Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]=2[CH:22]=1)([O-])=O.C(=O)([O-])O.[Na+].C(Cl)Cl>C(OCC)(=O)C.[Fe]>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]=2[CH:22]=1
Reactant: CCOC(=O)Cc1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nsc2ccc(N)cc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 10% acetic acid solution (31.0 mL) is stirred at 50° C., treated with iron powder (0.656 g), treated dropwise with a solution of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (1.03 g, 3.88 mmol) in ethyl acetate, stirred at 50° C. for two hours, treated with additional iron powder (0.305 g), stirred at 50° C. for 15 minutes, and poured into saturated sodium hydrogen carbonate solution. The resultant aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and methylene chloride gives the title product as a yellow oil.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([OH:14])=[CH:12][C:11]=1[OH:17].[Cl:18][CH2:19][CH2:20][C:21](O)=[O:22]>O>[Cl:18][CH2:19][CH2:20][C:21]([C:15]1[CH:16]=[C:10]([Cl:9])[C:11]([OH:17])=[CH:12][C:13]=1[OH:14])=[O:22]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Cl)c(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C(CCCl)c1cc(Cl)c(O)cc1O
Temperature: 6 °C
Yield: 98.6 %

Procedure:
A 2-liter 4-neck round-bottom flask was charged with trifluoromethanesulfonic acid (500 g, 3.33 mol) and the flask contents were cooled below 10° C. 4-Chlororesorcinol (100 g, 0.69 mol) was added in portions over 20-30 minutes, maintaining the temperature at 4 to 8° C. The reaction mixture was stirred at or below 10° C. until a clear solution formed (40 minutes). 3-Chloropropanoic acid (78.8 g, 0.73 mol) was warmed until melted and then added in liquid form dropwise over 45 minutes to the flask, maintaining the temperature at or below 10° C. The reaction mixture was stirred for an additional 10 minutes at or below 10° C., then slowly heated to 50-55° C. and maintained there for 6 hours. The reaction mixture was cooled to ambient temperature and added dropwise to water (1.1 L) contained in a 3-liter 4-neck round-bottom flask. The resulting mixture was stirred at ambient temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water (3×540 mL), and dried in a fan dryer at 40° C. until the moisture content fell below 0.5%, to afford 3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one as an orange solid (160 g, 98.4% yield).
Reaction SMILES: N#N.[C:3]([C:6]1[S:10][C:9]([CH2:11][C:12]2[O:13][CH:14]=[C:15](C(N=[N+]=[N-])=O)[N:16]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].CC1(C2SC(C[C:34]3[O:35]C=C(C(N=[N+]=[N-])=O)[N:38]=3)=CC=2)OCCO1.[Cl:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][OH:48]>C1(C)C(C)=CC=CC=1>[Cl:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][O:48][C:34](=[O:35])[NH:38][C:15]1[N:16]=[C:12]([CH2:11][C:9]2[S:10][C:6]([C:3](=[O:5])[CH3:4])=[CH:7][CH:8]=2)[O:13][CH:14]=1
Reactant: CC1(c2ccc(Cc3nc(C(=O)N=[N+]=[N-])co3)s2)OCCO1
Reactant: OCc1ccccc1Cl
Reactant: CC(=O)c1ccc(Cc2nc(C(=O)N=[N+]=[N-])co2)s1
Agent: N#N
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc(Cc2nc(NC(=O)OCc3ccccc3Cl)co2)s1
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of a mixture of 2-(5-acetyl-thiophen-2-ylmethyl)-oxazole-4-carbonyl azide and 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-oxazole-4-carbonyl azide (138 mg) in xylene (0.5 mL) was heated to 140° C. for 5 min. 2-chlorobenzyl alcohol (144 mg, 1.00 mmol) was then added and the reaction mixture was further stirred at 140° C. for 5 min. The solvent was removed under reduced pressure. Purification of the residue by FC (20:1→1:1 hept-EA) followed by preparative HPLC gave the title compound as a white solid. LC-MS-conditions 07: tR=1.50 min, [M+H]+=391.10.
Reaction SMILES: C([C:4]1O[N:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)(=O)C.[ClH:13].C(O)(=O)C1[C:16](=CC=CC=1)[NH2:17].C(Cl)([Cl:26])=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>CO>[ClH:26].[Cl:13][C:7]([NH2:6])=[NH:17].[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:17][CH:16]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(=O)c1onc2ccccc12
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Product: N=C(N)Cl
Product: c1ccc2ncncc2c1

Procedure:
treating the acetylanthranil compound of step (4) with MeOH, followed by hydrochloric acid, to obtain a compound of the formula: ##STR46## (5a') treating the anthranilic acid of step (3) with phosgene or triphosgene to form a compound of the formula: ##STR47## which is further treated with methanol; (5b) reacting the product of step (5a) or (5a') with chloroformamidine hydrochloride to obtain a quinazoline compound of the formula: ##STR48## then subjecting the resulting quinazoline compound to a displacement reaction as set forth in step (6) discussed above to obtain a compound according to formula I.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(O)=O.CCO.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyloxy-1-nitro-4-trifluoromethylbenzene (1.0 g. 3.4 mmol) in 16 mL HOAc/EtOH (1:3) is added iron powder and the mixture is refluxed for 2 h. The mixture is cooled to RT and water is added and it is extracted with EtOAc. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound as a reddish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].O.C(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(Cl)c(Cl)c1
Yield: 82.2 %

Procedure:
A solution of 16.3 g (0.1 mole) of 3,4-dichlorophenol in 100 ml of toluene was heated at reflux utilizing a Dean-Stark trap to remove any water that may have been present. The solution was cooled in an ice bath, treated with 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate, and heated at reflux overnight. The solution was cooled in an ice bath, vigorously stirred, and treated dropwise with water until carbon dioxide evolution ceased. The solid which precipitated was collected by filtration, washed with water and benzene, dried, and recrystallized from benzene to yield 19.9 g (82%) of a white solid, mp 121°-123° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:26]=[C:27]([NH2:40])[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:40][C:27]2[CH:28]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:30]=[C:25]([O:24][C:23]3[CH:41]=[CH:42][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[CH:26]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 10.4 g (42.79 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (14.0 g, 42.79 mmol) were used to afford 12 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (1H, t), 3.1 (1H, m), 6.81 (1H, d), 7.04 (1H, s), 7.2 (6H, m) 7.91 (4H, dd), 10.0 (1H, s).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=O)[CH2:5][CH2:4]1.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].P(Cl)(Cl)(Cl)=O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1([C:6]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(C2(C(F)(F)F)CC2)s1
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (1 g, 6.5 mmol) and thiosemicarbazide (0.6 g, 6.5 mmol) in dioxane (8 mL) was heated to 90° C. To the hot reaction mixture was added phosphorus oxychloride (0.6 mL, 6.5 mmol). The reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was then cooled, diluted with ethyl acetate (10 mL) and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (15 mL), dried (Na2SO4), filtered and concentrated. The residue was triturated in hot hexanes to afford 0.5 g (37%) of the title compound. LC/MS (ESI+) m/z 210 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]>ClC(Cl)C>[Br-:11].[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:12][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)C[n+]2cccc3ccccc32)cc1
Product: [Br-]
Yield: 46 %

Procedure:
A solution of quinoline (931 μl, 7.72 mmol) and 2-bromo-4′-methyl-acetophenone (1.828 g, 7.71 mmol) in dichloroethane (6 mL) was refluxed for 1 hour. The resulting brown paste was triturated with ether and filtered. After recristallization from methanol the product was isolated in 46% yield: mp 230-233° C.; 1H NMR 500 MHz (DMSO-d6) δ 2.45 (s, 3H), 7.02 (s, 2H), 7.49 (d, 2H, J=7.9 Hz), 8.05 (d, 3H, J=7.9 Hz), 8.21 (m, 1H), 8.32 (dd, 1H, J=6.1, 7.9 Hz), 8.41 (d, 1H, J=9.2 Hz), 8.55 (d, 1H, J=8.2 Hz), 9.45 (d, 1H, J=8.2 Hz), 9.56 (d, 1H, J=5.5 Hz); Elem. anal. found: C, 63.00; H, 4.77; N, 4.09% (calcd for C18H16BrNO: C, 63.17; H, 4.71; N, 4.09%).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[CH2:10][CH2:11][CH:12]([C:31](N1C(C2C=CC=CC=2)COC1=O)=[O:32])[CH:13]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C.O1CCCC1>[Si:1]([O:8][CH:9]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[CH2:10][CH2:11][CH:12]1[C:31](=[O:32])[N:22]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)[CH:13]1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(Nc2ccc(C#N)cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitdle (2) were dissolved in 380 ml of methyl tert-butylether. 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. After the reaction ended, 10 ml of acetic acid were added, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel using toluene/ethyl acetate 50/1. This produced 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl )4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75 (C32H37FN2O3Si); MS (ESI): 545.56 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]([OH:12])CO)[CH2:3][CH2:2]1.[H-].[Na+]>C1COCC1>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH:8]2[CH2:9][O:12]2)[CH2:3][CH2:2]1
Reactant: OCC(O)CCC=CCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C(=CCC1CO1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-Cyclopropyl-hept-5-ene-1,2-diol (1.45 g, 9.28 mmol) in THF (30 mL) was added 60% sodium hydride (1.1 g, 27.84 mmol) at 0° C. The mixture was slowly warmed to room temperature and stirred for 1 h. TrisIm (3.41 g, 10.2 mmol) was added in one portion at 0° C. followed stirring at room temperature for 1.5 h. The mixture was quenched with water and extracted with Et2O. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (7% EtOAc in hexanes gradient to 14% EtOAc in hexanes) gave 2-(4-Cyclopropyl-but-2-enyl)-oxirane as a clear oil; 1H NMR(400 MHz, CDCl3): δ 5.54-5.48 (m, 1H), 5.44-5.37 (m, 1H), 2.94-2.91 (m, 1H), 2.75 (dd, 1H, J1=4.9 Hz, J2=4.1 Hz), 2.48 (dd, 1H, J=5.0 Hz, J2=2.7 Hz), 2.19 (q, 2H, J=7.3 Hz), 1.98 (t, 2H, J=7.0 Hz), 1.62-1.56 (m, 2H), 0.75-0.66 (m, 1H), 0.44-0.39 (m, 2H), 0.09-0.05(m, 2H).
Reaction SMILES: [O:1]=[C:2]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1.Cl[CH:24]([C:27]1([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][CH:34]=[CH:33]3)[CH2:29][CH2:28]1)[CH:25]=O>C(O)(C)C.CO>[O:1]=[C:2]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:24]([C:27]4([C:30]5[CH:31]=[C:32]6[C:37](=[CH:38][CH:39]=5)[N:36]=[CH:35][CH:34]=[CH:33]6)[CH2:29][CH2:28]4)=[CH:25][N:17]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(OCC(=O)N3CCCC3)cc2)cn1
Solvent: CC(C)O
Solvent: CO
Product: O=C(COc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)N1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 5-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-2-amine (23.9 mg, 0.08 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (19.6 mg, 0.08 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. overnight. The mixture was diluted with methanol, and purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=490.1.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[NH:22][C@@H:21]([C@@H:23]([OH:25])[CH3:24])[CH2:20][O:19][CH2:18]2)=[CH:13][CH:12]=1.N1C=CC=CC=1>O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:17]2[CH2:18][O:19][CH2:20][C@@H:21]3[C@H:23]([CH3:24])[O:25][C:1](=[O:5])[C:2](=[O:3])[N:22]23)=[CH:15][CH:16]=1
Reactant: C[C@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (833 μL) was added dropwise into a dichloromethane (15 mL) solution of (S)-1-[(3R,5R)-5-(4-chlorophenyl)morpholin-3 yl]ethanol (833 mg) and pyridine (4 mL). Stirring was continued for 30 minutes at the same temperature and for 1 hour at room temperature. Water was added to the reaction solution, and the organic layer was partitioned. The resultant was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (686 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15](OCC)=[O:16])=[C:7]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:12])([CH3:13])[C:9](=[O:14])[C:8]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])=[C:7]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A mixture of ethyl 8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.320 g, 0.803 mmol), glycine tert-butyl ester hydrochloride (0.175 g, 1.04 mmol), DIEA (0.280 mL, 1.61 mmol), and 1,4-dioxane (12 mL) were heated at 120° C. for 2 hours in a sealed vessel. The mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with water (30 mL) and then with brine (50 mL), dried over MgSO4, and concentrated and dried in vacuo. The residue was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give 1,1-dimethylethyl N-((8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.214 g). MS m/e=378 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]([NH:20]C(=O)OC(C)(C)C)[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:11]([C:29](=[O:45])[NH:30][C@H:31]([CH:37]([OH:44])[C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])[CH2:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH2:10]2)=[N:6][CH:7]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[NH2:20][C@@H:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]([N:12]1[CH2:13][C@H:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10][C@H:11]1[C:29]([NH:30][C@H:31]([CH:37]([OH:44])[C:38]([NH:40][CH:41]1[CH2:42][CH2:43]1)=[O:39])[CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1)=[O:45])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](N)C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Reaction time: 1 h

Procedure:
To tert-butyl (2S)-1-((2S,4R)-4-(5-chloro-pyridin-2-yloxy)-2-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (313 mg, 0.482 mmol) in dichloromethane (2 mL) was added 4.0 M HCl in dioxane (3.0 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure and dried to give (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-(5-chloro-pyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide HCl salt as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:33]([O:35]C)=[O:34])=[CH:29][C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[Na+].CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:33]([OH:35])=[O:34])=[CH:29][C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)cc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cc(Cl)cc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 73.5 %

Procedure:
A solution of methyl 2-butyl-5-chloro-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazol-7-carboxylate (0.28 g) in 1N NaOH (2 ml) and methanol (4 ml) was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and the concentrate was dissolved in water (10 ml), which was made acidic with 1N-HCl. Crystals thus separated were collected by filtration, recrystallized from methanol-chloroform to afford colorless crystals (0.2 g, 72%), m.p. 232-234° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.I.CS[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[NH:21]>C(O)C>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(ccn2C2CCOCC2)c1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2C2CCOCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 21 h
Yield: 31.5 %

Procedure:
Compound 89 (95 mg, 0.439 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (219.2 mg, 0.769 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 21 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (methanol:CH2Cl2, 5:95 to 7.5:92.5) to yield a pale yellow residue, 90 (45 mg, 31.5%). 1H NMR (DMSO-d6) δ 1.82-2.11 (m, 4H), 3.57 (t, 2H, J=11.0 Hz), 3.92-4.07 (m, 2H), 4.50-4.68 (m, 1H), 6.33 (brs, 2H), 6.37 (d, 1H, J=2.5 Hz), 6.71 (d, 1H, J=8.2 Hz), 7.00 (s, 1H), 7.09-7.11 (m, 1H), 7.45 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=8.6 Hz), 7.60 (d, 1H, J=4.8 Hz), 7.72 (d, 1H, J=2.7 Hz); ESI-MS (m/z, %): 326 (MH+, 100%); ESI-HRMS calculated for C18H20N3OS (MH+): 326.1321, observed: 326.1332.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16].C(O)(=O)C>C(OCC)C>[O:9]=[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: COC(=O)c1ccncc1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)CC(=O)c1ccncc1
Reaction time: 2 h

Procedure:
To a suspension of methyl isonicotinate (96.0 g, 0.7 mol) and sodium methoxide (45.4 g, 0.84 mol) in ethyl ether (1 l), acetone (81.3 g, 1.4 mol) was added dropwise at 25°~30° C. and stirring was continued for 2 hrs. under reflux. After cooling, acetic acid (50.4 g, 0.84 mol) was added to the reaction mixture, the organic layer was separated, washed twice with H2O, dried over anhydrous MgSO4 and evaporated. The residue (87.5 g) was distilled under reduced pressure to give the title compound as a pale yellow oil which solidified in the refrigerator; yield: 40.2 g; bp 135°~138° C./10 mmHg; mp 62°~64.5° C. (Lit. bp 118°~120° C.; mp 66.5°~67° C.; R. Levine, J. K. Sneed, J. Am. Chem. Soc., 73, 5614 (1951).). ##STR30##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][N:4]=1.[O-:16]Cl=O.[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1
Reactant: COc1ncc(C=O)c2c(C)cccc12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ncc(C(=O)O)c2c(C)cccc12

Procedure:
To a stirred solution of 1-methoxy-5-methylisoquinolin-4-carbaldehyde (Intermediate-7) (2 g, 10 mmol) in ACN—H2O (120 mL, 1:1) was added, NaClO2 (5.4 g, 59.7 mmol), NaH2PO4 (5.5 g, 40 mmol) and the mixture was stirred at RT overnight. It was then extracted with EtOAc (3×150 mL), dried over Na2SO4, filtered and concentrated to give the desired acid derivative (1.2 g, 56%).