Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:45]1(C)C=CC=CC=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH3:45])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 3 h

Procedure:
To 30 mg of 4-((S)-4-Carboxy-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester, 2 ml of methanolic hydrochloric acid was added at RT and stirred for 3 h. Then, 10 ml of toluene was added and the solvents were removed under reduced pressure and the product was lyophilized to yield a white solid. Yield: 25 mg MS (ES+): m/e=614.
Reaction SMILES: Cl.C([NH:9][C:10]12[CH2:17][CH2:16][C:13]([C:18]3[C:22]4=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=[C:21]4[NH:20][N:19]=3)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[C:18]1([C:13]23[CH2:16][CH2:17][C:10]([NH2:9])([CH2:15][CH2:14]2)[CH2:11][CH2:12]3)[C:22]2=[C:23]3[CH:29]=[CH:28][NH:27][C:24]3=[N:25][CH:26]=[C:21]2[NH:20][N:19]=1
Reactant: c1ccc(CNC23CCC(c4n[nH]c5cnc6[nH]ccc6c45)(CC2)CC3)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2
Temperature: 65 °C
Yield: 70.5 %

Procedure:
To a solution of N-benzyl-4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine hydrochloride (0.150 g, 0.368 mmol) in MeOH (6 mL) was added ammonium formate (0.116 g, 1.84 mmol) and 20% PdOH2 on carbon (0.039 g, 0.055 mmol). The reaction mixture was heated at about 65° C. for about 2 h. The reaction mixture was filtered through a pad of Celite® while washing with EtOAc (about 10 mL) and the solvent was removed under reduced pressure. Water and EtOAc (10 mL each) were added and the layers were separated. The aqueous layer was extracted with EtOAc (5×5 mL) and the combined organics were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine (0.073 g, 71%) as an off white foam: LC/MS (Table 1, Method b) Rt=1.08 min; MS m/z: 282 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9]O)[CH:7]=1.P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][Br:13])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: O=c1ccc(Br)cn1CCO
Solvent: ClCCl
Product: O=c1ccc(Br)cn1CCBr
Temperature: 40 °C

Procedure:
To a solution of 5-bromo-1-(2-hydroxyethyl)pyridin-2(1 H)-one (460 mg, 2110 μmol) in CH2Cl2 (5 mL) at 0° C. under nitrogen was added phosphorous tribromide (595 μL, 6329 μmol). A precipitate formed at 0° C. The reaction mixture was heated at 40° C. for 3 days. The mixture was partitioned between CH2Cl2 and 5% NaHCO3 (vigorous gas evolution). The aqueous was extracted with CH2Cl2 (2×10 mL). The combined organics were dried over MgSO4, and concentrated to a white solid. MS (ESI pos. ion) m/z (MH+): 279/281/283. Calc'd exact mass for C7H7Br2NO: 278.
Reaction SMILES: [C:1]1([C:7]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:1]1([C:7]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH:9][C:20](=[O:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCC(CN)(Cn1cncn1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC(CNC(C)=O)(Cn1cncn1)c1ccccc1
Yield: 89.3 %

Procedure:
To a 100 mL flask stirring under nitrogen was charged 2.58 g (0.010 mole) of 2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]-1-hexylamine and 15 mL of acetic anhydride. To the mixture was added 1.5 mL of pyridine and the reaction was stirred at room temperature for 3 hours. After GLC indicated the reaction was complete, it was quenched with 20 mL of water and 100 mL of ether after the acetic anhydride and pyridine were removed under vacuum. The residue was dissolved in ether and washed with 2×50 mL water and 2×50 mL of saturated sodium bicarbonate. The organic phase was dried, concentrated and gave 2.68 g (89.3% yield) of a solid, melting point 112°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[C:8](/[CH2:31][CH3:32])=[C:9](\[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1)/[C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([F:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl>[C:28](/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[C:9](/[C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([F:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)=[C:8](\[C:7]2[CH:6]=[CH:5][N+:4]([O-:41])=[CH:3][C:2]=2[Cl:1])/[CH2:31][CH3:32])=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1cc(F)c2[nH]ncc2c1)c1ccncc1Cl
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1cc(F)c2[nH]ncc2c1)c1cc[n+]([O-])cc1Cl
Reaction time: 15 h

Procedure:
A mixture of (E)-3-(4-((E)-2-(3-chloropyridin-4-yl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (14.1 mg, 0.031 mmol, Compound 245), mCPBA (11 mg, 0.048 mmol), and dichloromethane (0.5 mL) was stirred vigorously for 15 h. Additional starting material (20 mg, 0.045 mmol) and mCPBA (15 mg, 0.065 mmol) were added and stirring was continued for 3 d. The reaction was concentrated and then purified by reverse-phase HPLC(CH3CN, H2O, TFA) to give 4-((E)-1-(4-((E)-2-carboxyvinyl)phenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-2-yl)-3-chloropyridine-1-oxide. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H), 8.25 (d, 1H), 8.16 (dd, 2H), 7.56 (s, 1H), 7.50-7.42 (m, 4H), 7.05-6.96 (m, 3H), 6.43 (d, 1H), 2.41 (q, 2H), 0.94 (t, 3H); LCMS: 464.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][C:13]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)NC(C)(C)C)c12

Procedure:
This compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and tert-butylamine by following the similar procedure as described for Intermediate-11a.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:31]12[C:38](=[O:39])[O:37][C:35](=[O:36])[C@@H:32]1[CH2:33][CH2:34]2>>[CH2:1]([N:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH2:10]1)[C:38]([CH:31]1[CH2:34][CH2:33][CH:32]1[C:35]([OH:37])=[O:36])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)[C@@H]2CC[C@H]12
Reactant: Cc1cccc(-c2nc(COCC3CCCC(NCc4ccccc4)C3)c(C)o2)c1
Product: Cc1cccc(-c2nc(COCC3CCCC(N(Cc4ccccc4)C(=O)C4CCC4C(=O)O)C3)c(C)o2)c1

Procedure:
Analogous to the reaction conditions of example 1, benzyl-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyl]amine and cis-cyclobutane-1,2-dicarboxylic anhydride give 2-{benzyl-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyl]carbamoyl}cyclobutanecarboxylic acid. C32H38N2O5 (530.67), MS (ESI): 531 (MH+).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[BrH:19]>C(O)(=O)C>[BrH:19].[CH3:18][C:16]1[N:15]=[CH:14][N:13]([C:4]2[C:3](=[O:2])[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Temperature: 25 °C

Procedure:
A solution of C2 (3.82 g, 15.9 mmol) in acetic acid (30 mL) and aqueous hydrobromic acid (48%, 30 mL) was heated at reflux for 4 hours. The reaction was allowed to cool to room temperature, and then chilled in an ice bath; the resulting precipitate was collected via filtration and washed with ice water (30 mL). Recrystallization from ethanol (20 mL) provided the title compound as a light yellow solid. Yield: 3.79 g, 12.6 mmol, 79%. LCMS m/z 220.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 12.6 (ν br s, 1H), 9.58-9.60 (m, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.88-7.91 (m, 1H), 7.09 (d, J=7.4 Hz, 1H), 2.34 (br s, 3H).
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2S[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=2[C:26]([OH:28])=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.N1(C(OC(C)(C)C)=[O:36])CCNCC1>>[C:20]1([C:18]2[O:36][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH2:9][CH2:10]3)=[C:16]([C:26]([OH:28])=[O:27])[N:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2sc(-c3ccccc3)nc2C(=O)O)CC1
Product: O=C(O)c1nc(-c2ccccc2)oc1CN1CCCC1
Yield: 38 %

Procedure:
The title compound was prepared by the procedure described for 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylic acid substituting pyrrolidine for t-butyl piperazine-1-carboxylate in 38% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[O:10].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)Cl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[O:26]
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1Br
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(F)cc1C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.95 g (10 mmol) of (2-amino-5-fluorophenyl)(2-bromophenyl)methanone in 50 mL of methylene chloride was layered with 50 mL of saturated sodium bicarbonate solution. Bromoacetyl bromide, 1.35 mL (15 mmol) was added to the organic layer and the mixture was stirred at room temperature for 15 minutes. The organic layer was separated, dried and evaporated. The residue was crystallized from ether/hexane to yield 3.85 g of product having the above formula with m.p. 110°-114° C. For analysis, a sample of product was recrystallized from ether/hexane to leave colorless crystals with m.p. 113°-115° C.
Reaction SMILES: C1CO[C:8]2([NH2:9])[N:3]([C:4]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[O:21][C:20]([CH2:22][OH:23])=[CH:19][C:18]=4[CH:24]=3)=[N:5][CH:6]=[C:7]2[F:12])O1.CC(C[AlH]C[CH:31]([CH3:33])[CH3:32])C>>[F:12][C:7]1[C:8]([NH:9][C:32]2[CH:31]=[CH:33][CH:22]=[C:20]([OH:21])[CH:19]=2)=[N:3][C:4]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([CH2:22][OH:23])=[CH:19][C:18]=3[CH:24]=2)=[N:5][CH:6]=1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OCc1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N-2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.06 (d, 1H, J=3.9 Hz), 8.01 (d, 1H, J=1.8 Hz), 7.41-7.35 (m, 2H), 7.26 (d, 1H, J=8.1 Hz), 7.11-7.05 (m, 2H), 6.60 (s, 1H), 6.51 (dd, 1H, J=2.4 and 8.4 Hz), 5.41 (t, 1H, J=6.0 Hz), 4.51 (d, 2H, J=5.7 Hz); LCMS: ret. time: 16.21 min.; purity: 95%; MS (m/e): 367 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:17][N:16]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C=NO)ccc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methyl 5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylamine hydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75 mmol) were combined in a ethanol/water mixture (1:1, 40 mL) and stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was poured in to ice water and extracted with methylene chloride (2×). The combined organic layers were washed with brine (2×), dried over sodium sulfate and concentrated to afford 1.04 g (97%) which was used without purification. LC/MS (HPLC method 3): tR=1.63 min, 210.06 (MH)+.
Reaction SMILES: [OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.F[C:14]1[C:23]([N+:24]([O-])=O)=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1>>[CH3:6][C@:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:5])[NH:24][C:23]2[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([C:27]([F:30])([F:28])[F:29])=[CH:15][C:14]=2[O:1]1
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Product: COC(=O)c1cc2c(cc1C(F)(F)F)O[C@@](C)(c1ccccc1)C(=O)N2

Procedure:
Using (2S)-2-hydroxy-2-phenylpropanoic acid and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)-benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34](Cl)=[O:35]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][NH:17][C:34]([C:26]3[O:25][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[CH:27]=3)=[O:35])[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3cc4ccccc4o3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 78 %

Procedure:
C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (141 mg, 0.600 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL) containing triethylamine (167 μL, 1.20 mmol). Benzofuran -2-carbonyl chloride (108 mg, 0.600 mmol) was then added and the reaction mixture was allowed to stir for 16 hours. The reaction mixture was filtered, evaporated to dryness, and purified by column chromatography on silica gel using a gradient of 5-50% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.1775 g, 0.4678 mmol, 78.0%) ESI-MS m/z calc. 379.5, found 380.2 (M+1)+. Retention time of 3.36 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.57-2.03 (m, 8H), 3.46 (d, J=6.4 Hz, 2H), 3.72 (s, 6H), 6.81-6.89 (m, 3H), 7.31 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.94 (t, J=6.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 23.1, 35.3, 47.2, 51.8, 55.5, 109.2, 111.5, 111.6, 111.7, 118.8, 122.6, 123.6, 126.7, 127.1, 139.3, 147.1, 148.3, 149.1, 154.1, 158.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2].[Na+].[C:17]([O:23][CH2:24]Br)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)P(N(C)C)(N(C)C)=O.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH2:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C:6]=1[C:13]([O:15][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C(C(=O)[O-])N2C(=O)CC2C1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)OC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (23 mg) and bromomethyl pivalate (29 mg) in hexamethylphosphoramide (0.5 ml) is stirred at room temperature and under a N2 atmosphere for 2.5 hrs. The mixture is diluted with toluene (10 ml), washed with H2O (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residue is purified by silica gel plc to afford pivaloyloxymethyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.NC(N)=[S:13].O1CCCC1>O>[SH:13][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1nsc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nsc(S)n1
Reaction time: 6.5 h
Yield: 92.4 %

Procedure:
A mixture of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (7.80 g), thiourea (3.32 g), tetrahydrofuran (24 ml) and water (8 ml) was gently boiled for 6.5 hours. The reaction mixture was post-treated according to conventional manner to give yellow powder of methyl 5-mercapto-1,2,4-thiadiazole-3-carboxylate (7.1 g), mp. 126° to 127° C.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: [Na+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 10 %

Procedure:
p-Acetaminophenol 15 g, and sodium carbonate 60 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 185° C., maintained for 24 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve sodium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 10%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH2:11])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2].[N-:15]=[C:16]=[O:17].[K+]>O.C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH:11][C:16]([NH2:15])=[O:17])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: [N-]=C=O
Reactant: NCCNc1ccc([N+](=O)[O-])cc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 2 h
Yield: 92.4 %

Procedure:
100 g (0.46 mole) of 4-nitro-2-chloro-N-(β-aminoethyl) aniline is dissolved in a liter of water to which 29 cm3 of acetic acid has been added. 41.3 g (0.51 mole) of potassium isocyanate is added to this reaction mixture, which is then left at the ambient temperature for 2 hours. Drying yields 110 g of 4-nitro-2-chloro-N-(β-ureidoethyl) aniline which, after washing with dilute acetic acid and with water, followed by recrystallization in nitromethane, melts at 188° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18]([CH:32]=O)=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].FC(F)(F)COP([CH2:51][C:52]([O:54][CH3:55])=[O:53])(=O)OCC(F)(F)F.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18](/[CH:32]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN(C)C(=O)C1CCCN(c2nc3cc(C(=O)Nc4nc(C(C)(C)C)cs4)ccn3c(=O)c2C=O)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(N2CCCC(C(=O)N(C)C)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
The N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-{3-[(dimethylamino)carbonyl]-piperidino}-3-formyl-4-oxo-4 H-pyrido[1,2-a]pyrimidine-8-carboxamide (84.2 mg, 0.18 mmol) obtained in (B) was dissolved in tetrahydrofuran (10 ml), added with lithium chloride (45.3 mg, 1.07 mmol), and added dropwise with bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (112.9 μl, 0.53 mmol) and 1,8-diazabicyclo-[5,4,0]undec-7-ene (73.4 μl, 0.53 mmol). After the reaction solution was stirred at room temperature for 2 hours, the solvent was evaporated, and the residue was purified by preparative TLC (chloroform:methanol=20:1, v/v) to obtain the title compound (63.7 mg, 68.2%) as a mixture of orange oil and solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]=O)[CH:22]=1>>[CH3:30][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(CC=O)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1cccc(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and m-Tolyl-acetaldehyde following the procedure of Example 457: MS (ES) m/z 378.0; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.1263.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[C:9]([OH:16])[CH:8]=[C:7]([OH:17])[C:6]=1[C:18](=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=O)C.[OH-].[K+].Cl>CO>[OH:4][C:5]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[C:9]([OH:16])[CH:8]=[C:7]([OH:17])[C:6]=1[C:18](=[O:28])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1
Reactant: CC(=O)Oc1c(CC=C(C)C)c(O)cc(O)c1C(=O)CCc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCc1c(O)cc(O)c(C(=O)CCc2ccc(O)cc2)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
To 10 ml of a methanol solution of 500 mg of the 1-[2-acetoxy-4,6-dihydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-hydroxyphenyl)-1-propanone obtained in Specific Example 24 was added an aqueous solution of potassium hydroxide (1.5 g/5 ml), and the mixture was stirred at room temperature for 45 minutes. After the reaction, the reaction mixture was carefully neutralized wit dilute hydrochloric acid, extracted with 300 ml of ethyl acetate, washed with water (100 ml×4 times), shaken with a saturated aqueous solution of sodium chloride (100 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was recrystallized from a mixed solvent of chloroform and methanol to obtain 325 mg (yield=73.0%) of 1-[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless prism.