Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1O
Yield: 92 %

Procedure:
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto. The reaction mixture was stirred at room temperature for 7 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:30])[NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:28][CH3:29])([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:30][C:20]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH2:28][CH3:29])=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Reactant: CCN1CCCCC1NC(N)=C[N+](=O)[O-]
Product: CCN1CCCCC1NC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 40 grams of 2-nitro-N-(N-ethylpiperidinyl)-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 95°-98° C.; spectrophotometric analyses confirm its structure.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[S:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:14][CH:13]=1)=[O:21]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Yield: 96 %

Procedure:
Methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate (4.630 g, 11.502 mmol) was take up in DCM (50 ml) and treated with trifluoroacetic acid (44.40 g, 389.405 mmol) at r.t for 4 h. The mixture was evaporated and azeotroped with toluene. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 3.825 g of [4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl-)phenoxy]acetic acid (yield for two steps 63.9% overall).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cc4)sc23)c(F)c1
Temperature: 60 °C
Yield: 94.4 %

Procedure:
To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was added morpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4 hours at 60° C., the solvent was removed under reduced pressure and the residual solid was triturated with EtOAc and collected by filtration. It was further washed with EtOAc until no color was observed in the filtrate, to form the title compound 53 (800 mg, 94% yield), which was used without additional purification. 1HNMR (DMSO) δ (ppm): 8.57 (d, J=4.7 Hz, 1H), 8.46 (dd, J=2.7 and 10.4 Hz, 1H), 8.18 (m, 1H), 8.07 (s, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.71 (t, J=8.02 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m, 2H), 2.50 (m, 2H).
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C1([C:25]2[C:26]3[CH:27]=[CH:28][C:29]([C:49]([O:51][CH3:52])=[O:50])=[CH:30][C:31]=3[N:32]3[CH2:38][C:37](C(OC)=O)=[CH:36][C:35]4[CH:43]=[C:44](OC)[CH:45]=[CH:46][C:34]=4[C:33]=23)CCCCC1>C1COCC1>[CH:46]1[C:34]2[C:33]3=[CH:25][C:26]4[CH:27]=[CH:28][C:29]([C:49]([O:51][CH3:52])=[O:50])=[CH:30][C:31]=4[N:32]3[CH2:38][CH:37]=[CH:36][C:35]=2[CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrabutylammonium hydroxide (1M in MeOH, 2.2 mL, 2.2 mmol) was added to a stirring solution of dimethyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (1.0 g, 2.2 mmol) in THF (75 mL) and stirred at rt overnight. The reaction mixture was concentrated to ˜30 mL, diluted with EtOAc (120 mL), washed with 0.5 M HCl (aq.) (2×50 mL) and brine (40 mL), dried (MgSO4), filtered and concentrated to dryness to yield methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 3-methoxy, 6-carboxylic acid (1.0 g, 2.2 mmol, quant.) as a yellow solid which was used without further purification. LCMS: m/e 446 (M+H)+, ret time 1.54 min, column A, 2 minute gradient.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]([O:12][CH3:13])=[CH:6][C:7](OC)([CH3:9])[CH:8]=1.C1C=CC=CC=1.C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[CH3:13][O:12][C:5]1[C:4](=[O:14])[C:3]([O:2][CH3:1])=[CH:8][C:7](=[CH2:9])[CH:6]=1
Reactant: COC1=CC(C)(OC)C=C(OC)C1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C1C=C(OC)C(=O)C(OC)=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 198 mg quantity of 2,4,6-trimethoxy-4-methyl-2,5-cyclohexadienone and 10 ml of benzene were dissolved in 10 ml of concentrated sulfuric acid, and stirred at room temperature for 2 hours. Thereafter the solution was neutralized by adding sodium hydrogen carbonate to the solution and filtered. The filtrate was concentrated at reduced pressure. The residue was extracted with dichloromethane, the solvent was removed at reduced pressure and the resulting residue was concentrated, thereby recovering 158 mg of an oily crude product. The crude product was purified by silica gel column chromatography using a 20:1 benzene-ethyl acetate mixture, giving 153 mg of 2,6-dimethoxy-4-methylidene-2,5-cyclohexadienone in 92% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OO
Reactant: COc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1OC
Product: COc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 2 from 8-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: CC([C:4]1[C:12]2[O:11][C@H:10]3[CH2:13][C@@H:14]([OH:26])[C@H:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=O.C(=O)([O-])O.[Na+].ClC1C=CC=[C:35]([C:39]([O:41]O)=[O:40])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:39]([O:41][C:4]1[C:12]2[O:11][C@H:10]3[CH2:13][C@@H:14]([OH:26])[C@H:15]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])[C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:40])[CH3:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cccc2c1O[C@H]1C[C@@H](O)[C@H](NS(=O)(=O)c3ccccc3)[C@@H]21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1O[C@H]1C[C@@H](O)[C@H](NS(=O)(=O)c3ccccc3)[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
(1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta [b]benzofuran-5-yl methyl ketone (111) (219 mg) was dissolved in methylene chloride (4 ml) followed by the addition of sodium hydrogencarbonate (197 mg, 2.3 mmol) and metachloroperbenzoic acid (potency: 70%, 289 mg) and stirring for 2 hours at room temperature. A 3% aqueous solution of sodium sulfite (15 ml) was added to the reaction mixture followed by extraction with methylene chloride (15 ml+10 ml×2). The organic layer was washed with water (15 ml) and saturated brine (15 ml) and concentrated after drying with anhydrous magnesium sulfate. The residue was purified with column chromatography (silica gel: cyclohexane/ethyl acetate 1:2) to obtain (1R, 2R, 3aS, 8bR)-1-benzenesulfonamido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl acetate (190 mg).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:3]
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCc1ccccc1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (obtained in Example 23(4)) (4.1 mg), 1-bromo-3-phenylpropane (7 mg), and potassium carbonate (4 mg) in N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed twice with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a colorless gummy oil of 1-{(2S,3R)-2-hydroxy-5-[2-(3-phenylpropoxy)phenyl]-3-pentyl}imidazole-4-carboxamide (4.9 mg).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a stirred solution of 300 mg of 2'-hydroxy-4,4',6'-trimethoxychalcone in 12 ml of pyridine were added 65 mg of p-(dimethylamino)-pyridine and 165 mg of pivaloyl chloride. After being stirred at room temperature for 4 hours, the reaction mixture was poured into 30 ml of ice-water. The mixture was acidified with hydrochloric acid and then extracted with 50 ml of ethyl acetate. The ethyl acetate extract was successively washed with 0.2N hydrochloric acid, 10% aqueous sodium carbonate and water, dried over sodium sulfate and then evaporated to give 440 mg of 2',4,4'-trimethoxy-6'-(pivaloyloxy)-chalcone;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCCO)cc2n1
Yield: 72 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using ethanolamine instead of aminomethylcyclopropane, to the title compound (78 mg, 72%) which was obtained as a light yellow foam. MS: m/e=363.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH2:14][C:15]([O:17]C)=[O:16])[NH:5][C:6]([O:8][C:9]1([CH3:13])[CH2:12][CH2:11][CH2:10]1)=[O:7].S(=O)(=O)(O)O>CO>[CH3:13][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:19])=[O:2])[CH2:14][C:15]([OH:17])=[O:16])=[O:7])[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC1(OC(=O)N[C@@H](CC(=O)O)C(=O)O)CCC1

Procedure:
An example of the use of the novel N-protected-α-amino acid compounds of this invention in peptide synthesis is the preparation of α-aspartyl-phenylalanine methyl ester, a known sweetening agent. The dipeptide is conveniently prepared by coupling N-(1-methylcyclobutyloxycarbonyl) aspartic anhydride with phenylalanine methyl ester hydrochloride. Introduction of the N-(1-methylcyclobutyloxycarbonyl blocking group into aspartic acid is accomplished by reacting 1-methylcyclobutylchloroformate with aspartic acid dimethyl ester in accordance with the process of this invention. Equimolar quantities of the chloroformate and aspartic acid dimethyl ester are reacted in chloroform at 0°C. at pH 8. Reaction is carried out by portion-wise addition of 1-methylcyclobutyl chloroformate to the aspartic acid suspended in chloroform. Triethylamine is added to the reaction during the addition to maintain pH 8. After allowing the reaction to run to completion at room temperature, the reaction mixture is treated according to the procedure outlined above to afford the N-(1-methylcyclobutyloxycarbonyl) aspartic acid dimethyl ester. The free acid is obtained by saponifying the ester in a basic aqueous methanol solution. After acidifying the reaction mixture with sulfuric acid, the N-(1-methylcyclobutyloxycarbonyl) aspartic acid is isolated by extraction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Yield: 105.1 %

Procedure:
tert-Butyl [3-(3-amino-4-nitrophenoxy)phenyl]carbamate (5.51 g, 15.6 mmol) and 10% palladium-carbon (875 mg) were dissolved in tetrahydrofuran (20 mL) and methanol (100 mL), and the mixture was stirred at room temperature for 18 hr under a hydrogen atmosphere (3 atm). Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.17 g) as a purple amorphous substance.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1)[CH3:12]>O1CCCC1>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:15]=1)[CH3:12]
Reactant: OCc1ccccc1
Reactant: CCOc1cc(C)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(Cc2ccccc2)n1

Procedure:
To benzyl alcohol (Compound II-64) (0.35 g, 0.0016×2.0 mol) in tetrahydrofuran, sodium hydride (0.085 g, (60% in mineral oil), 0.0016×1.3 mol) and 4-ethoxy-6-methyl-2-(methylsulfonyl)pyrimidine (Compound III-44) (0.35 g, 0.0016 mol) prepared as described in Reference synthesis example 1 below were successively added and the solution was allowed to react for about 1 hour at room temperature.
Reaction SMILES: C(=O)(O)[O-].[Na+].[O:6]=[C:7]1[N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:14][CH2:13][C:8]21[NH:12][CH2:11][CH2:10][CH2:9]2.[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>O.CC(C)=O>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([N:12]3[C:8]4([CH2:13][CH2:14][N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:7]4=[O:6])[CH2:9][CH2:10][CH2:11]3)=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C[C@@H](C(=O)O)N1CCC2(CCCN2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](C(=O)O)N1CCC2(CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Reaction time: 18 h
Yield: 72.1 %

Procedure:
Excess solid sodium bicarbonate was added to (S)-2-(6-oxo-1,7-diazaspiro[4.4]non-7-yl)propionic acid (0.42 g) in water (2 ml) and then 9-fluorenylmethyl succinimidyl carbonate (0.7 g) in acetone (3 ml) was added. The mixture was stirred for 18 hours. The mixture was then added to water (10 ml), extracted with ether (10 ml) and the aqueous layer separated. (The ether extracts were discarded). The pH of the aqueous layer was adjusted to ˜3 with concentrated hydrochloric acid and then it was extracted with dichloromethane (2×10 ml). The combined extracts were separated, dried (MgSO4) and evaporated to give (S)-2-[1-(9-fluorenylmethyloxycarbonyl)-6-oxo-1,7-diazaspiro[4.4]non-7-yl]propionic acid (0.62 g) as a white foam; NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.3 (2d, 3H), 1.6-2.0 (m, 6H), 3.05 (m, 1H), 3.2-3.45 (m, 3H) 4.2-4.4 (m, 1H), 4.5 (m, 1H), 6.2 (s, 2H), 7.35 (m, 4H), 7.8 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:33][CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[O:44][CH3:45])[CH2:35]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:45][O:44][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[CH2:42][CH2:43][CH:34]([CH2:33][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13]1)[CH2:35]2
Reactant: COc1cccc2c1CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A suspension of 6-diphenylmethyl-3(2H)-pyridazinone (0.58 g) and sodium hydride (60%, 110 mg) in dry N,N-dimethylformamide (7 ml) was stirred at 0° C. for 30 minutes. A solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methyl p-toluenesulfonate (0.77 g) in dry N,N-dimethylformamide (5 ml) was added dropwise to the suspension at room temperature. The mixture was stirred for 6 hours and poured into ice-1N hydrochloric acid and extracted with ethyl acetate. The extract was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate =5:1~3:1) to give 2-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.61 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Cl
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A 1 L 4-necked flask equipped with thermometer and mechanical stirrer (operating at 150 RPM) was charged with 2-chloro-5-iodobenzoic acid (14.1 g, 0.05 mol), DCM (70.5 mL) and oxalyl chloride (5.5 mL, 0.06 mol). After stirring for 10 min, the mixture was cooled to 10 to 15° C. and DMF (0.15 mL, 1.92 mmol) was added by syringe over 10 min in two bolus of 0.1 and 0.05 mL while keeping the reaction temperature below 20° C. After the addition was completed, the mixture was warmed to 25° C. and stirred for 16 h. The mixture was concentrated and the residue was dried under vacuum at 30° C. for 5 h to give 15.0 g of product as a white solid. Yield: 100%. LCMS-0013: 99% Purity. 1H NMR (CDCl3, 400 MHz): 8.33 (d, J=2.4 Hz, 1H), 7.81˜7.84 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C@:7]12[CH2:15][NH:14][CH2:13][C@H:12]1[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:8]2.Cl[C:26]1[N:31]=[C:30]([C:32]([OH:35])([CH3:34])[CH3:33])[C:29]([F:36])=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:36][C:29]1[C:30]([C:32]([OH:35])([CH3:33])[CH3:34])=[N:31][C:26]([N:14]2[CH2:13][C@@H:12]3[C@@:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)([N:8]=[C:9]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:10][CH2:11]3)[CH2:15]2)=[N:27][CH:28]=1
Reactant: O=C(NC1=N[C@@]2(c3cnccn3)CNC[C@H]2CS1)c1ccccc1
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cnccn3)C2)ncc1F
Temperature: 110 °C
Yield: 98.3 %

Procedure:
N-[(4aR,7aR)-7a-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (231 mg, 0.680 mmol) is dissolved in 1,4-dioxane (4 mL). 2-(2-Chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (648.60 mg, 3.40 mmol) and diisopropylethylamine (653 μL, 3.74 mmol) are added. The reaction is heated at 110° C. for 6 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (330 mg, 98%). ES/MS (m/e): 494 (M+1).