Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](Cl)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1.[N+](C)([O-])=O.C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:14]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:13])(=[O:16])[CH3:15]
Reactant: COc1ccc(O)c2ccccc12
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(O)c2ccccc12
Yield: 71.8 %

Procedure:
A solution of 4-methoxy-1-naphthol 11 (435 mg, 2.5 mmol) in toluene (5 mL) and nitromethane (0.75 mL) was treated with scandium triflate (61.52 mg, 0.125 mmol) and acetyl chloride (0.195 mL, 2.75 mmol) and irradiated in the microwave reactor (Personal Chemistry, Inc) at a temperature of 170° C. for 5 minutes. The cooled reaction was diluted with methylene chloride and filtered through a small pad of silica gel. The filtrate was evaporated to dryness and purified via flash chromatography, eluting the pure C-acylated product 12 with CH2Cl2/hexanes (1:1). Pooled fractions were evaporated to afford 12 as a greenish yellow solid (0.388 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 2.69 (s, 3H, COCH3), 3.99 (s, 3H, OCH3), 6.84 (s, 1H, Ar-3-H), 7.80 (m, 2H, Ar—H), 8.10 (d, 1H, Ar—H), 8.21 (d, 1H, Ar—H), 13.76 (s, 1H, OH).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38].O>CN(C)C=O>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([O:23][C:32]4[CH:33]=[CH:28][C:29]([N+:37]([O-:39])=[O:38])=[CH:30][C:31]=4[N+:34]([O-:36])=[O:35])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 270 mg, 6.75 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (2.0 g, 6.16 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 1-chloro-2,4-dinitrobenzene (1.37 g, 6.78 mmol) and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was poured into water (50 mL), and extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (1.5 g, yield 50%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH:21]=[O:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=CNCC1CNCCO1
Product: O=CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(formylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 210°-213° C.
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36]
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (14.63 g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was concentrated in vacuo to give the desired product, which was used directly in next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]3[C:19]([OH:25])=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:5]2=3)[CH2:3][CH2:2]1.C1(N2C3C(=CC(F)=C(F)C=3OC)C(=O)C(C(OCC)=O)=C2S)CC1.C1(N2C3C(=CC(F)=C(F)C=3)C(=O)C3C(O)=C(C(N)=O)SC2=3)CC1.[NH:73]1[CH2:77][CH2:76][C@@H:75]([C:78]([NH2:81])([CH3:80])[CH3:79])[CH2:74]1.Cl>N1C=CC=CC=1.CO>[NH2:81][C:78]([C@@H:75]1[CH2:76][CH2:77][N:73]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]4[C:19]([OH:25])=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:5]=4[N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:74]1)([CH3:80])[CH3:79]
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C(N)=O)sc3n(C3CC3)c12
Reactant: CC(C)(N)[C@@H]1CCNC1
Agent: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Agent: Cl
Agent: NC(=O)c1sc2c(c1O)c(=O)c1cc(F)c(F)cc1n2C1CC1
Solvent: c1ccncc1
Solvent: CO
Product: COc1c(N2CC[C@@H](C(C)(C)N)C2)c(F)cc2c(=O)c3c(O)c(C(N)=O)sc3n(C3CC3)c12
Temperature: 100 °C
Yield: 29 %

Procedure:
The starting material, 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide, is prepared from ethyl 1-cyclopropyl-6,7-difluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate. (See US 2008071086, and Hashimoto, et al., 2007) using a procedure analogous to that describing the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide. ((Chiba, et al., JP 03-223289) 1H NMR: δ 0.98-1.03 (m, 2H), 1.24-1.31 (m, 2H), 3.86-3.93 (m, 1H), 4.04 (d, J=1.5 Hz, 3H), 7.88 (dd, J=10.0 Hz, 8.5 Hz, 1H). 19F NMR: δ −145.5 (d, J=22.5 Hz, 1F), −139.4 (d, J=22.5 Hz, 1F). LCMS: m/z calcd for C16H12F2N2O4S ([M]+) 366. found ([M+H]+) 367. The title compound is prepared as follows. (R)-2-(Pyrrolidin-3-yl)propan-2-amine (175 mg, 1.4 mmol) is added to a mixture of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carboxamide (100 mg, 0.3 mmol) in pyridine (9 mL). The reaction mixture is heated at 100° C. for 24 h, cooled to rt, and evaporated under reduced pressure. The resulting residue is purified by preparative HPLC using mass-based fraction collection to provide the desired mass only fractions. The fractions containing product were combined and lyophilized. The resulting solid was treated with a solution of 1.25 M HCl in methanol (3 mL), evaporated, and triturated with diethyl ether. This step was repeated three times. The solid was dissolved in water and lyophilized to afford the desired product (40 mg, 29%, HCl salt).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][C:5](=O)[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[N:11]=1.O=S(Cl)[Cl:17].CN(C=O)C>C(Cl)(Cl)Cl>[Cl:17][C:5]1[N:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2
Reactant: O=c1[nH]c(C(F)(F)F)nc2nc[nH]c12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine and 300 mL of CHCl3 was warmed to reflux and treated with a solution of 26.7 mL (366 mmol) SOCl2 and 28.3 mL (366 mmol) DMF. The reaction was maintained at reflux for 1.5 h, cooled to room temperature, and poured into 1.2 L of ice-water. The organic layer was separated and washed with 2×300 mL of H2O. The pH of the combined aqueous phases was adjusted to 7 with saturated NaHCO3 and extracted with 3×1.2 L of ether. The combined ether and chloroform extracts were dried (MgSO4) and concentrated to dryness to give 7.4 g of crude product. 1H NMR (DMSO-d6) δ 14.45 (bs, 1H), 8.95 (s, 1H). MS (ES+) 222.96 (100%, M+H).
Reaction SMILES: [N+](C1C=CC2OCC3(COC=2C=1)OC(=O)N(C(C)C)C3)([O-])=O.[CH3:23][N:24]([CH3:44])[C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][C:31]3([CH2:40][O:41][C:27]=2[CH:26]=1)[O:35]C(=O)[N:33]([CH:37]([CH3:39])[CH3:38])[CH2:32]3>>[CH3:44][N:24]([CH3:23])[C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][C:31]([CH2:32][NH:33][CH:37]([CH3:39])[CH3:38])([OH:35])[CH2:40][O:41][C:27]=2[CH:26]=1
Reactant: CC(C)N1CC2(COc3ccc(N(C)C)cc3OC2)OC1=O
Agent: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Product: CC(C)NCC1(O)COc2ccc(N(C)C)cc2OC1

Procedure:
By replacing the 7-nitro-3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one employed in Example 143, Step C, by an equivalent quantity of 7-dimethylamino-3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one and following substantially the same procedure described in Example 143, Step C, there is obtained 7-dimethylamino-3-isopropylaminomethyl-3-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.Cl[C:9]1[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([CH2:6][O:7][C:9]2[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1
Reactant: NS(=O)(=O)c1cccnc1Cl
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccnc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.99 g of a 55% dispersion of sodium hydride are suspended in 40 ml of dimethylformamide and 13.04 ml of cyclopropylmethanol are added dropwise at 10° C. under a nitrogen atmosphere. The mixture is stirred for 15 minutes and then a solution of 21.16 g of 2-chloropyridin-3-ylsulfonamide in 40 ml of dimethylformamide is added dropwise. The reaction mixture is stirred for 30 minutes at 35°-40° C. and then taken up in a mixture of 275 ml of ethyl acetate, 275 ml of ice-water and 137.5 ml of 2N hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are washed with 4×100 ml of water, dried, concentrated by evaporation and the residue is triturated with ether/hexane (2:1). The crystals so obtained are isolated and dried, affording 22.25 g of 2-cyclopropylmethoxypyridin-3-ylsulfonamide with a melting point of 121°-122° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[O:8])C.[OH-].[K+].O>C(O)C>[CH2:14]([O:13][C:11]([CH2:10][CH2:9][N:6]([CH:7]=[O:8])[CH2:5][C:4]([OH:16])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)CCN(C=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
115.5 g of N-ethoxycarbonylethyl-N-formylglycine ethyl ester are dissolved in 150 ml of ethanol, and the solution is cooled to 0° C. To it is then added dropwise a mixture of 28.0 g of potassium hydroxide, 60 ml of water and 120 ml of ethanol. The reaction mixture is stirred for 18 h at RT, and is subsequently concentrated by evaporation under reduced pressure. After the addition of a small amount of water, the mixture is acidified with concentrated hydrochloric acid to pH 1. By extraction with chloroform, drying, and concentration of the organic phase by evaporation,there is obtained N-ethoxycarbonylethyl-N-formylglycine in the form of a yellowish oil (compound No. 1.3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.[C:14]([C:17]1[N:18]=[C:19]([CH3:22])[NH:20][CH:21]=1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].II.BrC1C(=O)NC2C(C=1)=CC=CC=2>CN1CCCC1=O.ClCCl.CO>[C:14]([C:17]1[N:18]=[C:19]([CH3:22])[N:20]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]3)[CH:21]=1)(=[O:16])[CH3:15]
Reactant: Cc1cc(Br)cc2ccc(=O)[nH]c12
Reactant: CC(=O)c1c[nH]c(C)n1
Agent: II
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c2ccccc2cc1Br
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1

Procedure:
A mixture of 6-bromo-8-methyl-2-(1H)-quinolone (2.38 g), (see Preparation 67 of European patent application publication No. 0148623), 4-acetyl-2-methylimidazole (2.48 g), finely divided copper-bronze (0.64 g), potassium carbonate (1.38 g), and a few crystals of iodine was stirred and heated in N-methyl-2-pyrrolidone (8 cm3) at 190° C. for 24 hours under nitrogen. The cooled mixture was then poured into methanol:dichloromethane (100 cm3, 1:10 by volume), stirred and filtered. The filtrate was poured into aqueous ammonia (20 cm3, S.G. 0.880) and the mixture was filtered through "Solkafloc" (Trademark for a cellulose-based filtering aid). The filtrate was separated and the aqueous phase was re-extracted with methanol:dichloromethane (3×100 cm3), 1:10 by volume). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trademark]). Elution with methanol:dichloromethane, 1:33 by volume, followed by combination and evaporation of the appropriate fractions, gave unreacted starting bromo-quinolone (0.68 g) and a solid which was recrystallised from ethyl acetate/methanol to afford the title compound, m.p. 306°-8°, (0.26 g), which was also confirmed spectroscopically to be identical to the product of Example 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([CH3:36])[CH:27]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[C:28]([CH3:36])[CH:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1C(F)(F)F
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 3.0 g, 9.48 mmol), copper(I) iodide (0.181 g, 0.948 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (0.333 g, 0.474 mmol) were combined. The reaction vessel was purged with nitrogen, followed by the addition of 4-bromo-2-methyl-1-(trifluoromethyl)benzene (2.493 g, 10.43 mmol), 1,8-diazabicycloundec-7-ene (8.66 g, 56.9 mmol) and tetrahydrofuran (32 ml) before the resulting mixture was allowed to stir at room temperature overnight. The reaction was quenched with brine and extracted into ethyl acetate (×2) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a dark brown gum. The gum was purified by column chromatography (silica, 0-50% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine as a dark brown oil (1.22 g, 27%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][N:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCCCC1
Reactant: CNc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl
Product: CN(CCN1CCCCC1)c1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound is prepared according to the general procedure outlined in Example 61, Step 2, utilizing methyl(6-nitro-benzothiazol-2-yl)-amine (979 mg, 4.68 mmol) and N-(2-chloroethyl)-piperidine hydrochloride (2.01 g, 10.92 mmol) to yield 1.43 g (79%) of the product. mass spectrum (ion-spray): (m/z)=321.3 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]12[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2.[O:14]1[CH2:33][CH:15]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH:15]([OH:14])[CH2:33][N:10]3[C:9](=[O:13])[CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]4[C:11]3=[O:12])[CH2:23][CH2:22]2)=[O:32])=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCC2CO2)CC1
Reactant: O=C1NC(=O)C2CCCCC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCC(O)CN2C(=O)C3CCCCC3C2=O)CC1
Yield: 10.2 %

Procedure:
To a mixture of 60% sodium hydride (0.26 g) and dimethylformamide (20 ml), cyclohexane-1,2-dicarboximide (1.13 g) was gradually added. A mixture of 1-(3,4-epoxybutyl)-4-(4-fluorobenzoyl)piperidine (1.7 g) and dimethylformamide (50 ml) was dropwise added thereto at room temperature, and the resultant mixture was kept at an inner temperature of 90° to 100° C. for 3 hours. Insoluble materials were removed by filtration, and the filtrate was distilled to eliminate dimethylformamide. The residue was dissolved in chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the objective compound (0.27 g). Yield, 10.2%. M.P., 129°-130° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[NH:48][C:47]=1[C:55](O)=[O:56].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(#N)C>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:55]([C:47]2[NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[N:46]=2)=[O:56])[CH2:21][C:22]2[N:23]=[CH:24][N:25]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A mixture of 355 mg (0.58 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-tritylimidazole-4-propionamide, 95 mg (0.58 mmol) of benzimidazole-2-carboxylic acid [Chem. Ber. 45, 3489 (1912)], 256 mg (0.58 mmol) of BOP and 0.12 ml (0.58 mmol) of Hunig base in 50 ml of acetonitrile is stirred at room temperature for 20 hours. Thereafter, the reaction mixture is evaporated under reduced pressure, the residue is taken up in 60 ml of ethyl acetate and washed twice with 20 ml of saturated potassium hydrogen carbonate solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure. For purification, the residue is chromatographed on 30 g of silica gel using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 379 mg of N-[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(1-tritylimidazol-4-yl)ethyl]-2-benzimidazolecarboxamide as a colourless foam; MS: 751 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20](O)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.[CH3:24][O:25][NH:26][CH3:27].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:1][C:2]1[C:3]([C:20]([N:26]([O:25][CH3:24])[CH3:27])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 0 °C
Yield: 77.6 %

Procedure:
3-Amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carboxylic acid (10 g, 31.12 mmol) was dissolved in THF (80 mL) and cooled to 0° C. N-methoxymethanamine hydrochloride (3.642 g, 37.34 mmol), 1-hydroxybenzotriazole hydrate (5.242 g, 34.23 mmol), DIPEA (8.044 g, 10.84 mL, 62.24 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (5.314 g, 34.23 mmol) was added and the reaction mixture allowed to warm to ambient temperature over 15 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc. The organic layer was washed water (×2), saturated aqueous NaHCO3 (×2) and brine (×1). The organic layer was dried (MgSO4), filtered and concentrated in vacuo and the residue purified by column chromatography (eluting with 30% EtOAc/petroleum ether) to give the sub-title compound as an off-white solid (8.8 g, 78% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.42 (s, 3H), 3.44 (sept, 1H), 3.67 (s, 3H), 6.95 (br s, 2H), 7.90 (d, 2H), 8.22 (d, 2H) and 8.82 (s, 1H) ppm; (ES+) 366.1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32](I)=[CH:31][C:30]=4[F:36])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:31][C:30]=4[F:36])=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(F)c2)S(=O)(=O)C1
Yield: 32.8 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (235 mg) described in Preparation Example 4 and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (570 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 1, the title compound (190 mg) was obtained.