Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:20])([F:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[Na+].[Cl-].CCOC(C)=O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]([S@:5](/[N:7]=[C:10](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)\[C:9]([F:8])([F:20])[F:19])=[O:6])([CH3:4])[CH3:3]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(/c1ccc(F)cc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
(R)-2-Methylpropane-2-sulfinamide (0.64 g, 5.28 mmol), 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (0.53 g, 2.76 mmol) and titanium(IV) isopropoxide (1.5 mL, 5.12 mmol) were stirred in THF (13 mL) at 70° C. for 18 hours. Room temperature was attained, saturated NaCl and EtOAc were added, and the resulting biphasic suspension was stirred for 5 minutes. The suspension was filtered through Celite to remove the titanium residues, and the organic phase was separated. The aqueous phase was extracted a second time with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo while loading onto silica. Purification of the residue by MPLC (0-20% EtOAc-hexanes) gave (R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide (0.23 g, 0.779 mmol, 28.2% yield) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[SH:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][S:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCBr
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCCCSc1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 mL 1-bromo-3-chloropropane was added to a mixture of 2 mL thiophen-2-thiol, 5.86 g potassium carbonate and 40 mL N,N-dimethylformamide under ice-cooling and then stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with water plus brine (×2) and then with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography (hexane) to give 4.19 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([O:17][CH3:18])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.[OH-].[Na+]>ClCCl>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[S:3][C:2]([NH:1][C:32]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:33])=[N:6][C:5]=2[CH:7]=1
Reactant: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc2c1
Reaction time: 6 h
Yield: 14.6 %

Procedure:
2-Amino-5-methoxy-7-phenyl-benzothiazol (45 mg, 0.18 mmol) is dissolved in dichloromethane (2 ml) and subsequently treated with triethylamine (0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6 h, further 0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol) are added and the mixture is stirred for additional 18 h at ambient. After addition of 0.1M aqueous sodium hydroxide, the mixture is stirred for additional 16 h. The organic layer is separated, dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1, containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the product as white solid. MS: m/e=380 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19](Cl)[C:18]=1[CH2:27][CH2:28][OH:29])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1.Cl>>[C:1]([O:5][C:6]([N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]2)[C:18]=1[CH2:27][CH2:28][OH:29])=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(Cl)nc3ccnn23)cc1
Agent: Cl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl[5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (300 mg) and (S)-3-amino-1-tert-butoxycarbonylpiperidine (900 mg) was stirred at 90° C. for 16 hr. To the reaction solution, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39]([C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[NH2:43])[CH3:40]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH:13]=[C:12]2[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[CH2:39][CH3:40])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccccc1N
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccccc1NC1=CC(=O)N(c2cccc(F)c2)C12CCN(Cc1ccccc1)CC2

Procedure:
To a solution of 100 mg (0.28 mmol) 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione in 0.71 mL dry toluene was added 70 mg (0.37 mmol)p-toluenesulfonic acid monohydrate and 61 μL (0.50 mmol) 2-ethylaniline. The reaction was heated to reflux for 18 h and then diluted with EtOAc, washed with 1N NaOH, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified on silica gel with 20-60% EtOAc/hexanes to afford title example 8-benzyl-4-[(2-ethylphenyl)amino]-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]dec-3-en-2-one as a tan foam. 1H NMR (CD3OD, 400 MHz) δ 7.43 (q, J=7.38 Hz, 1H), 7.32 (m, 1H), 7.24 (m, 6H), 7.16 (m, 3H), 7.08 (m, 2H), 4.55 (s, 1H), 3.41 (s, 2H), 2.80 (m, 2H), 2.64 (q, J=7.51 Hz, 2H), 2.38 (m, 2H), 2.19 (m, 2H), 2.10 (dt, J=11.5 and 3.85 Hz, 2H), 1.18 (t, J=7.51 Hz, 3H); LC/MS [M+H]=456.1.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.Cl[CH2:29][C:30]1[N:31]=[CH:32][N:33](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:34]=1[CH3:35].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(O)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][N:14]1[C:26]2[CH2:25][CH2:24][CH:23]([CH2:29][C:30]3[N:31]=[CH:32][NH:33][C:34]=3[CH3:35])[C:22](=[O:27])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 0.5 h
Yield: 244.5 %

Procedure:
n-Butyllithium (1.45M in hexane; 2.07 ml) was added dropwise to a cold (-70°) stirred solution of diisopropylamine (0.42 ml) in dry THF (20 ml) under nitrogen. The solution was allowed to reach 0° over 30 min, cooled to -70° and added to a cold (-70°) stirred solution of ) 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (500 mg) in dry THF (10 ml under nitrogen. Hexamethylphosphoramide (0.44 ml) was added and the mixture was allowed to reach 0° over 1 h. The solution was cooled to -70° and a suspension of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (936 mg) in dry THF (15 ml) was added and the mixture was allowed to reach ca. 20° over 2.5 h. It was stirred for a further 18 h, poured into 8% sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined, dried organic extracts were evaporated to give a semi-solid which was treated with a mixture of acetic acid (10 ml), water (10 ml) and THF (10 ml) and heated at reflux for 1.5 h. The solution was poured into saturated potassium carbonate solution (100 mml) and extracted with dichloromethane (3×50 ml). The combined, dried organic extracts were evaporated to give a solid (ca. 1.8 g) which was purified by SPCC eluting with System A (200:10:1) to give the title compound (17 mg). The 1H-n.m.r. and t.l.c. of this material were consistent with those obtained from the product of Example 8.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[CH3:23][O:24][CH2:25][CH2:26][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1
Reactant: COCCBr
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: COCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-methoxyethylbromide.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH2:2][C:3]#[CH:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C#CCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCCOS(=O)(=O)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A solution of 3-butyn-1-ol (365 g, 5.21 mol), triethylamine (526 g, 5.21 mol), and toluene (419 mL) was added to a cooled (0-5° C.) stirred solution of 4-chlorobenzenesulfonyl chloride (1.0 kg, 4.74 mol) and toluene (2.10 L). The reaction temperature was maintained below 20° C. during the addition. Precipitation of triethylamine hydrochloride salt occurred during the reaction. The reaction mixture was stirred at room temperature for 2-4 h. The triethylamine hydrochloride byproduct was separated by filtration and washed with toluene (2×350 mL). The combined filtrates were concentrated to remove toluene under reduced pressure above 45° C. to maintain the residue as a liquid. 2-Propanol (1.20 L) was added to the residue and the stirred solution was cooled to 20-25° C. Water (1.80 L) was added over 15 m. The slurry of product and solvent was cooled to 0-5° C. and stirred for 1 h. The white solid product was collected by filtration, washed with 33% aqueous 2-propanol (v/v), and vacuum dried to give 4-chloro-benzenesulfonic acid but-3-ynyl ester with 99% purity (as determined by HPLC.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[C:17](=[O:19])[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[K+]>O1CCCC1.CCOCC>[CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]([OH:19])[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCNc1c2c(nc3ccccc13)CCCC2O
Yield: 74.9 %

Procedure:
In 50 ml of dry tetrahydrofuran was suspended 2.49 g of 3,4-dihydro-9-(n-propylamino)acridin-1(2H)-one. The mechanically stirred suspension was cooled in ice and 4.50 ml (0.5 eq) of 1.1M LiAlH4 solution in ether was added dropwise, whereupon a solution formed. After the addition, the reaction appeared complete based on thin layer chromatography analysis. The excess hydride was neutralized with 0.5 ml of saturated NH4CL solution and thereafter 30% potassium hydroxide was added to dissolve the salts. The supernatent tetrahydrofuran solution was separated and evaporated to a solid. The solid was recrystallized from 1:4 dichloromethane/EtOAc to yield 1.88 g (75%) of needles, melting point 164° C.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C(Cl)(Cl)Cl.[C:29]1([CH3:41])[CH:34]=[CH:33][C:32]([S:35]([N:38]=[C:39]=[O:40])(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:39]([NH:38][S:35]([C:32]4[CH:33]=[CH:34][C:29]([CH3:41])=[CH:30][CH:31]=4)(=[O:37])=[O:36])=[O:40])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)C#N)cc1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(C(C)(C)CNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]-2-methylpropanenitrile (step 3, 102 mg, 0.28 mmol), PtO2 (one portion), chloroform (0.5 mL) in ethanol (15 mL) was stirred under hydrogen atmosphere (4.5 Kg/cm2) at room temperature. After 8 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was suspended in dichloromethane (10 mL). To the suspension was added p-toluenesulfonyl isocyanate (0.3 mL, 1.96 mmol), and triethylamine (0.3 mL, 2.1 mmol) at room temperature. After 0.5 h, the mixture was concentrated. The residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous citric acid (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by preparative TLC (ethyl acetate/hexane=2:1) to give 62 mg (37%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.83 (1H, s), 7.67 (2H, d, J=9.3 Hz), 7.55 (2H, d, J=9.3 Hz), 7.38–7.22 (4H, m), 7.18 (1H, s), 3.45 (1H, br), 2.76 (2H, q, J=8.4 Hz), 2.34 (3H, s), 1.37 (6H, s), 1.31 (3H, t, J=8.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][C:19]([F:32])=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[C:42]([CH3:58])=[N:41]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][C:19]([F:32])=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:46]3[CH:47]=[C:48]4[C:43]([C:42]([CH3:58])=[N:41][NH:40]4)=[CH:44][CH:45]=3)[C:3]=12
Reactant: CC(c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c2cc(-c3nn(C(C)c4oc5ccc(F)cc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 11.2 %

Procedure:
To a solution of Example 57f (0.400 g, 0.733 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), N-Boc-3-methyl-6-indazoleboronic acid pinacol ester 98 (0.393 g, 1.099 mmoles) and sodium carbonate (0.233 g, 2.19 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.045 g, 11% yield). MP: 234-236° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.06(s,1H), 7.86-7.70(m,4H), 7.61(s,1H), 7.33(m,2H), 7.06(dt, J=8.9,2.5 Hz, 1H), 6.87(m,2H), 6.07(q, J=7.0 Hz, 1H), 2.48(s,3H), 1.91(d, J=7.1 Hz, 3H). Mass: 549.95(M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Br:22][C:23]1[CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]3[CH:27]=[CH:26][C:25]([C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=3[Br:22])[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (8.18 g, 28.6 mmol), 3-bromo-4-fluorobenzotrifluoride (6.80 g, 28.0 mmol) and 325 mesh potassium carbonate (4.64 g, 33.68 mmol) in dry DMSO (80 mL) is heated to 100° C. and stirred 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4, and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford 11.74 g (81%) of the titled compound. Rf=0.76 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H20O4F3Br 509, found 526 and 528 (M+NH4, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:11]([F:37])[CH:10]=1.CC1(C)[O:43][C@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:37])([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 51.8 %

Procedure:
In a manner similar to the method described in Example 72a, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 mL, 1.78 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)on1
Yield: 78 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 4-trifluoromethylbenzeneboronic acid resulting in the final product in a 78% yield, m.p. 150-153° C. The product was recrystallized using an acetonitrile and water mixture.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[S:22]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]1=2
Reactant: CCOC(=O)C1(NC(=O)c2cc3ccccc3s2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cc2ccccc2s1
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A 50 mL flask containing the 2-[(Benzo[b]thiophene-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (0.37 g, 1.01 mmol) is charged with 1,4-dioxane (6 mL) and MeOH 6 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3.0 mL) is added followed by the LiOH (106 mg, 2.53 mmol). After 18 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜10 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 290 mg (89%) of dry white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([O-:14])=[O:13].[K+]>Cl>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: [K+]
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1C(=O)O
Reaction time: 0.08 h

Procedure:
2-Chloro-6-methylbenzoic acid (99 mg, 0.58 mmol) was dissolved in conc. hydrochloric acid (1 mL) and cooled in an ice bath. To this solution potassium nitrate in conc. hydrochloric acid (1 mL) was added drop wise. The reaction mixture was stirred for 5 min, then the ice bath was removed and stirring was continued for another 2 hours. The reaction mixture was poured onto ice (25 g) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give a mixture of the desired 3-nitro (70%) and the 5-nitro (30%) derivatives (118.6 mg, 95%). No effort was made to separate the two isomers, and the mixture was used in the next step.