Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccccc2)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of ethyl 5-phenylisoxazole-3-carboxylate (406 mg, 1.87 mmol) and N-iodosuccinimide (505 mg, 2.24 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 1.5 h. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (50 mL), washed with a 2.5% aqueous solution of sodium bisulfate (50 mL), washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 4-iodo-5-phenylisoxazole-3-carboxylate (641 mg, 1.87 mmol, 100% yield) as a light yellow oil. The compound had an HPLC retention time=3.36 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=343.97. 1H-NMR (400 MHz, CDCl3) δ ppm 1.47 (t, J=7.1 Hz, 3H), 4.50 (q, J=7.0Hz, 2H), 7.52-7.56 (m, 3H), and 8.05 (m, 2H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]1([CH3:27])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.CO[CH:30](OC)[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[CH:35][CH:34]=1.FC(F)(F)C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:44][N:42]([CH3:43])[CH2:41][CH2:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([N:32]2[CH:31]=[CH:30][N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH3:27])=[CH:25][CH:24]=3)[C:1]2=[O:2])=[CH:38][CH:37]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(CNc1ccc(OCCN(C)C)cc1)OC
Reactant: Cc1ccccc1Oc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1Oc1ccc(-n2ccn(-c3ccc(OCCN(C)C)cc3)c2=O)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (40 mg) was added to a solution of 4-o-tolyloxyphenylamine (50 mg) in dimethylformamide (2 mL) at 0° C. After 30 minutes, (2,2-dimethoxyethyl)-[4-(2-dimethylaminoethoxy)phenyl]amine (67 mg) was added, and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, trifluoroacetic acid (0.5 mL) was added and the mixture was left to stand for 72 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 429.52 (C26H27N3O3); MS (ESI): 430 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:24])[C@H:19]1[CH2:23][S:22][CH2:21][NH:20]1)[CH3:16].C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH2:15]([O:17][C:18](=[O:24])[C@H:19]1[CH:23]([C:12](=[O:14])[CH2:11][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[S:22][CH2:21][NH:20]1)[CH3:16]
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Reactant: CCOC(=O)[C@H]1CSCN1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: CCOC(=O)[C@@H]1NCSC1C(=O)C[C@H]1CCc2ccccc2C1
Yield: 83 %

Procedure:
Colorless crystals of 3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioproline ethyl ester were prepared in the same manner as in Reference Example 1, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and D-thioproline ethyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8](=[O:25])(=[O:24])[NH:9][CH2:10][CH2:11][O:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.O.NN>C(O)C>[NH2:13][O:12][CH2:11][CH2:10][NH:9][S:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a mixture of tert-butyl({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl}sulfamoyl)carbamate 77 (0.62 g, 1.61 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added hydrazine hydrate (0.092 mL, 1.61 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 78 (0.18 g, 44%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O[CH2:25][C:26]1[NH:31][C:30](=[O:32])[NH:29][C:28](=[O:33])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][C:26]2[NH:31][C:30](=[O:32])[NH:29][C:28](=[O:33])[CH:27]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: O=c1cc(CO)[nH]c(=O)[nH]1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3cc(=O)[nH]c(=O)[nH]3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of N-(2,4-dimethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (33 mg, 0.099 mmol), 6-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (17.1 mg, 0.12 mmol) and triphenylphosphine (26 mg, 0.099 mmol) was dissolved in tetrahydrofuran (THF) (0.6 mL) and treated with diisopropyl diazene-1,2-dicarboxylate (DIAD) (25 uL, 0.13 mmol). The vessel was capped and stirred at 20° C. for 2 days. Additional 6-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (17.1 mg, 0.12 mmol) and diisopropyl diazene-1,2-dicarboxylate (DIAD) (30 uL, 0.156 mmol) were added and reaction stirred for further 18 hours. The reaction was then filtered and purification attempted by mass directed autoprep (ammonium carbonate modifier), but this failed to isolate clean material. Purification successfully achieved by mass directed autoprep (formic acid modifier), to provide the required product, 1.1 mg. LCMS [LCMS1] Rt 1.13 min, m/z (ES+) 458 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][C:14]=2[Cl:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol) was added POCl3 (20 mL, 215 mmol). The mixture was heated to 100° C. for 17 h and cooled to rt. The excess POCl3 was removed under reduced pressure, and the residue quenched with sat. NaHCO3 (150 mL) and partitioned with dichloromethane (100 mL) and stirred for 30 minutes. The dichloromethane layer was collected, and the aqueous layer was extracted with dichloromethane (2×100). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 5-30% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-benzyl-5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine (2.334 g, 9.02 mmol, 85% yield) as a yellow oil. LC/MS: m/z 259.01 (M+H)+, 0.775 min (method 2). 1H NMR (500 MHz, chloroform-d) δ ppm 8.10 (d, J=4.88 Hz, 1H) 7.26-7.41 (m, 5H) 6.86 (d, J=4.88 Hz, 1H) 3.69 (s, 2H) 3.58 (s, 2H) 2.84-2.89 (m, 2H) 2.78-2.83 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O>[CH2:13]([O:20][C:21]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To the solution of azetidine-3-carboxylic acid (1 g, 10 mmol) of tetrahydrofuran/water (50 ml:50 ml) was added NaHCO3 (2.05 g, 25 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and adjusted to pH=2, extracted with ethyl acetate. The residue was dried in vacuum. 2.4 g of crude 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid was obtained.
Reaction SMILES: N(C([O:10][CH2:11][CH3:12])=O)=NC(OCC)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)C[C:14]1=O.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:14][N:13]1[C:21]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11]1=[O:10]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C1Cc2ccccc2N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)Cc2ccccc21
Yield: 58.9 %

Procedure:
Add diethyl azodicarboxylate (DEAD, 8.0 g, 44.9 mmol) dropwise to a solution of indolin-2-one (4.0 g, 30.0 mmol), methanol (1.4 g, 44.9 mmol) and triphenylphosphine (12.0 g, 44.9 mmol) in THF (40 mL) at 0° C., stir the reaction at room temperature overnight. Concentrate under reduced pressure, purify the resulting residue with flash chromatography (silica gel, EtOAc:PE=1:3) to afford the title compound (2.6 g, 59.1%). MS: (M+1): 148.2.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:31]1([CH2:30][CH2:29][CH2:28][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10](/[CH:13]=[CH:14]/[C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)(=[O:12])=[O:11])[CH2:5][CH2:4]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.402 g (0.925 mM) of (E)-4-[2-(piperidin-4-ylmethanesulfonyl)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.28 g (1.39 mM) of 1-bromo-3-phenylpropane, and 0.45 ml (3.24 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol : 9/1-1/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2ccccc2s1
Product: Cc1nc2c(S(=O)(=O)Cl)cccc2s1

Procedure:
2-Methylbenzothiazole (50 g) was added in a slow, dropwise manner to 86 mL of chlorosulfonic acid at room temperature. When the addition was complete, the dark reaction mixture was heated at 140°-145° C. for about 3 hours. The solution was allowed to cool and was slowly added to a large excess of ice. Insoluble solids were removed by filtration and the aqueous layer was extracted with benzene. Drying and evaporation of the solvent gave an off-white solid which was shown by 1H NMR analysis to consist of a mixture of sulfonyl chlorides, presumably the 4-, 6-, and 7-isomers. This crude material was recrystallized three times from hexane to remove the 6-isomer as a white solid, m.p. 100°-102° C. The combined mother liquors were concentrated to give a dark yellow oil which was carried on to the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4]C[C:2]1=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1.C(#[N:29])C>C(OCC)(=O)C>[I:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:29]2[CH2:4][C:5]3([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[O:1][C:2]2=[O:11])=[CH:21][CH:22]=1
Reactant: CC#N
Reactant: O=C1CCC2(CCCCC2)O1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(I)cc1
Temperature: 70 °C
Yield: 49 %

Procedure:
1-Oxa-spiro[4.5]decan-2-one (96 mg, 0.618 mmol), cesium carbonate (Cs2CO3) (605 mg, 1.855 mmol) and 1-bromomethyl-4-iodo-benzene (220 mg, 0.742 mmol) were mixed in acetonitrile (2.5 mL). The reaction mixture was heated at 70° C. for 5 hours, and the diluted with ethyl acetate (8 mL). The mixture was washed with water (2×4 mL) and brine (2×4 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 5 to 25% ethyl acetate in hexane to give the product as a white powder (112 mg, 49%). 1H NMR (300 MHz, CDCl3): δ 7.68 (dd, 2H), 7.03 (dd, 2H), 4.36 (s, 2H), 3.08 (s, 2H), 1.78 (m, 4H), 1.46 (m, 6H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:23]1([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1>CN(C)C=O.O>[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:32](=[O:34])[CH2:31][CH2:30][CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and 1-hydroxybenzotriazole (0.13 g) in N,N-dimethylformamide (5 mL) was added 0.12 g of 4-phenylbutyric acid at 0° C. and the mixture was stirred at that temperature for 5 minutes and further at room temperature for 2 hours. This reaction mixture was added to a solution of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine (0.20 g) in N,N-dimethylformamide (2 mL) at 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:2) to provide 0.22 g of the title compound. Yield 74%.
Reaction SMILES: C(#N)C.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14](F)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1.Cl.Cl.[CH3:27][NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>C(N(CC)CC)C>[OH2:17].[OH2:17].[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14]([N:31]4[CH2:32][CH2:33][CH2:34][CH:29]([NH:28][CH3:27])[CH2:30]4)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNC1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 276.2 %

Procedure:
An acetonitrile solution (30 mL) containing 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), 3-methylaminopiperidine dihydrochloride (2.1 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 2 hours. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 6 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 8 by use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 3.98 g of the title compound (yield: 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)=O.C(=O)([O-])[O-].CN(C)C=O>CCOCC.O>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][C@H:22]([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CCCc1ccccc1)OS(C)(=O)=O
Reactant: Oc1ccc(Br)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCCc1ccccc1)Oc1ccc(Br)c(OCc2ccccc2)c1
Yield: 72 %

Procedure:
A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-1-methyl-4-phenylbutyl methane sulfonate and 25.2 g. (200 mmole) of potassijm carbonate in 100 ml. dimethylformamide was heated at 85° C. for 13.5 hours. The reaction was cooled and added to 500 ml. water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 750 g. of silica gel eluted with 10% ether-hexane to yield 23.9 g. (72%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:3]=1.[OH-].[Na+:21].C>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:16]([O-:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])ccc12

Procedure:
A 151.7 g portion of 1-amino-3,6-naphthalenedisulfonic acid is added with stirring to 200 ml of water containing 44 g of sodium hydroxide. This solution is treated with activated charcoal and filtered. To the filtrate is added ethyl alcohol with the formation of a precipitate which is allowed to stand. The solid is collected by filtration and set aside. More ethyl alcohol is added to the filtrate with the formation of additional product. This product is collected after standing and is combined with the material previously set aside. The combined product is dissolved in water, treated with activated charcoal and is recrystallized from ethyl alcohol. The product is collected by filtration, washed with absolute ethyl alcohol and is dried to give 1-amino-3,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([NH:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)o1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)o1

Procedure:
To a solution of methyl 5-amino-2-furancarboxylate (1.00 g, 7.09 mmol) and pyridine (1.72 ml, 21.3 mmol) in tetrahydrofuran (24 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.96 ml, 14.2 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 662 mg (29.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([N:35]3[CH:39]=[CH:38]N=C3)=[O:34])[C:14]1=[O:40])=[O:11])[CH2:2]2.N[C:42]1[CH:43]=[C:44]([OH:48])C=C[CH:47]=1.C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32][C:33]([NH:35][C:39]3[CH:47]=[CH:42][CH:43]=[C:44]([OH:48])[CH:38]=3)=[O:34])[C:14]1=[O:40])=[O:11])[CH2:2]2
Reactant: Nc1cccc(O)c1
Reactant: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)n1ccnc1)N=C2c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)Nc1cccc(O)c1)N=C2c1ccccc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-3-(imidazol-1-yl)carbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one (250 mg), 3-aminophenol (55 mg) and triethylamine (93 mg) in N,N-dimethylformamide (1 ml) was stirred at 100° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, ethyl acetate and 1N aqueous hydrochloric acid were added thereto. The separated organic layer was washed with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine successively, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to give a colorless paste, which was washed with diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N ′-(3-hydroxyphenyl)urea (184.0 mg, 68.5% yield) as a crystalline.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].CO>ClCCl>[C:24]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2cccc3ccccc23)co1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc(-c2cccc3ccccc23)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/salt bath) mixture of 2-amino-4-(naphth-1-yl)oxazole (1)(0.5 g) and triethylamine (0.8 ml) in anhydrous dichloromethane (5 ml) was added dropwise acetyl chloride (0.2 ml) over a minute. The resulting mixture was warmed to room temperature and left overnight. Further acetyl chloride (0.1 ml) was added and the mixture left for a further hour. Dichloromethane (40 ml) and few drops of methanol were added. The mixture was washed twice with brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (9) (0.35 g; m.p. 188-190° C.) was obtained following silica gel column chromatography of the residue in 2% methanol in chloroform.