Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17])=O.O=P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17]
Reactant: Nc1ccncc1NC(=O)c1c(I)cc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]ccc(I)c1-c1nc2cnccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-amino-pyridin-3-yl)-amide (281 mg, 0.79 mmol) in 9 mL pyridine at 0 C was added (slowly) 0.5 mL POCl3 (5.3 mmol). The mixture was stirred at 0 C for 2 hours, then poured on a mixture of ice and saturated aqueous sodium bicarbonate solution. The product precipitates as a colloid. All attempts to filter or extract the product failed. The mixture was concentrated in vacuum, water removed by aceotropic destillation with n-propanol and the crude mixture used as it is. LCMS [M+H]+339, T=0.54 min product and [M+H]+357, T=0.29 min unreacted starting material [YMC ODS-A C18 S7 3.0×50 mm column; 0–100% gradient over 2 min*; 5 mL/min flow rate].* Gradient begins with 10% methanol/90% water (0.1% TFA) and end with 90% methanol/10% water (0.1% TFA)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCOCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C2(O)CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To an ice-cooled solution of 4-(3-t-butyloxycarbonylaminophenyl)-4-hydroxytetrahydropyran (2.0 g, 6.8 mmol), prepared as in step 2, in dichloromethane (14 mL) was added trifluoroacetic acid (14, mL). The resulting solution was stirred for 0.25 hours at 0° C. and 1 hour at ambient temperature. The volatiles were removed in vacuo and the resulting solution was basified with saturated aqueous potassium carbonate. The resulting mixture was diluted with dichloromethane and the layers separated. The aqueous layer was extracted (4x, dichloromethane). The combined organic layers were dried (MgSO4), and concentrated in vacuo to provide a solid. Trituration with hexanes provided 4-(3-aminophenyl)-4-hydroxytetrahydropyran as a colorless solid (1.01 g, 77%). mp 154°-155° C. 1H NMR (300 MHz, CDCl13) δ7.17 (1H, dt, J=7.5 ,1 Hz), 6.84-6.88 (2H, m), 6.62 Hz), (1H, br d, J=7.5 Hz), 3.93 (2H, td, J=12, 12, 2.5 Hz), 3.84 (2H, ddd, J=12, 5, 1.5 2.05-32 (4H, m). MS m/e 193 (M+NH4 -H2O)+, 211 (M+NH4)+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C1COCC1>O>[CH2:1]([N:8]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 90.5 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-(benzylamino)-3-[(2-methyl-2-propen-1-yl)oxy]piperidine-1-carboxylate obtained in Example (117c) (4.4 g, 12.2 mmol), sodium bicarbonate, benzyl chloroformate (2.81 g, 16 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 5.46 g of the title compound as a colorless oily substance (99%).
Reaction SMILES: C([Si](Cl)(CC)CC)C.Br[C:10]([Br:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18]1(=[O:23])[CH2:22][CH2:21][CH:20]=[CH:19]1.Cl>C(#N)C.[Zn].CCOC(C)=O>[Br:17][C:10]([F:16])([CH:20]1[CH2:21][CH2:22][C:18](=[O:23])[CH2:19]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C(F)(Br)Br
Agent: CC[Si](Cl)(CC)CC
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
Add 8.45 mL (50.4 mmol) of triethylsilyl chloride to a suspension of 2.99 g of activated Zn (45.8 mmol) in anhydrous acetonitrile (100 mL) at −20° C. and stir the mixture for 5 minutes. Add 8.0 mL (57.3 mmol) of ethyl 2,2-dibromo-2-fluoracetate and stir the mixture for 90 minutes at −20° C. Add 1.86 mL (22.9 mmol) of 2-cyclopenten-1-one, and stir the reaction mixture overnight, allowing the temperature to rise slowly to room temperature. Add HCl 1N (125 mL) and EtOAc (100 mL). Wash the organic layer with saturated NaHCO3 (2×150 mL), water (2×150 mL) and brine (2×150 mL), dry over anhydrous MgSO4, filter and concentrate under reduced pressure. Purify the residue by column chromatography using EtOAc/hexane (1:8) as eluent to give the title compound (5.36 g, 88% overall yield) as a colorless oil as a mixture of diastereoisomers.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][OH:19])[CH2:4][CH2:3][CH2:2]1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (0.12 g, 0.36 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 g, 0.36 mmol) and triphenylphosphine (0.10 mg, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes and the allowed to sit overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (71 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.16-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.84 (s, 2H), 4.05-3.97 (m, 1H), 3.93 (s, 3H), 2.43-2.31 (m, 4H), 2.14-2.02 (m, 1H), 1.97-1.89 (m, 1H). LRMS (APCI) m/z 559 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:25][C:16]1[CH:15]=[C:14]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([O:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:5]=2)[CH:19]=[C:18]([F:20])[C:17]=1[C:21]([F:22])([F:24])[F:23]
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Oc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A mixture of 2-chloro-α,α,α,6-tetrafluoro-p-tolyl 3,4-dinitrophenyl ether (10.0 g, 0.026 mol), 4methoxyphenol (6.45 g, 0.052 mol) and potassium carbonate (7.26 g, 0.052 mol) in acetonitrile is refluxed for 18 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. Column chromatography of the oil using silica gel and a (1:4) ether/hexanes solution gives the title product as a yellow oil (3.0 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[S:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11].FC(F)(F)S(O)(=O)=O>O>[CH3:12][C:10]([C:13]1[S:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)S1
Reactant: O=c1c(O)c(O)c1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)S1
Temperature: 90 °C

Procedure:
This Example illustrates the preparation, by a reaction analogous to D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-thiopyrylidene grouping and R1 is ahydrogen atom. 3-[2,6-Bis(1,1-dimethylethyl)-(4H-thiopyran-4-ylidene)methyl]-2,4,4-trichlorocyclobut-2-en-1-one (279 mg, 0.59 mmole, prepared in Example 51 above) was added to a solution of trifluoromethane sulfonic acid (1.0 mL) in water (35 mg). The colorless reaction mixture was stirred under nitrogen with heating to 90° C. for 5 hours, after which it was cooled to 20° C. and stirred for 12 hours at that temperature. The reaction mixture was quenched into ice/water (15 mL) dropwise, with efficient agitation. A brown precipitate formed which was initially crystalline, but become gummy after standing for several minutes. This was separated by filtration, washed with dilute aqueous sodium sulfate, and separated into two portions. One portion was dried, to give a red-brown amorphous solid (110 mg). The second portion was partly purified by flash chromatography on silica gel with 10-16-20 % methanol/dichloromethane as eluent to yield a still impure product (55 mg, exhibiting, inter alia, mle 363 in the mass spectrum), which was used directly in Example 70 without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Cl:1][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=1)[C:9]([NH2:17])=[O:16]
Reactant: NC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: NC(=O)c1cccc(Cl)c1

Procedure:
N-Chlorosuccinimide (2.4 parts) is added to a solution of the primary benzamide (from method D or E) in dry acetonitrile, and the mixture is refluxed for 1 hour. This is partitioned between ether and aqueous Na2S2O3 and the organic layer is washed with 10% NaOH followed with brine, dried (MgSO4), filtered through silica gel, and concentrated to give the crude 5-chlorobenzamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([CH3:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: N#Cc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: CO[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][N:4]=1.[Cl-:20].[NH4+:21]>CO>[ClH:20].[NH2:21][C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][N:4]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NCCCC1N1C(=O)c2ccccc2C1=O
Solvent: CO
Product: Cl
Product: NC1=NCCCC1N1C(=O)c2ccccc2C1=O
Yield: 94.6 %

Procedure:
To a solution of 23.224 g (89.92 mmol) of (+/−)2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione dissolved in 409 mL of methanol was added at room temperature 4.81 g (89.92 mmol) of ammonium chloride. The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The residue was triturated with diethyl ether and filtered to afford 23.8 g (95%) of the pure product as a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(-c2nc(N)nnc2Br)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1cccc(-c2nc(N)nnc2-c2cccc(Cl)c2)c1
Yield: 9.6 %

Procedure:
6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (18 mg 9%) was prepared from 6-bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.18 g, 0.60 mmol) and 3-chlorophenylboronic acid (0.10 g, 0.60 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:9]([OH:20])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]1[C:9]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OC)c(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (634 Π, 0.008 mol) was added dropwise to an ice-cooled solution of methyl 3,4-dimethoxy-2-hydroxybenzoate (1.58 g, 0.0075 mol) and triethylamine (1.27 ml, 0.009 mol) in dichloromethane (30 ml) and the reaction then allowed to warm to room temperature, with stirring. The reaction mixture was washed with water (2×25 ml) and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of diethyl ether:hexane (60:40 to 100:0, v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.94 g, 90%). MS m/z 308 (MNH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:40])[CH:10]([N:19]2[C:23](=[O:24])[CH:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34]C(C)(C)C)=[CH:27][CH:26]=3)[NH:21][C:20]2=[O:39])[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:4]([Cl:41])[CH:3]=1.C(#N)C.C[Si](Cl)(C)C.[I-].[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:40])[CH:10]([N:19]2[C:23](=[O:24])[CH:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][OH:34])=[CH:29][CH:30]=3)[NH:21][C:20]2=[O:39])[CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[C:4]([Cl:41])[CH:3]=1
Reactant: CC(c1ccccc1)C(C(=O)Nc1ccc(Br)cc1Cl)N1C(=O)NC(c2ccc(OCCOC(C)(C)C)cc2)C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1ccccc1)C(C(=O)Nc1ccc(Br)cc1Cl)N1C(=O)NC(c2ccc(OCCO)cc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
N-(4-Bromo-2-chloro-phenyl)-2-{4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (300 mg) was dissolved in dichloromethane (2 mL) and acetonitrile (2 mL) in an ice bath. Trimethylsilyl chloride (0.36 mL, 2.8 mmol) was added followed by sodium iodide (352 mg, 2.35 mmol). The mixture was stirred at 0° C. for 1.5 hours and then diluted with ethyl acetate. The mixture was washed with aqueous sodium bisulfite, washed with brine, dried over sodium sulfate and concentrated in vacuo. Trituration of the residue with hexanes gave N-(4-bromo-2-chloro-phenyl)-2-{4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (210 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:15]1[C:20](=O)[N:19](Br)C(=O)C1.[C:23](Cl)(Cl)(Cl)Cl>>[CH3:23][CH:20]([N:19]1[CH2:1][C:2]2[C:3](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[C:4]1=[O:6])[CH3:15]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Product: CC(C)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 5.9 grams (0.030 mole) of methyl 2-methyl-3-nitrobenzoate and 5.3 grams (0.030 mole) of NBS in 120 mL of carbon tetrachloride was exposed to uv light for about 18 hours. The reaction mixture was cooled and filtered to remove a solid material. The filtrate was concentrated under reduced pressure to a residue. The residue was the intermediate methyl 2-bromomethyl-3-nitrobenzoate, as determined by NMR analysis. The intermediate 2-bromomethyl compound was slowly added to 60 mL of diethyl ether, and the resulting solution was in turn added dropwise to 40 mL of stirred 1-methylethylamine at 25° C. Upon completion of addition, the reaction mixture was stirred at 25° C. for about 18 hours. The reaction mixture was then concentrated under reduced pressure to remove excess 1-methylethylamine. The resultant solid was washed with aqueous dilute hydrochloric acid and dried, yielding 6.0 grams of subject compound, mp 150-152 C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=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.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][O:86][CH2:87][CH2:88][O:89][CH2:90][CH2:91][OH:92]>O1CCCC1>[OH:92][CH2:91][CH2:90][O:89][CH2:88][CH2:87][O:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: NCCOCCOCCOCCO
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC(=O)NCCOCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethanol (43.0 mg, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with 0-10% methanol in ethyl acetate over 20 min gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-methyl ester as an off-white solid (20 mg, 10% yield). LCMS (ES+) m/z calcd. for C41H48Cl2F2N4O9 [(M+H)+]: 849. found: 849.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.CO>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:24][C:23]#[CH:22])[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Reaction time: 5 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (800 mg, 2.6 mmol) in acetone (20 ml) was added propargyl bromide (80% solution, 0.290 ml, 2.6 mmol) and potassium carbonate (720 mg, 5.2 mmol). The solution was heated to reflux and stirred for 5 hours. Thin layer chromatography (10:1 dichloromethane:methanol) showed formation of product. The solution was cooled and filtered. The filtrate was concentrated and purified by preparative chromatography (dichloromethane:methanol) to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (M+1=346.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]1([S:15][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Brc1cccc(Sc2ccccc2)c1
Yield: 90.5 %

Procedure:
The general procedure in example 39 was followed. 3-bromoiodobenzene (283 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 μL) were used to obtain the 3-bromophenyl phenyl sulfide (240 mg, 91% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.6 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.11-7.22 (m, 2 H), 7.28-7.40 (m, 7 H). 13C NMR (CDCl3, 75 MHz) δ 139.2, 134.1, 132.5, 132.4, 130.6, 129.8, 129.7, 128.6, 128.2, 123.2. MS (EI) m/z (relative intensity) 266 (40), 264 (40).