Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].[Br:11]Br>O>[BrH:10].[Br:10][CH:2]([Br:11])[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cccnc1
Agent: Br
Solvent: O
Product: O=C(c1cccnc1)C(Br)Br
Temperature: 57.5 °C
Yield: 99.4 %

Procedure:
3-Acetylpyridine (50 g, 0.41 mol), 47% aqueous HBr solution (106.6 g, 1.5 equivalent amount relative to 3-acetylpyridine) and water (80 ml) were charged in a reaction vessel and the mixture was stirred at 55-60° C. Bromine (135.2 g, 2.05 equivalent amount relative to 3-acetylpyridine) was added dropwise and the mixture was stirred for one more hour. The mixture was cooled to 5° C. under ice-cooling, and filtered to give 146.7 g of the titled compound as crystals (yield 99.0%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[C:19]([OH:21])[N:20]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:23]=[C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(O)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NC(=O)C(c2cccc(Cl)c2)S1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 168 h
Yield: 30.5 %

Procedure:
To a solution of 8-hydroxyquinoline-7-carboxylic acid (0.284 g,) of Preparation 1 and 2-amino-5-(3-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred at room temperature for 7 days. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is triturated with hot EtOAc, then with hot i-PrOH to yield 0.182 g of the title product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:10]1([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: N#Cc1cccnc1Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1cccnc1-n1cncn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of 2-chloro-nicotinonitrile (10.30 g, 74.4 mmol), 1H-[1,2,4]Triazole (5.36 g, 77.6 mmol), and Cs2CO3 (25.28 g, 77.6 mmol) in DMSO (30 mL) was stirred at 50° C. for C for 30 min. The resulting off-white semisolid was partitioned with water (600 mL) and DCM (600 mL), and the aq layer was extracted with DCM (2×200 mL). The combined organic layers were dried (Na2SO4), concentrated, and put under vacuum at 90° C. to remove the bulk of DMSO. The resulting white solid was briefly triturated with refluxing diethyl ether (100 mL), allowed to cool to rt, and filtered. The filter cake was washed with ether (3×50 mL) and dried to yield the title compound as white fluffy needles (11.37 g, 89%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[N+:11]([O-])([OH:13])=[O:12]>O>[N+:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Solvent: ClCCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100 mL three-necked reaction flask fitted with reverse dean-stark apparatus was charged with 7.8 g benzene (0.1 mol), 60 mL 1,2 dichloro ethane, and 1.56 g of catalyst as prepared in example 5. The flask was flushed with nitrogen. The reaction mixture was refluxed at 100° C. for 1 h followed by dropwise addition of 6.42 mL (0.1 mol) of 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this reaction 18.6% benzene conversion was obtained with 100% selectivity for mono nitro benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)c4ncccc4C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)c4ncccc4C)c3)cc12
Reaction time: 6 h
Yield: 14 %

Procedure:
The material from step 1 was dissolved in dichloromethane and 1 mL of trifluoroacetic acid was added. The resulting mixture was left at room temperature for 6 h. The solvent was then completely evaporated and the residue dissolved in dichloromethane. 0.5 mL (450 mg, 7.5 mmol) of ethylene diamine was added. After 2 h at room temperature the mixture was evaporated and the crude purified by mass-triggered reverse-phase HPLC to afford 52 mg (0.12 mmol, 14%) of {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-methyl-pyridin-2-yl)-methanol as an off-white solid. 1H-NMR (500 MHz, DMSO-d6) a 8.80 (d, 1H), 8.42 (d(d), 1H), 8.27 (d, 1H), 7.71 ((t), br. 1H), 7.68 (dd, 1H), 7.62 (d(m), 1H), 7.57 (d(m), 1H), 7.47 (dd(d), 1H), 7.43 (t, 1H), 7.34 (d(m), 1H), 7.26-7.23 (m, 2H), 7.10 (ddd, 1H), 5.99 (s, 1H), 3.84 (s, 3H), 2.27 (s, 3H) (exchangeable protons not visible in 1H-NMR); MS: m/z 423.2 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O.O>C(OCC)C>[C:21]([O:20][C:18]([NH:17][C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:9][OH:8])[CH2:16][CH2:15]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a suspension of 1.29 g of lithium aluminum hydride in 40 mL of anhydrous ethyl ether was treated dropwise with a solution of 5.80 g of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid methyl ester in 20 mL of anhydrous ethyl ether with cooling in ice, and stirred for 3 hours while allowing to gradually warm to room temperature. The reaction solution was cooled to 0° C., combined a small amount of water to decompose an excessive lithium aluminum hydride. The insolubles were filtered off through Celite, and the filtrate was concentrated, and then the residue was washed with n-hexane to obtain 3.60 g of the desirable compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[CH:8][CH:9]=1.O1CCCC1>[Fe].C(O)(=O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C#Cc1ccc(-c2ccccc2[N+](=O)[O-])s1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)C#Cc1ccc(-c2ccccc2N)s1
Temperature: 80 °C

Procedure:
A mixture of 2-(3,3-dimethyl-but-1-ynyl)-5-(2-nitro-phenyl)-thiophene (22 g, 76 mmol), tetrahydrofurane (100 ml) and acetic acid (425 ml of a 5% aqueous solution) was heated to 80° C. Iron powder (66 g, 1.2 mol) was added in small portions at this temperature. The reaction mixture was heated for 5 hours to reflux. After cooling, it was poured on ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering Compound No. 5.030.i (20 g).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[CH3:37][CH:38]([NH2:42])[C:39]#[C:40][CH3:41]>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([NH:42][CH:38]([C:39]#[C:40][CH3:41])[CH3:37])=[O:18]
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC#CC(C)N
Product: CC#CC(C)NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and pent-3-yn-2-amine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C29H35N3O2: 458.2802, found: 458.2813.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[CH:7]=1
Reactant: Brc1ccnc(Br)c1
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1cc(Br)ccn1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2,4-dibromo-pyridine and 2-chlorophenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Cl:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][CH:14]=2>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])=[C:11]2[Cl:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=S(=O)(c1ccccc1)c1c(Cl)[nH]c2ccccc12
Product: O=S(=O)(c1ccccc1)c1c(Cl)n(Cc2ccc(Cl)cc2)c2ccccc12
Reaction time: 4 h

Procedure:
This compound was prepared in the same manner as described in Example 17 except that following the addition of 4-chlorobenzylchloride to the anion of 2-chloro-3-phenylsulfonylindole, the reaction mixture was stirred at 90° for 4 hours. The crude product was crystallized from dichloromethane-hexane to give the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41].[I-].[K+]>CN(C)C=O>[CH2:43]([O:42][P:38]([CH2:37][CH2:36][CH2:35][O:23][C:19]1[CH:18]=[C:17]([CH3:24])[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]3[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=3)[CH:11]=2)=[C:21]([CH3:22])[CH:20]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Reactant: CCOP(=O)(CCCBr)OCC
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCCCP(=O)(OCC)OCC)cc3C)c2)cc1F
Yield: 49.5 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (315 mg, 0.74 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 31 mg, 0.78 mmol) at 0° C. with stirring, and the mixture was stirred at room temperature for 30 min. Diethyl (3-bromopropyl)phosphonate (578 mg, 2.23 mmol) and potassium iodide (37 mg, 0.22 mmol) were added, and the mixture was further stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/4) and then by preparative HPLC (gradient cycle A) to give the title compound (0.22 g, yield 50%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])=[O:25])[NH:16]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])=[O:25])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@@H](N)CCCNC(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl}amino)cyclopentanecarboxylate (2.5 g) and methanol (25 ml) was added p-toluene sulfonic acid hydrate (1.2 g) at room temperature, followed by stirring at 40° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. Sodium hydrogen carbonate was added thereto under ice-cooling to adjust the pH to about 8, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml), and the organic layer was combined and extracted with a 10% aqueous citric acid solution. To the aqueous layer was added sodium hydrogen carbonate under ice-cooling to adjust the pH to about 8, followed by extraction with ethyl acetate and washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (1.6 g).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33].[C:35]1([S:41]([C:44]2[CH:48]=[CH:47][S:46][C:45]=2[CH:49]=O)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[C:25]([CH2:49][C:45]2[S:46][CH:47]=[CH:48][C:44]=2[S:41]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:43])=[O:42])=[C:24]1[CH3:33]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of triethylsilane (2.7 g), trifluoroacetic acid (1.6 g) and dichloroethane (8.0 mL) at −20° C. was treated dropwise with a mixture of (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.36 g), 3-phenylsulphony-2-thiophenealdehyde (0.39 g) and dichloroethane (8.0 mL), and the resulting mixture was warmed to room temperature over a period of 1.5 hours. The mixture was treated with additional triethylsilane (2.7 g) and trifluoroacetic acid (1.6 g) and then stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound (0.55 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[ClH:17]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([Cl:17])=[O:8])[CH:5]=1
Reactant: Cl
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
A suspension of 5-nitro-isophthalic acid mono methyl ester (22.52 g, 100.0 mmol) in thionyl chloride (50 ml) was heated to reflux for 6 hours (until the production of SO2 and HCl-gas ceased). The excess of thionyl chloride was removed under reduced pressure, the residue was dissolved in DCM and the product was precipitated by addition of hexane to give a white solid. Yield: 24.10 g (99%).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCCCCCCCC(O)=O.[CH:51]1([N:57]=[C:58]=[N:59][CH:60]2[CH2:65][CH2:64][CH2:63]CC2)CCCCC1>O1CCCC1>[CH3:1][N:57]([C:58]1[CH:63]=[CH:64][CH:65]=[CH:60][N:59]=1)[CH3:51]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: COCCOCOCCCCCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 996 mg of 16-(methoxyethoxymethoxy)hexadecanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 946 mg of the title compound were obtained.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1)=[CH2:16].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:14][C:9]1[CH:8]=[C:7]([CH:2]([C:3]([F:6])([F:5])[F:4])/[CH:16]=[CH:15]/[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH:12]=[C:11]([Cl:13])[CH:10]=1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to RT and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
Reaction SMILES: C(OC[C:5]([CH2:27]OCC)([OH:26])[CH:6]([NH:18]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1)C.[ClH:31]>>[ClH:31].[NH2:18][CH:6]1[CH2:7][C:8]2[C:9](=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH2:27][C:5]1=[O:26]
Reactant: CCOCC(O)(COCC)C(Cc1cc(OC)cc(OC)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc2c(c(OC)c1)CC(=O)C(N)C2
Temperature: 0 °C

Procedure:
α,α-Diethoxymethyl-β-tert-butoxycarbonylamino-3,5-dimethoxy-benzenepropanol (200 g) was dissolved in aqueous 37% hydrochloric acid (20 ml) cooled at 0° C. The resulting red solution was warmed at 100° C. for 3 minutes and then immediate ly cooled at 0° C. Evaporation of the reaction mixture yielded a brown solid which was recrystallized from an ethyl acetate/methanol mixture to give the title compound as a brown solid (101 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:16][CH2:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: COc1ccccc1N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(C2CCNCC2)CC1
Yield: 95.6 %

Procedure:
A solution of 4-(1-benzylpiperidine-4-yl)-1-(2-methoxyphenyl)piperazine (Step 1, 20.0 g) in ethanol (120 mL) containing acetic acid (12 mL) was hydrogenated over 10% palladium on carbon (1 g) at 50 psig on a Parr apparatus for 12 hours. The catalyst was removed by filtration through Celite and the mixture was concentrated to dryness on a rotary evaporator. The residue was partitioned between chloroform and saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to provide the desired product (14.4 g) as a yellow oil which was used without further purification. The compound was characterized as the dihydrochloride salt, which was formed by dissolving the oil in ethanol and treating it with an excess of 1N HCl/Et2O to give an off-white precipitate, which was collected by vacuum filtration, washed with Et2O and dried in vacuo; MP. 274-288° C.; MS (ES) m/z (relative intensity): 276 (M+H)+ (100).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:9][C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C:6]([OH:8])=O.N=C=N.Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:16]1[C:15]2[CH:14]([CH2:13][O:12][C:10]([NH:9][C@@H:5]([C:6]([NH:35][CH2:34][C:33]([O:32][CH3:31])=[O:36])=[O:8])[CH2:4][CH2:3][CH2:2][CH3:1])=[O:11])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of fmoc-D-Nle-OH (10 g, 28.3 mmol, Novabiochem) and PS-carbodiimide (33 g, 42.45 mmol, 1.28 mmol/g, Argonaut Technologies Inc.) in dichloromethane (250 mL) was stirred at room temperature for 0.5 h. Then, glycine methyl ester hydrochloride (5.3 g, 42.45 mmol, Aldrich), HOAt (3.8 g, 28.3 mmol, Perseptive Biosystems) and diisopropylethylamine (16 mL, 84.9 mmol, Aldrich) were added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the resin was washed with dichloromethane (2×70 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography, eluting with EtOAc/hexane (1:2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 425 (M+1).