Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][NH:12][CH3:13])[C:3]=1[OH:14].CCN(C(C)C)C(C)C.[CH2:24]([O:31][C:32]([O:34]N1C(=O)CCC1=O)=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[F:1][C:2]1[C:3]([OH:14])=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:11][N:12]([CH3:13])[C:32](=[O:34])[O:31][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc([N+](=O)[O-])cc(F)c1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a flask containing 27A (1.6 g, 7.99 mmol), DIEA (2.088 ml, 11.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (2.19 g, 8.79 mmol). The mixture was stirred at rt for 1 h. The reaction was quenched with H2O and then extracted with EtOAc (3×). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by flash column chromatography (0-60% EtOAc/hexanes) to give 27B (1.8 g, 5.38 mmol, 67.4% yield). MS (ESI) m/z: 335.2 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[Cl:1][C:10]1[C:11]([CH3:21])=[CH:12][C:13]2[C:14]3[CH2:2][NH:3][CH2:4][CH2:5][C:6]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH:9]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(C)c(Cl)cc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 3-chloro-4-methylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:2]=2[CH3:1])=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(CN2CCCCC2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCCCC3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of 2-methyl-4-(piperidin-1-ylmethyl)benzoic acid (100 mg, 0.43 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.1 mmol), triethylamine (32 mg, 0.3 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(piperidin-1-ylmethyl)benzamide as white solid (35 mg, 19%). LRMS (M+H+) m/z: calcd 367.23. found 367. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.54-7.46 (m, 3H), 6.26 (s, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 3.10 (s, 4H), 2.54 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.93-1.89 (m, 4H), 1.77-1.75 (m, 2H).
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[ClH:29].O=S(Cl)[Cl:32]>C(Cl)Cl>[ClH:32].[Cl:29][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(Cl)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1

Procedure:
) (5S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.027 mol) was suspended in CH2Cl2 (250 ml). HCl, gas (excess) was allowed to bubble through the suspension for 2 minutes. SOCl2 (0.097 mol) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated under reduced pressure. Toluene was added and azeotroped on the rotary evaporator (2×). The residue was stirred in toluene. The precipitate was filtered off, washed with toluene and dried, yielding 11.5 g (100% crude yield) of (5S)-N-[4-(chlorophenylmethyl)phenyl]4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (compound 500).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CC(C)=O>[C:23]1([S:37]([OH:40])(=[O:39])=[O:38])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33]([OH:36])(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[C:41]([O:19][CH:4]([C:3]([CH2:21][F:22])([CH2:2][F:1])[CH3:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:43])[CH3:42]
Reactant: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1ccnc1)C(C)(CF)CF
Temperature: 100 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
12.2 g (0.037 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butan-2-ol were dissolved in 70 ml of acetic anhydride. The solution was stirred at 100° C. for 16 hours, the excess acetic anhydride was distilled off in vacuo and the residue was taken up in 300 ml of methylene chloride. The organic phase was washed twice with 800 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of acetone, and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate which had formed was filtered off and dried. 13 g (68% of theory) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butane 1,5-naphthalenedisulphonate of melting point 221°-224° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: CC[Mg]Br
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (intermediate 1) (81.6 mg) was dissolved in tetrahydrofuran (3 ml), and the solution was then cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.4 ml) of ethylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (41 mg, yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:3]=1.[ClH:20].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:20].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 7 h
Yield: 29.2 %

Procedure:
A solution of intermediate 130, 4-fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile, (500 mg, 1.89 mmol) in warm ethanol (30 mL) and ethyl acetate (30 mL) was mixed with conc.HCl (0.32 mL, 3.78 mmol, 2 eq.). To this was added 10% Pd—C (100 mg; Aldrich), and the mixture was hydrogenated at 1 atm of hydrogen for 20 hrs at room temperature. To this mixture was added an additional amount of 10% Pd—C (50 mg) and stirring continued for another 7 hrs. The mixture was filtered through Celite and the filtrate concentrated in vacuo to dryness. The residue was triturated with ethyl acetate, then with ethanol to obtain the title compound (168 mg, Yield 29%) as an off-white powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.55 (2H, t, J=5 Hz, NCH2), 3.62 (2H, t, J=5 Hz, NCH2), 3.70 (2H, t, J=5 Hz, OCH2), 3.75 (2H, t, J=5 Hz, OCH2), 4.17 (2H, s, NCH2), 5.17 (2H, s, OCH2), 6.82 (1H, dt, J=2.5, 8.5 Hz, Ar—H), 7.05 (1H, dd, J=2.5, 10.5 Hz, Ar—H), 7.43 (1H, dd, J=6.5, 8.5 Hz, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 39.40, 42.49, 44.97, 66.11, 66.46, 66.59, 101.38, 101.59, 108.40, 108.57, 118.40, 132.53, 132.62, 158.43, 158.52, 63.87, 165.83, 168.27. HRMS (ESI) calcd for C13H18N2O3F (M+H) 269.1301, found 269.1301.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:7]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[C:18](=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=3[O:2][CH3:1])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(=O)[nH]cnc3c2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-sulfonamide (0.990 g, 2.159 mmol) was dissolved in toluene (10.80 ml) and POCl3 (0.403 ml, 4.32 mmol) was added. The reaction was stirred for 90 minutes at room temperature, then heated to 90° C. and stirred for four hours. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford a brown oily solid. The solid was triturated in heptane, stirred for 30 minutes, and filtered. The resulting material was vacuum dried to afford crude 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a free flowing tan solid. (ESI) 499.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][C:14]2[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: NC(=O)c1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CSc2cccnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
By the procedure of Efxample 1, a solution of p-methoxybenzyl mercaptan in dimethylsulfoxide is added slowly to a stirred suspension of sodium hydride in dry dimethylsulfoxide under nitrogen. After stirring for one hour at room temperature, 3-bromopicolinamide is added and the mixture is kept about 75°C. for three hours, then worked up by cooling, diluting with ice water, filtering off the resulting solid, washing it with water, drying and recrystallizing from aqueous dimethylformamide to give 3-(p-methoxybenzylthio)picolinamide, m.p. 252°C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:22].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:23])=[C:7]([CH3:22])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1
Reactant: CCc1cc(Br)cc(Oc2ccc(CCC(=O)OC)c(C)c2)c1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: CCc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2Oc2ccccc2)c1
Yield: 36 %

Procedure:
The compound of 3-[4-(3-bromo-5-ethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.237 g (36%) of the title compound after saponification. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H28O5Cl 503.1625, found 503.1625.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:7]=1)=O)C.C(C1C=C(C2C=CC=CC=2)N(C2C=CC(S(N)(=O)=O)=CC=2)N=1)=O>>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:6]([CH:4]=[O:3])=[N:7]2)=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Yield: 65 %

Procedure:
The titled compound was prepared in 65% yield from the compound 3a using the procedure detailed for compound 12b. mp 133.0-135.5° C. 1H NMR (300 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.02 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.47-7.39 (m, 3H), 7.37-7.29 (m, 2H), 7.22 (s, 1H), 3.29 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(O)[CH2:5]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5]2
Reactant: OC1(c2ccccc2)Cc2cc(Br)ccc21
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)CC2c1ccccc1
Yield: 76 %

Procedure:
Using 3-bromo-7-phenyl-bicyclo[4.2.0]octa-1,3,5-triene-7-ol (4a) (2.1 g, 7.6 mmol), hexane (10 ml), triethylsilane (1.3 g, 11.5 mmol), trifluoro acetic acid (4.3 g, 38.2 mmol) afforded 3-Bromo-7-phenyl-bicyclo[4.2.0]octa-1,3,5-triene (5a) as a pale yellow oil (1.5 g, GC-MS: M+=258, M−=260, 76% yield, isolated as a mixture of isomers).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.C(NC1C=CC(S([N:32]=[N+:33]=[N-])(=O)=O)=CC=1)(=O)C.[N-]=[N+]=[N-].C(NC1C=CC(S([NH-])(=O)=O)=CC=1)(=O)C>C(N(CC)CC)C.ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[C:11](=[N+:32]=[N-:33])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=C[C@H](CC(=O)CC(=O)OC)c1cccc(F)c1
Agent: CC(=O)Nc1ccc(S([NH-])(=O)=O)cc1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=C[C@H](CC(=O)C(=[N+]=[N-])C(=O)OC)c1cccc(F)c1
Temperature: 21 °C
Reaction time: 9 h

Procedure:
A 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, addition funnel, nitrogen inlet, and steam pot, was charged with a solution of methyl (5S)-5-(3-fluorophenyl)-3-oxohept-6-enoate 8 (8823 g of solution, 1300 g of ketoester in 1,2-dichloroethane). Additional 1,2-dichloroethane (7 L) was charged to the flask, followed by 4-acetamidobenzenesulfonyl azide (1.25 kg). The solution was heated from about 18° C. to 21° C. with steam. (Note: the dissolution of azide was endothermic.) Triethylamine (2.17 L) was added over 40 min with water bath cooling to maintain a temperature of 19-23° C. The reaction was stirred at 18-23° C. for approximately 9 h. The reaction was mildly exothermic. The reagent product, 4-acetamidobenzenesulfonyl amide, began to precipitate from the reaction during the addition of triethylamine and eventually formed a thick slurry. The reaction was followed by HPLC and was judged complete when the amount of starting material was <0.5%. When completed, the reaction mixture was filtered, and the cake was washed four times with 1,2-dichloroethane (3×2 L displacement washes, 1×1 L slurry wash). The filtrate and washes were combined and extracted with cold (5-10 C) 2N HCl (7.4 L). The extraction was exothermic and was done in a 50 L extractor with cooling to maintain a temperature of 20-22° C. The pH of the aqueous phase was 1.0. The organic layer was extracted twice with water (2×7 L). The organic extract was charged to a 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, nitrogen inlet, and stopper. The solution was dried for 4 h with sodium sulfate (1 kg). The organic solution was passed through a 5 μ inline filter. The final weight of organic solution was 25.6 kg. Final yield of 9 was >95%.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:29]#[N:30])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:29]#[N:30])([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 56b (2.4 g, 7.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.7 g, 100%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCl.[S:12](=O)(=[O:15])([OH:14])[OH:13].C(C(CCCC)C([O-])=O)C.[K+:27]>C(OCC)(=O)C>[K+:27].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:12]([O-:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 77.9 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and dichloromethane (30 mL), was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 30-40° C. then stirred for 1-2 h. The to reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2B(O)O)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Br[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:4]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:20]2[CH:26]=[CH:25][CH:24]=[C:22]([NH2:23])[CH:21]=2)(=[O:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cccc(Br)c1
Reactant: O=S(=O)(c1ccccc1B(O)O)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
2-(morpholinosulfonyl)phenylboronic acid (0.188 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.113 g in 77% yield.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][C:7](=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>O.C(O)(=O)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Cl:5][CH2:6][C:7](=[O:16])/[C:8](=[N:1]/[OH:3])/[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)/C(=N\O)C(=O)CCl
Yield: 91 %

Procedure:
A solution of 35.6 g of sodium nitrite in 100 ml of water was added to a cold solution of t-butyl 4-chloro-3-oxobutanoate (100.9 g, 0.439 moles of 84% material*) in 400 ml of acetic acid containing 50 ml of water over a 0.5 hour period with stirring. The mixture was stirred in the cold for an additional hour, then stored in the cold overnight. The mixture was diluted with 500 ml portions of water, 500 ml of saturated sodium bicarbonate, 500 ml of water and 500 ml of brine, then dried over magnesium sulfate and evaporated to give an amber oil; yield 88.6 g (91% yield). This material was used in the next step without further purification. *This compound was obtained from Lonza Chemical Co., Fair Lawn, N.J.