Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: C=Cc1ccc(N)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A cooled solution of 2-Fluoro-4-vinylaniline (20-1, 0.96 g, 7 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.644 mL, 8.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant to afford N-(2-Fluoro-4-vinylphenyl)methanesulfonamide (20-2, LJO-325, 1.372 g, 91%) as a white solid.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O>ClCCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2cncc(Br)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium triacetoxyl-borohydride (245 mg, 1.16 mmol) was added to the solution of 5-bromo-pyridine-3-amine(100 mg, 0.57 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mmol) in 10 ml of 1,2-dicloroethtane (DCE), of HOAc (66 μL, 2eq. 1.16 mmol) was added, the mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water, and dried over sodium sulfate. The solvent was removed by under reduced pressure to give 200 mg of crude 5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]1)=[O:41])[CH3:38].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:16]=[CH:17][C:2]([O:1][CH:45]2[CH2:46][CH2:47][CH:42]([C:40]([O:39][CH2:37][CH3:38])=[O:41])[CH2:43][CH2:44]2)=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a solution of benzyl 4-hydroxybenzoate (50 g, 0.22 mol) and triphenylphosphine (63.2 g, 0.241 mol) dissolved in THF (800 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (35.3 mL, 0.22 mol). The reaction mixture was cooled on an ice bath and DEAD (38 ml, 0.241 mol) was added dropwise maintaining the temperature at 0° C. The resulting mixture was allowed slowly to reach room temperature and stirred for 16 hrs. at this temperature. The volume was reduced to app. 250 mL by evaporation and to the resulting mixture was added water (500 mL) followed by extraction with DCM (3×400 mL). The combined organic phases were washed with brine (400 mL), dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Crude product ˜80 g was purified on column chromatography (Flash 75) using first heptane (7.5 L) followed by a mixture of EtOAc-heptane (1:10) (5 L) and finally a mixture of EtOAc-heptane (1:6) (8 L). Combined fractions were evaporated in vacuo affording 18.1 g (22%) of 4-(4-ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]([C:23]1[N:24]=[CH:25][N:26]2[CH:30]=[CH:29][S:28][C:27]=12)=[O:22]>>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([CH:21]([OH:22])[C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[CH:29][S:28][C:27]=23)[CH:3]=[N:4][CH:5]=1
Reactant: O=Cc1ncn2ccsc12
Reactant: CSc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CSc1cncc(C(O)c2ncn3ccsc23)c1
Yield: 64 %

Procedure:
7-[(5-Methylthiopyridin-3-yl)hydroxymethyl]imidazo-[5,1-b]thiazole (119 mg) was prepared in substantially the same manner as in step a) of Synthesis Example 5, except that 204 mg of 3-bromo-5-methylthiopyridine, 0.656 ml of a 1.6 N n-butyllithium/n-hexane solution, and 102 mg of 7-formylimidazo[5,1-b]thiazole were used as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=1>CC(O)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([NH2:1])[CH:3]=2)=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: NNC(=O)c1ccc(O)c(N)c1
Reactant: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=O
Solvent: CC(C)O
Product: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=NNC(=O)c1ccc(O)c(N)c1
Yield: 47.8 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×4 ml) and dried by suction to afford 66 mg (48%) of the title compound as a solid. M.p.: 162-164° C.
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:18][CH2:17]2)=[N:12][CH:11]=1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a mixture of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt (141.6 mg, 0.38 mmol) and (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (150 mg, 0.38 mmol) in dioxane (10 mL) was added diisopropylethylamine (1 mL), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (230 mg, 95%) as a yellowish solid. (MS (ES+) C31H37N11O4 requires: 627, found: 573 [M-56+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
To a solution of 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.13 g, 0.53 mmol) and 3-chlorophenylboronic acid (0.42 g, 2.66 mmol) in methylene chloride (5 mL) was added triethylamine (0.4 mL, 2.87 mmol), and copper (II) acetate (0.19 g, 1.06 mmol) and stirred at room temperature for 2 days. The reaction was partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer washed with sodium bicarbonate solution (sat.), dried over magnesium sulfate, and concentrated. Flash silica gel column separation with 25% ethyl acetate/hexane followed by trituration with an ether/methylene chloride/hexane mixture gave the title compound as a white solid (0.08 g, 43%). 1H NMR (DMSO-d6): δ 8.32 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.13 (dd, J=8.6, 2.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.91 (m, 2H), 6.87 (dd, J=7.6, 1.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 3.27 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.3 Hz, 6H). MS (ESI) m/z 345/347 ([M+H]+); MS (ESI) m/z 343/345 ([M−H]−); Anal. calcd for C19H21ClN2O2: C, 66.18; H, 6.14; N, 8.12. Found: C, 65.70; H, 6.01; N, 7.90.
Reaction SMILES: [Si]([O:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@H:10]1[CH3:26])(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@@H:10]([CH3:26])[C@@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of 4-[(6S,7S)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-chlorobenzonitrile (89.0 mg) in a mixed solvent of THF (6 mL) and methanol (6 mL) was added 6 mol/L hydrochloric acid (4.0 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 48.7 mg, 66%).
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].CN([CH:28]=[O:29])C>C1COCC1>[F:14][C:15]1[C:23]([CH:28]=[O:29])=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(C(=O)O)c1F
Temperature: -75 °C
Yield: 11 %

Procedure:
A solution of TMEDA (10.5 mL, 70 mmol) in THF (50 mL) was cooled to <−80° C. and treated with sec-butyllithium (50 mL, 70 mmol). A solution of 2,4-difluorobenzoic acid (5.0 g, 31.6 mmol) in THF was added dropwise maintaining the temperature below −80° C. The reaction mixture was allowed to warm to −75° C. and treated with DMF (15 mL), the mixture then allowed to warm to 0° C. before quenching the reaction with water. The aqueous layer was separated, acidified to pH ˜2 (concentrated HCl) and extracted twice with diethyl ether. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil. The crude product was crystallized from cyclohexane/diethyl ether to give the title compound as a yellow solid (670 mg, 11%). 1H NMR (CDCl3, 400 MHz) 10.40 (1 H, s), 8.31 (1 H, ddd, J=8.96, 8.02, 6.08 Hz), 7.12 (1 H, td, J=9.09, 1.42 Hz).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13])=[O:7].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>O1CCCC1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[S:33])[NH:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=2)[CH:10]=1
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Product: O=C(NNC(=S)Nc1ccccc1Cl)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 200 mg (0.62 mmol) of 3-(3-trifluoromethylbenzamido)benzhydrazide in 2.5 mL of tetrahydrofuran was added 157 mg (121 μL, 0.93 mmol) of 2-chlorophenyl isothiocyanate. The reaction was stirred at room temperature overnight. After concentration by rotoevaporation, the residue was purified by preparative HPLC to give 219 mg (0.44 mmol, 72% yield) of 4-(2-chlorophenyl)-1-[3-(3-trifluoromethylbenzamido)-benzoyl]thiosemicarbazide. 1H NMR (CDCl3): δ7.28 (d of t, 1H), 7.36 (d of t, 1H), 7.49 (d of d, 1H), 7.55 (t, 1H), 7.69 (d, 2H), 7.74 (t, 1H), 7.94 (d of t, 2H), 8.21 (d, 1H), 8.27 (s, 1H), 8.36 (s, 1H), and 9.09 ppm (s, 1H). MS m/z: 493.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH:8]([CH3:10])[CH3:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:11][C:12]1[N:17]=[C:16]([S:18][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH:8]([CH3:10])[CH3:9])[N:15]=[C:14]([OH:19])[CH:13]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)c1ncsc1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2scnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole (5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (510 mg, 3.6 mmol), and triethylamine (2.2 mL, 15.8 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL). The solid material was dried in vacuo, affording the title compound (565 mg, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6.8 Hz), 2.24 (s, 3H), 3.27 (m, 1H), 4.61 (s, 2H), 6.03 (s, 1H), 8.84 (s, 1H); M+ 282.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2B(O)O)[CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[N:18]=[CH:19][CH:20]=[CH:21]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: OB(O)c1cccc2cccnc12
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1cccc2cccnc12

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 8-quinoline boronic acid. Yield 0.356 g
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)c2ccccc2)c(O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen was reacted with 16 g. of sodium methoxide and then with 14 g. of benzoyl chloride. The product was isolated as the free base, 3-hydroxy-4-(benzoyloxy)phenyl tert-butylaminomethyl ketone [20 g.; m.p 150°-165° C. (dec.) (uncorr.)], which was converted to 13 g. of its methanesulfonate, m.p. 245° C. (dec.)(uncorr.). By catalytically hydrogenating this salt, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2ccccc2OC)cc1
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 2-methoxyaniline (3.0 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 5.3 g (44%) of the product as a tan-colored oil: 1H-NMR (CDCl3) δ 7.70-7.67 (d, 2H), 7.53-7.50 (d, 1H), 7.05-6.99 (m, 2H), 6.91-6.83 (m, 3H), 6.73 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
p-dihydroxybenzene 12.1 g (0.11 mol), anhydrous potassium carbonate 15.2 g (0.11 mol) were added to 500 mL of three-necked flask with DMF (200 mL) in sequence, the reaction mixture was then heated to 60° C., forming pale yellow turbid liquid, a solution of 2-chloro-5-(trifluoromethyl)pyridine 18.2 g (0.1 mol) in DMF (50 mL) was added dropwise to the above solution, after completion of addition for 15 min, then the mixture was heated to 90° C. and stirred for another 4 hours at this temperature. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was cooled to room temperature, then poured into water (300 mL) and extracted with ethyl acetate (2×300 mL). The organic phases were combined, washed with brine (2×200 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified via silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1:8) to give the product (19.1 g) as a white solid in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][S:42]([CH3:41])(=[O:44])=[O:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1nc(NCCNS(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 157 (250 mg, 0.58 mmol), di-isopropylethylamine (111 uL, 0.64 mmol) and CH2Cl2 (10 mL) was cooled to −5° and methanesulfonyl chloride (50 uL, 0.64 mmol) was added and the resulting soln was warmed to 23°, stirred 15 min, diluted with CH2Cl2 (75 mL) and washed with 10% aq NaOH (2×20 mL) and satd aq NaCl, dried (Na2SO4), and concentrated to afford a brown solid. Chromatotron chromatography (CH2Cl2/CH3OH) and crystallization from Et2O afforded a pink solid. mp=105-115° (dec); LC MS (m/e)=504.2 (MH+). Rt=1.94 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Cl[C:9]1[N:14]=[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])[CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>O>[CH:20]([C@H:19]1[CH2:18][O:17][C:16](=[O:23])[N:15]1[C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[N:14]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](C)Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1
Temperature: 110 °C
Yield: 46.8 %

Procedure:
To a solution of (S)-methyl 2-aminopropanoate (270 mg, 2.0 mmol, 1.2 equv. in 10 ml of DMSO) and (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (430 mg, 1.8 mmol, 1.0 equv.) was added DIPEA (805 mg, 6.23 mmol, 3.5 equiv), and the reaction mixture was heated at 110° C. for 120 min. The reaction mixture was poured into water (40 ml) and extracted with EtOAc (2×30 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (ethyl acetate in heptane 10 to 80%) to provide (S)-methyl 2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate (260 mg, white solid) in 47.4% yield. LCMS m/z 309.1 (M+H)+ RT=1.53 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:4][CH:3]=1.CC(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[OH:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OC(c1ccc(Cl)cc1)c1ccccc1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred and refluxing mixture of 23.4 parts of (4-chlorophenyl) (2-fluorophenyl)methanone in 280 parts of 2-propanol are added portionwise 3.7 parts of sodium borohydride. Upon completion, stirring is continued for 2 hours at reflux temperature (±80° C.). The reaction mixture is cooled and decomposed by the addition of water. The 2-propanol is evaporated and the residual product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 4-chloro-α-(2-fluorophenyl)benzenemethanol as a residue.