Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([C:20]([OH:22])=O)[NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:12])[CH:3]=1.[C:23](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:20]([CH:9]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:22])[CH3:23]
Reactant: Cc1ccc(C(=O)NC(Cc2cccc(Br)c2)C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
1-Bromo-3-[2-carboxy-2-(p-toluoylamino)ethyl]benzene (16.84 g) was dissolved in 85 ml of pyridine, and 55 ml of acetic anhydride was added and stirred for 3 hours under argon atmosphere at 90–95° C. Water (55 ml) was added dropwise gradually so that the maximum temperature did not exceed 100° C., and the mixture was stirred for 20 minutes at 60–70° C. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with 10% hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution sequentially and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystals were washed with isopropyl ether to provide 13.31 g of the objective compound as brownish crystals. M.p. 106–107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=O)[NH:28][C:27]=1[CH3:39])=[O:25]>>[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([CH:37]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:39])=[O:25]
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN(C)C)c1-c1ccccc1
Yield: 44.2 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([Cl:3])=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (12 ml) and dimethylformamide (1 drop) were added to a solution of 4-benzyloxycarbonylaminomethylbenzoic acid (2.85 g) in dichloromethane (12 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to give 4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (5 ml), and the solution was dropwise added to a mixed solution of 4-amino-1H-pyrazolo[3,4-b]pyridine 2 trifluoroacetate (1.09 g) and diisopropylethylamine (1.7 g) in acetonitrile (10 ml-dimethylformamide (5 ml). The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The residue was extracted with ethyl acetate, dried and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 ml) and sodium methoxide (80 mg) was added, which was followed by stirring at room temperature for 4 hours. After the completion of the reaction, insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue and the mixture was extracted with chloroform:methanol=10:1. The extract was dried and the solvent was evaporated under reduced pressure. The obtained crystals were washed with ethyl acetate to give 540 mg of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-benzyloxycarbonylaminomethylbenzamide
Reaction SMILES: N1C=CN=CC=1[CH:7](C)[C:8]([OH:10])=[O:9].[CH3:12][C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1.ClC(Cl)(Cl)C=O.[OH-]>>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[CH:12]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: CC(C(=O)O)c1cnccn1
Reactant: Cc1cnccn1
Agent: O=CC(Cl)(Cl)Cl
Agent: [OH-]
Product: O=C(O)C=Cc1cnccn1

Procedure:
Scheme M depicts a specific synthesis of a pyrazinyl propionic acid. Methylpyrazine anion is condensed with trichloroacetaldehyde followed by treatment with base (hydroxide), then acidification to produce 3-(-Pyrazinyl) Acrylic Acid 75. This acid is then catalytically hydrogenated over palladium on charcoal to yield 3-(2-Pyrazinyl)propionic Acid 76.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[N+:6]([O-:22])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(C3CC3)cncc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(C2CC2)c2ccccc2c1
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of 4-cyclopropylisoquinoline (0.4 g, 2.364 mmol) in DCM (10 ml) was added m-CPBA (1.224 g, 7.09 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mass was diluted with DCM and washed with water and aqueous sodium bicarbonate solution. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get desired compound (0.35 g, 80%) as solid. The crude compound was taken further without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18]>>[C:19]1([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccccc1
Product: O=c1[nH]c2nccc(C#Cc3ccccc3)c2c2ccccc12
Yield: 68.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and ethynyl benzene (66 mg, 0.65 mmol) to provide 161 (87 mg, 67% yield) as a light-yellow solid. LC-MS (M+H=297, obsd.=297).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:16])[C:9]([CH2:12][C:13]([OH:15])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:29]([NH:32][C:13](=[O:15])[CH2:12][C:9]1[C:8](=[O:16])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: Cc1cccc2ncc(CC(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Cc1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture containing 2.18 g (0.01 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-acetic acid and 1.55 ml (0.011 mol) of triethylamine in 60 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.945 g (0.01 mol) of methyl chloroformate in 5 ml of chloroform is dropped to the above mixture at -12° C. during 7 minutes. After stirring for 5 minutes, 0.65 g (0.011 mol) of propylamine dissolved in 10 ml of chloroform is dropped to the above solution at -15° C. during 10 minutes. The reaction mixture is stirred at -15° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 40 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 40 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. After thoroughly triturating the residue with cold ethyl acetate, 0.8 g (30.9%) of the named compound is obtained, m.p.: 96°-98° C. after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]CN(CC)CC.S(Cl)(Cl)(=O)=O>CO>[CH3:11][O:9][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: CO
Product: COC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-2-pyrimidine carboxylic acid (6 g, 29.6 mmol) in MeOH (300 mL) was added Et3N (5.98 g, 59.2 mmol). The mixture was cooled to 0 degrees Celsius, and sulfonyl chloride (5.3 g, 44.4 mmol) was added dropwise to the solution. After addition, the mixture was stirred at rt for 12 hours. The solvent was removed and the residue was dissolved in ethyl acetate. The organic layer was washed with sodium bicarbonate, brine, and dried with sodium sulfate. The solvent was removed to give the pure product. MS: calc'd 217 (MH+), exp 217 (MH+).
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.C1C2C(=CC=CC=2)CCC1.[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: CO
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a mixture of 308 mg (purity: 98%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added tetralin (2.76 g) and 334 mg (5.67 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 324 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 64%) and 2.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br.Br[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[O:19]=[C:20]1[NH:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O-:30])=[O:29]>>[O:19]=[C:20]1[N:24]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O:30][CH3:2])=[O:29]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: BrCc1cccnc1
Agent: Br
Product: COC(=O)c1ccnc(N2CCN(Cc3cccnc3)C2=O)c1
Yield: 47 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with 3-(bromomethyl)pyridine hydrobromide to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 47% yield: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 8.56-8.54 (m, 2H), 8.36 (d, J=5.1 Hz, 1H), 7.69-7.66 (m, 1H), 7.46 (dd, J=5.4 Hz, 1.5 Hz, 1H), 7.30-7.26 (m, 1H), 4.50 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.92 (s, 3H), 3.39 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 156.9, 153.2, 149.6, 149.4, 148.0, 138.8, 136.0, 132.1, 123.8, 116.9, 112.5, 52.6, 45.5, 41.3, 41.2; MS (ES+) m/z 312.9 (M+1).
Reaction SMILES: N1C=CN=C1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.O1CCCC1>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si:20]([CH3:22])([CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
1.55 g of imidazole were added to a solution fo 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26][C:5]=1[C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7]>[Pd].C(O)(=O)C>[ClH:3].[C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)(=[O:7])[C:5]1[NH:26][C:27](=[O:31])[NH:28][C:29](=[O:30])[CH:4]=1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1[nH]c(=O)[nH]c(=O)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cl
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1cc(=O)[nH]c(=O)[nH]1

Procedure:
100 mg of 5% palladium on charcoal in 15 ml of glacial acetic acid are pretreated with hydrogen. Then a solution of 850 mg of 5-chloro-orotyl-L-histidyl-L-prolinamide in 30 ml of glacial acetic acid are added and the mixture is shaken in a hydrogen atmosphere at normal pressure and at room temperature. After consumption of 2 m moles of hydrogen the catalyst is filtered off, the filtrate evaporated to a small volume and treated with absolute ether. The precipitate is separated, washed with ether and dried to give orotyl-L-histidyl-L-prolinamide-hydrochloride in almost quantitative yield.
Reaction SMILES: [C:1]([Li])(C)(C)[CH3:2].[CH:6](NC(C)C)(C)C.[CH3:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16].C(I)CC.Cl>CCCCC.O1CCCC1>[CH3:13][C:14]([CH3:6])([CH2:18][CH2:1][CH3:2])[C:15]([OH:17])=[O:16]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)NC(C)C
Reactant: CC(C)C(=O)O
Agent: Cl
Solvent: CCCI
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCC(C)(C)C(=O)O

Procedure:
A 240 ml (285 mmol) portion of a solution of t-butyllithium in pentane (1.18 M) was added dropwise to a solution of 42 ml (290 mmol) of diisopropylamine in 300 ml of dry tetrahydrofuran while it was stirred with -5° bath cooling under argon. A 12.7 ml (135 mmol) portion of 2-methylpropionic acid in 15 ml of dry tetrahydrofuran was then added dropwise to the reaction mixture. A 14.3 ml (140 mmol) portion of n-propyliodide was then added dropwise to the reaction mixture as stirring was continued with ice bath cooling. The resultant mixture was stirred two hours without cooling and then acidified by the slow addition of 10% hydrochloric acid. The resultant mixture was extracted several times with ether and the combined extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 16.3 g of 2,2-dimethylpentanoic acid, having the following spectral characteristics: nmr (CDCl3) δ 0.94 (3H, t, J= 8.5 Hz), 1.20 (6H, s), 1.2-1.8 (4H, m) and 11.3 ppm (1H, broad s); ir (CHCl3) 860, 945, 1185, 1240, 1290, 1310, 1370, 1410, 1480, 1700 and 2400-3400 cm-1 (broad).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[F:21][C:22]([F:28])([F:27])[CH2:23][C:24]([NH:7][C:6]1[S:5][C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1nc(-c2cccnc2)sc1N
Reactant: O=C(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2)sc1NC(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
286 mg (1.49 mmol) of 4-methyl-2-(pyridin-3-yl)-1,3-thiazole-5-amine were dissolved in THF, 0.52 ml of triethylamine was added, and 263 mg of trifluoropropionyl chloride were added while cooling with an ice bath. The mixture was stirred at room temperature overnight and then concentrated. Ethyl acetate, saturated sodium chloride solution and aqueous phosphate buffer pH=7 were added to the residue, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography (silica gel, cyclohexane, acetone).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:27])[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H]1CCN(Cc2ccccc2)C1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
A solution of 1a (0.80 g, 2.06 mmole) in 40% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 4 h. The solvent was removed by rotary evaporation, and the resulting organic residue was carefully partitioned between dichloromethane and a saturated solution of sodium bicarbonate (30 mL each). The organic extract was dried over anhydrous sodium sufate, filtered, and concentrated to give 2a as a light brown oil. This amine was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O-:42])=[O:41])=[O:2].[O-:43]Cl=O.[Na+:46].NS(O)(=O)=[O:49]>CC(O)(C)C.O>[Na+:46].[Na+:46].[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O-:42])=[O:41])([OH:43])=[O:2].[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O-:42])=[O:41])([OH:49])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: NS(=O)(=O)O
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C=O)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C(=O)O)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of Methyl (1RS, 2SR, 3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added a solution of NaClO2 (34 mg, 0.28 mmol) and NH2SO3H (40 mg, 0.42 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 2 h and it was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (Mg2SO4). The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (90 mg, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26]CC)=O)[C:6]1=[O:29].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:24]([C:7]2[C:6](=[O:29])[N:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:31])=[O:30])[C:14]3[C:9]([C:8]=2[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:13]=3)=[O:26])[CH2:34][CH2:33]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NC1CC1
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC2CC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 9. The product was obtained as a white solid: 1H NMR (CDCl3) δ 9.96 (1H, br), 8.54 (1H, d, J=1.4 Hz), 7.13 (2H, m), 7.04-7.00 (3H, m), 4.92 (2H, s), 4.10 (2H, s), 3.11 (3H, s), 2.96 (3H, s), 2.93 (1H, m), 0.86 (2H, m, J=13, 7), 0.66 (2H, m); HRMS calcd for C23H23FN4O4+H+: 439.1781. Found: 439.1774.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:47]([O:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:42])[CH3:41])=[C:35]([O:43][C:44](=[O:46])[CH3:45])[CH:34]=3)/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:63]1([CH:69]([O:76][C:77]([C:79]2[N:80]3[C@H:83]([S:84][CH2:85][C:86]=2[CH2:87][O:88][C:89](=[O:91])[CH3:90])[C@H:82]([NH2:92])[C:81]3=[O:93])=[O:78])[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:63]1([CH:69]([O:76][C:77]([C:79]2[N:80]3[C@H:83]([S:84][CH2:85][C:86]=2[CH2:87][O:88][C:89](=[O:91])[CH3:90])[C@H:82]([NH:92][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:22][CH:23]=2)=[N:30]\[O:31][CH:32]([C:47]([O:49][CH:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:42])[CH3:41])=[C:35]([O:43][C:44](=[O:46])[CH3:45])[CH:34]=2)[C:81]3=[O:93])=[O:78])[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C(=O)OC(c3ccccc3)c3ccccc3)c3ccc(OC(C)=O)c(OC(C)=O)c3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.9 %

Procedure:
To an ice-cooled solution containing the product obtained in Step 5 of Example 8 (3.0 g) and (6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1.58 g) in dichloromethane (90 ml) was added dicyclohexylcarbodiimide (0.74 g), and the mixture was stirred at room temperature for 4 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, giving 2.42 g of the objective compound.