Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH2:33]O)[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH2:33][N:8]3[C:6]4=[N:7][C:2]([F:1])=[CH:3][CH:4]=[C:5]4[N:10]=[C:9]3[CH2:11][CH2:12][CH3:13])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: CCCc1nc2ccc(F)nc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CO)cc2COc2cc(F)ccc21
Product: CCCc1nc2ccc(F)nc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 42.3 %

Procedure:
[step 3] Using 5-fluoro-2-propyl-3H-imidazo[4,5-b]pyridine (47 mg, 0.262 mmol) obtained in step 2 and (E)-2-[3-fluoro-8-(hydroxymethyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (70 mg, 0.238 mmol) obtained in Reference Example 1, step 5, and in the same manner as in Reference Example 3E, the title compound (46 mg, 42%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH2:13])[CH3:12]>O>[CH2:11]([NH:13][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1)[CH3:12]
Reactant: CCN
Reactant: CSc1nc(C)cc(Cl)n1
Solvent: O
Product: CCNc1cc(C)nc(SC)n1
Temperature: 50 °C
Yield: 90 %

Procedure:
To the 4-chloro-6-methyl-2-(methylthio)pyrimidine from above was added 30 mL of a solution of 70% ethylamine in water. The reaction mixture was heated to 50° C. for 3 h. After completion, excess ethylamine was evaporated on rotary evaporator under vacuum. The solid was filtered and dried under vacuum to afford N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(Cl)Cl.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18].[OH-].[Na+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:29]([NH:28][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:17]([O:16][CH3:15])=[O:18])(=[O:27])=[O:26])=[O:30])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture containing 1.6 g of 2-amino-4,6-dimethoxypyrimidine, 30 ml of anhydrous methylene chloride and 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate was stirred at ambient temperature and pressure for 16 hours. It was then filtered to remove unreacted amine and the filtrate evaporated at temperatures up to 40° and reduced pressure. The residue thus obtained was stirred in 25 ml of water, the pH adjusted to 10 by the addition of 50% aqueous sodium hydroxide and the solution filtered. Acidification of the filtrate to pH 3 caused the formation of a precipitate. Filtration and drying the precipitate yielded 1.7 g of the desired product, melting at 185°-190°. Its infrared absorption peaks at 1700 and 1710 cm-1 are consistent for the desired structure and the nuclear magnetic resonance absorption peaks at 3.8 and 3.85 are consistent for the two different types of methoxy groups brought together in this product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH2:14])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.9 %

Procedure:
3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8 g, 69 mmol) were set stirring in CH2Cl2 (230 mL). Sodium triacetoxyborohydride (14.6 g, 69 mmol) was added in portions over 10 min. Acetic acid (1.3 mL, 25 mmol) was then added and the mixture left to stir. After 18 h saturated NaHCO3 was added and the organics separated. The organics were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g (66%) of a light beige solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C21H29ClN2O4, 408.18. m/z found, 409.1 [M++H]. 1H NMR (400 MHz, CDCl3): 7.64 (d, J=15.65 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d, J=9.00 Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89 (t, J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m, 2H), 1.30 (t, J=7.24 Hz, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:42][CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:48][CH2:47]1)=[O:45]>CN(C=O)C>[O:45]=[C:44]([N:46]1[CH2:47][CH2:48][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:50][CH2:51]1)[CH2:43][NH:42][C:17]([C:14]1[CH:13]=[N:12][C:11]([OH:10])=[CH:16][N:15]=1)=[O:19]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnc(O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (553 mg, 0.732 mL, 4.28 mmol) was added to a stirred solution of 5-hydroxy-pyrazine-2-carboxylic acid (200 mg, 1.42 mmol) in DMF (3 mL). HOBT (231 mg, 1.71 mmol) and EDCI (328 mg, 1.71 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (600 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, methanol was then added, filtered the solid precipitated. The solid obtained was purified by column chromatography (using silica gel of 60-120 mesh and 10% MeOH in CHCl3 as eluent) to afford 205 mg (32.85%) of 5-hydroxy-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 91.22%. 1H NMR (DMSO-d6): δ 8.3 (bt, 1H), δ 8.0 (m, 2H), 7.9-7.76 (m, 2H), 7.7 (m, 1H), 7.6-7.5 (d, 2H), 4.26-4.1 (dd, 2H), 3.8-3.68 (m, 2H), 3.6-3.5 (m, 2H), 3.4 (m, 2H), δ 3.2-3.0 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:33]([O:35]CC1C=CC=CC=1)=[O:34])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:33]([OH:35])=[O:34])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(CCCCCCCCCCC(CC(=O)OCC)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CCCCCCCCCCC(CC(=O)OCC)C(=O)O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Diethyl 2-t-butoxycarbonylamino-13-benzyloxycarbonyl-1,14-tetradecanedicarboxylate (5.0 g, 8.87 mmol) is dissolved in ethyl acetate (150.0 mL), and 10% Pd-C (2.6 g) is added. The reaction flask is put under an atmosphere of hydrogen and stirred for 2 hours. The product is then filtered through a pad of Celite, and the solvent is evaporated to give diethyl 2-t-butoxycarbonylamino-13-carboxy-1,14-tetradecanedicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8](/[C:11](=[N:15]\[OH:16])/[O:12][CH2:13][CH3:14])[CH2:7][C:6]=2[CH:5]=[C:4]([C:17](=[O:20])[CH2:18][CH3:19])[C:3]=1[OH:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:16]/[N:15]=[C:11](\[CH:8]1[CH2:7][C:6]2[CH:5]=[C:4]([C:17](=[O:20])[CH2:18][CH3:19])[C:3]([OH:21])=[C:2]([Cl:1])[C:10]=2[O:9]1)/[O:12][CH2:13][CH3:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCO/C(=N/O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1
Product: CCO/C(=N/OC(C)=O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1
Yield: 89.2 %

Procedure:
5b (3.45 g, 0.011 mol) was stirred in acetic anhydride overnight. Evaporation ad trituration in ethanol gave 89.2% of white crystals, M.P. 140°-142° C. Anal. (C16H18ClNO6) C,H,N.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:13][CH:12]=1)=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 11 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.00 g, 3.40 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.61 g, 6.79 mmol). Purification on .2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.185 g (11%) of the title compound as an off white solid, mp 143-145° C. 1H NMR (DMSO-d6) δ 0.76 (t, 3 H), 1.12-1.22 (m, 2H), 1.60 (quintet, 2H), 2.69 (t, 2H), 7.21-7.38 (m, 7H), 7.61 (d, 1H), 7.76 (d, 2H), 7.98 (d, 1H). IR (KBr) 2950, 1690, 1600, 1380 and 1150 cm−1. mass spectrum (+ESI) m/z 495 (M+H). Anal. Calcd. for C26H22O8S.0.2H2O: C, 62.24; H, 4.58; N, 0.00. Found: C, 62.38; H, 4.59; N, 0.13.
Reaction SMILES: ClC(OCC)=O.[F:7][C:8]1[CH:45]=[CH:44][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:23]3[C:41]([OH:43])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.CN1CCOCC1.C[Si](C)(C)[O:55][NH2:56]>CN(C=O)C>[OH:55][NH:56][C:41]([CH:23]1[C:24]2[C:29](=[C:28]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:44]=[CH:45][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)(=[O:20])=[O:21])=[O:43]
Reactant: O=C(O)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)ON
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NO)C1c2cccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
8.16 μl (85.6 μmol) of ethyl chloroformate are added to a solution of 38 mg (68.5 μmol) of 2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-(2-piperidin-1-ylethoxy)-1,2,3,4-tetra-hydroisoquinoline-1-carboxylic acid and 16.6 μl (151 μmol) of N-methylmorpholine in 2 ml of DMF at −20° C., and the mixture is stirred at −20° C. for 30 minutes. Then 37.2 μl (274 μmol) of O-trimethylsilylhydroxylamine are added, and the solution is warmed slowly to room temperature. After standing overnight, it is concentrated in vacuo and the residue is purified by chromatography on silica gel, allowing the title compound to be isolated as a colorless solid. Yield 46%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(OCC)(=O)C.CO>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CCCBr)s1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCCBr)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution consisting of 5-(3-bromopropyl)thiophene-2-carboxylic acid (from procedure above, 24 g, 78 mmol) in ethyl acetate (150 mL) and methanol (15 mL) at 0° C. was added TMS-diazomethane (50 mL, 100 mmol, 2 M) dropwise over one hour. The reaction mixture was then allowed to warm to room temperature and was stirred for 16 hours, The reaction mixture was concentrated under reduced pressure without workup. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (1:80 v/v) afforded the title compound as a white solid (4.95 g; 24% over two steps); TLC Rf 0.45 (solvent system: 15:85 v/v ethyl acetate-hexanes); MS (ESI+) m/z 263, 265 (isotopic bromines, each (M+H)+); 1HNMR (CDCl3) δ 7.5 (d, 1H), 6.7 (d, 1H), 3.75 (s, 3H), 3.3 (t, 2H), 2.9 (t, 2H), 2.1-2.0 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: Brc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A 5 L, 3-necked round bottomed flask equipped with an overhead stirrer, dropping funnel, N2(g) inlet was charged with AlCl3 (432.5 g, 3.24 mol). The solids were cooled to 0° C. with an ice-H2O bath. DMF (71 ml) was added dropwise over a period of 35 min and the temperature was kept under 32° C. during the addition. The reaction mixture was heated to 50° C. and treated with 3-Nitrobenzoyl chloride (63.2 g, 0.34 mol). The reaction that ensued was exothermic and caused the internal reaction temperature to rise to 65° C. The reaction was stirred for 50 min then bromobenzene (33.5 ml, 0.32 mol) was added. The reaction was heated at 90° C. for 3 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 1:1) indicated completion of reaction. The reaction was cooled and ice-H2O (3 L) was added dropwise over a period of 1.5 h. The reaction was allowed to stir overnight. The solids were filtered, washed with H2O (1 L), saturated NaHCO3(aq) (1 L), another portion of H2O (500 mL) and Hexanes (500 mL). The product was dried in the vacuum oven at 40° C., 28 in Hg for 30 hours to yield (4-Bromo-phenyl)-(3-nitro-phenyl)-methanone in 88% (85.34 g, 0.28 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+:16].S([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[Na+:16].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S([O-])c1cccc(Cl)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
A solution of 3-chlorobenzenesulfonyl chloride (3.0 g) in dioxane (40 mL) was treated with a mixture of sodium hydrogen carbonate (2.7 g), sodium sulfite (3.6 g) and water (20 mL), and the resulting mixture was stirred at 75° C. for 30 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ethanol to afford the title compound as a white solid (0.20 g).
Reaction SMILES: O=[C:2]1[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cn1c(Cl)nc2cccnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)acetate (14.5 g) and phosphoryl chloride (100 mL) was stirred at 100° C. overnight. The mixture was poured into ice, neutralized with saturated sodium bicarbonate solution and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was diluted with AcOEt and insoluble crystals were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-40% AcOEt in hexane) to give the title compound (5.46 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([O:32][CH:33]([CH3:35])[CH3:34])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:37][S:38]([O:17][C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[C@H:15]([O:32][CH:33]([CH3:34])[CH3:35])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:36])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(C(=O)N1C(=O)OCC1Cc1ccccc1)C(O)c1cccc(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](OS(C)(=O)=O)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
12.9 g of 4-Benzyl-3-(3-(3-benzyloxyphenyl)-3-hydroxy-2-isopropoxy propionyl]oxazolidin-2-one was dissolved in 30 ml of pyridine, and 3.06 ml of methanesulfonyl chloride was dropwise added thereto under ice-cooling. After stirring was continued at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated, to give 3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-1(R)-(3-benzyloxyphenyl)-2(S)-isopropoxy-3-oxopropyl methanesulfonate. This product was then dissolved in 300 ml of ethanol, and 2 g of 10% palladium carbon was added, and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 5.87 g of the title compound as a colorless oil in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[O:39][CH2:38]1>CCOC(C)=O>[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:47]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=4[CH:43]=3)=[O:48])[CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)CC1COc2cc(Br)ccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 150 °C
Yield: 57.9 %

Procedure:
TEA (0.737 mL, 5.32 mmol) and T3P (50 wt. % in EtOAc, 2.372 mL, 3.99 mmol) were added to a solution of ethyl (7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (Intermediate 27, 399 mg, 1.33 mmol) and 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (308 mg, 1.60 mmol) in EtOAc (7 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 2 h. Additional T3P (50 wt. % in EtOAc, 1.2 mL, 2.02 mmol) and TEA (0.3 mL, 2.16 mmol) was added and the mixture was heated in a microwave reactor at 150° C. for another 2 h. EtOAc (50 mL) was added and the mixture washed with sat. aq. Na2CO3 (2×30 mL), HCl (30 mL, 0.5M) and brine, dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm). The title compound (366 mg, 58%) was obtained after removal of solvents in vacuo.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C@@H:18]([CH2:22][CH3:23])[CH:19](N)[OH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([N:26](CC)CC)C.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[C:11]([C@:18]([NH2:26])([CH2:22][CH3:23])[CH:19]=[O:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCN(CC)CC
Reactant: CC[C@H](C(=O)OC(C)(C)C)C(N)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
A solution of oxalyl chloride (40.39 g, 265 mmol) in MeCl2 (700 mL) was stirred and cooled to −60° C. Dimethylsulfoxide (51.7 g, 663 mmol) in MeCl2 (100 mL) was added dropwise. After 10 min., a solution of 2(S)-Boc-amino-1-butanol (50 g, 265 mmol) in MeCl2 (100 mL) was added dropwise at −70° C. The reaction mixture was allowed to warm to −40° C. for 10 min. and then cooled to −70° C. again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 mL) was added, and then the organic layer was washed with brine and dried over MgSO4. The solvent was removed to yield 45 g of 2(S)-Boc-aminobutyraldehyde.