Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccc(C(C)(C)C)cc1
Yield: 61.3 %

Procedure:
Following general N—C coupling procedure 1, 7-(4-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) which gave 3-{6-[7-(4-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg) in 58% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H) 1.43 (s, 9H) 1.47-1.69 (m, 2H) 1.80 (br. s., 2H) 2.90 (br. s., 3H) 3.05 (br. s., 3H) 4.12 (br. s., 2H) 6.92 (s, 1H) 7.41 (m, J=8.59 Hz, 2H) 7.59 (m, J=8.59 Hz, 2H) 7.68 (dd, J=8.84, 2.27 Hz, 1H) 8.28-8.34 (m, 2H) 8.95 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)+.
Reaction SMILES: [Mg].[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1Br)([CH3:5])[CH3:4].[CH2:17]=[O:18]>O1CCCC1>[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[CH2:17][OH:18])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(Br)c(C(C)(C)C)c1
Reactant: C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 243 mg (10 mmoles) of magnesium turnings in 10 ml of tetrahydrofuran is added dropwise a solution of 2.69 grams (10 mmoles) of the title product of Example 9 in 5 ml of tetrahydrofuran. After the addition is complete, the mixture is refluxed for one hour. Paraformaldehyde (1.0 g, excess) is then added, and refluxing continued for one hour. The mixture is cooled to room temperature and partitioned between saturated ammonium chloride and diethyl ether. The aqueous layer is further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].[ClH:17].[H][H]>[Pd].C(O)C>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:14][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(CN)cc1O
Yield: 71 %

Procedure:
Palladium on carbon (0.5 g; 10% [w/w]) was added to a 1 L hydrogenation flask under a nitrogen atmosphere. The crude ethyl 4-azidomethylsalicylate was dissolved in ethanol (200 mL) and transferred to the hydrogenation flask. Concentrated aqueous hydrochloric acid (2 mL) was then added, and the flask was affixed to the Parr hydrogenator. The reaction mixture was shaken under 35 psi of hydrogen for 4 hours at room temperature. The mixture was then filtered through Celite to remove the catalyst, and the filtrate was evaporated to dryness to afford an off-white solid. Finally, this solid was crystallized from EtOH to afford 3.1 g (71% yield) of ethyl 4-aminomethylsalicylate hydrochloride (m.p. 240°-241° C. ).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:18][O:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2)(C1C=CC(C)=CC=1)(=O)=O.[CH3:23][O:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+].[ClH:43]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[ClH:43].[O:17]1[CH2:18][CH:14]([CH2:13][CH2:12][N:34]2[CH2:35][CH2:36][N:31]([C:26]3[C:25]([O:24][CH3:23])=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:32][CH2:33]2)[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COc1cccnc1N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1cccnc1N1CCN(CCC2COc3ccccc32)CC1
Yield: 39 %

Procedure:
To CH3CN (100 mL) was added 2,3-dihydro-3-benzo[b]furanethanol tosylate (1.50 g, 4.7 mmol), 1-(3-methoxy-2-pyridinyl)piperazine (0.91 g, 4.7 mmol), anhydrous K2CO3 (1.95 g, 14.1 mmol), KI (0.04 g, 0.24 mmol), and tetra-n-butylammonium hydrogen sulfate (0.08 g, 0.24 mmol). The mixture was heated at reflux under N2 atmosphere for 24 h. The reaction was concentrated in vacuo, several mL of H2O added and the reaction extracted with three portions of CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl solution, dried with anhydrous K2CO3, filtered, and concentrated in vacuo. Silica gel chromatography (EtOAc) of the concentrate afforded the free base which was treated with ethanolic HCl to yield the title compound (0.85 g, 39%, mp 100°-140° C.)
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])(=O)=O.Cl>C1(C)C=CC=CC=1.C(NCC(C)C)C(C)C.S(Cl)(Cl)(=O)=O>[Cl:22][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][CH2:11][C:12]=2[C:2]=1[OH:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Agent: CC(C)CNCC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 24 °C
Reaction time: 0.83 h
Yield: 88.8 %

Procedure:
Heat a mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 g, 0.4629 mol) and toluene (14.4 L) to 70° C. for 45 min until most of the starting material is dissolved. Add diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol) followed by addition of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360 mL) over 20 min. Stir the reaction mixture for 50 min and then add additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at 70° C. Cool the reaction mixture to 24° C. over 30 min and then add 1N hydrochloric acid (2.00 L). Separate, wash the organic layer with saturated aqueous NaHCO3 (2.00 L), brine (2.00 L) and then dry over Na2SO4. Filter and remove the solvent with a rotary evaporator at 70° C. until about 672.5 g remains using the minimum effective vacuum in order to maintain a vapor phase sufficient to prevent drying above the solvent line and self-seeding, thus preventing crystallization under these conditions. Using toluene heated to 70° C., transfer the light-yellow solution to a preheated (70° C.) 3-neck flask equipped with a mechanical stirrer. Lower the temperature to 58° C. over 1 h. If available, seed the solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine from a prior synthesis to enhance crystallization. After 30 min, reduce the temperature further to 55° C. and observe the initiation of the crystallization process. Hold the temperature at 55° C. for 2 h. followed by 4 h. at 45° C., then turn off the heat allowing the mixture to slowly reach 24° C. (ambient temperature). After stirring for 8 h. with the heat off, cool the mixture to 0° C. for 2 h. followed by 2 h. at −10° C. Collect the resulting dense, white, granular crystals by vacuum filtration at −10° C. Rinse the crystals twice with cold (−10° C.) toluene and vacuum dry at 50° C., 5 Torr, for 12 h., to obtain the desired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp 133-134° C. MS (ES+) m/z 294 (M+H)+. Anal. Calc'd for C12H11ClF3NO2: C, 49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])[OH:16])=O)C1C=CC=CC=1.C1OC1C>Cl.CO>[NH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[OH:17]
Reactant: CCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CCCCP(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A solution of 6.7 g of 3-(benzyloxycarbonylamino)propyl(n-butyl)phosphinic acid in 125 ml of 36 % hydrochloric acid is heated at reflux for 1.5 hour. The mixture is evaporated to an oil and the oil is co-evaporated with water (2×50 ml) to give a white solid. This solid is then dissolved in 50 ml of dry methanol, 1-3 ml of propylene oxide is added and the solution is stirred at room temperature. The precipitated product is collected by filtration and dried to give 3-aminopropyl(n-butyl)phosphinic acid, m.p. 231-234° (dec.), 31P-NMR : δ=+44.6 ppm (D2O).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH2:8][Br:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(Cl)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(CBr)ccc1Br
Temperature: 90 °C
Reaction time: 1 h

Procedure:
In 21 mL of carbon tetrachloride, 3-bromo-2-chloro-6-methylpyridine (880 mg, 4.26 mmol) was dissolved, and N-bromosuccinimide (682 mg, 3.83 mmol) and AIBN (70 mg, 0.426 mmol) were added, followed by stirring at 90° C. for one hour. The resulting reaction solution was concentrated, and the residue thus obtained was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5), whereby 3-bromo-6-(bromomethyl)-2-chloropyridine was obtained as a crude purified product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([CH3:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2cc(Cl)ncn2)cn1
Yield: 36.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (11.92 g, 80 mmol), 4-methyl-1H-imidazole (6.57 g, 80 mmol), and cesium carbonate (26.1 g, 80 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. The reaction was diluted into 200 mL water and extracted three times with 200 mL EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 300 g silica gel cartridge with 25 to 75% ethyl acetate in hexane to yield a mixture of the two regioisomeric products. The pooled fractions were concentrated to about 200 mL volume and cooled to yield 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine (5.70 g, 37% yield). The positive identification of the 4-methylimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1H, d, J=0.50 Hz), 8.36 (1H, d, J=1.26 Hz), 7.29-7.31 (1H, m), 7.25 (1H, d, J=1.01 Hz), 2.27 (3H, d, J=1.01 Hz). LCMS: RT=0.50 min, MH+=195.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([N+:22]([O-])=O)[CH:8]=2)[N:3]=1.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:22][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH:21]=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(-c2ccc(CNC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)no1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(CNC(=O)OC(C)(C)C)c(N)c2)no1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
To a solution of compound 58a (0.752 g, 2.25 mmol) in ethanol (12 mL) was added tin(II) chloride (1.62 g, 8.5 mmol). The reaction mixture was heated at 70° C. for 50 min, then cooled to rt. Saturated sodium bicarbonate solution was added. The resulting emulsion was filtered through Celite®, followed by ethyl acetate washes. The combined organic layers were washed with brine, dried, and concentrated to give compound 58b (0.57 g, 83%) as a yellow solid. ESI-MS m/e 305.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[OH-:13].[K+].O.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[OH:13]
Reactant: Cc1cc2ncccc2cc1Br
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2ncccc2cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A vial was purged with nitrogen and charged with 6-bromo-7-methyl-quinoline (2.0 g, 9 mmol), grounded KOH (2.02 g, 36 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.18 mmol), and X-Phos (Strem ligand, 343 mg, 0.72 mmol). Water (6 mL) and 1,4-dioxane (6 mL) were added, and the reaction mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified to pH 5 with 1 N aqueous HCl and extracted with ethyl acetate (2×). The combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-100% ethyl acetate/hexane afforded 1.37 g of 7-methyl-quinolin-6-ol as a light yellow solid (95% yield): 1H NMR (DMSO-d6) δ 2.34 (s, 3H), 7.12 (s, 1H), 7.32 (dd, 1H), 7.73 (s, 1H), 8.07 (dd, 1H), 8.60 (dd, 1H), 10.1 (broad s, 1H); MS (m/z) 160 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([CH:23]=[O:24])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-pyridine described in Manufacturing Example 230-1-1 (34 g, 128 mmol) in tetrahydrofuran (120 mL) was added dropwise n-butyl lithium (50 mL, 2.6 M hexane solution, 134 mmol) at −78° C. After stirring for 30 minutes, N,N-dimethyl formamide (10 mL, 134 mmol) was added dropwise to this reaction solution at −78° C., which was stirred at room temperature. Water and ethyl acetate were added to the reaction solution, and liquid separation was carried out. The ethyl acetate layer was washed with water (twice) and sodium chloride water (once). The aqueous layers were combined and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water (twice) and aqueous sodium chloride (once). The previously obtained ethyl acetate layer and the ethyl acetate layer obtained this time were combined, dried over anhydrous magnesium sulfate, and then filtered. This filtrate was concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])[CH3:2].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.9 %

Procedure:
To a stirred mixture solution of 2-(3-methoxycarbonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.7 g, 10.0 mmol) in tetrahydrofuran (20.0 mL) was added 4.0 N lithium hydroxide in water (12.0 mL). The reaction mixture was stirred at room temperature for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.6 g, quant.) as a light white solid which was used for next step without further purification: MS (ESI) M+1=354.1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>[OH-].[Na+]>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)c2oc(C3CC3)cc2c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(Br)c2c(c1)CC(C1CC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
To a solution of the title compound from Step 1 (250 mg, 0.79 mmol) in Et3SiH (516 mg, 4.44 mmol) at 0° C. was added TFA (5.43 g, 47.59 mmol) in one portion. The reaction mixture was warmed up to rt and stirred for 48 hours. Aqueous NaOH solution (10 mL, 1 N) was added slowly to the above solution. The mixture was extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE to PE/EA=2/1) to give the title compound (83 mg, 33%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H), 4.47-4.43 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.17 (m, 1H), 3.04 (s, 3H), 1.24-1.22 (m, 1H), 0.7-40.55 (m, 3H), 0.44˜0.41 (m, 1H).
Reaction SMILES: [C:1]([O:9][C:10]([N:12]1[CH2:21][C@@H:18]2[C@H:19]([OH:20])[C@H:13]1[C@H:14]([O:17]2)[O:15][CH3:16])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(Cl)Cl>[C:28]([O:20][C@H:19]1[C@H:18]2[CH2:21][N:12]([C:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])[C@@H:13]1[C@H:14]([O:17]2)[O:15][CH3:16])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CO[C@H]1O[C@@H]2CN(C(=O)OC(=O)c3ccccc3)[C@H]1[C@H]2O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@@H]2CN(C(=O)OC(=O)c3ccccc3)[C@H]1[C@H]2OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Methyl N-benzoyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (Tetrahedron, 1986, vol. 42, p. 5685-5692) (13.9 g, 49.8 mmol) was dissolved in methylene chloride (200 mL) and pyridine (20 mL, 249.0 mmol) and benzoyl chloride (11.6 mL, 99.6 mmol) were added thereto, followed by stirring of the mixture at room temperature for 2 hours. After 1N hydrochloric acid (200 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with methylene chloride (100 mL), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine (200 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-3:1, V/V) to obtain the desired title compound (15.82 g, yield 83%) as a colorless solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@@:11]2([F:20])[C:16]([O:18][CH3:19])=[O:17])(C(C)(C)C)(C)C.Cl>>[F:20][C@@:11]1([C:16]([O:18][CH3:19])=[O:17])[C@@H:12]2[C@H:10]1[C:9](=[O:8])[CH2:14][C@H:13]2[OH:15]
Reactant: COC(=O)[C@]1(F)[C@@H]2[C@H]1C(=O)C[C@H]2O[Si](C)(C)C(C)(C)C
Agent: Cl
Product: COC(=O)[C@]1(F)[C@H]2[C@H](O)CC(=O)[C@H]21
Temperature: 22 °C
Reaction time: 3.5 h

Procedure:
The above organic layer, containing TBS-ketone 6 (6.83 mol) was warmed to 22° C. and 1 M HCl (1.37 L) was added. The mixture was stirred at 22-24° C. for 3.5 h until all TBS groups were removed. To the mixture was added saturated sodium bicarbonate solution (4.8 L). The mixture was stirred for 15 min, diluted with isopropyl acetate (20 L), and the organic layer was separated. The aqueous layer was back extracted with isopropyl acetate (6 L). The combined organic solutions were concentrated to dryness and the compound was purified by silica gel chromatography in a filter pot (first eluted with 30% MTBE in hexane, then MTBE alone) to give compound 7 as an off white crystal. Analytical pure sample was obtained by further flash silica gel column as colorless crystals: mp 61-62° C.; 1H NMR (400 MHz, CDCl3): δ 4.92 (br s, 1H), 3.85 (s, 3H); 2.86 (dd, J=6.2, 2.1 Hz, 1H), 2.71 (d, J=6.2 Hz, 1H), 2.61 (dt, J=19.4, 5.7 Hz, 1H), 2.59 (br s, 1H), 2.30 (dd, J=19.4, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 206.9, 167.0 (d, J=26.2 Hz), 79.0 (d, J=246.6 Hz), 67.0 (d, J=3.1 Hz), 53.5, 46.8 (d, J=4.2 Hz), 41.6 (d, J=11.8 Hz), 39.4 (d, J=13.1 Hz); 19F NMR (376 MHz, CDCl3): δ −210.6; [α]D25=+77 (c 0.50, CH3OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:9][C:17](=[O:19])[CH3:18])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1C
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccnc1CC(C)=O
Temperature: 0 °C

Procedure:
To a stirred solution of 3-methoxy-2-methylpyridine (844 mg) in tetrahydrofuran (10 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 5.6 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.955 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(3-methoxypyridin-2-yl)propan-2-one (1.12 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]3)[C:6]=2[CH:12]=1
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Yield: 66 %

Procedure:
Commercially available 6-methyl-2H-1,4-benzoxazin-3(4H)-one (326 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a colorless solid.