Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)C.C(O)C.[OH-].[Na+]>O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:9]([N:10]1[CH2:15][CH2:14][C:13]2[S:16][CH:17]=[CH:18][C:12]=2[CH2:11]1)[CH2:8][CH2:7][CH2:6][C:5]([CH3:26])([CH3:27])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 55.7 %

Procedure:
6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid ethyl ester (2.5 g, 7.33 mmol) was added to a solution of ethanol (100 mL) and sodium hydroxide (1.8 g, 43.8 mmol) in water (32 mL). The mixture was heated to reflux for 6.5 hours. The solution was evaporated under reduced pressure and water (100 mL) was added to the residue. The water solution was extracted with ethyl acetate/heptane=1/10 (100 mL). The organic layers were discarded and the aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with dichloromethane (3×100 mL), which was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid (1.6 g, 68.7%) as a yellow oil. 6-(2-Chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid (3.97 g, 10.2 mmol) was dissolved in 36% HCl (0.95 mL) and water (59 mL). After stirring for 10 minutes, the aqueous solution was extracted with ethyl acetate/heptane (20/80, 110 mL). The organic extract was discarded and the aqueous fraction was freeze-dried to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid, hydrochloride salt (Compound Ic hydrochloride, 3.48 g, 79.8% yield, 99.7% purity by HPLC) as a white solid melting at 136-138° C. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.69 (s, 1H), 7.47-7.38 (m, 3H), 7.21 (d, 1H, J=3.9 Hz), 6.71 (d, 1H, J=3.9 Hz), 4.92 (m, 1H), 4.31-4.15 (m, 2H), 3.15-3.05 (m, 4H), 2.24-2.14 (m, 2H), 1.47-1.36 (m, 2H), 1.08-1.06 (m, 2H), 0.99 (s, 6H). (mixture of rotation isomers in NMR). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 181.10, 137.13, 132.80, 132.77, 132.04, 131.79, 130.48, 129.73, 128.73, 126.62, 126.14, 66.14, 51.52, 42.87, 40.92, 32.04, 25.88, 25.47, 23.45, 22.50. MS (FIA-ESI-TOF): Calculated for C21H26ClNO2S (MH)+: 392.1446; found 392.1453. CHN analysis: Calculated; 58.87 C, 6.35 H, 3.27 N, 16.55 Cl, 7.48 S, found; 57.80 C, 6.44 H, 3.15 N, 16.14 Cl, 7.15 S, Best fit for CHN Data: C21H27Cl2NO2S+0.55 H2O
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[C:28]([Si:25]([CH3:27])([CH3:26])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(Oc3ccccc3)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Yield: 74.7 %

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[3-hydroxy-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (668.3 mg, 2.05 mmol) was reacted with tert-butyldimethylsilyl chloride (341 mg, 2.26 mmol). Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (673 mg). 1H NMR (CDCl3) δ 7.32 (m, 2H), 7.22 (m, 1H), 7.09 (m, 1H), 6.99 (d, 2H), 6.89 (d, 1H), 6.83 (m, 2H), 3.85 (m, 1H), 3.58 (m, 1H), 2.76-2.62 (m, 2H), 2.32 (m, 2H), 2.23 (m, 1H), 1.73-1.34 (m, 5H), 0.84 (s, 9H), −0.03 (d, 3H), −0.16 (d, 3H); MS 440.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH:47]2[CH2:50][O:49][CH2:48]2)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:47]2[CH2:50][O:49][CH2:48]2)[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(N(C3COC3)S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reaction time: 2 h
Yield: 36.4 %

Procedure:
The title compound of Example 102 (46 mg, 0.11 mmol), Cs2CO3 (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 mL) were microwaved at 130° C. for 2 h. Additional oxetan-3-yl 4-methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs2CO3 (126 mg, 0.39 mmol) were added and microwave resumed at 130° C. for 2 h more. The mixture was purified by silica gel chromatography (EA) to give the title compound (20 mg, 0.04 mmol) as cream solids in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.98 (s, 3H) 3.50 (s, 3H) 4.41 (t, J=6.82 Hz, 2H) 4.58 (t, J=6.95 Hz, 2H) 5.30 (quin, J=7.01 Hz, 1H) 6.83 (d, J=8.84 Hz, 1H) 7.06-7.20 (m, 1H) 7.22-7.35 (m, 2H) 7.39 (d, J=2.53 Hz, 1H) 7.43-7.57 (m, 1H) 7.60 (s, 1H) 7.83 (d, J=2.27 Hz, 1H). LCMS (M+H)+ 477
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([OH:44])=O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([NH:63][S:64]([C:67]2([CH3:70])[CH2:69][CH2:68]2)(=[O:66])=[O:65])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][C@H:39]1[CH2:40][N:36]([C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C@H:37]([C:42](=[O:44])[NH:55][C@:56]2([C:61](=[O:62])[NH:63][S:64]([C:67]3([CH3:70])[CH2:69][CH2:68]3)(=[O:66])=[O:65])[CH2:58][C@H:57]2[CH:59]=[CH2:60])[CH2:38]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
HATU (7.60 g, 20.00 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (7.86 g, 19.05 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide HCl (5.62 g, 20 mmol), and Hunig's Base (13.31 mL, 76 mmol) in DCM (110 mL). The reaction mixture was stirred at rt for 16 h. The reaction was washed with 1N HCl (3×), and then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (9 g, 74.0% yield) as a light orange foam. MS: MS m/z 639.3 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Temperature: 25 °C
Yield: 8.9 %

Procedure:
A mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (4.35g, 9.86 mmol), phenylacetyl chloride (4.0 mL, 30 mmol) in two portions and tin (IV) chloride (4.3 mL, 37 mmol) in chloroform (220 mL) was refluxed for five hours. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. After stirring the residue in ether and filtering, the filtrate was concentrated and purified by flash chromatography using (1) 25–35% methylene chloride in hexane and 100% methylene chloride and (2) 1–8% ethyl acetate in hexane. It was then purified by HPLC using 85% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for one hour yielded [1-bromo-6-(3-phenylacetyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as a yellow semi-solid (0.491 g, 8.89%); mass spectrum (+EI, [M+H]+) m/z 559/561. 1H NMR (500 MHz, DMSO-d6): δ8.28 (d, 1H, J=7.19 Hz), 8.17 (d, 1H, J=1.98 Hz), 8.12 (d, 1H, J=9.01 Hz), 8.06–8.10 (m, 1H), 7.90–7.93 (m, 1H), 7.81 (dd, 1H, J=8.78 Hz and 1.91 Hz), 7.54 (d, 1H, J=9.16 Hz), 7.45–7.50 (m, 2H), 7.13–7.19 (m, 3H), 6.91–6.94 (m, 2H), 5.13 (s, 2H), 4.19 (q, 2H, J=7.13 Hz), 3.81 (s, 2H), 1.22 ppm (t, 3H, J=7.10 Hz). Elemental Analysis for C30H23BrO4S+0.10 mol H2O: Calcd: C, 64.19; H, 4.17; N, 0.00; Found: C, 63.85; H, 4.03; N, 0.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]1[OH:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH:33]4[OH:41])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: NC1CCCC(C(=O)O)C1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(C(=O)O)C4O)n3)c3cc(Cl)cnc32)cc1

Procedure:
5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol), iPr2NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL) solution was heated in microwave at 130° C. for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparatory HPLC to give 240 mg of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, as a mixture of stereoisomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:34][O:35][Si](C(C)C)(C(C)C)C(C)C)[C@@H:31]([CH3:33])[N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:34][OH:35])[C@@H:31]([CH3:33])[N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5R)-4-methyl-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (1.23 g, 1.83 mmol) synthesized in Example (89g) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 2.11 mL, 2.11 mmol) is added at room temperature, followed by stirring at room temperature for 1 hour under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=90%-100%) to afford the desired compound (715 mg, yield 76%) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].NC(C(C)C)C(=O)[CH2:28][CH2:29][N:30]([C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[O:46][N:45]=[C:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[CH:43]=2)[CH:37]=1)[C:31](=[O:35])[CH:32]([Cl:34])[Cl:33]>C(Cl)Cl>[Cl:34][CH:32]([Cl:33])[C:31]([N:30]([CH2:29][CH2:28][C:22](=[O:24])[CH:18]([NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:19]([CH3:20])[CH3:21])[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[O:46][N:45]=[C:44]([C:47]3[C:48]([Cl:54])=[CH:49][CH:50]=[CH:51][C:52]=3[Cl:53])[CH:43]=2)[CH:37]=1)=[O:35]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C(N)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pybop (164 mg, 0.32 mmol), diisopropylethylamine (50 mg, 0.39 mmol) and N-boc-L-valine (69 mg, 0.32 mmol) were added to a solution of N-(4-amino-5-methyl-3-oxohexyl)-2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamide (Cpd. No. 3, lot 2, 75 mg, 0.11 mmol) in methylene chloride (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was then diluted with methylene chloride (15 mL) and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to provide tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (Cpd. No. 49,100 mg) as a white solid. 1H NMR (CDCl3): 8.86 (d, 1H), 7.98 (s, 1H), 7.45-7.33 (m, 5H), 5.98 (s, 1H), 5.66 (br s, 1H), 4.98 (br s, 1H), 4.55-4.51 (m, 2H), 4.11-4.02 (m, 3H), 3.00-2.93 (m, 2H), 2.20 (m, 1H), 1.48 (s, 9H), 1.09 (d, 3H), 0.90 ppm (d, 3H).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:7]([SH:8])=[N:6][N:5]=[N:4]1.Br[CH2:10][Cl:11]>CN(C)C=O.O>[Cl:11][CH2:10][S:8][C:7]1[N:3]([CH3:2])[N:4]=[N:5][N:6]=1
Reactant: ClCBr
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1SCCl
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 1-methyltetrazole-5-thiol sodium salt (2.00 g: 14.5 mMol.) in dimethylformamide (20 ml) under ice cooling is added bromochloromethane (20 ml) in one portion, and the mixture is stirred for 1.5 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=20:1-10:1) to give 5-chloromethylthio-1-methyltetrazole as colorless crystals (1.73 g). Yield: 72%. m.p. 55° to 56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
The mixture of (2,4-dichloro-phenoxy)-acetic acid (110.5 mg, 0.5 mmol), 4-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), 4-dimethylaminopyridine (122.7 mg, 1.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 mg, 1.0 mmol) in DMF (8.0 mL) was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (169.6 mg, 95.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([Cl:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2ccccc2n1
Yield: 90 %

Procedure:
2.18 g (10 mmol) of 2-ethoxycarbonylquinazolin-4-one was suspended in 20 ml of phosphorus oxychloride. The mixture was refluxed for one hour, and the solvent was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate, and the obtained solution was washed with saturated sodium bicarbonate solution three times, dried over anhydrous sodium sulfate, filtered, and evaporated to give 2.13 g (90% mmol) of 2-ethoxycarbonyl-4-chloroquinazoline as a pale-yellow solid. LC/MS (m/z) 237 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([C:18](=[O:23])N(OC)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of the amide 482 (328 mg, 1.0 mmol) in THF (20 mL) is added 0.5M 4-methoxyphenylmagnesium bromide in THF (8.0 mL, 4.0 mmol), and the mixture is allowed to come to rt and stirred at this temperature for 3 h. The reaction mixture is poured into a mixture of ammonium chloride/ice followed by the addition of EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (85:15) gives 2.12 g of the product 483. 1H NMR (CDCl3) δ 7.95 (d, 2H), 7.45-7.20 (m, 10H), 6.88 (d, 2H), 6.50-6.20 (m, 2H), 5.25-5.00 (m, 2H), 3.81 (s, 3H)
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(Br)sc1C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ncsc1C
Yield: 13.1 %

Procedure:
A solution of 4-acetamido-2-bromo-5-methylthiazole (2.3 g) and sodium acetate (0.8 g) in methanol (60 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the filtrate was evaporated to dryness. The residue was extracted with hot CCl4 and the extracts were evaporated. The residue was recrystallised once from petroleum ether (b.p. 60°-80° C.) and once from hexane to give 4-acetamido-5-methylthiazole (0.2 g) m.p. 62°-4° C. (Found: C, 46.6; H, 5.3; N, 18.1. C6H8N2OS requires C, 46.1; H, 5.2; N, 17.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].[CH3:15]O>C1COCC1>[CH3:15][C:9]1([OH:12])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Step AA (1): To a solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (24 g) in methanol (150 mL) and THF (50 mL) at 0° C. was added sodium borohydride (5.6 g), and the resulting suspension was stirred at 0° C. for 1 h and rt for 30 min. Solvents were evaporated, and water was added. The aqueous solution was extracted with EtOAc (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give methyl 6-methoxy-2,3-dihydro-1H-inden-1-ol as a colorless oil (24.3 g), which was carried forward without purification. 1H NMR (400 MHz, CDCl3): 7.12 (1H, d), 6.95 (1H, d), 6.81 (1H, dd), 5.19 (1H, br. S), 3.79 (3H, s), 2.95 (1H, m), 2.74 (1H, m), 2.50 (1H, m), 1.94 (1H, m).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=2[CH3:19])[CH2:5][O:4]1.C(OC(=O)C)(=[O:22])C>>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:22])[C:12]=2[CH3:19])[CH2:5][O:4]1
Reactant: CC(=O)OC(C)=O
Reactant: COC1OCC(COc2cc[n+]([O-])c(C)c2C)CO1
Product: COC1OCC(COc2ccnc(CO)c2C)CO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
The 4-((2-methoxy-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (1.8 g, 6.68 ml) obtained in the step (6b) was mixed with acetic anhydride (8 ml). The mixture was stirred at 100° C. for 2 hours. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (10 ml) and a 5N aqueous sodium hydroxide solution (5 ml) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was separated with a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (0.41 g, yield: 22.8%), which is a cis and trans (1:1) mixture, as a yellow oil.