Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and trioctylmethylammonium chloride (335.5 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane ethyl acetate=4:1), to thereby yield 706.2 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+].ClCCl.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(=O)(=O)(O)O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 123.2 %

Procedure:
To a solution of sodium (6R, 7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate (4.2 g, 10 mM) in water (50 ml) was added dichloromethane (30 ml) containing diphenyldiazomethane (2.1 g, 11 mM). The solution pH was adjusted to 3.0 over 15 minutes using 10% v/v sulphuric acid. The mixture was separated and the solvent phase washed with water (4 × 50 ml). The solvent was removed in vacuo to give the title compound (6.96 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2(=[O:33])=[O:32])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C.C(O)(C)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2(=[O:32])=[O:33])[CH2:20][CH2:21]1
Reactant: OC(CBr)C1COc2ccccc2O1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1c2ccccc2S(=O)(=O)N1C1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
Erythro 1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (1.29 g, 0.005 m), 2-(piperid-4-yl)-1,2-benzisothiazolin-3-one-1,1-dioxide hydrochloride (1.44 g, 0.005 m) and triethylamine (4 cm3) were refluxed for 24 hours in ethanol (50 cm3). The solution was cooled, the solvent evaporated and the residue treated with water. The product was extracted with chloroform, washed with water and dried (MgSO4). Evaporation gave a gum which was dissolved in isopropyl alcohol. The crystallised solid was collected by filtration, dissolved in ethanol and treated with ethanolic HCl. Ether was added and the resulting precipitate filtered off and recrystallised from isopropyl alcohol to give the title compound as the hydrochloride salt, m.p. 216°-218° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][NH:5][C:4](=[S:17])[NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39]I)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[C:41]([F:44])([F:43])[F:42]>CC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][S:17][C:4]3[NH:5][CH:6]=[C:7]([CH2:8][C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[C:2](=[O:1])[N:3]=3)=[CH:36][CH:37]=2)=[CH:27][C:26]=1[C:41]([F:42])([F:43])[F:44]
Reactant: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 604.4 %

Procedure:
To a suspension of 4-[(4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]benzonitrile (40 mg, 0.164 mmol) and K2CO3 (25 mg, 0.181 mmol) in Acetone (5 mL), which was stirred at room temperature for 5 min was added 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (42 mg, 0.098 mmol) under argon. The mixture was heated with a microwave reactor at 80° C. for 45 min. Purification via MDAP then afforded the title compound (321 mg, 37.4% yield). LCMS: rt=4.07 min, [M+H+]=542
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:14])[CH3:13])[CH:2]=[CH2:3].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:14])/[CH:13]=[CH:17]/[N:18]([CH3:20])[CH3:19])[CH:2]=[CH2:3]
Reactant: COC(OC)N(C)C
Reactant: C=CCOc1cc(C)ccc1C(C)=O
Product: C=CCOc1cc(C)ccc1C(=O)/C=C/N(C)C

Procedure:
To 1-[2-(allyloxy)-4-methylphenyl]ethanone (Step 1, 13.9 g, 73 mmol) was added dimethylformamide dimethylacetal (56 mL, 422 mmol), and the reaction was heated to reflux for 18 hours. The reaction was then concentrated in vacuo to give the title compound as an orange oil, 17.9 g, which was taken crude into the next reaction.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11](C(=O)C)[CH2:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH:6]=1)C.O.Cl>C(O)C.[OH-].[Na+]>[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:33])=[O:3])[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cccc(N(CCCN2c3ccccc3CCc3ccccc32)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(NCCCN2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a solution of the above ester (1.0 g, 0.0023 mol) in ethanol (5 ml), 4N sodium hydroxide (0.6 ml) was added and the mixture was stirred at room temperature for 6 h and then left in a freezer overnight. The reaction mixture was allowed to warm up to room temperature and additional 4N sodium hydroxide (0.6 ml) was added. The mixture was stirred at room temperature for 3 h. Water and 4N hydrochloric acid (1.7 ml) were added, and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The residue was stripped twice with dichloromethane and dried in vacuo affording 0.5 g (59%) of the title compound as an amorphous solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][CH2:23][C:24]([OH:26])=O)[C:15]1=[O:27].[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>O1CCCC1>[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH:32][C:24](=[O:26])[CH2:23][CH2:22][N:16]1[C:17]([CH3:20])([CH3:21])[C:18](=[O:19])[N:14]([CH3:13])[C:15]1=[O:27]
Reactant: COC(CN)OC
Reactant: CN1C(=O)N(CCC(=O)O)C(C)(C)C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CNC(=O)CCN1C(=O)N(C)C(=O)C1(C)C)OC

Procedure:
82.7 g (0.51 mol) of 1,1'-carbonyldiimidazole in 5.0 l of tetrahydrofuran are allowed to react as described in Example 1, with 93.08 g (0.5 mol) of 3-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)propionic acid and are subsequently reacted with 53.62 g (0.51 mol) of 2-aminoacetaldehyde dimethyl acetal. The reaction mixture is evaporated in a rotary evaporator, and the imidazole present in the residue is removed by distillation at a bath temperature of 120° C./0.1 mmHg for 3 hours, giving 134.1 g (98.1% of theory) of a brownish, liquid crude product, which is recrystallized from 130 ml of ethyl acetate, giving 88.1 g (65.0% of theory) of colourless, crystalline N-(2,2-di methoxyethyl)-3-(3,5,5-trimethyl-2,4-dioxoimidazolidin-1-yl)propionamide, whose melting point is 86.4° C.
Reaction SMILES: Cl.C([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[C:14]([Cl:18])[N:15]=[C:16]([Cl:17])[C:11]=2[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH:32]([Cl:34])[CH3:33])=[O:30].O>ClCCCl>[Cl:18][C:14]1[N:15]=[C:16]([Cl:17])[C:11]2[CH2:10][N:9]([C:29]([O:31][CH:32]([Cl:34])[CH3:33])=[O:30])[CH2:20][CH2:19][C:12]=2[N:13]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cl)OC(=O)N1CCc2nc(Cl)nc(Cl)c2C1

Procedure:
6-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (35.0 g, 0.106 mol) prepared according to Process Step 2 was dissolved in 1,2-dichloroethane (850 mL), and the solution was mixed with triethylamine (14.9 mL, 0.107 mol) and 1-chloroethyl chloroformate (34.1 mL, 0.316 mol), followed by stirring under reflux for five hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was cooled and was mixed with water, followed by separation. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate and was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and thereby yielded a 2,4-dichloro-6-(1-chloroethoxycarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine fraction. After distilling off the solvent, the residue was dissolved in methanol (850 mL), followed by stirring under reflux for one hour. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was concentrated and thereby yielded 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (23.5 g, in a total yield from 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride of 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: COC(=O)CCNc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCNc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.7 %

Procedure:
To a solution of example 57 (0.080 g, 0.165 mmol) in methanol (0.8 ml), lithium hydroxide (0.064 g, 1.54 mmol) in water (0.8 ml) was added and stirred at RT. After 12 h, pH was adjusted to ca. 7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale green solid (0.075 g, 68%). M.P.: 132-135° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:22](=[O:25])[CH2:23][NH:24][C:34](=[O:37])[CH2:35][CH3:36])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: CCC(=O)Cl
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg), pyridine (25 mg) and methylene chloride (2 ml) was added propionyl chloride (0.02 ml) at ambient temperature and the mixture was stirred at the same temperature for 30 minutes. The mixture was partitioned between methylene chloride and water, and the organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(propionylglycyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (111 mg).
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture stirred at 40° C. overnight. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[Acetyl-(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylbutanoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4](Cl)[N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1nc(N)c(Br)c(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1nc(N)c(Br)c(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-5-bromo-6-chloropyrimidine (Phillips et. al., J. Org. Chem., 29, 1488-1490 (1963)) (2.3 g, 10 mmol) was added to a solution of sodium (0.29 g, 12.5 mmol) in benzyl alcohol (10 mL) under argon. The solution was heated in a 130° C. oil bath for 3 h and the benzyl alcohol was evaporated under reduced pressure to give a white solid. This solid was washed with water, and air dried. Crystallization from 50% aqueous ethanol gave white crystalline needles of 3f: yield, 2.32 g (76%); mp 165-166° C. (lit. 136° C.; Kosary et. al., Acta Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) lmax 236 nm (e=0.873×104), 291 (1.388×104); (pH 6.9) 236 (0.850×104), 277 (0.835×104); (pH 13) 234 (0.869×104), 277 (0.827×104); 1H NMR d 5.30 (s, 2 H, ArCH2), 6.15 (s, 2 H, NH2, exchange with D2O), 6.32 (s, 2 H, NH2, exchange with D2O), 7.31-7.45 (m, 5 H, ArH); MS (EI) calcd. m/z for C11H11N4O79Br 294.0115, found 294.0127; calcd. m/z for C11H11N4O81Br 296.0094, found 296.0083; Anal. (C11H11N4OBr) C, H, N.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=C.CSC.[C:11]([NH:18][NH2:19])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl>[C:11]([NH:18][N:19]=[CH:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: C=CCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=CCCC(=O)O
Temperature: -78 °C
Yield: 63 %

Procedure:
4-Pentenoic acid (10.00 g, 99.88 mmol) was dissolved in methylene chloride (150 mL), and the mixture was cooled to −78° C. under N2(g). Ozone was bubbled through the reaction mixture, and the course of the reaction was monitored by TLC. After TLC showed disappearance of the starting material (ca. 2.5 h), methyl sulfide (15.0 mL, 205.23 mmol) was added and the reaction mixture was allowed to warm to room temperature. Subsequently, solvent was removed under reduced pressure, and the residue was dissolved in THF (200 mL). BocNHNH2 (13.2 g, 99.88 mmol) was then added, and the reaction mixture was refluxed overnight under Ar(g). Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 6% v/v methanol in methylene chloride) to give BocNHN═CHCH2CH2CO2H as a white solid (13.60 g, 63%). HRMS (ESI) [M−H]− calcd for C9H15N2O4, 215.1032; found, 215.1035; 1H NMR (300 MHz, d6-DMSO) δ 12.16 (s, 1H), 10.45 (s, 1H), 7.30 (app bs, 1H), 2.45-2.30 (m, 4H), 1.41 (s, 9H); 13C NMR (100 MHz, d6-DMSO) δ 173.5, 152.4, 145.6, 78.9, 30.4, 28.1, 27.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C(#N)C>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
Methyl 4-amino-2-chlorobenzoate (407 mg, 2.2 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.3 ml, 2.4 mmol) and phenyl chloroformate (0.21 ml, 2.6 mmol) and the mixture was stirred at room temperature for 1 h under N2. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound methyl 2-chloro-4-(phenoxycarbonylamino)benzoate (713 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C.O.CN(C)C(=O)C>[CH2:28]([O:27][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCCOCCCl
Reactant: COC(=O)c1cc(N)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.54 g), potassium iodide (0.11 g), and bis(2-chloroethyl)ether (0.22 mL) were sequentially added to an N,N-dimethylacetamide (3.2 mL) solution of methyl 5-amino-2-(benzyloxy)benzoate (0.40 g), followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-60% hexane/ethyl acetate] to obtain 0.27 g of methyl 2-(benzyloxy)-5-(morpholin-4-yl)benzoate as a light yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
A solution of 2-fluorobenzoyl chloride (5.82 g, 0.0367 mol) and 4-bromoaniline (6.31 g, 0.0367 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (5.21 g, 0.0407 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold diethyl ether (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluorobenzamide (9.6 g, 0.0326 mol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([C:14](OCC)=[O:15])=[O:13])[CH:7]([CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:6][CH2:5]2.F[B-](F)(F)F.O=[N+:31]=O.[N+]([O-])([O-])=O.[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][CH:7]([CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[N:8]3[C:12](=[O:13])[C:14](=[O:15])[NH:31][C:10]([CH:11]=1)=[C:9]23
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1C(C)C(=O)OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23

Procedure:
The title compound was prepared by the route outlined in Example 22-6 to 7 starting with 6-bromo-N-ethoxalyl-2-(1-methoxycarbonylethyl)tetrahydroquinoline (more polar). In nitration step of Example 22-6, conditions of nitronium tetrafluoroborate in dichloromethane at room temperature were employed instead of those of refluxing ammonium nitrate-trifluoroacetic anhydride in chloroform: mp 256°~257° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 5.11 (bd, 1H, J=9 Hz), 3.58 (s, 3H), 2.89 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.72~2.87 (m, 2H), 2.03 (dm, 1H, J=13.5 Hz), 1.76~1.94 (m, 1H), 0.97 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:20]([O:21][CH3:22])[CH3:19])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
4-Benzyloxybenzoic acid (5.0 g) and N,O-dimethyl-hydroxylamine hydrochloride (2.5 g) were suspended in dimethylformamide (50 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 g), 1-hydroxybenzotriazole (3.5 g) and triethylamine (3.6 ml) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.6 g, yield 94%).