Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52](Cl)(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1>C(#N)C>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2[S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4cccnc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0297 g, 0.0643 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.386 mmol) and 8-quinolinesulfonyl chloride (0.0440 g, 0.193 mmol) to obtain 4-(8-quinolinesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0164 g, yield 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:19]=[C:20]([Cl:27])[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 360 mg of 6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-ol (1.07 mmol, 1 eq) in 5 mL of ACN was added 0.98 mL of POCl3 (10.7 mmol. 10 eq). The mixture was heated to 65° C. and stirred for 1 h. The solution was then diluted with EtOAc, washed with NaHCO3, dried on MgSO4, filtered and concentrated (210 mg, 55%) m/e+=355 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9].Br[CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[C:31]([CH:33]1[CH2:35][CH2:34]1)=[O:32].[ClH:43]>C(N(CC)CC)C>[ClH:43].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:31]([CH:33]2[CH2:34][CH2:35]2)=[O:32])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9]
Reactant: COC(=O)Cn1nncc1/C=C1\CNCCC1SC(C)=O
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Yield: 50 %

Procedure:
Following a procedure similar to that described in Example 150-(g), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}piperidine hydrogen trifluoroacetate (1.06 g) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone and triethylamine and the free base that was obtained by silica gel chromatography was similarly treated with hydrogen chloride to yield the title compound (650 mg, yield: 50%) as a pale yellow amorphous solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCSCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
To the compound (352 mg, 0.931 mmol) obtained in Example 179a were added ethanol (4 mL), tetrahydrofuran (1 mL) and 2N aqueous sodium hydroxide solution (0.93 mL, 1.86 mmol), and the mixture was stirred overnight. The reaction mixture was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (261 mg, 77%) as colorless crystals.
Reaction SMILES: FC(F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].CN(C)C=O.[Br:19][C:20]1[N:21]=[C:22]2[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]2=[N:24][C:25]=1[CH3:26]>ClCCl>[Br:19][C:20]1[N:21]=[C:22]2[C:29]([CH:3]=[O:4])=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:23]2=[N:24][C:25]=1[CH3:26]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1nc2c(ccn2COCC[Si](C)(C)C)nc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(nc1Br)c(C=O)cn2COCC[Si](C)(C)C
Yield: 84.8 %

Procedure:
Trifluoroacetic anhydride (10.2 mL, 60.8 mmol) was added dropwise, with cooling (ice bath), to N,N-dimethylformamide (24 mL) under an argon atmosphere. The cooling bath was removed for 15 min to facilitate stirring and then replaced. A solution of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (3.47 g, 10.1 mmol) in dichloromethane (5 mL) was added dropwise. The cooling bath was removed; the mixture was stirred for 15 min, then set in a bath at 45° C. and stirred for 16 h. The mixture was cooled, then poured onto ice water (200 mL) containing sodium carbonate (13 g) and extracted four times with ether. The combined ether extracts were washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on (silica, 20% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.17 g, 84%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 9H), 0.85 (t, J=8.0 Hz, 2H), 2.71 (s, 3H), 3.58 (t, J=8.0 Hz, 2H), 5.68 (s, 2H), 8.87 (s, 1H), 10.04 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([OH:32])=O)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH2:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([C:30]([NH:40][CH3:39])=[O:32])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COc1cccc(-c2c(C(=O)O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1sc2nc(C)cc(NS(=O)(=O)c3cccc(Cl)c3)c2c1-c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
In an dried round bottom flask was added 4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-2-carboxylic acid (50 mg, 0.102 mmol) (Example 35), DCM (1 mL), oxalyl chloride (0.013 mL, 0.153 mmol) and DMF (10 μL). The resulting mixture was stirred at RT for 10 min. Methylamine (2M in THF) (0.256 mL, 0.511 mmol) was then added dropwise and the mixture stirred at RT for 30 min. Aqueous NaHCO3 solution (25 mL) and DCM (25 mL) were then added and the organic layer separated. The aqueous was re-extracted with DCM (2×20 mL) and the combined organics washed with brine (30 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-10% MeOH in DCM was followed by further purification by chromatography on silica gel, eluting with a gradient of 20-50% ethyl acetate in DCM, to give the title compound (28 mg). LCMS (A) m/z: 502 [M+1]+, Rt 1.21 min (acidic), Rt 0.91 min (basic).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=4)[CH2:20][O:19][C:18]3=[O:30])=[N:13][C:12]=12)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:28][C:26]1[CH:25]=[N:24][C:23]2[O:29][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:7])[C:8]3=[C:12]4[N:13]=[C:14]([CH:15]=[CH:16][N:11]4[N:10]=[CH:9]3)[N:17]3[C@H:21]([CH2:20][O:19][C:18]3=[O:30])[C:22]=2[CH:27]=1
Reactant: O=C(NCCCCl)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCOc2ncc(F)cc2[C@H]2COC(=O)N2c2ccn3ncc1c3n2
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of (S)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (35 mg, 0.08 mmol) in DMF (3 mL) was added cesium carbonate (79 mg, 0.24 mmol). The mixture was stirred at 65° C. for 30 minutes then at ambient temperature for 48 hours. The mixture was treated with water (30 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography eluting with 2% MeOH/DCM to afford the title compound (13 mg, 41% yield) as an amorphous white solid. MS (apci) m/z=399.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH4-].[Na+]>C1COCC1.C(O)(C)(C)C>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a suspension of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) in THF:t-butanol (1:1) (10 mL) was added NaBH4 (0.46 g, 12.4 mmol). The reaction stirred at room temperature under argon overnight. The reaction mixture was quenched with acetic acid (2 mL) and the solvent was removed in vacuo. The residue was triturated with water and filtered. The solid was washed with fresh water followed by ethanol. The solid was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired compound (1.58 g, 44%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, 1H), 8.56 (s, 1H), 7.52 (m, 1H), 7.01 (m, 2H), 6.55 (m, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.71 (2H), 2.54 (s, 3H); ES-HRMS m/z 408.0940 (M+H calculated for C19H17N3O3ClF2 requires 408.0921).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[C:22](=[CH:14]/[C:13]2[O:16][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:11][CH:12]=2)/[C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Product: COc1ccc(/C(C#N)=C/c2ccc(-c3cccc([N+](=O)[O-])c3)o2)cc1OC
Yield: 98 %

Procedure:
5-(3-Nitrophenyl)furfural (1.09 g) was condensed with 3,4-dimethoxybenzyl cyanide (889 mg) through Method A (production step 2), to thereby yield the target product (yield: 1.85 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([SiH2:12][O:13][C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[C:22]([CH3:24])[CH:23]=[C:17]2[CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:23]1[C:22]([CH3:24])=[N:21][N:18]2[CH:19]=[CH:20][C:15]([C:14]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:13][SiH2:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:16][C:17]=12)=[O:5]
Reactant: Cc1cc2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ccn2n1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1c(C)nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc12
Temperature: 120 °C
Yield: 91.8 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid methyl ester (2.47 ml, 26.0 mmol, 4.0 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridine (2.6 g, 6.49 mmol) in THF (20 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 15 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (2.9 g, 92%). 1H NMR (400 MHz, d6-DMSO): δ=8.76 (d, J=7.8 Hz, 1H), 8.11 (br s, 1H), 7.61-7.59 (m, 4 H), 7.44-7.35 (m, 6H), 7.10 (dd, J=7.1/1.9 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H), 1.03 (s, 9H). MS (ES+): 487 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[C:12]([O:16][C:17](=[O:31])[NH:18][CH2:19][CH:20](O)[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[C:12]([O:16][C:17](=[O:31])[NH:18][CH2:19][CH:20]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Nitro-5-fluorophenol (8.4 g) and (3-tert-butoxycarbonylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (17.0 g) were dissolved in THF (60 ml) and triphenylphosphine (21 g) and di-tert-butyl-azodicarboxylate (18.4 g) were added. The exothermic reaction was cooled in an ice bath. Then the mixture was stirred at room temperature overnight. It was concentrated in vacuo and the residue was dissolved in dichloromethane, washed with water and 1M NaOH. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography (silica/dichloromethane:methanol 25:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[NH:14][C@H:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].CS(O[CH2:26][C:27]1[C:32]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([F:42])=[CH:35][C:34]=2[O:43][CH3:44])=[CH:31][N:30]=[C:29]([S:45][CH3:46])[N:28]=1)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:26][C:27]3[C:32]([C:33]4[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([F:42])=[CH:35][C:34]=4[O:43][CH3:44])=[CH:31][N:30]=[C:29]([S:45][CH3:46])[N:28]=3)[C@H:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(Br)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(SC)nc1COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 67(c)—(Table 8), 145 mg, 0.447 mmol) in THF (4 mL) at 0° C. was added sodium hydride (60 wt %, 23.3 mg, 0.582 mmol). The reaction was stirred at 0° C. for 1 hour and a solution of {5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-2-(methylsulfanyl)pyrimidin-4-yl}methyl methanesulfonate (188 mg, 0.470 mmol) in THF (500 μL) was added. The reaction was allowed to warm to room temperature and was stirred at room temperature for 6 hours. The reaction was quenched with HCl (1 N) and the reaction was poured into saturated aqueous NaHCO3 and ethyl acetate. The organic was washed with brine, was dried (Na2SO4), filtered, and concentrated. The resultant residue was purified by column chromatography to yield (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-2-(methylsulfanyl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (190 mg, 0.302 mmol). LCMS calc.=628.1/630.1. found=628.2/630.2
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccnc1Br
Yield: 48 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, 2-bromopropane (0.53 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-isopropyloxy pyridine (300 mg, yield: 48%) was obtained as an oil phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:32][CH:33]=2)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)cc1
Yield: 89.1 %

Procedure:
A mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (0.11 g, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), (4-acetamidophenyl)boronic acid (0.115 g, 0.64 mmol) and cesium carbonate (0.46 g, 1.40 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was sealed in a tube and subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (0.100 g, 91%). LCMS (AA): m/z=510 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[OH-].[Na+].[NH3:12]>>[NH2:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: N
Reactant: COc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cncc(N)c1
Temperature: 135 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-methoxypyridine (15 g) was added to a pressure vessel, and CUSO4 (3.9 g) and 25% aq. ammonia (150 mL) were added. The reaction mixture was stirred for 4 h at 135° C., then cooled to RT, basified with aqueous NaOH solution, and extracted with CH2Cl2. After evaporation of volatiles, 3-amino-5-methoxypyridine was obtained as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>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]>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Reaction time: 2 h
Yield: 105.7 %

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 1.25 equiv), Pd(dppf)Cl2.CH2Cl2 (19 mg, 10% mol), 2M aq Na2CO3 (1 mL), 1,4-dioxane (3 mL) was degassed, refilled with N2 gas for 3 times before being put into microwave oven for 2 h at 130° C. LC-MS found the reaction was completed. The mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0 to 10% MeOH in CH2Cl2 gradient to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (112 mg, quant yield). LC-MS Method 1 tR=1.66 min, m/z=461 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11])[CH:9]=1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC#N)cc1S(N)(=O)=O
Yield: 20.8 %

Procedure:
A suspension of 3.0 g of the compound from Example 2 and 0.1 g p-toluenesulfonic acid in 100 ml of dry toluene was refluxed in a flask equipped with a Dean-Stark apparatus. After being refluxed overnight the solution was concentrated and allowed to cool. The precipitate was filtered off to give 0.5 g light brown solid. The mother liquor was chromatographed over silica gel with 20:73:2:5, ethyl acetate:methylene chloride:methanol:THF to give additional product, m.p. 173°-177° C.