Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[O:9][C:8]=2[C:25]=1[CH:26]=[C:27]([N+]([O-])=O)[CH2:28][CH3:29])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([O:14][CH2:13][CH:10]2[O:9][C:8]3=[C:25]4[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11]2)[NH:1][C:27]([CH2:28][CH3:29])=[CH:26]4)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: CCC(=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2)[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
0.70 g (1.5 mmole) of toluene-4-sulfonic acid (2R)-7-nitro-8-(2-nitro-but-1-enyl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester was dissolved in 100 mL of ethyl acetate and 0.10 g of platinum oxide added. The mixture was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 5 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with 1:1 ethyl acetate/hexane to give 0.52 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.3 δ (2H); doublet 6.76 δ (1H); doublet 6.64 δ (1H); singlet 6.16 δ (1H); multiplet 4.5 δ (1H); multiplet 4.3 δ (3H); quartet 4.1 δ (1H); quartet 2.75 δ (2H); singlet 2.5 δ (3H); triplet 1.3 δ (3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23]>C1COCC1>[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)COC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid which is used without purification; [M+H]+ 342.00
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[C:22]([Cl:27])[C:21]([Cl:28])=[C:20]([Cl:29])[C:19]=1[Cl:30]>O1CCOCC1>[Cl:17][C:18]1[C:23]([C:24]([N:8]2[C:9](=[O:10])[C:4]3=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]3[C:6]2=[O:7])=[O:25])=[C:22]([Cl:27])[C:21]([Cl:28])=[C:20]([Cl:29])[C:19]=1[Cl:30]
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentachlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(pentachlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>>[CH3:14][CH:13]([CH3:15])[CH2:12][N:16]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: CC(C)CN
Product: CC(C)Cn1sc2ccccc2c1=O

Procedure:
This was prepared by the process described in Example 17 except using 2-chlorosulphenylbenzoyl chloride (4.14 parts, 0.02M) and isobutylamine (7.95 parts, 0.08M). The product (4 parts, 97% theory) was obtained as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C.O1CCOCC1>[ClH:32].[ClH:32].[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Fc1ccccc1-c1nc(NC2CCNCC2)nc2ccccc12

Procedure:
A solution of 4-[4-(2-fluoro-phenyl)-quinazolin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 2.04 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 322.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH:22]([CH3:26])[C:23]([NH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])=[O:24]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)C(=O)NCCc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
A solution of 2,4-dichlorophenethylamine (1.0 g, 5.3 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.82 g, 6.3 mmol) and 2-chloropropionylchloride (0.67 mL, 5.3 mmol) sequentially, and stirred at 20° C. for 4 hours. The mixture was diluted with dichloromethane (50 mL), washed with 10% aqueous HCl, brine (20 mL), dried with Na2SO4 and concentrated, resulting in 1.5 g of the desired product as a brown oil. MS calculated for C11H12Cl3NO+H: 280, observed: 280.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([Zn]CC)[CH3:13]>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1)[CH3:13]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCc1cncc(C(=O)OC)c1
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of methyl 5-bromopyridine-3-carboxylate (10.0 g, 46.29 mmol) in anhydrous dioxane (100 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (677 mg, 0.925 mmol). Then, diethylzinc (5.71 g, 38 mL, 46.29 mmol, 15% solution in toluene) was added dropwise. The reaction mixture was heated at 70° C. for 45 minutes, then cooled to room temperature and quenched with MeOH. The mixture was extracted with ethyl acetate (2×250 mL) and washed with water, 0.1 N HCl, and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate and hexane to provide methyl 5-ethylpyridine-3-carboxylate as a yellow oil (4.20 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1. (t, 3H), 1.45 (t, 3H), 2.78 (q, 2H), 3.99 (s, 3H), 8.15 (s, 1H), 8.65 (s, 1H), 8.89 (s, 1H); M+ 165.1.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[N:7](C)[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].P([O-])(OC)O[CH3:17].CS(O)(=O)=O>>[F:1][CH:2]([F:14])[C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:6]([CH3:17])[N:7]=1
Reactant: CCOC(=O)c1cnn(C)c1C(F)F
Reactant: COP([O-])OC
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 170 °C
Reaction time: 7 h
Yield: 69.1 %

Procedure:
To 20.4 g of ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) was added 11.3 g of dimethyl phosphite and 0.82 g of methane sulfonic acid. The mixture was heated to 170° C. and stirred for 7 hours. The solution was cooled and distilled to recover recycled trimethyl phosphate and 0.9 g of starting ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE). The remaining solution was added to 50 g of cold water. The solution was allowed to stir for 30 min. The precipitating solid was filtered and dried to give 14.1 g of product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[N:19](COCC[Si](C)(C)C)[C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12.C(OCC)(=O)C.Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[NH:19][C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3cccn4ccnc34)cc2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(Oc3ccc(-c4cccn5ccnc45)cc3)nc2c1
Yield: 76.6 %

Procedure:
A mixture of 2-[4-(imidazo[1,2-a]pyridin-8-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.53 g), 4 M hydrogen chloride-ethyl acetate solution (20 ml) and methanol (4 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.29 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](=[O:19])([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:9]([C:8]1[CH:11]=[C:16]([CH:13]=[CH:14][CH:7]=1)[O:19][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Yield: 188.6 %

Procedure:
m-Hydroxybenzaldehyde (12.2 g), N-(3-bromopropyl)phthalimide (26.8 g), anhydrous potassium carbonate (13.8 g) and potassium iodide (1.7 g) were suspended in acetonitrile (600 ml), and the suspension was heated under reflux for 18 hours. After cooling, the precipitate was removed, and the solvent was evaporated under reduced pressure. The residue was distributed between benzene and water. The organic layer was washed successively with a 1N aqueous NaOH solution, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 29.16 g (yield 94%) of N-[3-(3-formylphenoxy)propyl]phthalimide as crystals.
Reaction SMILES: C1CO[C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][C:7]([CH3:9])=[CH2:8])[O:2]1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:9][C:7]([CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH3:10])=[CH2:8]
Reactant: C=C(C)CCCC1(C)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)CCCC(C)=O
Yield: 70.8 %

Procedure:
A solution of 6,6-ethylenedioxy-2-methyl-hept-1-ene (12.2 g) in acetone (300 ml) and 10% hydrochloric acid (12 ml) is stirred at room temperature for 1.5 hours. The reaction is neutralized to pH 7 with a sodium bicarbonate solution and the resulting solids are filtered. The acetone is removed in vacuo and the residue is partitioned between ether and brine. The ether extract is dried (Na2SO4) and evaporated in vacuo to give 2-methyl-6-oxo-hept-1-ene as a pale yellow liquid (6.4 g), nmr (CDCl3,δ) 1.7 (br, s, CH3 --C=), 2.12 (s, CH3C=O), 2.4 (t, J=6 Hz, CH2C=O), 4.69 (br, s, 2H, H2C=C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26]C)[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[OH:26])[C:5]([N:7]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)c(F)c1)N(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
Compound 3-fluoro-N-(4-fluorophenyl)-4-methoxy-N-(4-methoxyphenyl) benzamide (2a′) (138.0 g, 0.374 mol) was dissolved in dry CH2Cl2 (600 mL) at room temperature under an argon. BBr3 (374.75 g, 1.496 mol) was added dropwise with stirring via a syringe at 0° C. in an ice-bath under an argon. The reaction solution was allowed to stir at room temperature overnight. Then, the solution was poured to 1 L of ice water with stifling. The slurry mixture was stirred at room temperature for 2 hours. The white precipitate was filtered, washed with water (2×100 mL) and dried under vacuum. The CH2Cl2 layer was separated, dried over anhydrous MgSO4 (50 g), filtered and concentrated under reduced pressure to dryness. The white precipitate and residue from CH2Cl2 solution were combined and purified by flash column chromatography (silica gel, CH2Cl2/Acetone/MeOH=90/7/3 v/v/v) to give a light tan solid which was recrystallized from hot EtOAc/Hexanes solution twice to afford a white crystalline solid, 104.0 g, 81.6% yield. M.p. 110-112° C. MS (ESI) m/z 364.1 [M+Na]+, 1H NMR (DMSO-d6) δ 10.14 (bs, 1H), 9.71 (bs, 1H), 7.25-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][OH:20])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][O:20][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 800 mg (2.88 mmol) 7-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7c) in 10 mL DCM is added at 0° C. subsequently 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM. The reaction mixture is warmed to RT and is stirred 5 h at RT. Additional 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM are added and the mixture is stirred over night. The reaction mixture is poured into ice-water and the organic phase is separated, washed with aqueous KHSO4-solution and aqueous NaHCO3-solution, dried over MgSO4. After evaporation of the solvent, the residue is purified via chromatography (silica gel; cyclohexane/EtOAc 8:2 to 1:1).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Br)c2)c(Cl)c1CC
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)c3ccc(F)cc3)c(Br)c2)c(Cl)c1CC
Yield: 89.2 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (70 mg) was coupled with p-fluorobenzoyl chloride (35 mg), using the method described in Example 1(h). After recrystallization (ethyl acetate/petrolium ether), 80 mg of ethyl(3,5-dichloro-4-[3-bromo-4-p-fluorobenzamidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 60 mg of 3,5-dichloro-4-(3-bromo-4-p-fluorobenzamidophenoxy)phenylpropionic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CCCCCCC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:33]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)nccc3c2)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ; 100 mg, 0.227 mmol), (5-chloro-2-methoxyphenyl)boronic acid (63.4 mg, 0.340 mmol), potassium carbonate (94 mg, 0.680 mmol), and pd(ph3p)4 (26.2 mg, 0.023 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (851 μl) and water (284 μl) were added. The vial was sealed and heated to 100° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-40% EtOAc/Heptane, then 70% EtOAc/Heptane) to give 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (91.2 mg, 0.167 mmol, 73.5% yield) as an off-white foam. m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of (5S)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 1010 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol, 1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h. When HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the (5S)-N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 1037 (18.8 g, 94%) as brown solids. This product was directly used in subsequent reactions without further purification. C18H24BFN2O5, HPLC/MS (ESI) m/e 379 (M++H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OC(C)C)=CC=3OC)N=2)=CC=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:46][C:47]([CH3:53])([CH3:52])[C:48]([CH3:50])([CH3:51])[O:49]5)[CH:42]=[N:41]4)[O:30][CH:31]([CH3:32])[CH3:60])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(O)OC(C)C)cc2OC)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CP(=O)(OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)OC(C)C)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 44A replacing Compound 38C with propan-2-yl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 72B). MS (ESI): m/z 867.90/869.91 [M+H]+. UPLC: tR=1.60 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (0.50 g, 1.476 mmol, Example #5, Step C) in DCM (10 mL) was added cyclohexanecarbonyl chloride (0.221 mL, 1.623 mmol) followed by DIEA (0.644 mL, 3.69 mmol). The reaction mixture was stirred for about 4 h at ambient temperature and then saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with 20-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.49 g, 80%) as a colorless solid: LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [C:1]1([C:11](=[O:23])[CH2:12][C:13](=[O:22])[CH2:14][C:15](=O)[C:16]([O:18]CC)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([C:11]2[O:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13](=[O:22])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(=O)cc(-c2cccc3ccccc23)o1

Procedure:
This crude ester was dissolved in dioxan (50 ml) and concentrated hydrochloric acid (50 ml), and the solution was heated under reflux for 11/2 hours then concentrated under vacuum to give a brown solid. The solid was recrystallised from ethanol and from ethanol-water to give the title product (mp 248°-249° C. with decomposition).