Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].C(OC([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=O)(C)(C)C>O1CCOCC1.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>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9]([C:30]3[CH:29]=[N:28][N:27]([CH:24]4[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]4)[CH:31]=3)=[C:4]2[C:3]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2c(Cl)c(Cl)oc12
Temperature: 100 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (300.0 mg, 0.9121 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (516 mg, 1.37 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was degassed and refilled with argon (3×). The reaction was heated at 100° C. for 20 h using a Biotage Initiator microwave reactor. The reaction was concentrated in vacuo to give a solid which was purified by flash chromatography (30 to 60% EtOAc:hexanes), which afforded the desired intermediate. 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 4.80 (br s, 2H), 4.32 (m, 3H), 2.99 (m, 2H), 2.18 (m, 2H), 1.97 (m, 2H), 1.47 (s, 9H); MS (ESI): 452.00 [M+H]+; HPLC tR=3.14 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:8]([Br:29])[S:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.CO>[Br:29][C:8]1[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]=1[N:10]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1csc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)csc2Br)cc1
Yield: 93.3 %

Procedure:
To a solution of 0.40 g (0.860 mmol) of the product of Example 24 in 9.0 mL of THF-MeOH (1:1) was added 0.072 g (1.72 mmol) of lithium hydroxide monohydrate. The reaction mix was heated to reflux for 18 h and then concentrated in vacuo. The residue was was washed with THF and filtered. The filtrate was concentrated in vacuo to provide 0.388 g (100%) of the desired product as a white foam. Electrospray Mass Spec: 483 (M+H).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13](=[O:16])([O-])[O-:14].[K+].[K+].ClC[C:21](OC)=[O:22].[OH-].[K+].Cl>O.C1COCC1>[N+:10]([C:7]1[C:6]2[O:22][C:21]([C:13]([OH:14])=[O:16])=[CH:4][C:3]=2[CH:2]=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)CCl
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2o1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
3.0 g (17.9 mmol) of 2-hydroxy-5-nitrobenzaldehyde, 0.66 g (1.80 mmol) of tetra-N-butylammonium iodide and 9.92 g (71.81 mmol) of potassium carbonate are mixed, 4.09 g (37.7 mmol) of methyl chloroacetate are added and the mixture is heated at 130° C. for 4 h. 35 ml of THF and, with ice cooling, 6.04 g (107.71 mmol) of potassium hydroxide are added. Following the addition of 50 ml of water, the mixture is stirred at RT for 20 h. Using concentrated hydrochloric acid, the pH is adjusted to 0. The mixture is extracted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. After the addition of silica gel, the mixture is concentrated and chromatographed on silica gel (mobile phase gradient: toluene to toluene/methanol/glacial acetic acid 35:5:1). Concentration of the product fractions and drying under reduced pressure gives 2.00 g (54% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[Br:11]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:5]#[N:6]
Reactant: N#CCc1ccccc1Cl
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#CC(Br)c1ccccc1Cl
Yield: 65.7 %

Procedure:
To a solution of 2-chlorobenzylcyanide (1.0 g, 6.60 mmol) in CCl4 (25 mL) was added N-bromosuccinamide (1.29 g, 7.26 mmol) and 2,2′-azobis-(2-methylpropionitrile) (0.05 g, 0.33 mmol). The reaction mixture was allowed to reflux for 48 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with 0.1 M NaOH (50 mL). The organic phase was concentrated to dryness yielding 1.0 g (66%) product.
Reaction SMILES: [OH:1][P:2]([F:5])([OH:4])=[O:3].[CH2:6]([NH2:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[P:2]([F:5])([OH:4])([OH:3])=[O:1].[CH2:6]([NH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: O=P(O)(O)F
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCNCCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C

Procedure:
14 gms (0.14 mole) of monofluorophosphoric acid is slowly added to 58.66 gm (0.22 moles) of oleylamine in 300 ml toluene immersed in an ice bath to maintain the temperature at about 0° C since the reaction in exothermic, while continuously stirring for about 20 minutes to 2 hours. A solid reaction product settles out of solution and is filtered, and washed while on the filter with aliquot portions of the toluene solvent. The solid reaction product is removed from the filter and is vacuum dried at a temperature of 27°-45° C for 12 hours to 2 days to remove the toluene solvent. Transmission infrared spectra of the oleylamine monofluorophosphate exhibit peaks at 720 cm-1 and 790 cm-1 indicative of the absorptions of the PO3F= structure; peaks from 1300-1700 cm-1 and 2300-3000 cm-1 which are typical of RNH3+ absorptions; and the P-O peak (110 cm-1) is located at an energy intermediate between that of hydroxyapatite (1070 cm-1) and Na2PO3F (1175 cm-1).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[OH:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[I:21][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][CH:2]([CH3:4])[CH3:3])[CH:20]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of methyl 2-hydroxy-4-iodobenzoate (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60 C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (14.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)[N:3]=1.C[O-].[Na+]>C(O)C(C)C.CO.C(OCC)(=O)C>[N:29]1([C:27]([C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:4]3[N:3]=[C:2]4[NH:1][C:9]([C:11]5([C:14]6[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=6)[CH2:13][CH2:12]5)=[N:8][C:7]4=[CH:6][CH:5]=3)[CH2:22]2)=[O:28])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2ccc[n+]([O-])c2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)CO
Solvent: CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5ccc[n+]([O-])c5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Yield: 29.4 %

Procedure:
To a solution of (R)-3-(1-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamoyl)cyclopropyl)pyridine 1-oxide (0.25 g, 0.55 mmol) in isobutanol (5 mL) was added a solution of sodium methoxide (0.15 g, 2.77 mmol) in methanol (2 mL) at room temperature. The reaction mixture was heated to 110° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified first via flash chromatography (100-200 mesh silica gel, 0-10% methanol in dichloromethane) then via preparative HPLC to obtain the product which was further purified by chiral separation to afford (R)-3-(1-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropyl)pyridine 1-oxide (70 mg). Chiral HPLC retention time: 13.808 min (Method: CHIRAL PAK IA, 4.6×250 mm 5 μm column, Mobile Phase: A: 0.1% DEA in n-hexane, Mobile Phase B: ethanol; isocratic; 70:30, 1 mL/min, Temperature 25 C) min MS (ES+APCI) (M+H) 433.1; LCMS retention time 4.698 min (Method B1). 1H NMR (400 MHz, CD3OD) δ 1.52-1.57 (m, 2H), 1.59-1.69 (m, 1H), 1.71-1.84 (m, 4H), 1.86-2.08 (m, 5H), 2.75 (t, 2H), 2.88-3.00 (m, 2H), 3.43 (t, 2H), 3.47-3.57 (m, 1H), 3.68 (br s, 1H), 4.27 (d, 1H), 4.52 (d, 1H), 6.78 (d, 1H), 7.50-7.56 (m, 1H), 7.58-7.72 (m, 2H), 8.26 (d, 1H), 8.31 (br s, 1H).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16].O>ClCCl>[O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Br:16])[CH3:2]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)c1OC
Yield: 86.7 %

Procedure:
Dissolving 3,4,5-trimethoxyl benzyl alcohol (14.05 g, 70.89 mmol) in dichlormethane (100 ml) in a three-necked bottle (250 ml); dissolving phosphorus tribromide (6.73 ml, 70.89 mmol) in dichlormethane (25 ml) for it to react at room temperature for 50 minutes, cooling in refrigeratory, slowly adding deionized water (18 ml, 1.0 mol) dropwise to quench, washing with deionized water (100 ml) twice, drying with anhydrous magnesium sulfate, filtering, washing the filter residue with dichlormethane (20 ml), conflating the filtrate, concentrating in rotarory evaporater, and vacuum drying to get 3,4,5-trimethoxyl benzyl bromine (16.05 g of faint yellow solid), yield: 84.44%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+].COCCOC>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(OCC)(=O)C.O>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1-c1ccc(OC)nc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.35 g (5.89 mmol) of methyl (2-bromophenyl)acetate are introduced together with 1 g (6.55 mmol) of 6-methoxypyridin-3-ylboronic acid and 1.98 g (13.09 mmol) of caesium fluoride into 20 ml of 1,2-dimethoxyethane under argon. After addition of 0.22 g (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0), the reaction mixture is stirred at 100° C. for 4 h. Cooling to room temperature is followed by addition of a mixture of ethyl acetate and water and extraction with ethyl acetate. After the organic phase has been dried over magnesium sulphate and the solvent has been removed in vacuo, the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 1.1 g (68% of theory) of the product are obtained.
Reaction SMILES: [ClH:1].C[C:3]1[CH:4]=[C:5]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][NH:6]2.C(O[CH:18](OCC)[CH2:19][N:20]([CH3:22])[CH3:21])C.Cl.[CH2:27](O)CCC>>[ClH:1].[ClH:1].[CH3:27][C:14]1[CH:13]=[C:12]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:7]1[CH:18]([CH2:19][N:20]([CH3:22])[CH3:21])[NH:11][CH2:10][CH2:9][C:8]2=1
Reactant: CCOC(CN(C)C)OCC
Reactant: CCCCO
Reactant: Cc1ccc2c(CCN)c[nH]c2c1
Agent: Cl
Product: Cc1ccc2[nH]c3c(c2c1)CCNC3CN(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To a stirred suspension of 6-methyltryptamine hydrochloride (2.00 g, 9.5 mmole) and dimethylaminoacetaldehyde diethyl acetal (1.53 g, 9.5 mmole) in dry n-butanol (45 mL) at RT was added concentrated hydrochloric acid (1.6 mL, 19.0 mmole). The reaction solution was heated to reflux under an atmosphere of nitrogen. After 6 hr, the reaction solution was cooled to RT without stirring for 12 hr. The precipitate was filtered and then washed sequentially with n-butanol and diethyl ether. Drying under high vacuum afforded the title compound (0.74 g, 25%) as a light yellow solid: MS (ES) m/e 244 (M+H-2HCl)+.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([O:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:19]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Yield: 80.3 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.08 mmol), 2,6-dichlorobenzoic acid (0.4 g; 2.09 mmol), and triethylamine (0.3 mL; 2.08 mmol) in 20 ml of toluene was allowed to react at 90°-100° C. for 15 hours and at 100° C. for 19 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flesh chromatography to afford 0.66 g (80%) of 2-(2,6-dichlorophenylcarbonyloxy-methyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =methyl) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.[O:17]=[C:18]([CH2:24][CH2:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.O.[Br-].[Li+]>O.O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:6]1[N:7]=[CH:8][C:3]([CH2:2][CH:19]([C:18](=[O:17])[CH2:24][CH2:25][CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:5]=1)#[N:12]
Reactant: CCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cn1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Yield: 91.5 %

Procedure:
Process 1: Under argon atmosphere, tetrahydrofuran (20 mL) mixture containing 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile (1.1 g, 3.9 mmol), methyl 3-oxohexanoate (0.68 g, 4.7 mmol), diisopropylethylamine (1.0 g, 7.8 mmol), and lithium bromide monohydrate (0.49 g, 4.7 mmol) was refluxed under heating for 18 hours. The reaction mixture was added water and extracted three times with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (SNAP100HP manufactured by Biotage) (hexane/ethyl acetate; 5/1→1/1) to give methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.2 g, 91%) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:37](=[O:39])[CH3:38]>C1COCC1>[C:19]([CH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:37](=[O:39])[CH3:38])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (5 g, 0.01 mol) in 15 mL dry THF stirring at −78° C., was added 2.0 M of n-Butyllithium in hexane (8.3 mL, 0.017 mol) dropwise. The reaction was then stirred at −78° C. for 15 minutes, yellow color results. N-Methoxy-N-methyl-acetamide (1.6 mL, 0.015 mol) in 5 mL THF was then added dropwise while the reaction was stirred at −78° C. (r×n went colorless upon addition of B). Reaction was then quenched with water and extracted three times with ethyl ether. Organics were dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. Material was purified via column chromatography using a gradient of 0-10% EtOAC/Hexanes (ran neat hexanes for 5 min to elute desbromo SM) on 125 g of SiO2 to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid piperidine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:35]1[CH:36]=[CH:37][C:38]([N+:48]([O-:50])=[O:49])=[C:39]([CH:41]([CH3:47])[CH2:42][O:43][C:44](Cl)=[O:45])[CH:40]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][C:44]([O:43][CH2:42][CH:41]([C:39]2[CH:40]=[C:35]([C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:36]=[CH:37][C:38]=2[N+:48]([O-:50])=[O:49])[CH3:47])=[O:45])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(COC(=O)Cl)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 57 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (23.63 g, 67 mmol) was dried by coevaporation with abs. pyridine (3×100 mL), dissolved in pyridine (400 mL) and cooled to 0° C. A solution of 2-(5-benzoyl-2-nitrophenyl)-1-propyl oxycarbonylchloride (19f) (35 mmol, prepared from 10.00 g of alcohol 40 in abs. CH2Cl2 (100 mL) was added drop wise over a period of 2.5 hours. After stirring over night at ambient temperature the reaction mixture was concentrated in vacuo, dissolved in CH2Cl2 and washed with water (2×200 mL). Excess N6-benzoyl-2′-deoxyadenosine precipitated as a crystalline solid from the aqueous phase and was recovered by filtration. The organic phase was diluted with toluene (100 mL), concentrated in vacuo and purified by silica column chromatography (315 g silica, column diameter 5.5 cm, gradient: CH2Cl2 to CH2Cl2/methanol 100:5) to provide 13.20 g (19.8 mmol, 57%) of the product 29 as a slightly yellow foam. 1H-NMR (250 MHz, DMSO-d6): δ11.02 and 11.01 (2s, 2H, NH), 8.67 (s, 1H, H—C(2)), 8.51 and 8.50 (2s, 2H, H—C(8)), 8.00-7.48 (m, 13H, arom.), 6.46 (m, 1H, H—C(1′)), 5.47 (d, 1H, HO—C(3′)), 4.46 (m, 1H, H—C(3′)), 4.28 (m, 4H, 2×CH2), 4.03 (m, 1H, H—C(4′)), 3.50 (m, β-CH), 2.86 (m, 1H, H—C(2″)), 2.40 (m, 1H, H—C(2′)), 1.28 (d, 3H, γ-CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC(N(C)C)C(C)C.C(OC([N:31]1[CH2:36][CH2:35][NH:34][C:33]([CH3:38])([CH3:37])[CH2:32]1)=O)(C)(C)C>C1COCC1>[CH3:37][C:33]1([CH3:38])[CH2:32][NH:31][CH2:36][CH2:35][N:34]1[C:13]([C:10]1[N:11]=[CH:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]=1)=[O:15]
Reactant: O=C(O)c1ncn(-c2cccc(F)c2)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)C(Cl)N(C)C
Solvent: C1CCOC1
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 460 mg (2.22 mmol) 1-(3-fluoro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 330 μL (2.49 mmol) 1-chloro-N,N,2-trimethylpropylamine in 10 mL THF was stirred at RT for 30 min, 500 mg (2.22 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 620 μL (4.45 mmol) TEA were added and the mixture was stirred at RT for 1 h. The solvent was removed by distillation and the residue was purified by HPLC.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)#[N:18]>C1C(O)=CC=CC=1C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:3]([NH:2][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[NH:18])[CH:8]=1
Reactant: N#CN1CCOCC1
Reactant: COc1ccc(-c2ccccc2)c(N)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(-c2ccccc2)c(NC(=N)N2CCOCC2)c1

Procedure:
A mixture of 2-amino-4-methoxybiphenyl hydrochloride (4.4 g) and 4-cyanomorpholine (3.14 g) in m-cresol (25 ml) was heated at 90°-95° C. for 20 hours to yield N-(4-methoxy-2-biphenylyl)morpholine-4-carboxamidine (m.p. 140°-142° C.) which was recrystallised from ethylacetate. N-(4-Methoxy-2-biphenylyl)morpholine-4-carboxamidine (1.2 g) was dissolved in methanol (10 ml) and treated with fumaric acid (1.45 g) to give N-(4-methoxy-2-biphenylyl)morpholine-4-carboxamidine fumarate [m.p. 120° (dec)] which was recrystallised from a 1:1 mixture of methanol and ether.