Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:16])[CH2:8][CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][CH2:13]O.P(Br)(Br)[Br:20]>CCOCC>[CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:16])[CH2:8][CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][CH2:13][Br:20]
Reactant: COC(C)(C)CCCC(C)CC=CC(C)=CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COC(C)(C)CCCC(C)CC=CC(C)=CCBr
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1.90 g. of 11-methoxy-3,7,11-trimethyldodeca-2,4-dien-1-ol in 20 ml. of ether is added a solution of 0.80 g. of phosphorus tribromide in 10 ml. of ether, under nitrogen, with stirring at -50°. The reaction mixture is stirred for three hours at -60° to -40° and then poured into ice water, which is then washed with sodium bicarbonate solution water and brine, dried over calcium sulfate and evaporated under reduced pressure to yield 11-methoxy-3,7,11-trimethyldodeca-2,4-dienyl bromide.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1
Reactant: O=C(C=Cc1ccccc1)Nc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A mixture of methyl bromoacetate (0.230 g, 1.93 mmol), Cs2CO3 (0.525 g, 1.60 mmol), and N-(3-hydroxy-phenyl)-3-phenyl-acrylamide (1/91) (0.370 g, 1.55 mmol) in acetonitrile (5 ml) was stirred at 45° C. for 3 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 0.1N KHSO4. The organic layer was washed successively with water, brine, and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed silicagel with chloroform-ethyl acetate (10:1) as eluent to give the title compound 8 (0.235 g, 48%). 1H NMR (CDCl3, HMDSO) δ: 3.75 (3H, s); 4.62 (2H, s); 6.53 (1H, d, J=15.6 Hz); 6.68 (1H, t, J=2.0 Hz); 7.01-7.60 (9H, m); 7.71 (1H, d, J=15.6 Hz).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:5]#[N:6].[CH3:13][I:14]>CO>[I-:14].[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:8]=[N+:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[C:5]#[N:6]
Reactant: CON=C(C#N)c1cccnc1
Reactant: CI
Solvent: CO
Product: CON=C(C#N)c1ccc[n+](C)c1
Product: [I-]
Yield: 100 %

Procedure:
α-(Methoxyimino)-α-(pyridin-3-yl)acetonitrile (D4) (0.155 g, 0.00096 mol) was heated under reflux with methyl iodide (5 ml) in methanol (5 ml) for 60 h. The mixture was evaporated to dryness to give the title compound (D6) (0.3 g, 100%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([N:6]1[C:5]2[CH:26]=[CH:27][C:2]([C:32]3[CH:33]=[N:34][C:29]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)nn1C
Temperature: 110 °C
Yield: 76 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (38 mg, 0.09 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (24 mg, 0.109 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and 2 M aqueous Na2CO3 (0.2 mL, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-10% MeOH/CH2Cl2 as the eluent to afford the title compound (30 mg, 76%) as an off-white solid. LCMS (ESMS): m/z 439.72 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([CH3:42])[CH3:41])=[N:11]2
Reactant: CC(C)I
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(OC(C)C)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 4 hour. The mixture was diluted with water (20 mL), extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a cream solid, 0.023 g.
Reaction SMILES: C[C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1)=[O:18]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2c[nH]c(=O)[nH]2)cc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 6.5 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 14.6 g of aluminum chloride in 65 ml of nitrobenzene is added 17.6 g of 3,4-dimethoxybenzoyl chloride in portions. The mixture is stirred for 3 hours at 60° C., cooled and poured over ice water. The gummy solids are filtered and recrystallized twice from ethyl alcohol-water to afford the title compound. M.P. 257°-259° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([NH:7][S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(N)C1C=CC=CC=1.C(OCC)(=O)C>C(O)(=O)C>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([O:32][CH3:33])[CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[CH:12]=[CH:11][S:8]([NH:7][C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=1)(=[O:10])=[O:9]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 4-methoxy-3-nitroanilinesulfonylacetic acid (10 mmol) and 2,4,6-trimethoxy-benzaldehyde (10 mmol) in glacial acetic acid (15 mL) was stirred at room temperature for 10 min. A catalytic amount of benzylamine (300 microliters) was added to the solution. The solution was then refluxed for 8 h. The reaction mixture was then cooled to room temperature. To the cooled reaction mixture was added ethyl acetate. A solid precipitate formed and was separated by filtration. Additional of ethyl acetate (30 mL) was added and the resulting mixture was washed sequentially with saturated sodium bicarbonate, dilute HCL and brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under vacuum. The solid residue obtained was recrystallized from 2-propanol. (m.p 177–179° C.; yield 48–52%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]([O:16]CC3C=CC=CC=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCOCC1>[Pd].C(O)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]([OH:16])=[O:15])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
2.34 g (5.38 mmol) of benzyl 3-(1-adamantyl)-4-methoxycarbonylmethyloxybenzoate, 40 ml of dioxane, 500 μl of acetic acid and 234 mg of palladium (10%) were introduced into a reactor. The mixture was hydrogenated at 40° C. and at a pressure of 7 bar for three hours. The catalyst was filtered off and the mixture was evaporated to dryness. The solid obtained was triturated from hexane, filtered off and dried. 1.74 g (94%) of the expected acid, having a melting point of 230°-1° C., was recovered.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4](S(C(C)C)(=O)=O)[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].[H-].[Na+].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>O1CCCC1.O>[N:27]1([C:2]2[C:7]([I:8])=[C:6]([C:9]([F:10])([F:11])[F:12])[N:5]=[C:4]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[N:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: O=C1CCCN1
Reactant: c1c[nH]cn1
Reactant: CC(C)S(=O)(=O)c1nc(Cl)c(I)c(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1c1nc(-n2ccnc2)c(I)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
4-Chloro-5-iodo-2-isopropylsulfonyl-6-trifluoromethypyrimidine (0.50 g) was dissolved in tetrahydrofuran (5.0 ml) and added 2-pyrrolidinone (0.10 g). The mixture was cooled to ice bath temperature and added sodium hydride (oily 80%, 36 mg). The mixture was stirred at that temperature for 10 minutes, and then added imidazole (0.25 g) at the same temperature. The mixture was stirred at that temperature for 30 minutes, and then it warmed to room temperature After stirg over night, the mixture was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 1-(4-imidazol-1-yl-5-iodo-6-trifluoromethylpyrimidin-2-yl)-pyrrolidin-2-one (0.20 g) as colorless crystalline solid, mp 195-197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Cc1cc(C(=O)/C=C/c2ccc(F)c(Cl)c2)c(O)c([N+](=O)[O-])c1
Yield: 93.1 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 3-chloro-4-fluorobenzaldehyde (486 mg, 3.07 mmol) were reacted according to the same procedure as Preparation 22 to give 800 mg (Yield 94%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), 4-bromo-2-methyl-2-butene (1.21 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.51 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 1.53 (m, 6 H) 1.63 (m, 3 H) 2.60 (m, 1 H) 2.80 (m, 1 H) 4.94 (m, 1 H) 5.11 (m, 2 H) 7.26 (m, 10 H). MS (ESI+) m/z 326 (M+NH4)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].C(NC(C)C)(C)C>CN(C)C=O>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:8]3[CH2:9][CH2:10][CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[F:18])[CH2:6][CH2:7]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: Fc1ccccc1CN(C1CCNCC1)C1CC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccccc2F)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-(2-fluoro-benzyl)-piperidin-4-yl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (60%, colourless oil). HPLC-MS m/z=(M+1), Rt: 3.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]2)[CH2:6]1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][O:27][C:33](=[O:35])[CH3:34])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: OCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.02 g (0.04 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-hydroxypropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine (Example 17), 0.25 mL (0.12 mmol) of acetic anhydride, 0.25 mL (0.3 mmol) of pyridine and a catalytic amount of DMAP in 0.5 mL of CH2Cl2 was stirred at rt for 2 h. TO the reaction mixture was added 10 mL of sat'd Na2CO3 solution and it was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give the title compound. Mass Spectrum (ESI) m/e=539 (M+1 35Cl, 35Cl), 541 (M+1 35Cl, 37Cl), and 543 (M+1 37Cl, 37Cl).
Reaction SMILES: [Li+].[OH-].[C:3]([C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(C(C)(C)C)cc1C(=O)O
Temperature: 50 °C
Yield: 97.8 %

Procedure:
A solution comprised of LiOH (2.3 g, 9 mmol) in water (12 mL) was added to a solution of ethyl 3-tert-butyl-1-isopropyl-1H-pyrazole-5-carboxylate (2.3 g, 9 mmol) in THF (24 mL) and the reaction mixture was heated to 50° C. overnight. The reaction was concentrated under reduced pressure and diluted with water. The solution pH was adjusted to pH 5 and the solution was extracted with EtOAc. The organics were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give 3-tert-butyl-1-isopropyl-1H-pyrazole-5-carboxylic acid (1.85 g, 93% yield). 1H NMR (300 MHz, DMSO-d6): 6.62 (s, 1 H), 5.37 (m, 1 H), 1.35 (d, J=6.6 Hz, 6 H), 1.22 (s, 9 H). MS (ESI) m/z: (M+H+) 211.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][F:10])=[CH:4][CH:3]=1.O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:27][C:28]([F:37])([F:36])[C:29](N1C=CN=C1)=[O:30].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]([F:10])[C:29](=[O:30])[C:28]([F:37])([F:36])[F:27])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: O=C(CF)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C(F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.9 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-fluoro-1-ethanone (3.54 g, 16.3 mmol) in tetrahydrofuran (50 ml) was added dropwise 1M lithium hexamethyldisilazide tetrahydrofuran solution (19.6 ml, 19.6 mmol) at −78° C. After stirring for 45 min., N-trifluoroacetylimidazole (2.3 ml, 19.6 mmol) was added. The resulting mixture was allowed to warm up to room temperature and stirred for 1.5 hr. The mixture was acidified with 2M hydrochloric acid and extracted with diethyl ether (300 ml). The separated organic layer was washed with water (100 ml×3) and dried over magnesium sulfate. The solution was evaporated to give 5.2 g of 1-(4-bromophenyl)-2,4,4,4-tetrafluoro-1,3-butanedione as a brown oil. This residue was heated with 5-hydrazino-2-pyrisinesulfonamide hydrochloride (1.10 g, 4.89 mmol) at refluxing temperature for 18 hr. After evaporation, the obtained residue was chromatographed on a column of silica gel (500 g) eluting with ethyl acetate/hexane (1:3 to 1:1) to afford 930 mg (12%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:31]([O:33]CC1C=CC=CC=1)=O)[CH3:30])=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:48][NH2:49]>CO>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:31]([NH:48][NH2:49])=[O:33])[CH3:30])=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: NN
Reactant: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)C(=O)NN

Procedure:
Box-Lys(Z)-Asn-Ala-OBzl (XXIV) (2.3g, 3.5 mmol) was dissolved in MeOH (20 ml) with heating and treated with H2NNH2 (1.1 ml) at 4° C for 72 hr. The precipitated product was filtered and washed with MeOH and ether, yield 1.0g (49.3%). The white powder was crystallized from DMF with isopropanol; mp 177°-180° C; [α]D25 -14.9° (c 1.5, DMF). Anal. Calcd for C26H41N7O8 (579.67): C, 53.87; H, 7.13; N, 16.91. Found: C, 53.75; H, 7.19; N, 17.00.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].C([CH:17]([C-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)[C:18]([O:20][CH2:21]C)=O)C.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:33].Cl>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([C:27]2[CH:23]=[CH:17][C:18]([O:20][CH3:21])=[CH:25][CH:26]=2)=[C:11]([C-:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)[CH2:12][CH3:13])=[CH:3][CH:4]=1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:33]
Reactant: COc1ccc(I)cc1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(CC)[c-]1cccc1
Agent: [Fe+2]
Agent: Cl
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CCC(=C(c1ccc(OC)cc1)c1ccc(OC)cc1)[c-]1cccc1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
1.20 g (5.5 mmol) of 4-iodoanisole are dissolved in 20 ml of anhydrous ether under an argon atmosphere. The solution is cooled to 0° C. and then 2.9 ml (4.6 mmol) of a 1.6M n-butyllithium solution are added dropwise. After complete addition, the mixture is maintained at 0° C. for 15 minutes. A solution of ethyl 2-ethyl-2-ferrocenylacetate (0.69 g, 2.3 mmol) dissolved in 10 ml of anhydrous ether is placed in the dropping funnel. The latter solution is added dropwise to the first solution, the temperature being maintained at 0° C. Stirring is maintained for 30 minutes at 0° C. and 2 hours at room temperature. A 1N hydrochloric acid solution is then added to a pH of 1 and the reaction mixture is heated at reflux for 4 hours. After cooling, the product is extracted with ether. The ethereal phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on 60GF254 silica gel plates with a 1/9 ether/pentane mixture as eluent. 0.65 g of the desired compound is obtained (Rf =0.45) with a yield of 62.5%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[S:11][C:12]([CH3:17])=[CH:13][C:14]=2[C:15]#[N:16])=[C:4]([N+:18]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:24].Cl>C(O)C>[ClH:24].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:18]=[C:15]([NH2:16])[C:14]3[CH:13]=[C:12]([CH3:17])[S:11][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1cc(C#N)c(Nc2cc(F)c(F)cc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Temperature: 86.5 °C
Yield: 99.7 %

Procedure:
Add 2-(4,5-difluoro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (94.0 g, 318 mmol) and tin (II) chloride dihydrate (225 g, 997 mmol) to ethanol (1400 mL) and aqueous 6N HCl (1400 mL) with stirring under nitrogen. Heat at gentle reflux (86-87° C.) for 0.3 hours, and then allow cooling to ambient temperature. Filter, rinse with water (3×250 mL) and dry at 50-60° C. to give 95.7 g (100%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (bs, 1H), 9.84 (bs, 1H), 9.33 (bs, 1H), 8.93 (bs, 1H), 7.00 (m, 2H), 6.85 (s, 1H), 2.28 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9F2N3S (freebase) 266.0563; found 266.0555.