Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[NH:13][CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[NH:13][CH:12]=[CH:11][C:10]1=2)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]ccc21
Yield: 44.3 %

Procedure:
A mixture of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.026 ml), water (0.026 ml) and ethanol (10 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 4N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 1) (70 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:19][CH:20]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccccc1SNc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC(=O)N(Sc1ccccc1[N+](=O)[O-])c1ccc(Cl)cc1)c1c(F)cccc1F
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g of 2,6-difluorobenzoyl isocyanate in 15 ml of dry toluene was added over 15 minutes to a stirred solution of 2.8 g of N-(4-chlorophenyl)-2-nitrobenzenesulphenamide in 35 ml of the same solvent at room temperature. After stirring overnight, the reaction was incomplete. A few drops of triethylamine were added, and after a further 24 hours, the reaction mixture was cooled to -5° C. and filtered, and the pale yellow product was washed with cold toluene. Traces of toluene were removed by drying under reduced pressure at about 40° C. for 3 days, to give 5, as a solid, m.p.: 176°-178° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:57]=[C:58]([NH2:65])[C:59]4[CH:60]=[N:61][NH:62][C:63]=4[CH:64]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1>CN(C=O)C>[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:64]=[C:63]4[C:59]([CH:60]=[N:61][NH:62]4)=[C:58]([NH:65][C:11]([C:6]4[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=[CH:8][N:7]=4)=[O:13])[CH:57]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1
Reactant: CS(=O)(=O)c1cccnc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
To 3-(methylsulfonyl)-2-pyridinecarboxylic acid (which may be prepared as described by Blank, Benjamin; DiTullio, Nicholas W.; Owings, Franklin F.; Deviney, Linda; Miao, Clara K.; Saunders, Harry L. Journal of Medicinal Chemistry (1977), 20(4), 572-576.) (89 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (29 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:67]([O:71][CH3:72])(=[O:70])[CH:68]=[CH2:69]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](/[CH:69]=[CH:68]/[C:67]([O:71][CH3:72])=[O:70])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(/C=C/C(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 74.7 %

Procedure:
(2R,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.5 mmol), palladium(II) acetate (15 mg, 0.05 mmol), tri(o-tolyl)phosphine (36 mg, 0.1 mmol), triethylamine (0.2 mL, 1.5 mmol), and methyl acrylate (0.15 mL, 1.5 mmol) are dissolved in DMF (5 mL) and heated in a microwave at 150° C. for 30 minutes. The reaction mixture is filtered through Celite with EtOAc and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-((E)-2methoxycarbonyl-vinyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (225 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.O=[C:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[NH2:11][C:10]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[N:1]=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)c(C#N)n1
Product: CCOC(=O)c1c(C)nc2ccc(OC)nc2c1N

Procedure:
Prepared as in Example 2a from 3-amino-6-methoxypicolinonitrile (Example 11b) and ethyl 3-oxobutanoate as an off white solid (45%). MS 262 (MH+).
Reaction SMILES: C(N(CC)CC)C.N1(O)C2C=CC=CC=2N=N1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([OH:30])=O)=[CH:21][CH:20]=1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([NH:43][O:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)=[O:30])=[CH:23][CH:24]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Yield: 76.5 %

Procedure:
Triethylamine (5.49 g, 54.3 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (7.5 g, 49 mmol) were added to a solution of the (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (9.1 g, 27.1 mmol) in dichloromethane (100 mL). After 10 minutes O-tetrahydro-2H-pyran-2yl-hydroxylamine (4.6 g, 39 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (7.2 g, 38 mmol). After 12 h the reaction was quenched by the addition of saturated aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 7:3-6:4) afforded the title compound as a white solid (9.0 g, 76%). LCMS m/z 434.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.90 Hz, 6H) 1.69 (br. s., 3H) 1.78-2.06 (m, 1H) 2.27-2.55 (m, 2H) 2.59-2.72 (m, 1H) 3.03 (d, J=6.64 Hz, 3H) 3.50 (d, J=11.32 Hz, 1H) 3.95-4.22 (m, 1H) 4.97 (d, J=9.37 Hz, 1H) 7.22 (dd, J=8.39, 4.49 Hz, 2H) 7.49 (d, J=8.20 Hz, 2H) 11.36 (br. s., 1H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.BrP(Br)Br.[CH3:15][C:16]1[N:21]=[C:20]([SH:22])[N:19]=[C:18]([OH:23])[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][S:22][C:20]2[N:19]=[C:18]([OH:23])[CH:17]=[C:16]([CH3:15])[N:21]=2)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(C)c1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2c(C)ccnc2C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
(2,4-dimethylpyridin-3-yl)methanol was dissolved in dichloromethane (100 mL). Tribromophosphane (1.5 mL, 16 mmol) was added slowly. After 2 hours, the mixture was evaporated to dryness. The crude solid was dissolved in cold ethanol (100 mL), and 6-methyl-2-sulfanylpyrimidin-4-ol (1.13 g, 8.0 mmol) and triethylamine (4.5 mL, 32 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the crude solid was washed with THF (200 mL). After evaporation of solvent, the crude was purified by CombiFlash (0-6% MeOH in DCM) to provide 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.5 g, 64% yield); 1H NMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.68 (s, 3H), 2.84 (s, 3H), 4.62 (s, 2H), 6.05 (br, 1H), 7.71 (s, 1H), 8.62 (s, 1H); M+ 232.
Reaction SMILES: NC1S[C:4]2[C:9](=[O:10])[NH:8][C:7]([NH2:11])=[N:6][C:5]=2[N:12]=1.NC1NC(=O)C=C(N)N=1.[Br:22]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:11][C:7]1[NH:8][C:9](=[O:10])[C:4]([Br:22])=[C:5]([NH2:12])[N:6]=1
Reactant: Nc1nc2nc(N)sc2c(=O)[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Nc1cc(=O)[nH]c(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(N)c(Br)c(=O)[nH]1

Procedure:
FIG. 21 shows the method of synthesis of 2,5-diamino-6H-thiazolo[4,5-d]pyrimidin-7-one 14. 2,6-diamino-3H-pyrimidin-4-one 1 was reacted with Br2 in the presence of sodium acetate and acetic acid to produce 2,6-diamino-5-bromopyrimidin-4-one 13. 2,6-diamino-5-bromopyrimidin-4-one 13 was then reacted with CN2SH4 in ethanol to produce 2,5-diamino-6H-thiazolo[4,5-d]pyrimidin-7-one 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([O:16]C)=[O:15])[CH2:8][C:7]=2[CH:19]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH2:8][C:7]=2[CH:19]=1
Reactant: COC(=O)C(=O)N1CCSc2ccc(OC)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CN(C(=O)C(=O)O)CCS2
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.3 %

Procedure:
Compound 5 (740 mg) was dissolved in 30 mL of a mixture of THF, methanol and 1 M NaOH (1:1:1). The solution was stirred at r.t. for 6 hr and acidified with 1 N HCl. The organic solvent was removed and the resulting solid was collected and washed with water. The solid was dried under vacuum to give 600 mg solid with the yield of 85%.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1)[CH3:3].C(N(CC)CC)C.[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25](Cl)=[O:26])=[N:18]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[O:17]1[CH2:21][CH2:20][C:19]([C:22]2[C:23]([CH3:35])=[C:24]([CH:28]=[CH:29][C:30]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:25]([C:7]2[CH:6]=[N:5][N:4]([CH2:2][CH3:3])[C:8]=2[OH:9])=[O:26])=[N:18]1
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0.76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 183~184.5° C.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:25]=[O:26])[C:18]([SH:21])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Sc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=Cc1cc(Cl)ccc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
Tetramethylethylenediamine (TMEDA) (10.44 mL, 8.035 g, 69.15 mmol) was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol) and the solution was chilled to 0° C. A solution of 4-chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 mL) was added with stirring over 1 hour. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (2.94 mL, 2.78 g, 38.03 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 30 hours and became a powdery suspension. A mixture of 2 N HCl and ice was added to the reaction mixture until the pH became acidic (pH=1). During this addition, the mixture warmed and became first red and then pale yellow. This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear red-brown oil. This oil was triturated with hexanes yielding a red-brown semisolid. This semisolid was purified by plug flash chromatography over silica gel, eluting with 1:1, hexanes:dichloromethane to afford 5-chloro-thiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22]>C1COCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:21]([OH:22])[C:20]([CH3:24])([CH3:23])[CH3:19])([O-:10])=[O:9]
Reactant: CC(C)(C)C=O
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-iodo-2-nitrobenzene (3.0 g, 12 mmol) in anhydrous THF (30 mL) was cooled to minus 40° C., and then phenylmagnesium chloride (2 M in THF, 7.2 mL, 14.5 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. After the mixture was stirred for 20 minutes at minus 40° C., trimethylacetaldehyde (1.85 mL, 16.8 mmol) was added dropwise and the mixture was stirred for another 30 minutes at minus 40° C. The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (60 mL), poured into water (60 mL), and extracted with ethyl acetate three times (60 mL each). The combined organic phase was dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (1.82 g, 72%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 1 H, J=6.4 Hz, Ph-H), 7.76 (d, 1 H, J=6.4 Hz, Ph-H), 7.61 (t, 1 H, J=6.4 Hz, Ph-H), 7.39 (t, 1 H, J=6.4 Hz, Ph-H), 5.39 (d, 1 H, J=2.8 Hz, Ph-CH), 2.14 (d, 1 H, J=3.2 Hz, OH), 0.89 (s, 9 H, C(CH3)3).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O>Cl.O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[NH:21][N:22]=[N:23][CH:24]=1)=[O:19])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: COCCOCCO
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COCCOCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (100 mg, 245 μmol, 1.0 eq) was dissolved in 4 M of HCl in dioxane (0.6 mL) and 2-(2-methoxyethoxy)-ethanol (3 mL). The resulting mixture was stirred overnight at 65° C. The solvent was evaporated and AcOH was added. The product was then purified by preparative HPLC to yield the title compound (70 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H34N4O6, 511.25. found 511.4
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[NH2:10][CH2:11][C@H:12]([OH:14])[CH3:13]>O1CCOCC1>[CH2:7]([O:6][C:4]([NH:10][CH2:11][C@H:12]([OH:14])[CH3:13])=[O:5])[CH3:8]
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)NC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an amount of 246 mg of (R)-1-amino-2-propanol was dissolved in 5 ml of 1,4-dioxane, added with 722 ml of 5 N aqueous sodium hydroxide, then added with 345 μl of ethyl chloroformate, and stirred at room temperature for 30 minutes. The reaction mixture was added with water, and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 465 mg of (R)-1-ethoxycarbonylamino-2-propanol. Physicochemical Properties of this Compound
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1.CN(C=O)C>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (5.0 mL, 57.3 mmol) was added under nitrogen to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) in 150 mL of methylene chloride at room temperature. A catalytic amount of DMF (10 μL) was added and the reaction stirred at room temperature for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride (2.21 g, 99%) as a yellow solid that was used in the next step without additional purification
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0115 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(N(CCCC)CCCC)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 56.9 %

Procedure:
To a mixture of 314 mg (purity: 96.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 828 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added tributylamine (2.76 g) and 334 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 288 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 57%) and 2.5 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:11])=[CH:7][C:6]=2[C:5]([F:12])=[CH:4][CH:3]=1.[CH:13](=[O:16])[CH2:14][CH3:15].Cl>O1CCCC1>[F:12][C:5]1[C:6]2[CH:7]=[C:8]([CH3:11])[O:9][C:10]=2[C:2]([CH:13]([OH:16])[CH2:14][CH3:15])=[CH:3][CH:4]=1
Reactant: Cc1cc2c(F)ccc(Br)c2o1
Reactant: CCC=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(F)c2cc(C)oc12
Temperature: 10 °C
Yield: 68.9 %

Procedure:
A solution of 5.75 g (25.1 mmol) of 7-bromo-4-fluoro-2-methylbenzofuran in 90 ml of tetrahydrofuran was added dropwise to a suspension of 0.625 g (27.5 mmol) of Mg in 100 ml of boiling tetrahydrofuran and the mixture was stirred at reflux for 2.5 hours. Subsequently, it was cooled to 10° C., 2.75 ml (37.5 mmol) of propionaldehyde were added dropwise thereto and the mixture was stirred for 30 minutes. The mixture was poured into 200 ml of 1N hydrochloric acid and extracted three times with 150 ml of dichloromethane. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloro-methane/hexane 4:1). 3.6 g (55%) of 1-(4-fluoro-2-methyl-benzofuran-7-yl)-propan-1-ol were obtained as a pale yellow oil.