Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:25]=1[O:26][C@@H:27]([CH3:31])[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:25]=1[O:26][C@@H:27]([CH3:31])[C:28]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)[C:2](=[O:1])[CH2:7]1)=[O:29]
Reactant: C[C@H](Oc1cccc(Cl)c1Cl)C(=O)O
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: C[C@H](Oc1cccc(Cl)c1Cl)C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), (S)-2-(2,3-dichlorophenoxy)propanoic acid (23 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=555.3; tR=2.85 min.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])C)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C@H:10]([OH:11])[CH2:9][NH:7][CH3:6])=[CH:17][CH:16]=1
Reactant: CN(C[C@@H](O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of (2S)-[2-(4-fluorophenyl)-2-hydroxyethyl]methylcarbamic acid t-butyl ester (1.25 g) in ethyl acetate was added dropwise a solution of 4N hydrochloric acid-ethyl acetate (40 mL). The solution was allowed to stand at room temperature for 1 hour. After removing the solvent by evaporation, the solution was alkalinized by addition of an aqueous solution of 5N sodium hydroxide, and saturated with sodium chloride. The solution was extracted with dichloromethane, then washed with saturated sodium chloride water. After drying with anhydrous sodium sulfate, the solvent was removed by evaporation. The resulting solid in a mixed solvent of diethyl ether-hexane was collected by filtration, and the title compound (480 mg) was obtained as a colorless solid. The NMR data matched the racemic mixture described in Preparation Example 17.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=[N:13][O:14][CH3:15])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[Cl:16]>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:11]([CH:12]=[N:13][O:14][CH3:15])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:16]
Reactant: CON=Cc1cc(C(=O)OC)cc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=Cc1cc(C(=O)O)cc(Cl)c1N

Procedure:
The methyl 4-amino-3-chloro-5-methoxyiminomethylbenzoate made in the previous step was dissolved in a mixture of 25 ml of methanol and 8 g ml of 10% of aqueous sodium hydroxide and the solution was then was refluxed for 2 hours. The methanol was removed using a rotary evaporator and the residue was partitioned between 25 ml of water and 25 ml of methylene chloride. To the cooled aqueous layer was added 6N aqueous hydrochloric acid, dropwise, with stirring, until the pH of mixture reached a value of 1. The resulting solid was filtered and dried yielding 1.4 g 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][OH:5].F[C:7]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>CN(C=O)C>[CH2:4]([O:5][C:7]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH3:3]
Reactant: N#Cc1cccc(F)c1F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
NaH 60% dispersion in mineral oil (575 mg, 14.4 mmol) was added to a rt solution of EtOH (1.0 mL, 17.1 mmol) in DMF (6.0 mL). After stirring for 40 min at rt, the solution was cooled to 0° C., 2,3-difluorobenzonitrile (1.59 mL, 14.4 mmol) was added dropwise and stirring was continued for 1 h at rt. The rxn mixture was quenched with water and extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield 2-ethoxy-3-fluorobenzonitrile as an orange oil. LC-MS B: tR=0.74 min; [M+H]++=no ionization. 1H NMR (CDCl3) δH: 7.66 (m, 2H), 7.27 (m, 1H), 4.32 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:12]4[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(=O)[nH]c34)cc2F)cc1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to give the title compound as a white solid. Yield: 33 mg (44%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]=1[CH2:25][N:26](C)[C:27](OCC1C=CC=CC=1)=O)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:11]([CH3:23])[CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:24])=[CH:6][C:5]=1[CH2:25][NH:26][CH3:27]
Reactant: CN(Cc1cc(C(=O)N(C)Cc2cc3ccccc3n2C)ccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc(C(=O)N(C)Cc2cc3ccccc3n2C)ccc1N
Reaction time: 6 h
Yield: 82.8 %

Procedure:
To a solution of N-[(2-nitro-5-{N-methyl-N-[(1-methylindol-2-yl)methyl]carbamoyl}phenyl)methyl]-N-methyl(phenylmethoxy)carboxamide (6.1 g, 12.2 mmole) in CH3OH (50 mL) contained in a Parr hydrogenation flask was added a 0.75 g of 10% Pd/C. The contents were shaken on a Parr shaker under H2 (50 psi) for 6 hours. The suspension was filtered through celite and concentrated under vacuum. Purification on silica [CHCl3/CH3OH (containing 5% NH4OH), 9:1] afforded the title compound (3.40 g, 83%) as a viscous yellow oil: MS (ES) m/e 337 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:1][CH2:2][CH2:3][C:4]2[CH:16]=[C:15]3[N:6]([C:7](=[O:17])[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=43)[N:5]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c2ccccc2c2cc(CCO)nn12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cc3c4ccccc4[nH]c(=O)n3n2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
12.0 g (0.052 mole) of 2-(2-hydroxyethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one is taken up in pyridine (120 ml), cooled down to 0° and treated with 11.0 g (0.058 mole or 1.1 equivalent) of 98% tosyl chloride. The mixture is stirred for 4 hours, keeping the temperature below 20° during the reaction period, after which it is poured onto 1.8 l. of ice-water and stirred until solids form. The off-white precipitates are filtered off and dried in vacuo at 100° for 3 hours. Yield: 17.43 g, m.p. 194°-196°; 87.4% crude yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 2-ethylamino-ethanol were converted to yield 2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as yellowish oil, MS: 452 (MH+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:41])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:40])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[F:40][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:39])(=[O:38])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.39 mmol) was added to a stirred solution of {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.038 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-phenyl-sulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.031 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 10.56 (br. s, 1 H), 7.99 (dd, J=9.00, 6.40 Hz, 1 H), 7.90 (m, J=8.30 Hz, 2 H), 7.88 (s, 1 H), 7.42 (m, J=8.30 Hz, 2 H), 7.37 (td, J=8.80, 2.40 Hz, 1 H), 7.21-7.31 (m, 4 H), 6.49 (dd, J=11.00, 2.60 Hz, 1 H), 3.82 (s, 2 H), 1.99 (s, 3 H). MS calcd. for C26H18F4NO5S [(M−H)−] 532, obsd. 532.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[OH:23].Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCCO)C>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:6]1[C:5]2[CH:4]=[C:3]3[O:23][CH2:25][CH2:26][NH:1][C:2]3=[CH:11][C:10]=2[N:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cc(N)c(O)cc2c1Nc1ccc(Cl)cc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Cl)cc1Cl)OCCN3
Temperature: 150 °C
Yield: 14.7 %

Procedure:
An amount of 1100 mg (3.2 mmol) of 7-amino-4-(2,4-dichloroanilino)-6-hydroxy-3-quinolinecarbonitrile was stirred in 2-ethoxyethanol (250 mL), and to this were added 1,2-dibromoethane (6.5 g, 34 mmol), and potassium carbonate (2.7 g, 19.2 mmol). The mixture was heated at 150° C. for 0.5 hours, cooled to room temperature, and filtered through a Magnesol pad. The filtrate was evaporated to a brown oil, taken up in ethyl acetate and basified with saturated sodium bicarbonate solution. After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate, and evaporated to a brown oil. Purification was carried out by flash chromatography (ethyl acetate), to give a yellow solid (175 mg, 15% yield), mp 254-255° C.; 1H NMR (DMSO-d6) δ 9.20 (s, 1H), 8.25 (s, 1H), 7.70 (dd, 2H), 7.41 (dd, 2H), 7.14 (s, 1H), 6.92 (s, 1H), 4.23 (t, 2H), 3.43 (t, 2H); I-IRMS (EI) m/z 371.04502 (M+1). Analysis for C18H12Cl2N4O.0.1CH3CO2C2H5: Found: C, 58.03; H, 3.45; N, 14.49. Calcd: C, 58.10; H, 3.37; N, 14.74.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:10]=2[CH:11]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc2c(cc1F)C(=O)CCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1F)C(N1CCOCC1)=CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a mixture of methyl 3fluoro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.155 g, 0.698 mmol) and morpholine (0.304 mL, 3.49 mmol) in toluene (5.0 mL) at 0° C. was added titanium(IV) chloride (1M in toluene) (0.384 mL, 0.384 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature for 16 hours. The heterogeneous, orange reaction mixture was filtered under reduced pressure through a pad of Celite which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give methyl 3fluoro-5-morpholino-7,8-dihydronaphthalene-2-carboxylate (0.122 g, 0.419 mmol, 60.0% yield). The product had an LC/MS M+1=292.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.O>CO>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (700 g, 2.1 mol) in methanol (14 L) was added Quinidine (617 g, 1.90 mol). The mixture was stirred at 90° C. under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for 0.5 hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6%.
Reaction SMILES: [Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12]O)=[C:8]([Cl:17])[CH:7]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12][Br:20])=[C:8]([Cl:17])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A stirred solution of 2.5 grams (0.0075 mole) of 2-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]ethan-1-ol and 3.1 grams (0.0094 mole) of carbon tetrabromide in 150 mL of methylene chloride was cooled to 0-4° C. and 6.0 grams (0.0152 mole) of triphenylphosphine was added portion-wise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:5 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[OH-].[Na+].Cl>ClCCl.C1COCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:16])=[CH:3][CH:4]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)C1CCCCC1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 4-aminophenol (5.00 g, 45.8 mmol) in dichloromethane (50 ml) were added cyclohexanecarbonyl chloride (6.72 g, 45.8 mmol) and pyridine (3.70 ml, 45.8 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. Water (100 ml) was added, the organic phase was removed and the resulting solution was extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with water (2×200 ml), dried, filtered and evaporated, yielding an off-white solid. The crude product was purified by flash column chromatography (SiO2, ethyl acetate/heptane (40:60)), yielding a mixture of two compounds, which were dissolved in THF. 6N NaOH (aq, 32 ml) was added and the mixture was stirred at room temperature for 2.5 h. The solution was acidified with concentrated hydrochloric acid and the organic solvent was removed by evaporation. The solid material was collected by filtration, dried and recrystallised from ethyl acetate/heptane, yielding the title compound (4.20 g, 41%, off-white solid).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([OH:13])=[O:12].C(Cl)Cl.[C:17]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:17]([S:25][CH2:26][CH:27]([CH3:31])[C:28]([N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([OH:13])=[O:12])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 5.0 g of indoline-2-carboxylic acid hydrochloride and 50 ml of methylene chloride are added 7.9 g of triethylamine, and after 5 minutes 6.1 g of 3-benzoylthio-2-methylpropanoyl chloride during 3 minutes. After stirring the mixture at room temperature for 2 hours, it is extracted thrice with 50 ml of saturated aqueous sodium bicarbonate. The combined aqueous solutions are adjusted to pH=1 with 4N hydrochloric acid and reextracted thrice with 50 ml of methylene chloride. The combined extracts are dried and evaporated, to yield the 1-(3-benzoylthio-2-methylpropanoyl)-indoline-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][C:54]([F:58])([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 80 mg, 0.106 mmol) in THF (5 mL) was added 3,3-difluoroazetidine hydrochloride (41.1 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (72 mg, 88% yield). LCMS (M+H)+: 770.1. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.82 (d, 9.0 Hz, 1H), 5.50 (m, 1H), 4.75 (m, 1H), 4.58-4.34 (m, 4H), 4.09 (m, 1H), 3.75 (s, 3H), 1.33 (s, 9H), 0.81 (d, 7.0 Hz, 3H). RTA IC50: 800 nM.
Reaction SMILES: [Mg].BrC(Br)C.[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][CH2:10]Br.Cl[SiH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]>O1CCCC1>[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][CH2:10][SiH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: COC(CCBr)OC
Reactant: CC(C)=C[SiH2]Cl
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(CC[SiH2]C=C(C)C)OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirring magnesium granules (365 mg) in anhydrous tetrahydrofuran (15 mL), few drops of dibromoethane (˜50 μL) was added at room temperature under argon and the resultant mixture was stirred for 10 min. The reaction mixture was cooled to 10° C. and 3-bromopropionaldehyde dimethyl acetal (2.2 g) was introduced dropwise during 10 min. and allowed to stir at room temperature for 2 hours. After the completion of the Grignard formation, the reaction mixture was cooled to 0° C. and chlorodimethylvinylsilane (1.2 g) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL) at 0° C. and the organics were extracted with t-butyl methyl ether (2×20 mL). The combined organic layers were dried and concentrated under reduced pressure to obtain the crude product. The pure product was obtained upon vacuum distillation of the crude material at 100° C. (2 mm Hg) in 80% yield (1.5 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C(#N)C>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=2)=[O:4])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g, 4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) was added TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture was poured onto aq. citric acid and EA then stirred for 10 min before the solid was collected by filtration. The cake was washed with water and iso-hexanes then dried to provide 905 mg (57%) of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z) calculated for C22H25BrO4: 432.1. found 433.2 [M+H]+, tR=3.24 min (Method 8).