Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].C[O-].[Na+].C(Cl)(=O)C(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[C:23]([C:25]1[C:26]([NH:32][CH2:33][CH3:34])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=O>CO.C1COCC1.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[C:25]3[C:26](=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[N:32]([CH2:33][CH3:34])[C:6](=[O:8])[C:5]=2[CH2:4][CH2:3][C:1]#[N:2])[CH:35]=[CH:36][CH:37]=1
Reactant: N#CCCCC(=O)O
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CCn1c(=O)c(CCC#N)c(-c2cccc(Cl)c2)c2ccc(C)nc21

Procedure:
After the treatment of 4-cyanobutanoic acid with sodium methoxide in methanol, the treated compound was reacted with pivaloyl chloride in THF. Thus obtained compound was reacted with 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine under heating. Then, the compound obtained by usual work-up was reacted in ethanol in the presence of sodium methoxide under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one as a pale yellow solid. MS: 352.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[N:13]=[C:12]([O:18]C)[CH:11]=[CH:10]3)[C:5]([CH3:20])=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH3:20][C:5]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:2]([CH3:1])=[N:3][N:4]=1
Reactant: COc1ccc2cc(-n3c(C)nnc3C)cc(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-n2c(C)nnc2C)cc2ccc(=O)[nH]c12

Procedure:
A stirred solution of 6-[3,5-dimethyl-1,2,4-triazol-4-yl]-2-methoxy-8-methylquinoline (0.24 g) in 5M hydrochloric acid (20 cm3) was heated under reflux for 1 hour. The cooled solution was then basified to pH8 with 10% aqueous sodium carbonate solution and extracted with chloroform (5×50 cm3). The combined and dried (MgSO4) organic phases were evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 20:1, to afford 6-[3,5-dimethyl-1,2,4-triazol-4-yl]-8-methyl-2-(1H)-quinolone, 0.66 H2O, m.p. 208°-310° (0.17 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][CH:9]=[N:8][CH:7]=1)CCC.[F:19][C:20]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:21]=1[C:22]#[N:23].N#N>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:6]2[S:10][CH:9]=[N:8][CH:7]=2)=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1cc(I)ccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: N#N
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cncs2)ccc1F
Temperature: 85 °C
Yield: 81.6 %

Procedure:
To 5-(tributylstannyl)thiazole (1.00 g, 2.7 mmol) in THF (10 mL) was added 2-fluoro-5-iodobenzonitrile (0.791 g, 3.2 mmol). The solution was degassed with N2 and bis(triphenylphosphine)palladium(II) chloride Pd(Ph)2Cl2 (0.187 g, 0.27 mmol) was added. The solution was further degassed for five minutes before heating to 85° C. for 2 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and washed with EA (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (10% EA/Hexanes) to afford 0.450 g (82%) of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 as a tan solid. LCMS-ESI (m/z) calculated for C10H5FN2S: 204.2; found 205.0 [M+H]+, tR=3.00 min.
Reaction SMILES: N[C:2]1[C:10]2[N:9]([CH2:11][CH:12]([OH:14])[CH3:13])[N:8]=[C:7]3[CH2:15][CH2:16][CH2:17][C:5]([C:6]=23)=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O.O>>[OH:14][CH:12]([CH3:13])[CH2:11][N:9]1[C:10]2=[C:2]([OH:18])[CH:3]=[CH:4][C:5]3=[C:6]2[C:7]([CH2:15][CH2:16][CH2:17]3)=[N:8]1
Reactant: CC(O)Cn1nc2c3c(ccc(N)c31)CCC2
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(O)Cn1nc2c3c(ccc(O)c31)CCC2
Yield: 86 %

Procedure:
The product from Step C (0.70 g, 3.2 mmol) was dissolved in H2SO4/H2O (1:2, 30 mL) and treated as described in Step E of Example 1 to provide a solid (0.60 g, 86%): m.p 162-163° C.; MS (ES) m/z 233(M+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)[CH3:3]>N.[H][H].[Ni]>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: [H][H]
Reactant: CN(C)Cc1ccc(CC#N)cc1
Agent: [Ni]
Agent: N
Product: CN(C)Cc1ccc(CCN)cc1

Procedure:
3.60 g (20.7 mmol) of (4-dimethylaminomethylphenyl)acetonitrile (IX.1.a) is dissolved in 50 mL of methanolic ammonia and hydrogenated for 5 hours at 50° C. at a pressure of 3 bar with hydrogen and 0.45 g of Raney nickel as catalyst. Then the catalyst is filtered off and the solvent is eliminated. Yield: 3.60 g (98% of theory); Rf value: 0.20 (silica gel, methylene chloride/methanol=9:1); C11H18N2; EII mass spectrum: m/z=179 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: Cc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Cc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 1 g (7.6 mmol) of 7-methylindol and 2.9 g (19 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 0.8 g (50% of yield) of the desired product were obtained.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(=O)(O)[O-].[Na+].S(Cl)(O[CH2:19][Cl:20])(=O)=O>O.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:9][CH2:19][Cl:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCCl)c1cccnc1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a suspension of nicotinic acid 1.23 g. 0.01 mol) in a mixture of 10 mL of water and 20 mL of tetrahydrofuran were added tetrabutylammonium hydrogensulfate (0.34 g, 1 mmol) and sodium bicarbonate (3.19 g, 0.038 mol), with vigorous stirring. Chloromethyl chlorosulfate (1.81 g, 0.011 mol) in 5 mL of tetrahydrofuran was added dropwise, keeping the temperature below 30° C. The reaction mixture was stirred for 1 hour, then the layers were separated and the organic layer was dried by azeotroping with 1:1 acetonitrile/benzene. The residue was passed through a column of neutral alumina, eluting with chloroform. The chloroform layer was evaporated to give 1.28 g (74.8%) of an oily residue, which was confirmed by NMR analysis to have the structural formula: ##STR157##
Reaction SMILES: [SH2:1].[CH3:2][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17]#[N:18])[N:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:5][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17](=[S:1])[NH2:18])[N:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C(N)=S)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Hydrogen sulfide is bubbled through a solution of 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 19.3 mmol) and triethylamine (4.3 g, 42.4 mmol) in pyridine (20 nil) at room temperature for 6 hours. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum and the residue is recrystallized from ether/hexane to give pure 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbothioamide (3.0 g, 58%); mp 169°-171° C.
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[C:13]1([CH2:19][O:20][C:21](=[O:36])[NH:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:34]O)[CH:32]=3)[NH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[C:13]1([CH2:19][O:20][C:21](=[O:36])[NH:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][NH2:1])[CH:32]=3)[NH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 4 h

Procedure:
A solution of diethyl azodicarboxylate (1.48 g) in dry tetrahydrofuran (THF) (8 ml) was added over 2 min., keeping the temperature at 25°, to a stirred solution of phenylmethyl[2-[5-(hydroxymethyl)-1H-indol-3-yl]ethyl]carbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4 h, the solvent was evaporated in vacuo and the residue was dissolved in a solution of hydrazine hydrate (15 ml) in ethanol (100 ml).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[NH:17][C:16]2=[O:26])[CH2:11][CH2:10]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:23]1[CH:24]=[CH:25][C:18]2[NH:17][C:16](=[O:26])[N:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:21][CH2:20][C:19]=2[CH:22]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1

Procedure:
801 mg (6.00 mmol) N-chlorosuccinimide were added to 1.23 g (5.00 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 10.0 mL carbon tetrachloride and the mixture was refluxed for 72 h. The solvent was eliminated i. vac. and the crude product was purified by flash chromatography. The fractions containing the product were concentrated by rotary evaporation and purified by preparative HPLC.
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH:39]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[NH:43][C:42]3=[O:50])[CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH:39]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]([S:56]([CH3:55])(=[O:58])=[O:57])[C:42]3=[O:50])[CH2:38]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)N1CCC(N2CC(n3c(=O)[nH]c4ccccc43)C2)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)C2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-azetidin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 4 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained which was colorless and amorphous.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)C>C(O)(=O)C>[CH2:24]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1)[CH3:25]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CCc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 60 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.42 ml), 4-ethylaniline (0.05 ml, 0.39 mmol), and acetic acid (0.05 ml) were used to give 59.5 mg (0.18 mmol, 60% yield) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=O)=[CH:11]2)([O-:7])=[O:6].[Cl-].[Cl-].[Ca+2].C([O-])(O)=O.[Na+].[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>O1CCOCC1.O1CCOCC1.O>[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH:32][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=2)=[O:19]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(CNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (8 ml, 110 mmol, 5 eq.) was added to a suspension of the compound of formula (III) (4.53 g, 22 mmol, 1 eq.) in dry dioxane (50 ml). The final suspension was refluxed in dry atmosphere (CaCl2 valve) for 2 h, and the reaction turned to a light brown solution while proceeding. The reaction was cooled to 25° C. and organic volatiles were removed under reduced pressure, then dry toluene (25 ml) was added and removed under vacuum, this operation was repeated twice. The brown residue (22 mmol, 1 eq.) was added portion wise to a cooled solution at 0° C. of NaHCO3 (3.7 g, 43.95 mmol, 2 eq.) and 2,2-dimethoxy-ethylamine (2.39 ml, 21.97 mmol, 1 eq.) in dioxane/water 4:1 (100 ml), the suspension was stirred for 2 hours at rt. Organic volatiles were removed under reduced pressure and the yellow precipitate was filtered and dried to give 5-nitro-1H-indole-2-carboxylic acid (2,2-dimethoxy-ethyl)-amide (IV). Yield=5.80 g (90%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][N:29]=[C:21]([Br:20])[CH:22]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
3-(3,4-Dimethoxyphenyl)-L-alanine ethyl ester hydrochloride (66 g), triethylamine (33.3 ml), 2-bromoisonicotinic acid (50.6 g), 1-hydroxybenzotriazole monohydrate (38.4 g) and 1,3-dicyclohexylcarbodiimide (51.7 g) are added to methylene chloride (660 ml), and the mixture is stirred at room temperature for four hours. The reaction mixture is washed, dried, and concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=10:1) to give N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)-L-alanine ethyl ester (93.5 g).
Reaction SMILES: C([O:4][CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH:8]1[CH:12]([C:13]#[N:14])[CH2:11][CH:10]([OH:15])[C:9]1=[O:16])(=O)C.[BH4-].[Na+]>CO.[OH-].[Na+]>[OH:16][CH:9]1[CH:10]([OH:15])[CH2:11][CH:12]([C:13]#[N:14])[CH:8]1[CH2:7][CH2:6][CH:5]([OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(CCC1C(=O)C(O)CC1C#N)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(O)CCC1C(C#N)CC(O)C1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A stirred solution of 2-(3-acetoxyoctyl)-3-cyano-5-hydroxycyclopentanone (23.5 g.) [prepared as described in (j) above] in methanol (135 ml.) was treated dropwise, during 15 minutes, with a solution of sodium borohydride (13.2 g.) in 0.2N aqueous sodium hydroxide solution (70 ml.) at 15°-20° C. After 1 hour the solution was slowly heated to 50° C., stirred at 50° C. for 3 hours, and then allowed to stand at room temperature overnight. Methanol was removed in vacuo, water (75 ml.) was added and the mixture acidified by means of concentrated hydrochloric acid. The mixture was extracted with diethyl ether and the ethereal extract was washed with water, dried with magnesium sulphate and evaporated in vacuo to give crude 3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentane carbonitrile (16 g.), which was used in the following preparation (1) of 3,4di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbonitrile without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1)=[N+:17]=[N-:18]
Reactant: Fc1cccnc1-c1ccc(CCl)nn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(-c2ncccc2F)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine. A solution of 3-(3-fluoropyridin-2-yl)-6-methylpyridazine (200 mg, 1.05 mmol) in 5 mL of DCE was treated with trichloroisocyanuric acid (98 mg, 0.42 mmol). The mixture was heated at 90° C. for 1 h. The mixture was cooled to RT and the precipitate was filtered off with a fritted funnel and rinsed with 2×20 mL of DCM. The brown solid was discarded. The filtrate was washed with 2×5 mL of 0.5 M NaOH (aq.) followed by brine (5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine as a brown crystalline solid. MS (ESI, pos. ion) m/z: 224.0 (M+1). A solution of the 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine in 1 mL of DMF at RT was treated with NaN3 (69 mg, 1.05 mmol) and stirred at RT for 5 h. The mixture was filtered through a fritted funnel and the collected solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated and the crude material was purified by silica gel chromatography (35-75% EtOAc in hexanes) to give 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (100 mg, 41% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 231.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, m), 8.27 (1 H, d, J=8.8 Hz), 8.00 (1 H, m), 7.94 (1 H, m), 7.69 (1 H, dt, J=8.4, 4.2 Hz), 4.89 (2 H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-121.47.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N+:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:2][C:3]#[C:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[N:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC#CCn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
The 2-(4-hydroxy-but-2-ynyl)-isoindole-1,3-dione (1.29 g, 6.00 mmol), 3-Nitro-1H-pyrazole (prepared in example 3, 655 mg, 5.80 mmol) and triphenylphosphine (1.57 g, 6.00 mmol) were combined and dissolved in tetrahydrofuran (30 mL) and then chilled to 0° C. While stirring, diisopropyl azodicarboxylate (1.77 mL, 9 mmol) was added dropwise. The ice bath was removed and the reaction continued to stir at 25° C. for 1 h. At this point the desired product had precipitated. Collection of the precipitate using in vacuo filtration followed by rinsing with tetrahydrofuran (2×10 mL) then drying in vacuo for 2 h afforded 2-[4-(3-nitro-pyrazol-1-yl)-but-2-ynyl]-isoindole-1,3-dione (1.54 g, 86%) as a white powder: ESI-LRMS m/e calcd for C15H10N4O4 [M+] 310.07. found 311.17 [M+H+], 621.20 [2M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][N:34]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)Nc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 224 mg, 0.67 mmol) in methylene chloride was cooled to 0° C. and then was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.37 mL, 0.74 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 20 min. The reaction mixture was then treated with a solution of N-(6-amino-pyridin-3-yl)-methanesulfonamide (190 mg, 1.01 mmol) and pyridine (0.08 mL, 1.01 mmol) in tetrahydrofuran (3.38 mL). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL), and the organic layer was washed consecutively with a 1N aqueous hydrochloric acid solution (1×100 mL) and a saturated aqueous sodium bicarbonate solution (1×100 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfonylamino-pyridin-2-yl)-propionamide (34.4 mg, 10.2%) as a light tan solid: mp 146–150° C.; EI-HRMS m/e calcd for C21H26ClN3O5S2 (M+H)+ 500.1075, found 500.1081.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: C=CC(=O)CCCCC
Solvent: CCO
Product: CCCCCC(=O)CCN1CCC(CCCc2ccccc2)CC1

Procedure:
1 equivalent of 4-(3-phenylpropyl)piperidine was reacted with 1 equivalent of 1-octen-3-one in ethanol, at room temperature. The product was worked up and purified on a column of silica. The results of the NMR and mass spectrometry analyses were in accordance with the expected structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[C:17]([CH2:16][CH2:15][CH2:14][S:13][C:7]1[C:8](=[O:12])[NH:9][C:10]2[C:5]([C:6]=1[OH:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)([OH:19])=[O:18]
Reactant: COC(=O)CCCSc1c(O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCSc1c(O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
895 mg (2.73 mmol) of 7-chloro-4-hydroxy-3-(3-methoxycarbonylpropylthio)-2(1H)-quinolone are dissolved in 10 ml of 2N sodium hydroxide solution and the resulting solution is stirred for one hour at room temperature. The reaction mixture is adjusted to pH 2 with concentrated hydrochloric acid and the resulting white suspension is filtered and washed with water. The resulting colourless crystals are dried under a high vacuum at 70°, yielding 3-(3-carboxypropylthio)-7-chloro-4-hydroxy-2(1H)-quinolone in the form of colourless crystals having a melting point of 239°-241° (decomp.).