75 mL) is treated with ethylenediamine (0.84 mL, 12.53 mmol). The reaction is stirred for 30 minutes as the product precipitates. The precipitate is filtered and dried in an oven to yield 0.85 g of 5-[N'-(2-aminoethyl)thioureido]-4-methylbenzoxazole as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[N:15]=1.CCCCCCC.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:12]1[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[N:15]=[C:10]([CH3:9])[N:11]=1
Reactant: CCc1cc2c(Cl)nc(C)nc2n1Cc1ccccc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc2c(OCC(=O)OC)nc(C)nc2n1Cc1ccccc1
Temperature: 60 °C
Yield: 62.6 %

Procedure:
To a suspension of 240 mg (10.0 mmol) of sodium hydride in 15 mL of benzene was added 783 mg (8.69 mmol) of methyl glycolate and 1.91 g (6.68 mmol) of 2-methyl-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine. The mixture was heated at 60° C. and monitored by TLC (silica, 7:3 heptane-ethyl acetate) for conversion to product. After 5 days the reaction was cooled to ambient temperature and partitioned by the addition of 10 mL of 2 M sodium hydrogen sulfate and 30 mL of ethyl acetate. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated to 2.5 g of oil. The residue was purified by flash chromatography (200 g silica, 7:3 heptane-ethyl acetate) to provide 1.42 g (62%) of [[2-methyl-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.27 (t, J=7.4 Hz, 3H), 2.57 (q, J=7.4 Hz, 2H), 2.60 (s, 3H), 3.80 (s, 3H), 5.08 (s, 2H), 5.44 (s, 2H), 6.34 (s, 1H), 7.02 (d, J=7.1 Hz, 2H), 7.25 (m, 3H)
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C@@H:34]([C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])[C:35]([OH:5])=[O:36])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)acetic acid (4J) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethanol (4I) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.97-8.91 (m, 1H), 8.86-8.82 (m, 1H), 8.11 (s, 1H), 7.95-7.90 (m, 1H), 7.72-7.65 (m, 3H), 7.50-7.45 (m, 1H), 5.23 (s, 1H), 2.73 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClNO3: 384.9. Found: 384.1, 386.1.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH3:13])=[C:9]([O:14][CH3:15])[C:8]([O:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:19].[Na+]>O.[Cu]>[CH2:12]([O:11][C:10]1[C:2]([OH:19])=[C:3]([CH:7]=[C:8]([O:16][CH2:17][CH3:18])[C:9]=1[O:14][CH3:15])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: [OH-]
Reactant: CCOc1cc(C(=O)O)c(Br)c(OCC)c1OC
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(=O)O)c(O)c(OCC)c1OC
Temperature: 120 °C

Procedure:
68 g of 2-bromo-3,5-diethoxy-4-methoxybenzoic acid prepared in Referential Example 4 was suspended in 260 ml of water and 32 g of caustic soda and 0.88 g of copper powder were added thereto. The mixture was heated at 120° C. for 3 hr while stirring, and then cooled. Carbon was added thereto, and the mixture was filtered through Celite. The filtrate was neutralized with 140 ml of 6N hydrochloric acid and 1 l of chloroform was added thereto. The mixture was subjected to liquid-liquid separation. The organic phase was washed with water, dried and then concentrated to prepare 53 g of the crude product (ocherous solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[Br:21])=[N:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2sccc2Br)CC1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Stir a mixture of 4-(3-bromo-thiophene-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 3a) (41.5 g, 0.11 mol), hydroxylamine hydrochloride (15.4 g, 0.23 mol) and pyridine (190 mL) at ambient temperature overnight. Pour the reaction into water (500 mL) and extract with dichloromethane (3×). Wash the combined extracts with saturated CuSO4 solution (2×), dry (MgSO4) and concentrate to a green solid. Dissolve the solid in toluene (175 mL) and let stand at ambient temperature for 3 h. Collect the resulting crystals that form and wash with toluene (60 mL). Concentrate the filtrate and again dissolve the residue in toluene and proceed to collect additional crystals to obtain a total yield of 25 g (58%) of the title compound as a light, green solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][C@@H:25]([CH3:29])[NH:24]1>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][C@H:25]([CH3:29])[NH:24][C@H:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 1, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-2,6-dimethylpiperazine, and dimethylformamide was stirred at room temperature for 24 hours to give 1-cyclopropyl-5,6,8-trifluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which was recrystallized from chloroform-ethanol, m.p. 259°-260° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O:29]C1C=C(O)C=CC=1)C1C=CC=CC=1>>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:2][C:3]([N:4]([CH3:6])[CH3:5])=[O:29])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CN(C)CCCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: CN(C)C(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared by substituting 2-chloro-N,N-dimethylacetamide for 2-chloro-N,N-dimethylethanamine and 4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.
Reaction SMILES: [CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([O:11]CC=C)[CH:8]=2)[C:3]1=[O:17].Cl.C(N(CC)[C:28]1[CH:33]=CC=C[CH:29]=1)C>>[CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([OH:11])[C:8]=2[CH2:33][CH:28]=[CH2:29])[C:3]1=[O:17]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: Cl
Product: C=CCc1c(O)c(Cl)c(Cl)c2c1CC(C)(c1ccccc1)C2=O

Procedure:
A mixture of 2-methyl-2-phenyl-5-allyloxy-6,7-dichloro-1-indanone (12.5 g., 0.036 mole) in N,N-diethylaniline (120 ml.) is refluxed for one and one-half hours then poured into excess cold dilute hydrochloric acid. The product is extracted into ether, washed with water and dried over anhydrous magnesium sulfate. Evaporation of the ether affords 2-methyl-2-phenyl-4-allyl-5-hydroxy-6,7-dichloro-1-indanone which melts at 125°C. after crystallization from butyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
The product from Example 44B (1.15 g, 3.22 mmol) was reacted with 4-mercapto-phenol (403 mg, 3.22 mmol) and K2CO3 (890 mg, 6.44 mmol) in 25 mL of DMF at 80° C. for 18 h. Cooled to room temperature and poured into water. Extracted with CH2Cl2 and washed several times with water. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (980 mg, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:18]([C:23]1[CH:24]=[CH:25][C:26]([O:14][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)=[CH:27][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 99.9 %

Procedure:
12.6 g (55.0 mmol) of 4-benzyloxy-benzoic acid, 8.2 g (50.0 mmol) of 4-pentylphenol and 0.61 g (5.0 mmol) of 4-dimethylaminopyridine were added to 150 mL of methylene chloride followed by the addition of 11.4 g (55.0 mmol) of dicyclohexylcarbodiimide while stirring in the presence of argon. After stirring for 6 hours in the presence of argon, the mixture was filtered followed by concentrating the filtrate. The residue was purified by silica gel column chromatography to obtain 18.7 g of a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:28].[C:40]([O-])(=[O:42])C.[Na+]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH:39][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:42])=[S:38])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: CCc1cccc(C)c1NC(N)=S
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Na+]
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39). Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.154 g, 47%): 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.07 (s, 1H), 9.41 (s, 1H), 8.13-8.05 (m, 2H), 8.03-7.92 (m, 2H), 7.62 (dt, J=7.8, 1.1 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.5 Hz, 1H), 7.21-7.14 (m, 1H), 7.14-7.04 (m, 3H), 3.18 (q, J=6.6 Hz, 2H), 2.83-2.67 (m, 2H), 2.48 (d, J=2.6 Hz, 2H), 2.17 (s, 3H), 1.92-1.76 (m, 2H), 1.11 (t, J=7.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+].O>CS(C)=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC(=O)C(C)(C)C)cc1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 1-bromo-3,3-dimethyl-2-butanone (33.3 g, 0.19 mole) in dimethylsulfoxide (330 ml), sodium p-toluenesulfinate (34.9 g, 0.20 mole) was added at 30°-40° C., and reacted with stirring at 60°-70° C. for 18 hours. The reaction mixture was poured into cold H2O (2 liter). The precipitate was filtered, washed with H2O and dried to afford 41.6 g of 1-(p-toluene-sulfonyl)-3,3-dimethyl-2-butanone as white crystals. m.p. 119°-122° C.