Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1cc(CBr)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2csc(C#N)c2)C1=O
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (3.2 g, 16 mmol) in 80 mL of THF:DMF (10:1) at 0° C. is added 4-bromomethylthiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60%) (0.67 g, 16.8 mmol). After addition, the solution is allowed to warm to ambient temperatures. After 2 hours, the solution is quenched by the addition of sat NH4Cl. The solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to afford the title compound (4 g, 13.8 mmol) as a white solid.
Reaction SMILES: CI.[Br:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.[C:13](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH3:13])=[CH:8][C:9]=1[Cl:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
Methyl iodide (1.861 mL, 29.76 mmol) was added to a stirred suspension of 4-bromo-2,5-dichlorophenol (4.8 g, 19.84 mmol) and potassium carbonate (8.23 g, 59.53 mmol) in DMF (20 mL) at ambient temperature under air. The resulting suspension was stirred at 50° C. for 90 minutes. The reaction mixture was allowed to cool and diluted with EtOAc (200 mL), and washed sequentially with saturated brine (2×150 mL) and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-bromo-2,5-dichloro-4-methoxybenzene (3.82 g, 75%) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+].O>S1(CCCC1)(=O)=O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Yield: 92.5 %

Procedure:
18.6 g (0.1 mol) of 4-chloro-3-nitrobenzaldehyde and 8.7 g (0.15 mol) of potassium fluoride in 100 ml of sulpholane are stirred for 1 hour at 180° C. The mixture is stirred with 300 ml of water and the aldehyde is extracted with methylene chloride. After the customary working-up , 17.1 g of 92% strength 4-fluoro-3-nitrobenzaldehyde are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([S:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:6])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Sc1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1ccccc1)Sc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (2.44 g, 10 mmol), in THF (100 ml) at 4° C., lithium bis(trimethylsilyl)amide (1 M solution, 15 ml, 15 mmol) was added slowly. The orange colored reaction mixture was stirred at room temperature for 15 minutes and then it was cooled to 0° C. at which time it was stirred for an additional hour. The temperature of the mixture was again brought to −40° C. and benzylbromide (1.72 gm, 10 mnmol) was added dropwise in THF. The reaction was warmed to room temperature and stirred overnight before it was quenched with ice water, extracted with chloroform and washed with water. The organic layer was dried over MgSO4, filtered and concentrated and chromatographed on a silica-gel column with 10% ethyl acetate:hexane to afford 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield: 860 mg, (26%); MS: 331 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[NH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=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>C1COCC1.O>[I:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2I)cc1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(-c3ccc(OC)cc3)c(I)c3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25-mL flask under argon, 4-iodo-7-methoxy-3-(4-methoxyphenyl)isoquinolin 1(2H)-one (500 mg, 1.23 mmol) is dissolved in 15 mL of anhydrous THF. 4-methoxybenzyl alcohol (217 μl, 1.84 mmol), triphenylphosphine (482 mg, 1.84 mmol) and diisopropyl azodicarboxylate (261 μl, 1.84 mmol) are added to the previous solution. After stirring overnight at ambient temperature, the medium is hydrolyzed with 20 mL of water and extracted with 3×20 mL of dichloromethane. The organic phases are washed with 3×10 mL of water, dried over MgSO4 and concentrated under vacuum. Compound 69 is obtained by recrystallization from ether (358 mg, 55%). 1H NMR CDCl3 δ 7.94 (s, 1H), 7.89 (d, 1H), 7.34 (d, 1H), 6.98 (d, 2H), 6.91 (d, 2H), 6.81 (d, 2H), 6.72 (d, 2H), 5.19 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H);
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C(OCC)(=O)C.O>[F:23][C:12]1[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester 8a (63 mg, 0.167 mmol) is suspended in MeOH (1.5 mL) and 20% NaOH (400 μl) is added. After 16 hours, the reaction is cooled to 0° C. and 1 N NCl solution is added dropwise until pH is 2 to 3. The reaction mixture is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 58 mg (95%) of desired product: MS APCI (+) m/z 366, 364 (M+1 Br pattern) detected; MS APCI (−) m/z 364, 362 (M−1 Br pattern) detected.
Reaction SMILES: [CH2:1]=O.[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]>C(O)=O>[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:1])[CH2:19][CH2:20]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21

Procedure:
To a solution of 37% formalin (12 ml) and formic acid (18 ml) was added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, and the mixture was heated at 120°-125° C. for 4 hours with stirring. The mixture was then concentrated to dryness under reduced pressure. The residue was adjusted to pH 8 by addition of aqueous 7% sodium bicarbonate, and extracted with chloroform. The extract was dried and the solvent was evaporated. The crystalline residue was recrystallized from a mixture of dichloromethane and ethanol to give 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 228°-230° C.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]([CH2:5][C:6]([OH:8])=[O:7])[NH2:4].S(Cl)([Cl:12])=O.[CH2:14](O)[CH3:15]>ClCCl>[ClH:12].[CH2:14]([O:7][C:6](=[O:8])[CH2:5][CH:3]([NH2:4])[CH:2]([F:9])[F:1])[CH3:15]
Reactant: NC(CC(=O)O)C(F)F
Reactant: CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(N)C(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 mmole of beta-difluoromethyl beta-alanine in 15 ml of dichloromethane is treated with 2 mmole of thionyl chloride at 25° C. for one hour after which 20 ml of ethanol is added. The solution is stirred at 25° C. for one hour and concentrated to afford 3-amino-3-difluoromethylpropionic acid ethyl ester hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:16]C(C1C=CC=CC=1)C)([CH3:15])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1>C(O)(=O)C.CCO.[OH-].[OH-].[Pd+2]>[CH3:15][C:3]([NH2:16])([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH2:1]
Reactant: CC(NC(C)(CN)CC1CCc2ccccc2C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(N)(CN)CC1CCc2ccccc2C1
Reaction time: 20 h

Procedure:
A suspension of 0.50 g (1.55 mmol) of the compound obtained in Step 3 and 0.14 g of Pd(OH)2 in a mixture of 0.8 ml of acetic acid and 50 ml of EtOH is hydrogenated at 20° C. under 1 bar for 20 hours. After filtration of the mixture and concentration in vacuo, the residue is taken up in 1N aq. NaOH (10 ml) and extracted with CH2Cl2 (3×10 ml); the combined organic phases are washed with saturated aq. NaCl, dried and concentrated to yield the title compound in the form of an oil, which is used in the following reaction without being otherwise purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccnc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 50 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (3 mL). Pyridine 3-boronic acid (23.822 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) dissolved in 1.25 mL water] were added at room temperature, and the reaction mixture was purged with argon for 30 min. Then, Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added and the reaction mixture was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 4 h (monitored by LC-MS). The reaction mixture was filtered through a pad of cellite and the filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (389) (50 mg, 50.1%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]#N)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:24].C(OC(=O)[C@H](CCCCNC=NOCC)[NH:32][C:33](OC(C)(C)C)=[O:34])(C)(C)C.Cl.C(OC(=O)[C@H](CCCNCOC=N)NC(OC(C)(C)C)=O)(C)(C)C.CO>ClCCl>[ClH:24].[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][O:34][CH:33]=[NH:32])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC#N)C(=O)OC(C)(C)C
Reactant: CCON=CNCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCOC=N)C(=O)OC(C)(C)C

Procedure:
From 1.6 g (4.89 mmol) N2-(tert-butoxycarbonyl)-N6-(cyano)-L-lysine tert-butyl ester was prepared 1.5 g (75%) of foamy solid N2-(tert-butoxycarbonyl)-N6-(ethoxyiminomethyl)-L-lysine tert-butyl ester hydrochloride by the method described for N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride. TLC (methanol:dichloromethane/1:9) Rf=0.36. Mass spectrum (CI) 360 (MH+, 60%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][P:34]([O:38]CC)[O:35][CH2:36][CH3:37].CO.O>C1(C)C=CC=CC=1>[CH2:36]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1)[CH3:37].[CH3:33][PH:34](=[O:35])[O-:38]
Reactant: CCOP(C)OCC
Reactant: BrCCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCCCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Product: C[PH](=O)[O-]
Yield: 57.3 %

Procedure:
A solution of 1,4,5-triphenyl-2-(7-bromoheptyloxy)-imidazole (1.75 g) and diethyl methylphosphonite (2.45 g) in toluene (10 ml) was heated at reflux temperature for 48 hours. Methanol and water were added and the mixture evaporated to an oil. This was chromatographed on silica gel (ethyl acetate/ethanol). The resulting oil slowly crystallised and was triturated with ether/petroleum ether, filtered then recrystallised from ethanol/ether to give ethyl 7-(1,4,5-triphenyl-imidazol-2-yloxy)heptane-methylphosphinate (1.06 g, 57%) as a white solid, m.p. 101°-2° C. Found: C, 72.05; H, 7.26; N, 5.52%; C31H37N2O3P; Requires: C, 72.07; H, 7.22; N, 5.42%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1ccc(C=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C=C2N=C(c3cccs3)OC2=O)cn1
Temperature: 90 °C
Yield: 65.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OC)(OC)(OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(C)(OC)OC
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Yield: 10 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (1.0 g, 3 mmol) and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic acid (250 mg) in acetonotrile (10 mL) was heated to reflux for 7 days. The suspension was filtered and washed with ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (108 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.17 min (98.7%); mp: 273-275° C.; 1H NMR (DMSO-d6) δ 2.14-2.27 (m, 1H, CHH), 2.56-2.69 (m, 2H, 2CHH), 2.64 (s, 3H, CH3), 2.72-2.90 (m, 1H, CHH), 5.29 (dd, J=6, 11 Hz, 1H, NCH), 7.58 (d, J=9 Hz, 1H, Ar), 7.98 (dd, J=2, 9 Hz, 1H, Ar), 8.12 (d, J=2 Hz, 1H, Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95, 137.51, 145.76, 155.74, 159.32, 167.24, 172.49; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 48.02; H, 3.18; N, 11.76.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH3:12])=[O:10].[H][H].[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C=O)C.CCCCCC>[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18][C:5]1([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:7][CH2:8][C:4]1=[O:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)C1CCCC1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(F)cc2F)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of n-hexane-washed sodium hydride (0.58 g, 24 mmol, 1.2 eq), there was added a solution of methyl 2-oxocyclopentanecarboxylate (2.84 g, 20.0 mmol, 1.0 eq) in DMF (20 ml) at 10° C. After the suspension had been heated at room temperature and then stirred for 30 min, the suspension became yellowish. Upon confirmation of the terminal evolution of hydrogen, the resulting solution was again warmed to 10° C. and 2,4-difluorobenzyl bromide (5.38 g, 26.0 mmol, 1.3 eq) was added. The solution was warmed to room temperature and stirred for 2 h. After the terminal reaction had been confirmed by TLC, the resulting solution was poured onto ice-cold water (30 ml) and washed with diethyl ether (100 ml×2).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][C:24]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[C:24]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CNC(=NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.25 g, 1.3 mmol) was dissolved in methanol (10 ml), and 3,4-(dibenzyloxy)phenethylamine hydrochloride (0.54 g, 1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) were added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide (0.13 g, 0.3 mmol, yield: 21%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol diethyl ether to give N-cyano-N'-[ 2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(NCc2ccccc2)C1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 425.9 %

Procedure:
A solution of tert-butyl 3-(benzylamino)azetidine-1-carboxylate (13a) (0.55 gm, 2.09 mmol) in DMF was added methyl iodide (0.26 ml, 4.18 mmol) and cesium carbonate (1.36 gm, 4.18 mmol). The resultant reaction mixture was then warmed to 60° C. and stirred for 2 h. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (3×25 ml), brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to give compound (13b) (2.46 gm, 72%). 1H NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.40 (m, 5H), 4.00 (m, 2H), 4.20 (m, 2H), 5.2 (m, 1H), 7.50 (m, 3H), 7.70 (d, 2H); MS: m/z 277.10 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([F:14])[C:3]=1[F:15].O=P(Cl)(Cl)Cl.O>C(#N)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]#[N:8])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred suspension of 4-amino-2,3-difluoro-5-nitrobenzamide (90 g, 0.416 mol) in acetonitrile (630 mL) was added POCl3 (96 mL, 1.04 mol) in one portion. The mixture was then heated to 70° C. and as the reaction proceeded the suspension become a brown solution. After 1.5 hours, HPLC analysis showed no remaining starting material. The reaction mixture was cooled to 30° C., then added to water (4.5 L) over 30 minutes while the temperature was held at 17-25° C. The resultant bright yellow slurry was stirred for 1 hour, filtered under vacuum, and the remaining solid was then dried in a vacuum oven at 50° C. to provide 4-amino-2,3-difluoro-5-nitrobenzonitrile as a yellow solid, (74.4 g, 90% yield). HPLC 95a %. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (2H, br s, NH2), 8.53 (1H, apparent dd, J 1.8, 6.4, Ar—H). 19F NMR (376 MHz, DMSO-d6) δ −128, −152. 13C (100 MHz, DMSO-d6) δ 87.1 (C, d, J 15), 113.6 (C, d, J 4), 128.6 (CH, s), 128.8 (C, d, J 5), 139.3 (CF, dd, J 245, 14), 141.5 (C, dd, J 13, 5), 152.8 (CF, dd, J 259, 12). IR νmax/cm−1 3446, 3322, 2235, 1647, 1551, 1287, 1275. MS APCI (−) 198 (M−1) detected, APCI (+) 200 (M+1) detected.