Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[NH:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][CH2:10]4)=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCN(Cc5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-piperidin-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1](=[C:8]([C:12]([O-:14])=[O:13])C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+]>C(O)C.O>[C:15]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][C:12]([OH:14])=[O:13])#[N:16]
Reactant: [C-]#N
Reactant: O=C([O-])C(=Cc1ccccc1)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CC(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzalmalonate (124 g., 0.5 mole) in ethanol (560 ml.) and water (240 ml.) was heated at reflux for 60 hours with potassium cyanide (45 g., 0.7 mole). The solution was cooled, concentrated to remove ethanol, and then acidified with concentrated hydrochloric acid. The product was extracted with dichloromethane, and the extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (500 ml.) and treated with dicyclohexylamine (82 ml.) to yield 118 g. (67%) of white crystals which were collected by filtration and washed sequentially with ethyl acetate and ether and dried. A suitable cation-exchange resin in the acid form, such as Dowex® 50x8-100 ion-exchange resin, (20 g.) was washed with acetone and suspended in methanol (130 ml.) with dicyclohexylammonium salt (15 g.). After stirring at ambient temperature for 1 hour, the cation exchange resin was removed by filtration and the filtrate was concentrated to yield 3-cyano-3-phenylpropionic acid as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH3:28])[C:8]2[C:9]([F:27])=[CH:10][C:11]3[C:12]([CH:26]=2)=[N:13][C:14]2[N:15]([CH3:25])[CH:16]=[C:17]([C:22]([OH:24])=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>CO>[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].[CH:1]1([N:7]([CH3:28])[C:8]2[C:9]([F:27])=[CH:10][C:11]3[C:12]([CH:26]=2)=[N:13][C:14]2[N:15]([CH3:25])[CH:16]=[C:17]([C:22]([O-:24])=[O:23])[C:18](=[O:21])[C:19]=2[CH:20]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C)C1CCCCC1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Product: CN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)[O-])cn3C)C1CCCCC1

Procedure:
Choline 8-[(cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 1, but from 1.5 g of 8-[(cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid in 15 cm3 of methanol and 1.5 cm3 of a 45% solution of choline hydroxide in methanol. After recrystallizing from 15 cm3 of 2-propanol, choline 8-[(cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained in the form of a yellow solid melting at about 245-250° C.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[N:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:27]([OH:28])[C:26]4[C:21](=[N:22][CH:23]=[CH:24][N:25]=4)[C:20]3=[O:29])=[N:16]2)=[CH:11][CH:10]=1>C(#N)C.C(Cl)Cl>[CH2:1]([NH:5][C:6]([O:28][CH:27]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[C:20](=[O:29])[N:19]1[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[N:18][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCNC(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 50.7 %

Procedure:
n-Butyl isocyanate (5 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (7.8 g.) in anhydrous acetonitrile (156 cc.) and the mixture is heated at the reflux temperature for 7 hours. The insoluble product is filtered off and washed with anhydrous acetonitrile (2 × 10 cc.). The product obtained is dissolved in methylene chloride (430 cc.) and the resulting solution is washed by successive decantations with 0.1N sodium hydroxide solution (85 cc.) and water (85 cc.). After drying, the organic phase is concentrated to dryness under reduced pressure (20 mm.Hg). Recrystallisation of the residue obtained, from acetonitrile (230 cc.), gives 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.2 g.) melting at 264° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:14]1([CH:13]2[O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=3[CH2:9][O:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: OCc1ccc(CO)c(CO)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)COC(c1ccccc1)OC2

Procedure:
4 g of (3,4-bis-hydroxymethylphenyl)methanol (23.8 mmol), 40 ml of toluene, 3.06 g of benzaldehyde (28.5 mmol) and 0.24 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask equipped with a Dean-Stark. The medium is heated under reflux for 3 hours. After filtration, the toluene is evaporated under vacuum at 30° C. The residue is chromatographed on silica gel (heptane/ethyl acetate=7/3) to give 1.8 g of (7-phenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol in the form of a white powder.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)(O)[O-].[Na+].[Br:25]Br>CO.C(Cl)Cl>[Br:25][C:9]1[CH:8]=[C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Yield: 29.7 %

Procedure:
To a chilled suspension of 4-methylaminosulfonylmethyl-N-trifluoroacetylaniline(10.9 g) in methanol (100 mL) was added sodium bicarbonate (28 g), followed by bromine (18.3 g) in methylene chloride (30 mL). The reaction mixture was then diluted with methylene chloride (70 mL) and quenched by the addition of sodium sulfite (20 g), filtered through CELITE and concentrated in vacuo to a yellow residual solid. This solid was twice reslurried in methylene chloride (300 mL) then refiltered and the filtrates evaporated in vacuo. The residual materials were combined in 10% acetone/methylene chloride solution and concentrated then purified by column chromatography (eluting with 4% acetone in methylene chloride) to give the title compound (4.10g) mp 170° C.; TLC (methylene chloride/acetone 15:1) Rf=0.36, and the corresponding dibromide (5.56 g) TLC (methylene chloride/acetone 15:1) Rf=0.31.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14]Cl)[C:5]=1[OH:16])(=[O:3])[CH3:2].[OH-:17].[K+].Cl>C(O)C.O>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][OH:17])[C:5]=1[OH:16])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1cc2c(c(CCl)c1O)CCCC2
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc2c(c(CO)c1O)CCCC2

Procedure:
To a solution of the product of step (a) (23.8 g) in ethanol (500 ml) was added a solution of potassium hydroxide (11.2 g) in ethanol (250 ml) and water (100 ml). The resulting mixture was heated on a steam bath for 30 minutes, poured into water (2 l) and the mixture was made acid with concentrated hydrochloric acid. It was then extracted with ethyl acetate and the extracts were dried (MgSO4), filtered and the filtrate was evaporated to dryness leaving 7-acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-hydroxymethylnaphthalene as an oil, 21 g (95%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)Cc2ccccc21
Agent: O=S(=O)(O)O
Product: CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 g 1-methyl-1,3-dihydro-indol-2-one are dissolved in 10 ml concentrated sulphuric acid and cooled to 0° C. To this is added dropwise a solution of 620 μl concentrated nitric acid in 2 ml concentrated sulphuric acid and the mixture is stirred for 30 minutes. Then it is poured onto 50 g ice, stirred for 1 hour, the solid is removed by suction filtering and dried in vacuo.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](=O)[CH2:32][C:33]#[N:34])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(#N)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:32]([C:33]#[N:34])=[C:31]([CH:28]4[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]4)[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C2=C(C#N)C(c3cccc4nonc34)c3c[nH]nc3N2)CC1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a solution of ethyl isonipecotate (10.0 g) in THF (200 mL) was added triethylamine (7.8 g), 4-dimethylaminopyridine (0.8 g) and di-tert-butyldicarbonate (15.3 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-piperidine-4-carboxylate (16.3 g) as a colorless oil. To a solution of acetonitrile (3.2 g) in THF (300 mL) was added n-BuLi (44 mmol) at −78° C. and stirred for three hours. Further, ethyl N-Boc-piperidine-4-carboxylate (16.3 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 1-(N-Boc-piperidin-4-yl)-2-cyanoethan-1-one (11.6 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (1.0 g), 3-aminopyrazole (0.6 g) and 2-(N-Boc-piperidin-4-yl)-1-cyanoethan-2-one (1.7 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.0 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.C=O.[C:24]([BH3-])#N.[Na+].C(#N)C>O.[OH-].[Na+].C(O)(=O)C>[CH3:24][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CNc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reaction time: 8 h

Procedure:
To the mixture of 1.4 g of 2-(p-aminophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 4.1 ml of 37% aqueous formaldehyde, 1.0 g of sodium cyanoborohydride and 20 ml of acetonitrile, 0.6 g of glacial acetic acid are added while stirring. Stirring is continued overnight at room temperature and the mixture diluted with water. The precipitate formed is dissolved in diluted sodium hydroxide, the aqueous solution washed with diethyl ether and its pH adjusted to 8.5 by addition of aqueous ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried to yield the 2-(p-methylaminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting at 302°-304°.
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(OCC)/C(C)=C/COc1ccc(NC(C)=O)cc1
Reaction time: 96 h
Yield: 57.9 %

Procedure:
A solution of 1.0 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene in 10 ml of sieve dried dimethyl formamide is treated with 0.7 g of p-acetylaminophenol and 0.64 g anhydrous potassium carbonate. The suspension is stirred under nitrogen for four days and the mixture is then poured into 100 ml water and the hazy solution extracted with two 100 ml portions of benzene. The benzene extract is washed with water and dried with sodium sulfate. The benzene extract is concentrated and vacuum dried to give 0.75 g of (E)-4-(4-acetylaminophenoxy)-1,1-diethoxy-2-methyl-2-butene which is dissolved in about 5 to 10 ml acetone and treated with about 1 ml water and a spatula of p-toluenesulfonic acid monohydrate. The resulting solution is agitated occasionally for 30 minutes and the solution is evaporated at room temperature giving a solid, ethylether insoluble residue. The residue is dissolved in about 150 ml methylene chloride and washed twice with water. The residue is dried with sodium sulfate and concentration gave 0.45 g of a solid. The material is filtered in about 50 ml of hot carbon tetrachloride-benzene then boiled down to about 10 ml. The product is filtered and washed with room temperature carbon tetrachloride giving 0.2 g white solid, m.p. 127°-30° C. Elemental Analysis. Calculated for C13H15NO3 : C,66.94; H,6.48; N,6.00. Found: C,66.64; H,6.29; N,5.75.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].Cl>C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][C:4]([C@@:6]1([CH3:14])[N:10]([C:22](=[O:24])[CH3:23])[C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@]1(C)SC[C@@H](C(=O)O)N1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
L-cysteine hydrochloride monohydrate (50 g, 285 mmol) was dissolved in water (100 ml), and the pH of the solution was adjusted to 5.15 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (38 ml, 342 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4 hr. Water was added, and the mixture was cooled to room temperature to precipitate the crystals and the crystals were collected by filtration. The obtained crystals were washed with water, and dried under reduced pressure at 50° C. to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (trans form:cis form=88:12, 12.1 g, yield 19%). The synthesized 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (5 g, 22.8 mmol) was dissolved in ethyl acetate (40 ml), and triethylamine (6.4 ml, 45.9 mmol) was added under argon. Acetyl chloride (2.4 ml, 33.8 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After completion of the reaction, water (15 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (10 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to precipitate crystals. The crystals were collected by filtration, washed with heptane/ethyl acetate=1/1 (10 ml), and dried under reduced pressure at 50° C. to give (2S,4R)-N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (3.3 g, yield 55%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)CBr)cccc2c1=O
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 11.2 g of bromine in 250 ml of chloroform was added, over a period of two hours at 20°-25° C., to a solution of 19.5 g of Intermediate III in 700 ml of chloroform. After stirring for 1 hour at 20°-25° C., the solution was washed with 400 ml of an aqueous 2N sodium hydroxide solution and then repeatedly with water, dried with anhydrous sodium sulphate and stripped in vacuo. The crude product was treated with diethyl ether, collected by suction filtration and crystallized from acetone, to give 16 g of the title compound, melting point 134°-135° C.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH:11]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:8]=2)[NH:3]1.Cl>CO>[O:1]=[C:2]1[CH:10]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:8]=2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3ccc(NC(=N)c4cccs4)cc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(C1CCNC1)C(=O)N2)c1cccs1
Yield: 107.7 %

Procedure:
A solution of compound 5 (0.21 g, 0.492 mmol) in methanol (10 mL) was treated with 1 N HCl solution (10 mL) and the resulting solution was refluxed for 30 min. The reaction was brought to room temperature and solvent was evaporated. The crude was dissolved into water (10 mL), filtered and washed with water (2×5 mL). The combined water layer was evaporated to obtain compound 43 (0.173 g, 88%) as a solid. 1H NMR (DMSO-d6) δ 11.50 (brs, 1H), 10.87 (d, 1H, J=3.0 Hz), 9.79 (s, 1H), 9.69-9.46 (m, 2H), 8.80 (d, 1H, J=7.5 Hz), 8.19-8.16 (m, 2H), 7.43 (s, 1H), 7.37 (t, 1H, J=4.5 Hz), 7.30 (d, 1H, J=8.1 Hz), 7.01 (d, 1H, J=8.1 Hz), 3.50-3.32 (m, 1H), 3.30-3.02 (m, 3H), 2.75-2.50 (m, 2H), 2.18-2.08 (m, 1H), 1.96-1.40 (m, 1H); HPLC purity 95.52% by area.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.Cl.NC1NC=C(CCCCCC2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4C=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:44]=3)=[O:42])C=2)N=1>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41](=[O:42])[C:43]3[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:45][CH:44]=3)[CH:13]=2)[N:6]=1
Reactant: Nc1nc(CCCCCc2cn(CCNC(=O)c3ccc(-c4ccccc4)cc3)nn2)c[nH]1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: Cl
Product: CCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.113 g, 0.408 mmol) was reacted with N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)biphenyl-4-carboxamide hydrochloride (0.106 g, 0.408 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-pentylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), δ 7.67 (d, J=7.5 Hz, 2H), δ 7.27 (s, 1H), δ 7.12 (d, J=7.8 Hz, 2H), δ 4.48 (s, 2H), δ 3.84 (s, 2H), δ 2.55 (m, 4H), δ 2.22 (s, 2H), δ 1.50 (s, 13H), δ 1.23 (s, 8H), δ 0.80 (t, J=5.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 168.3, 150.5, 149.5, 148.2, 147.2, 138.6, 131.5, 128.7, 127.4, 106.4, 84.8, 49.4, 40.2, 35.9, 31.6, 31.0, 29.3, 28.9, 28.1, 27.9, 25.6, 22.6, 14.2; HRMS (ESI) calcd for C29H43N7O3 (M+) 537.3427. found 537.3420, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-pentylbenzamide hydrochloride (0.178 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.41 (s, 1H), δ 7.69 (d, J=7.5 Hz, 2H), δ 7.21 (d, J=7.2 Hz, 2H), δ 6.46 (s, 1H), δ 4.84 (s, 2H), δ 3.90 (s, 2H), δ 2.79 (s, 2H), δ 2.58 (t, J=7.8 Hz, 2H), δ 2.39 (t, J=7.2 Hz, 2H), δ 1.68 (s, 2H), δ 1.55 (s, 4H), δ 1.26 (s, 6H), δ 0.84 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 159.5, 158.9, 147.5, 147.3, 131.1, 128.5, 127.6, 127.4, 108.5, 54.2, 51.9, 39.5, 35.6, 31.4, 30.9, 30.6, 28.4, 27.9, 27.6, 26.9, 24.1, 23.5, 22.9, 22.4, 13.3 ppm; HRMS (ESI) calcd for C24H35N7O (M+) 437.2903. found 437.2892.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:19][CH2:20][CH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[C@H:31]2[C@H:35]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@H:34]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:33]([CH2:52][O:53][CH3:54])[O:32]2)=[C:24]([NH:55][CH2:56][CH:57]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:23]=1.[CH2:70]([C:72]([CH2:74][CH3:75])=O)[CH3:71]>ClCCl.C(OCC)(=O)C>[Si:37]([O:36][C@@H:35]1[C@H:34]([O:44][Si:45]([C:48]([CH3:49])([CH3:50])[CH3:51])([CH3:47])[CH3:46])[C@@H:33]([CH2:52][O:53][CH3:54])[O:32][C@H:31]1[N:28]1[CH:27]=[N:26][C:25]2[C:29]1=[N:30][C:22]([CH2:21][CH2:20][NH:19][CH:72]([CH2:74][CH3:75])[CH2:70][CH3:71])=[N:23][C:24]=2[NH:55][CH2:56][CH:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Sodium triacetoxyborohydride (105 mg, 0.51 mmol) and glacial acetic acid (24 mg, 0.40 mmol) were added to a stirred solution of N-{2-(2-aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl}-N-(2,2-diphenylethyl)amine (250 mg, 0.34 mmol) (preparation 18) and diethyl ketone (58 mg, 0.68 mmol) in dichloromethane (15 ml) and the resulting mixture stirred under an atmosphere of nitrogen gas at room temperature overnight. Additional portions of diethyl ketone (30 mg, 0.35 mmol) and sodium triacetoxyborohydride (60 mg, 0.29 mmol) were then added and stirring continued at room temperature for a further 24 hr. The mixture was diluted with ethyl acetate (20 ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution, brine and water. The organic phase was separated and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4) to give the title compound (250 mg) as a gum. MS: 803 (MH+).