Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.Br.[CH3:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([O:24]C)=[N:16][N:17]([CH3:23])[C:18]=2[C:19]([F:22])([F:21])[F:20])[CH2:8]1>>[CH3:6][C:7]1([CH3:26])[O:11][N:10]=[C:9]([S:12][CH2:13][C:14]2[C:15]([OH:24])=[N:16][N:17]([CH3:23])[C:18]=2[C:19]([F:22])([F:21])[F:20])[CH2:8]1
Reactant: COc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Agent: Br
Solvent: CC(=O)O
Product: Cn1nc(O)c(CSC2=NOC(C)(C)C2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To 20 ml of a 25% hydrogen bromide acetic acid solution was added 3.3 g (10.6 mmoles) of 5,5-dimethyl-3-(3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water. The resulting crystals were collected by filtration, washed with water and dried to obtain 3.1 g (yield: 96.0%) of intended 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:15]([O:17]CC)=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:10]1([F:14])[CH2:11][C:12]2[N:4]3[CH2:3][CH2:2][NH:1][C:15](=[O:17])[C:5]3=[CH:6][C:7]=2[CH2:8][CH2:9]1
Reactant: CCOC(=O)c1cc2c(n1CCN)CC(F)(F)CC2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1NCCn2c1cc1c2CC(F)(F)CC1
Yield: 53.3 %

Procedure:
Into a 250-mL round-bottom flask was placed a solution of 113n (10 g, 36.73 mmol, 1.00 equiv) in toluene (100 mL) and acetic acid (1.1 g, 18.32 mmol, 0.50 equiv). See FIG. 14. The resulting solution was heated to reflux for 2 h, cooled and concentrated under vacuum. The residue was triturated in 100 mL of dry ether. The crude product was purified by recrystallization from ethanol to afford 4.43 g (53%) of 113o as a white solid. MS-ESI: [M+H]+ 227. 1H NMR (300 MHz, DMSO) δ 2.10-2.24 (2H, m), 2.59-2.64 (2H, m), 3.17-3.27 (2H, m), 3.43-3.48 (2H, m), 3.88-3.92 (2H, m), 6.44 (1H, s), 7.56 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH:6]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:16][CH2:15][C:7]1[CH:6]=[C:5]([NH:4][C:3](=[O:24])[O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)Nc1ccc(OC(C)C)c(CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1ccc(OC(C)C)c(CN)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8G (17 mg, 0.05 mmol) was dissolved in CH2Cl2 (1 mL) and trifluoroacetic acid (0.2 mL) was added. After stirring at rt for 10 min, the reaction was concentrated to provide 8H (10 mg, 57%). LC-MS: 239.21 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH3:28][C:26]1[O:25][N:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:3]([CH2:4][NH:5][C:6](=[O:18])[C:7]3[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=3)=[C:2]([NH:1][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:22]=2)[N:27]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCOc2ccccc2)cc(OC)c1C
Temperature: 80 °C

Procedure:
To a solution of compound 1g (38 mg, 0.099 mmol) in DMF was added potassium carbonate (28 mg, 0.20 mmol) and 2-bromoethoxybenzene (20 mg, 0.1 mmol). The reaction mixture was heated at 80° C. in a pressure tube for seven days. During this time, two additional portions of 2-bromoethoxybenzene (20 mg each) were added. The reaction mixture was concentrated and purified by preparative thin layer chromatography in 1:1 hexane/ethyl acetate to give compound 42a. ESI-MS m/e 503.3 (M+1).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:19]([C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:36][C:34]1[CH:35]=[C:27]2[C:28](=[CH:32][CH:33]=1)[C:29](=[O:30])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH3:18])=[C:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxybutylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH3:22])[C@H:11]([C:19]([OH:21])=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])C.[OH-].[Na+]>C(O)C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH3:22])[C@H:11]([C:19]([NH:29][CH:28]([C:27]([OH:37])=[O:26])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)NC(Cc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:24][CH:23]=1)(=[O:41])=[O:40]
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a mixture of 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml) was added dropwise, under ice-cooling, methanesulfonyl chloride (0.345 g). The mixture was stirred for 2 hours at room temperature, which was washed with water and dried (MgSO4). The solvent was distilled off to leave 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate (1.21 g, 92%). Recrystallization from dichloromethane-ether gave colorless prisms, m.p.132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: COc1ccccc1B(O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (1.0 g, 5.0 mmol), 2-methoxyphenyl boronic acid (1.1 g, 7.2 mmol), [RhCl(cod)]2 (110 mg, 0.25 mmol) and TEA (5 mmol) in H2O (14 ml) and 1,4-dioxane (1 ml) was stirred at 90° C. in a sealed vial for 6 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc; The combined organic layers were dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/acetone) to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (300 mg, 20% yield) as a yellow film.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[C:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:4]=1
Reactant: O=C1CCCC1=Cc1cc(C(F)(F)F)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC1Cc1cc(C(F)(F)F)ccn1

Procedure:
A solution of 2-{[4-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentan-1-one (0.513 g, 2.13 mmol) in ethyl acetate (20 mL) was added palladium on carbon (10% wt, 50% wet, 0.226 g, 0.11 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[C:30]([CH2:31][CH2:32]O)=[C:29]([F:34])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl.CCCCCC>[Br:20][CH2:32][CH2:31][C:30]1[C:23]([Cl:22])=[C:24]([CH:27]=[CH:28][C:29]=1[F:34])[C:25]#[N:26]
Reactant: BrBr
Reactant: N#Cc1ccc(F)c(CCO)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: N#Cc1ccc(F)c(CCBr)c1Cl
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stirrer was added triphenylphosphine (1.57 g, 6 mmol) and methylene chloride (8 mL). Upon cooling the mixture to −10° C., bromine (0.28 mL, 5.5 mmol) was added dropwise. After 10 min, 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (1 g, 5 mmol) in methylene chloride (6 mL) was added and stirring was continued for 20 min while the internal reaction temperature was allowed to warm to 15° C. The mixture was then diluted with hexane (30 mL) and purified via a silica plug [hexane-Et2O (20:1) as eluent]. The combined filtrates were concentrated to furnish the title compound (1.26 g, 96%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.92 (dd, J=6 and 9 Hz, 1H), 7.42 (t, J=9 Hz, 1H), 3.70 (t, J=7 Hz, 2H), 3.13 (dt, J=2 and 7 Hz, 2H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])([O-])=[O:23].[Na+].[Na+].OO>C(O)C.O>[CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:23])=[CH:19][CH:20]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CC=CCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccc(C(N)=O)cc2)sc1=NC1CC=CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-[5-(cyclohex-3-enylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-benzonitrile from protocol I76 (0.94 mmol, 280 mg) in ethanol (41 mL), a solution of Na2CO3 [3N] (12.3 mmol, 4.1 mL), and a solution of H2O2 at 30% in water (3.33 mL) were added. The mixture was stirred overnight at RT and concentrated under reduced pressure. The residue was stirred in water several hours, filtered, and dried under vacuum to afford the pure product. Yield: 64%.
Reaction SMILES: O[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[C:21]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=4)[CH:11]=[N:10][CH:9]=3)[CH2:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2cncc(N3CCC(O)(c4ccccc4)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc2cncc(N3CC=C(c4ccccc4)CC3)c2c1
Yield: 84.9 %

Procedure:
4-(4-Hydroxy-4-phenylpiperidin-1-yl)isoquinoline-6-carboxamide (134 mg, 0.386 mmol) produced in Example 23 was dissolved in trifluoroacetic acid (1 mL)/dichloromethane (1.5 mL), and the resulting mixture was heated to reflux overnight. Upon completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 50:50-0:100, V/V) to give the desired title compound (108 mg, yield 85%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[CH:29]=[C:28]([CH2:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[N:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[CH:29]=[C:28]([CH2:30][CH2:31][P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOP(=O)(CCc1cc(O)nn1-c1ccccc1)OCC
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1)OCC
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.32 g), diethyl 2-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)ethylphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethylphosphonate as colorless crystals (0.29 g, yield 47%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 76-77° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:37][N:38]([CH3:43])[S:39]([NH2:42])(=[O:41])=[O:40]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:42][S:39](=[O:41])(=[O:40])[N:38]([CH3:43])[CH3:37])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Product: CN(C)S(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(dimethylsulfamoyl)acetamide was prepared from {5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxo-1,3-thiazolidin-3-yl}acetic acid (Example 59) and N,N-dimethylsulfamide following General Procedure L.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:14]([CH3:16])[CH3:15])=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19]1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:18]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:14]([CH3:16])[CH3:15])=[CH:4][C:5]=2[O:11][CH2:12][CH3:13])[CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CCOc1cc(N(C)C)c(Cl)cc1C(=O)O
Product: CCOc1cc(N(C)C)c(Cl)cc1C(=O)NC1CCN(Cc2ccccc2)C1

Procedure:
Following the procedure set forth in general method A supra using 1.22 g. of 5-chloro-4-dimethylamino-2-ethoxybenzoic acid and 0.97 g. of 3-amino-1-benzylpyrrolidine, 1.7 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-dimethylamino-2-ethoxybenzamide was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:17][C:14]([F:15])([F:16])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[S:21]([N:20]([CH3:25])[CH3:19])(=[O:23])=[O:22])=[CH:8][CH:7]=1)([OH:18])[C:10]([F:12])([F:13])[F:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To 5.4 g (20 mmole) N-methyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline in 50 ml pyridine add 4.3 g (30 mmole) dimethylsulfamoyl chloride. Stir 16 hours, pour onto water, acidify and extract with Et2O. Wash with 1N NaOH, acidify the aqueous layer, and extract with Et2O. Dry, concentrate and recrystallize first from CCl4, and then from Et2O-hexane to obtain the product; m.p. 63°-65° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[N:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:39][CH:40]1[CH2:44][CH2:43][O:42][CH2:41]1)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:22]1[CH:21]=[C:20]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][C:13]4[C:18](=[CH:17][C:16]([O:19][CH2:39][CH:40]5[CH2:44][CH2:43][O:42][CH2:41]5)=[CH:15][CH:14]=4)[C@:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:26]4)[C:6]=3[CH:7]=2)[CH:25]=[N:24][CH:23]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: O=S(=O)(OCC1CCOC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@]2(CO1)c1cc(OCC3CCOC3)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(S)-2-Amino-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.075 g, 0.217 mmol) and cesium carbonate (0.106 g, 0.325 mmol) were dissolved in DMF (0.7 mL) and stirred for five minutes before being cooled in an ice bath. (Tetrahydrofuran-3-yl)methyl trifluoromethanesulfonate (0.056 g, 0.238 mmol) was dissolved in DMF (0.15 mL) and added dropwise to the reaction, which was stirred for one hour. An additional equivalent of triflate was added and the reaction was stirred for five days. The reaction was cooled to 0° C. and 0.5 eq. of triflate was dissolved in 0.1 mL of DMF and added dropwise to the reaction. The reaction was stirred for two days. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) but the material was impure so the material was repurified via Gilson HPLC (10-90% MeCN:H2O). The product fractions were partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford (S)-2′-(pyrimidin-5-yl)-7′-((tetrahydrofuran-3-yl)methoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. LC-MS MH+ 431.4
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:9][CH2:10]1)=[O:11])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1

Procedure:
The method described in Referential Example 492 was performed by use of isonipecotic acid ethyl ester and p-fluorobenzoyl chloride, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][CH:31]([NH:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]5[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=5)[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and 4-[(2S)-3-amino-2-hydroxy-propoxyl]-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a pale yellowish solid; mp>175° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.5 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.70-4.00 (m, 5 H), 4.92 (brs, 1 H), 6.66 (d, J=6.8 Hz, 2 H), 6.75 (d, J=6.8 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 8.89 (brs, 1 H), 9.29 (brs, 1 H); MS (ES) m/z:321.6 ((M+2H)2+, 100%); 642.1 (MH+, 5%); HRMS Calcd. for C36H44N5O4S (MH+): 642.3114. Found: 642.3095.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: Cc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2 was coupled with 2-methylbenzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (m, 2H) 7.3 (m, 7H), 6.8 (d, 2H), 4.4 (s, 2H), 3.7 (t, 2H), 3.3 (d, 2H), 3.2 (d, 2H) 184 (s, 3H), 2.3 (s, 3H), 1.8 (m, 2H).