Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10].[C:17]([N:19]=[C:20]([N:23]([CH3:32])[N:24]=CC1C=CC=CC=1)SC)#[N:18].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:18][C:17]1[N:19]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([N:11]([CH3:12])[CH3:13])=[O:10])[N:23]([CH3:32])[N:24]=1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: CN(C)C(=O)c1cccc(NCCCN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)c1cccc(NCCCNc2nc(N)nn2C)c1
Yield: 42.7 %

Procedure:
3-[(3-Aminopropyl)amino]-N,N-dimethylbenzamide (0.8 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid, methyl ester (0.84 g) were heated together under reduced pressure of 14 mm Hg during 4 hr at 100°. The cooled reaction mixture was dissolved in acetone, treated with 1 N hydrochloric acid (2 ml) and heated at 60° for 0.5 hr. The mixture was cooled, basified with potassium carbonate and extracted with ethyl acetate. Evaporation of the organic extracts gave a viscous oil which was triturated with ether to give the title compound (0.49 g). TLC silica; methanol:ammonia (80:1) Rf 0.63. NMR (CDCl3) 2.9 m (1H); 3.2-3.7 m (3H); 5.28 t (1H); 6.12 s (2H); 6.7 s (3H); 7.0 s (6H); 6.4-7.4 m (5H); 8.23 t (2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])[NH:20][C:19]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 37 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 4-methyl-2-oxindole and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 60 mg (37%) of the title compound as a green solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncccn1
Yield: 32 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 42 mg, 32%) which was obtained as a brown solid. MS: m/e=262.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cn(-c2ccccc2)cn1
Reaction time: 48 h
Yield: 26.4 %

Procedure:
4-Bromo-1H-imidazole (500 mg, 3.4 mmol, 1 eq), phenylboronic acid (830 mg, 6.8 mmol, 2 eq), anhydrous cupric acetate (926 mg, 5.1 mmol), activated 4 Å molecular sieves (2 g) and pyridine (0.3 ml) were combined in dichloromethane (20 ml) and stirred for 2 days in the presence of air. The reaction mass was then filtered through Celite, washed with methanol, and concentrated and purified by silica gel chromatography (eluent 15% ethyl acetate/hexane) to afforded yellowish sticky solid 4-bromo-1-phenyl-1H-imidazole (200 mg, 26%).
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]>CCO.[Pd]>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([NH2:17])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2ccccc2c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1c2ccccc2c2cc(N)ccc21
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 9-Isopropyl-3-nitro-9H-carbazole(1.5 g, 5.89 mmol) in EtOH (100 ml) was added 10% Pd-C (150 mg) and the reaction mixture was hydrogenated with a Parr hydrogenation apparatus at 45 psi H2 pressure for 3 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to afford the desired product as a solid (1.3 g, 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[C:18]([F:23])[CH:17]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: Cn1c(Oc2ccc(Br)cc2F)nc2cccnc21
Temperature: 180 °C

Procedure:
A suspension of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (700 mg), 4-bromo-2-fluorophenol (0.399 mL) and NaH (60% in oil, 159 mg) was heated at 180° C. for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (691 mg).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5]1)([CH3:3])[CH3:2].[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:14][C:7]1[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)n1ccc(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of 1-isopropyl-3-(2-thienyl)-1H-pyrazole (27.5 mmol) in 98 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (28.9 mmol) in small portions. The reaction mixture was stirred overnight at room temperature. N-Iodosuccinimide (4.4 mmol) was added and stirring was continued for 24 h. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 3.70 g 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole (38% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Reaction time: 10 h
Yield: 75.9 %

Procedure:
Three grams of said 3-fluoro-4-methoxybiphenyl was dissolved in 14 ml of carbon disulfide, and 1.17 g of acetyl chloride and 2.36 g of aluminum chloride were added, followed by stirring the mixture for 10 hours. Twenty milliliters of 10% hydrochloric acid and then 5 ml of water were added, and the precipitate was filtered and washed with water. The resulting crude crystals were recrystallized from ethanol to obtain 2.75 g of 3'-fluoro-4'-methoxy-4-acetylbiphenyl (yield 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C(#N)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CC(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CCOC(=O)CC(C)Nc1c(N)cnc2ccccc12
Yield: 101.4 %

Procedure:
A Parr vessel was charged with a solution of ethyl 3-[(3-nitroquinolin-4-yl)amino]butanoate (11.5 g, 37.9 mmol) in acetonitrile (150 mL) followed by 5% platinum on carbon (1.2 g). The mixture was placed under hydrogen pressure overnight and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure and further dried under high vacuum to provide 10.5 g of ethyl 3-[(3-aminoquinolin-4-yl)amino]butanoate as a sticky, yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[NH:4][C:5]1[C:6]([C:17]([OH:19])=[O:18])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]2=O>CO.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[CH:11]2)[CH:9]=[CH:8][CH:7]=[C:6]1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cccc2c(=O)c3cccc(F)c3[nH]c12
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2cc3cccc(F)c3nc12
Yield: 90 %

Procedure:
Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-fluoro-9-oxoacridan-4-carboxylic acid as above gave 5-fluoroacridine-4-carboxylic acid (90%), mp (MeOH/H2O) 295-298° C. (dec). 1H NMR [(CD3)2SO] δ 7.74-7.80 (m, 1 H, ArH), 7.90-7.96 (m, 2 H, ArH), 8.19 (d, J=8.6 Hz, 1 H, ArH), 8.61 (dd, J=8.6, 1.2 Hz, 1 H. ArH), 8.81 (dd, J=7.0, 1.0 Hz, 1 H, ArH), 9.65 (s, 1 H, H-9). Anal. (C14H8FNO2) C, H, N, F.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Br:11]Br.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: Nc1ccc(C2CC2)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ncc(C2CC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyclopropylpyridin-2-amine (1.33 g) in acetic acid (15 mL) was added bromine (762 μL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with 1N aqueous sodium hydroxide solution at 0° C., and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.11 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1O>COCCOC.ClCCl>[O:20]=[C:19]1[C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]3[C:11]=2[C:12](=[O:21])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]1=2
Reactant: O=C1C(O)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1ccc(N)nc1
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc2nc3c(n2c1)C(=O)c1ccccc1C3=O
Yield: 16.9 %

Procedure:
0.55 g (5.08 mmol) of 2-amino-5-methylpyridine is added to a suspension of 0.45 g (2.16 mmol) of 3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in 15 mL of 1,2-dimethoxyethane. The reaction medium is brought to reflux for 21 h. After complete cooling, it is diluted with 120 mL of dichloromethane. The organic phase is washed successively with a saturated solution of sodium hydrogen carbonate and sodium chloride, then dried on sodium sulfate and evaporated under reduced pressure. The raw product obtained is purified on a medium-pressure column (support: silica; eluent: dichloromethane/heptane/ethyl acetate, 68/40/2) to produce 0.096 g of 6,11-dihydro-6,11-dioxo-2-methyl-naphtho[2',3':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals after decoloration with animal black.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7])#[N:2].[CH3:19][Mg]Br.Cl>O1CCCC1>[C:6]([C:5]1[CH:4]=[C:3]([CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=1)[C:1]#[N:2])(=[O:7])[CH3:19]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(C#N)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Yield: 103.3 %

Procedure:
A solution of 3-cyano-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (196 mg, 0.76 mmol) in anhydrous tetrahydrofuran (2 mL) was added with methylmagnesium bromide (0.96 M solution in ether, 0.95 mL, 0.91 mmol) with stirring on an ice bath, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 3-acetyl-5-(trifluoromethyl)benzonitrile (167.4 mg, 100%) as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH:6]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:9]=[C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[C:11]([OH:10])=[O:12]
Reactant: c1ccccc1
Reactant: O=C1CC(NC(=O)C(F)(F)F)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CC(NC(=O)C(F)(F)F)C(=O)O)c1ccccc1

Procedure:
A solution of 3-[(trifluoroacetyl)amino]succinic anhydride (4.00 g, 19.0 mmol) and aluminum chloride (5.56 g, 41.7 mmol) in benzene (80 mL) was refluxed for 5 h, then cooled in an ice bath and quenched by the slow addition of water. The reaction mixture was worked up with ethyl acetate and 10% hydrochloric acid. The residue was purified by chromatography (silica gel, 100% methylene chloride to 90/10/1/1 methylene chloride/methanol/acetic acid/water gradient elution). Recrystallization of the resulting oil from methylene chloride/hexanes produced the title compound as a white solid (3.00 g). 1H NMR (500 MHz, (d6-acetone) □ 11.56 (bs, 1H), 8.63 (bs, 1H), 8.06 (dd, J=8.3, 1.2 Hz, 2H), 7.70-7.67 (m, 1H), 7.57 (t, J=7.7 Hz, 2H), 5.14-5.10 (m, 1H), 3.84 (dd, J=18.3, 6.8 Hz, 1H), 3.77 (dd, J=18.1, 4.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][C:15]2([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[C:15]([CH3:22])([CH3:21])[CH2:16]2)=[O:10])[CH:3]=1
Reactant: CC1(C)CNc2ccc(F)cc21
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(Cl)ccn2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (1.1 mmol) 4-chloro-pyridine-2-carboxylic acid, 0.18 g (1.1 mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole, 0.28 mL (2.0 mmol) TEA and 3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirred overnight at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.C(O)C.[C].[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(-c2cc(/C=C/c3ccccc3)[nH]n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
5-[(E)-2-Phenylvinyl]-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (1.56 g, 4.96 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (30 mL), 10% palladium-carbon (50% water-containing product, 500 mg) was added, and the mixture was stirred at room temperature under an atmospheric hydrogen atmosphere for 2 hr. The catalyst was filtered off and the filtrate was concentrated to give the title compound (880 mg, yield 56%) as colorless crystals. MS: m/z 317 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[NH:44])[NH:42]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[N:44]=[C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt3 (3.6 g, 36 mmol) in toluene (150 mL) was added isobutylchloroformate (4.1 g, 30 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.4˜7.3 (5H, m), 4.7 (2H, s), 4.69 (2H, s), 4.2˜4.04 (2H, m), 3.02˜2.84 (3H, m), 2.04˜4.94 (2H, m), 1.84˜4.7 (2H, m), 1.46 (9H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]([Cu])#[N:19].Cl>CN1C(=O)CCC1>[CH2:9]([O:8][C:6]1[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]([N+:15]([O-:17])=[O:16])=[C:2]([CH:7]=1)[C:18]#[N:19])[CH3:10]
Reactant: CCOc1cc(Br)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 91.2 %

Procedure:
A mixture of 1-bromo-5-ethoxy-2-nitro-4-trifluoromethyl-benzene from step 2 (61.81 g, 197 mmol) and CuCN (18.51 g, 207 mmol) in NMP (197 mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl, extracted with TBME, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil. Silica gel column chromatography with heptane/EtOAc 4:1 gave the title compound as a yellow solid (46.73 g, 91%). MS (EI) 260.1 [M].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:22]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[N+:23]=[N-:24]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) and sodium azide (10.6 g) in dimethyl sulfoxide (350 ml) was stirred at 90° C. overnight and the solution was diluted with ethyl acetate (600 ml). The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-4-azido-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (20.0 g) as a pale brown oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([O:48][CH:49]([CH3:51])[CH3:50])[C:42]([F:47])=[C:43]([CH:46]=1)[CH:44]=[O:45])[CH3:37]>C1COCC1>[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([O:48][CH:49]([CH3:50])[CH3:51])[C:42]([F:47])=[C:43]([CH:44]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:45])[CH:46]=1)[CH3:37]
Reactant: CCOc1cc(C=O)c(F)c(OC(C)C)c1
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(OC(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 75.8 %

Procedure:
To a solution of Intermediate 8.1 (200 mg, 0.517 mmol) in 3 mL THF at 0° C., was added BuLi (1.4 M in THF, 0.406 mL, 0.569 mmol). The mixture was stirred at 0° C. for 25 min, then a solution of Intermediate 7.2 (117 mg, 0.517 mmol) in 1 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 240 mg of Intermediate 25.1 as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH3:37])[C:25](=[O:27])[CH2:24][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCNCc1ccccc1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1ccccc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:9]2[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A mixture of 2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine (30.2 mg, 0.108 mmol), 2-(4-bromo-butyl)-isoindole-1,3-dione (33.5 mg, 0.119 mmol), DMF (3 mL), DIPEA (0.3 mL), and KI (4 mg) were heated to 110° C. for 4 h and overnight at 90° C. The solvent was removed and CH2Cl2 (20 mL) was added to the residue. It was washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted two more times with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 2:1 hexanes:EtOAc) provided 13.3 mg of 2-{4-[2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-azepin-1-yl]-butyl}-isoindole-1,3-dione as a film. 1H NMR(CDCl3) δ 0.53-0.59 (m, 1H), 0.65-1.00 (m, 3H), 2.36 (s, 6H), 2.36-2.41 (m, 1H), 2.47-2.50 (m, 2H), 3.02-3.24 (m, 5H), 4.72 (dd, 2H, J=9.6, 1.8 Hz), 5.80-5.83 (m, 2H), 6.90 (dd, 2H, J=7.5, 4.2 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.67-7.73 (m, 2H), 7.76-7.86 (m, 2H), 8.35 (d, 2H, J=4.2 Hz).