Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I([Cl:16])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([Cl:38])=[C:36]([Cl:39])[C:35]([Cl:40])=[C:34]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)[N:33]=1)=[O:31]>C(O)(=O)C.C(OCC)C>[Cl:38][C:37]1[C:32]([C:30]([O:29][CH3:28])=[O:31])=[N:33][C:34]([C:41]2[O:42][C:43]([Cl:16])=[CH:44][CH:45]=2)=[C:35]([Cl:40])[C:36]=1[Cl:39]
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1nc(-c2ccco2)c(Cl)c(Cl)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1nc(-c2ccc(Cl)o2)c(Cl)c(Cl)c1Cl
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Benyltrimethylammonium tetrachloroiodate (292 mg, 0.70 mmol) was added to a solution of methyl-3,4,5-trichloro-6-(2-furyl)pyridine-2-carboxylate (101 mg, 0.33 mmol) in acetic acid (5 mL). After one hour, the suspension was diluted with diethyl ether and the organic mixture was washed with 0.1 N sodium thiosulphate, 0.1 N sodium bicarbonate and dried (MgSO4). The residue was purified by column chromatography (diethyl ether:hexane, 5:95) to give methyl 3,4,5-trichloro-6-(5-chloro-2-furyl)pyridine-2-carboxylate (58 mg, 0.17 mmol): 1H NMR (CDCl3): δ 7.41 (d, J=3.6 Hz, 1H), 6.40 (d, J=3.6 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring a troom temperature for 1 h, the slurry was partitioned between NaHCO3 solution and EtOAc (warmed to dissolve solid). The organic phase was washed with H2O, 4% aqueout HCl solution, H2O, saturated NaHCO3, brine and dried with Na2SO4. After concentrating in vacuo the residue was triturated with EtOAc to give the title compound (47.4 mg, 82%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[N:3]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:20])=[N:3]1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccn(CCCCO)n1
Solvent: CC#N
Product: OCCCCn1ccc(NC(=S)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.9 %

Procedure:
To a solution of 3-amino-1-(4-hydroxybutyl)pyrazole (1.0 g.) in dry acetonitrile (3 ml.) was slowly added phenylisothiocyanate (0.95 g.) and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel using EtOAc as eluant to give 1-(4-hydroxybutyl)-3-(3-phenylthioureido)pyrazole (0.54 g.; 29%), m.p. 112°-117°.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Product: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde was prepared from 3-iodo-1H-indazol-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][O:24][C:25]2[C:30]([N+:31]([O-])=O)=[CH:29][CH:28]=[CH:27][C:26]=2[F:34])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:34])[C:25]=1[O:24][CH2:23][C@H:13]1[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Dissolved tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(2-fluoro-6-nitrophenoxy)methyl]morpholine-4-carboxylate (1.68 g, 3.36 mmol) in ethyl acetate (11.19 mL) and to this solution, carefully added 10% Pd/C (0.714 g, 0.671 mmol). A hydrogen filled balloon was attached and the contents were evacuated and backfilled with H2 several times. Stirred at room temperature for 4 hours. Complete at this time by LC/MS. The solids were filtered off through a pad of celite and washed with ethyl acetate and ethanol. The contents were concentrated and then purified on silica gel (40 g) eluting with a gradient of 0-90% EtOAc/hexanes afforded the title compound (1.57 g, 3.34 mmol, 100% yield) as a yellow oil,
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Temperature: 50 °C
Yield: 18.5 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.346 g, 3.83 mmol) was heated with anhydrous potassium carbonate (2.118 g, 15.33 mmol) in dry DMF (17 ml) at 60° C. for 1 hour. Phenylmethyl 2-(2-bromoethyl)-1-piperidinecarboxylate (1.500 g, 4.60 mmol) was added and the reaction mixture heated at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 ml) and ethyl acetate (150 ml). The aqueous was further extracted with 2×100 ml ethyl acetate. The combined organic layers were washed with 100 ml brine and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator). The residue was dissolved in DCM and loaded onto a 70 g silica cartridge and purified by chromatography using a gradient 0-100% ethyl acetate in dichloromethane+0-12% MeOH finish on a Flashmaster 2. Appropriate fractions were combined and evaporated in vacuo. The material was re-purified by chromatography on silica (70 g cartridge using a gradient of 0-100% ethyl acetate in dichloromethane over 40 mins. and subsequently a flush of 0-100% ethyl acetate in DCM+0-20% MeOH). Product fractions combined and evaporated in vacuo to give the title compound as a colourless oil (0.342 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.II.Cl[P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([P:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)P(c1ccccc1-c1ccc(C(F)(F)F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 10.7 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with magnesium turnings (90 mg, 3.69 mmol), 2-bromo-4′-(trifluoromethyl)biphenyl (1.01 g, 3.35 mmol), and a crystal of iodine. The tube was purged with argon for 5 minutes, then THF (6 mL) was added through a rubber septum and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and cuprous chloride (365 mg, 3.69 mmol) and chloro-di-t-butylphosphine (0.765 mL, 4.03 mmol) were added. Heating was resumed for 14 hours. The reaction mixture was then cooled to room temperature and diluted with ether (40 mL). The suspension was filtered to isolate the solid. The solid was partitioned between ethyl acetate (60 mL) and 38% ammonium hydroxide (75 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The -combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH (10 mL) to afford 131 mg (11%) of pale yellow needles. A second crop was isolated by concentrating the mother liquor and recrystallizing the solid from MeOH (20 mL) and water (2 mL) to afford 260 mg (21%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])=[O:17])=[CH:13][CH:14]=2)=[O:38])=[N:6][CH:7]=1
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(S(=O)c2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a stirred solution of 6n (1.0 g, 2.11 mmol) in DCM (50 mL) at 0° C. was added MCPBA (0.364 g, 2.11 mmol) in portions. The resulting mixture was stirred at room temperature for 6 h and then diluted with water and made slightly basic with Na2CO3 solution. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried and evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-methanol 5:1) to give 8g, yield 48%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.38 (br, s, 1H), 9.15 (s, 2H), 8.20 (m, 1H), 7.88 (m, 1H), 7.72-7.80 (m, 6H); EI-MS m/z 489 [M]+, 491 [M+2]+; HRMS calculated for C18H12BrN5O5SNa [M+Na]+: 511.9634, found: 511.9632. Anal. (C18H12BrN5O5S) C, H, N.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[N:16][OH:17])[CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19](=[CH2:22])[C:20]#[N:21].Cl[O-].[Na+]>O1CCCC1>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]4[CH2:18][C:19]([CH3:22])([C:20]#[N:21])[O:17][N:16]=4)[CH:13]=3)[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ON=Cc1ccc2cnn(C3CCCC3)c2c1
Reactant: C=C(C)C#N
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CC1(C#N)CC(c2ccc3cnn(C4CCCC4)c3c2)=NO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of compound obtained from step b above (50 mg, 0.218 mmol) and methylacrylonitrile (29.3 mg, 0.436 mmol) was added tetrahydrofuran (5 ml) and stirred the reaction mixture for 10 minutes at room temperature. To the resulting reaction mixture was added sodium hypochlorite (3 ml) with vigorous stirring, which was continued for 15 hours. The solvent was evaporated under reduced pressure and extracted the compound with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. The residue thus obtained was purified by column chromatography using ethylacetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 65 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 1, step d.) (1.13 g, 2.53 mmol) was dissolved in dimethylformamide (DMF) (30 mL), treated with K2CO3 (524 mg, 3.79 mmol), benzyl bromide (340 uL, 2.78 mmol), and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure. This compound was purified by chromatography (EtOAc/Hex) prior to use in subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([OH:10])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cn1c(Cl)ncc(O)c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cnc(Cl)n(C)c2=O)cc1
Temperature: 60 °C
Yield: 59.6 %

Procedure:
To a solution of 9.60 g (59.8 mmol) 2-chloro-5-hydroxy-3-methylpyrimidin-4(3H)-one in 300 ml DMF was added 20.4 ml (149 mmol) PMBCl, and 48.7 g (149 mmol) Cs2CO3. The reaction mixture was heated to 60° C. for 3 h, cooled to rt, quenched with 200 ml water, extracted with 500 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (330 g silica gel, 3-80% EtOAc:hexane) gave 10 g (60% yield) of 2-chloro-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one. LCMS [M+H]+=281.0.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]#[N:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:7]([N:6]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[C:3]([C:11]#[N:12])[CH:4]=[N:5]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)n1ncc(C#N)c1N
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1c(C#N)cnn1C(C)(C)C

Procedure:
The title compound was prepared from the reaction of 5-Amino-1-tert-butyl-1H-pyrazole-4-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:3]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1F
Yield: 45.9 %

Procedure:
Mix 4-bromo-1-fluoro-2-nitrobenzene (2 g, 9.17 mmol) and stannous chloride dihydrate (8 g, 35 mmol) in ethanol (20 mL), heat the mixture to reflux for 4 hrs. Cool the reaction to room temperature, dilute with water and adjust pH=12 with sodium hydroxide solution, filter off the solid. Partition the filtrate in water and dichloromethane, collect the organic layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give crude product (800 mg, 46.5%). MS: (M+1): 190/192.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([F:15])[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[C:9]([F:15])[CH:8]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.1 eq) in tetrahydrofuran (0.13M) at −78° C., was added n-butyllithium (2.5M in hexanes, 1.1 eq) dropwise over 20 min. The reaction mixture was stirred at −78° C. for 15 min, warm to 0° C., stirred for 15 min and cooled back to −78° C. A solution of 4-bromo-2-fluoro-benzaldehyde (1 eq) in 100 mL THF was added dropwise over 30 min. Final mixture was allowed to warm slowly to rt and stirred for 1 h. The resulting mixture was quenched with a saturated NH4Cl solution and diluted with 2 volume of hexane. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with Hexane/EtOAc (9:1) and filtered on a pad of Silica gel. The fractions were combined and concentrated to afford the desired material.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-].CS[C:22]1[S:26][CH:25]=[CH:24][S+:23]=1>COCCOC>[S:23]1[CH:24]=[CH:25][S:26][C:22]1=[C:13]([C:11](=[O:12])[NH:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CSc1scc[s+]1
Reactant: CCOC(=O)CC(=O)NCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)NCc1ccccc1)=C1SC=CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
Sodium hydride (a 60% of dispersion in oil) (189 mg) is suspended in 1,2-dimethoxyethane (20 ml), and the mixture is cooled with ice-water. A solution of ethyl (N-benzylcarbamoyl)acetate (1.002 g) in 1,2-dimethoxyethane (23 ml) is added dropwise to the mixture. The mixture is stirred for 30 minutes. Then, 2-methylthio-1,3-dithiolium iodide (1.309 g) is added to the mixture, and the mixture is stirred at room temperature for 2 hours and then at 40° C. to 50° C. for one hour. After cooling, the mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue thus obtained is treated in the same manner as described in Example 22-(2), whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (595 mg) is obtained.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[OH-].[K+]>C1COCC1.[H][H]>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Boc-Gly-Pro-Nleu-OEt (4.3 g, 0.0104 mol.) was dissolved in 80 ml THF/H2) (v/v, 1:1) and the solution was chilled to 0° C. on a water-ice bath. KOH (1.1 g dissolved in 20 ml H2O) was added while stirring the solution. After a while, the bath was removed and the stirring was continued for one more hour. The THF was removed under reduced pressure. The aqueous solution was extracted by ethyl acetate 2×50 ml. Then, the aqueous layer was chilled to 0° C. and was acidified to about pH=3 by addition of concentrated HCl while swirling the solution vigorously at the same time (the aqueous layer was covered by 50 ml ethyl acetate). The product was extracted from the aqueous layer by ethyl acetate 3×50 ml. The organic layer was combined and dried by Na2SO4. The ethyl acetate was removed under reduced pressure. Column chromatography (E/H:5:2) was carried out to obtain the pure product (white solid, 3.6 g, 92%). TLC Rf=0.44 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+=386. Analytical RP-HPLC chromatogram, single peak, retention time RT=13 min. (25-60% B in 30 min.). 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ12.50 (s, 1H, carboxyl), 6.62 (m, 1H, Gly-NH), 4.92 (d, Pro-α), 4.72 (d, Pro-α), 4.56 (d, Nleu-α), 4.48 (d, Pro-α), 4.12 (m, Nleu-α), 4.00-3.90 (m, Nleu-α), 3.83-3.66 (m, Nleu-α, Gly-α), 3.64-3.50 (m, Gly-α, Nleu-α), 3.50-3.33 (m, Pro-δ), 2.34-1.60 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 1.38 (s, 9H, Boc-CH3), 0.88 (dd, Nleu-δ), 0.75 (dd, Nleu-δ).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12]C(OCC)=O.O.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 87.6 %

Procedure:
According to the procedure of Example 2, ethyl 2-chloro-3-nitro-β-oxobenzenepropanoate (14.0 g, 51.5 mmol) is reacted with 30% water/trifluoroacetic acid to give 1-(2-chloro-3-nitrophenyl)ethanone (9.0 g, 87%), mp=41-43° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=1)([O-])=O>O1CCCC1.CO.[Pt]=O>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2[N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
tert-Butyl 4-(1-nitro-2-naphthylamino)phenylcarbamate (18.67 g, 49.21 mmol) was dissolved in tetrahydrofuran (180 mL) and methanol (180 mL), the mixture was added with platinum oxide (360 mg), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was separated by filtration, then the solvent was evaporated under reduced pressure, and the residue was washed with methanol to give the title compound (15.67 g, yield 91%) as off-white crystals.
Reaction SMILES: [I-].[N:2]1([C:12]([N:14]2[CH:18]=[CH:17][N+](C)=[CH:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.ClCCl.N1CC[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25]C1>C(N(CC)CC)C>[N:2]1([C:12]([N:14]2[CH2:15][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:18]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16.5 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-3-methyl-1H-imidazol-3-ium iodide, 224 ml of dichloromethane and 8.45 g of ethyl isonipecotate, followed by 31.22 ml of triethylamine, are introduced into a 500 ml round-bottomed flask. The reaction medium is stirred at ambient temperature for 20 hours. The solvent is evaporated under reduced pressure and the residue is taken up in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure to result in 15.2 g of ethyl 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylate.