Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][S:16][CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:19]([CH2:18][CH2:17][S:16][CH3:15])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSCCN
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: CSCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Yield: 53.9 %

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (1.00 mmol, 209 mg) and 2-aminoethyl methyl sulphide (1.00 mmol, 91 mg) in glacial acetic acid (2 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The residue was partitioned between water and CH2Cl2. The organic phase was evaporated and the crude product was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 152 mg (54%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.97-7.90 (m, 2H), 7.53-7.47 (m, 3H), 3.86 (t, J=6.8 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:40])=[C:14]([C:18]4[C:30]5[C:29]6[CH:28]=[CH:27][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:25][C:24]=6[NH:23][C:22]=5[C:21]([C:36]([O:38]C)=[O:37])=[N:20][N:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:40])=[C:14]([C:18]4[C:30]5[C:29]6[CH:28]=[CH:27][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:25][C:24]=6[NH:23][C:22]=5[C:21]([C:36]([OH:38])=[O:37])=[N:20][N:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)nnc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)nnc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Reaction time: 2.25 h
Yield: 42.2 %

Procedure:
To a yellow, homogeneous solution of methyl 1-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino [4,5-b]indole-4-carboxylate (0.05 g, 0.090 mmol) in THF (1.924 mL) and MeOH (0.641 mL) was added a solution of lithium hydroxide hydrate (0.015 g, 0.359 mmol) in water (0.5 mL). After 2.25 hr, the reaction was concentrated in vacuo, acidified with aqueous 1 N HCl to pH ˜4-5 by litmus paper. The precipitate was filtered and dried over Drierite to give the desired product (0.0206 g, 0.038 mmol, 42.3% yield) as a light tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:23][CH:24](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]3[CH:23]=[CH:24][N:1]=[C:2]3[CH:3]=[C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: COC(CBr)OC
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(N)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc3nccn23)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl 2-amino-6-(4-methylphenyl)isonicotinate (57 mg, 0.2 mmol) in N,N-dimethylformamide (1.3 mL) were added 2-bromo-1,1-dimethoxyethane (33.9 mg, 0.2 mmol) and 4-methylbenzenesulfonic acid (5.2 mg, 0.03 mmol). The mixture was heated to 90° C. After 18 h, the mixture was filtered. The filtrate was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (30 mg): LC-MS [M+1]=309.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:20]1[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=1)=[O:14])[CH3:10]
Reactant: COc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Aluminum chloride (84.30 g, 632 mmol) was added to chloroform (300 ml) and chloroglyoxylic ethyl ester (60 g, 439 mmol) was added dropwise to the resulting suspension over 20 minutes at 0° C. The reaction mixture was stirred for 40 minutes at 5° C. At the same temperature, anisole (68.79 g, 636 mmol) was slowly added dropwise to the reaction solution and then stirred for 12 hours at 10° C. When the reaction is completed, the reaction solution was cooled and, after adding cooling water (100 ml), extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound as a yellow solid (TLC identification). The resulting compound was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:25])=[CH:9]/[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
2-(4-fluorophenyl)-1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-2-ol (4.6 g, 13.05 mmol, 1 equiv.) was heated to reflux with 25% aqueous sulfuric acid (14 mL) for 2 h. The reaction mixture was cooled to 0-5° C. and made alkaline with 15% aqueous KOH solution and extracted with THF:EtOAc (1:1 mixture, 2×30 mL). The combined organic layer was washed with water (15 mL) and brine, dried over sodium sulfate and evaporated under vacuum to obtain the crude product that was purified by flash chromatography on silica gel using EtOAc as eluent. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 10.0 (bs, 1H), 7.7 (m, 2H), 7.2 (m, 3H), 7.10 (d, 2H), 7.0 (d, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 3.7 (bs, 1H), 3.49 (bs, 1H), 3.0 (bs, 2H), 3.0 (s, 3H), 2.4 (s, 3H), 1.8 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)O1.C1(C)C=CC=CC=1.C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.O>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]ccc3c2)c1
Temperature: 80 °C
Yield: 57 %

Procedure:
5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5 mmol) and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate 3) (1.6 g, 5 mmol) were added to a solution of toluene/ethanol/water (6/6/5 ml) previously purged with argon (10 min). The reaction mixture was purged with argon for a further 15 mins, followed by the addition of sodium carbonate (1.64 g, 15 mmol) and PdCl2(dppf) (181 mg, 0.2 mmol) and DME/water (10/5 ml). The resulting mixture was heated to reflux at 80° C. overnight. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was cooled and diluted with ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford crude product. Purification by column chromatography on silica gel (40% ethyl acetate in hexane) afforded 800 mg (57% yield) MS: m/z=287.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[Li]CCCC.[Br-].[Mg+2].[Br-].CON(C)[C:19]([C:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[N:34]=2)[CH:22]=1)=[O:20]>C1COCC1.S1C=CN=C1>[Br:39][C:35]1[N:34]=[C:33]([CH2:32][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30](=[O:31])[C:21]([C:19]([C:4]3[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=3)=[O:20])=[CH:22]2)[CH:38]=[CH:37][CH:36]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1ncsc1C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)sc1C
Temperature: -78 °C

Procedure:
585 mg (5.17 mmol) of 4,5-dimethylthiazole was dissolved in 10 mL of anhydrous THF and cooled down to −78° C. 2.07 mL of 2.5 M BuLi in hexanes was added dropwise, followed after 15 minutes by 1.0 g of anhydrous magnesium bromide. The solution was warmed up to rt. The final compound was prepared from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 1.64 mL of the thiazole salt solution. Yield: 13 mg of a white solid. LC-MSD, m/z for C21H16BrN3O2S [M+H]+=454.0, 456.0; HPLC retention time: 2.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][S:25]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=2[CH3:36])(=[O:27])=[O:26])[C:21]([F:37])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:38]OC(OC)N(C)C.C(OC(=O)C)(=O)C.Cl.C(OC(C)C)(C)C>C(Cl)Cl.O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:37])=[C:22]([O:24][S:25]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])(=[O:26])=[O:27])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:38]1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C)cc(C)cc3C)c(F)cc2c1=O
Yield: 85.1 %

Procedure:
In 6 ml of methylene chloride was dissolved 300 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate, and 135 mg of N,N-dimethylformamide dimethylacetal and 115 mg of acetic anhydride were added thereto, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. To the reaction mixture were added 0.31 ml of 2N hydrochloric acid and 3 ml of ethanol, and the resulting mixture was subjected to reaction at room temperature for 1 hour, after which 6 ml of methylene chloride and 6 ml of water were added thereto. The organic layer was separated, washed with 6 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 260 mg (yield 85.1%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate having a melting point of 170°-173° C. The physical properties of this compound were identical with those of the compound obtained in Example 41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:68]=[CH:67][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:64]([NH2:66])=[O:65])=[N:52][N:53]([C:55]4[CH:63]=[CH:62][C:58]5[O:59][CH2:60][O:61][C:57]=5[CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1>CN(C=O)C>[O:59]1[C:58]2[CH:62]=[CH:63][C:55]([N:53]3[C:54]4[C:46]5[CH:45]=[C:44]([NH:43][C:5](=[O:7])[C:4]6[C:8]([Cl:11])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=6)[CH:68]=[CH:67][C:47]=5[CH2:48][CH2:49][C:50]=4[C:51]([C:64]([NH2:66])=[O:65])=[N:52]3)=[CH:56][C:57]=2[O:61][CH2:60]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of step 4 of Example 161 (2 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of step 4 of Example 161 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was triturated in warm CH3CN (80° C.) to give 2.2 g of the title compound (yield 73%). Mp: 292-293° C. 1H NMR (300 MHz, d6-DMSO): δ 2.90-2.92 (m, 4H), 6.09 (s, 2H), 6.94-7.04 (m, 2H), 7.12 (d, 1H, J=2 Hz), 7.26-7.38 (m, 4H), 7.51 (s, 1H), 7.81 (s, 1H), 8.61 (s, 1H), 10.54 (s, 1H). M+1=523.
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)([Cl:14])=O.ClCl.S1C2C=CC=CC=2C=N1>ClC1C=CC=CC=1>[Cl:14][C:5]1[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccccc1C=NO
Agent: ClCl
Agent: c1ccc2sncc2c1
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 96.1 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, 15.6 g (0.22 mol) of chlorine was continuously blown into the reaction mixture containing 1,2-benzisothiazole while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was subjected to distilling off of the solvent and then to distillation under reduced pressure to give 32.6 g of 3-chloro-1,2-benzisothiazole. The yield was 96% to the 2-(methylthio)benzaldehyde oxime.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=5[CH3:35])[NH2:31])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.[C:45]([C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][CH2:60]2)[CH:57]=1)[C:52](O)=[O:53])([CH3:48])([CH3:47])[CH3:46]>>[C:45]([C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([CH2:58][N:59]2[CH2:60][CH2:61][CH2:62][CH2:63]2)[CH:57]=1)[C:52]([NH:31][C:30]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:28]([N:27]2[C:22]3[N:23]([N:24]=[C:20]([C:18]4[CH:17]=[N:16][N:15]([CH2:14][C:13]5[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:37][CH:36]=5)[CH:19]=4)[CH:21]=3)[CH:25]=[CH:26]2)[CH:29]=1)=[O:53])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1cc(CN2CCCC2)cc(C(=O)O)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(CN7CCCC7)cc(C(C)(C)C)c6)ccc5C)ccn4n3)cn2)cc1

Procedure:
70 mg (0.14 mmol) of the compound of Example 8A and 51 mg (0.14 mmol) of the compound of Example 22A were reacted analogously to the procedure of Example 48A. This gave 83 mg (88% pure, 83% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]O)[CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[C:39]([CH2:40][OH:41])=[CH:38][NH:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[OH:41][CH2:40][C:39]1[C:35]([C:34]([F:43])([F:42])[F:33])=[N:36][N:37]([CH2:20][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C@@H:11]([NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]3)[CH:38]=1
Reactant: O=C(N[C@@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reactant: OCc1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)OCc1ccccc1
Temperature: 60 °C
Yield: 76.9 %

Procedure:
(R)-benzyl-5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (5.08 mmol, 1.51 g) was dissolved in DCM (20 mL), thionyl chloride (10.16 mmol, 0.741 mL, 1.208 g) added and the resultant solution stirred at room temperature for 45 min. The sample was concentrated and azeotroped with DCM (×4). Potassium carbonate (15.23 mmol, 2.105 g) was added followed by DMF (20 mL) and (3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (5.08 mmol, 0.843 g) and the mixture heated to 60° C. for 1 h. The mixture was concentrated and partitioned between EtOAc/water. The aqueous layer was twice extracted with EtOAc and combined organics dried, filtered and concentrated to give a yellow oil which was purified on silica eluting with 0.5% MeOH/DCM to give (R)-benzyl 5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate as a light coloured oil (1.74 g, 77%). 1H NMR (400 MHz, CDCl3) δ 1.83 (t, 1H) 2.79 (m, 2H) 3.27 (m, 2H) 4.52 (bs, 1H) 4.64 (d, 2H) 4.99 (bs, 1H) 5.09 (bs, 2H) 5.25 (s, 2H) 7.05-7.11 (m, 2H) 7.19 (m, 1H) 7.26-7.40 (m, 6H).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]([OH:30])[CH2:28][CH3:29])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[OH:30][CH:27]([C:24]1([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCC(O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (±)-1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-propan-1-ol, which may be produced as in Example 174 (2.1 g) in 60 mL of anhydrous THF is added tetrabutylammonium fluoride hydrate (2.4 g.) The reaction mixture is stirred at room temperature for 4 hrs. Saturated ammonium chloride (50 mL) is added to the reaction mixture, followed with 300 mL of ethyl acetate. The aqueous layer is separated and then the organic layer is washed with additional saturated ammonium chloride (2×50 mL), followed with brine (50 mL.) The organic layer is dried (sodium sulfate), filtered, and the filtrate is evaporated to give a white solid, which was purified by flash chromatography (silica gel, 40% ethyl acetate in hexane) to afford the white solid (±)-4-{5-{1-(1-hydroxy-propyl)-cyclopropyl]-4-phenyl-isoxazol-3-yl}-phenol; MS (APCI+) m/z 336 (MH+.)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])=[O:3].C[C:30]([CH3:33])([O-:32])[CH3:31].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][C:8]([N+:25]([O-:27])=[O:26])=[C:7]([CH:12]=1)[C:6]([N:5]([C:6](=[O:28])[C:7]1[CH:33]=[C:30]([O:32][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[Cl:24])[CH:31]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])[S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To N-methylsulfonyl-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro-benzamide (20.0 grams, 45.6 millimoles) dissolved in 100 ml tetrahydrofuran was added potassium tertiary butoxide in tetrahydrofuran with cooling. A solution of the acid chloride product as described in Example 1 in tetrahydrofuran was then added and the mixture stirred at ambient temperature for forty eight hours under nitrogen with precautions taken to exclude moisture throughout this procedure. The mixture was then diluted with toluene, washed three times with water and saturated sodium chloride solution. The organic phase was concentrated by vacuum to dryness. The residue was shaken with toluene then reconcentrated three times. The final residue was covered with toluene, shaken, the insolubles filtered off, and washed several more times with toluene and hexane. The material was triturated for 30 minutes by stirring with 50 ml hexane. The insolubles were filtered off and dried. The material was purified further by trituration with 5% potassium carbonate followed by drying and recrystallization from toluene/hexane mixtures. The desired product had a melting point of 165.5°-167.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH:3]1([CH2:2][NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2 mL (23 mmol) of aminomethyl cyclopropane in 25 mL methylene chloride was added 4.8 mL (28 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 4.49 g (23 mmol) of 4-fluorobenzene sulfonyl chloride was added and the mixture was allowed to stir for 4 hours. The reaction mixture was quenched with water and the organic layer was washed twice with 1N HCl, twice with water, dried over magnesium sulfate and then concentrated in vacuo. Then the solid was dried under vacuum to give 4.65 g of the title compounds as an off white solid; 1H NMR (CDCl3) δ 0.08-0.13 (m, 2H), 0.45-0.51 (m, 2H), 0.83-0.94 (m, 1H), 2.86 (t, J=6.9 Hz, 2H), 4.66-4.71 (m, 1H), 7.12-7.23 (m, 2H); MS (ES) m/z 218.23 (MH+); HRMS for C10H12FNO2S: 218.0637.