Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5 %

Procedure:
A mixture of 5.0 g (50 mmol) 2-aminothiazole, 10.0 g (50 mmol) tert-butyl 4-aminopiperidine-1-carboxylate, 21.2 g (100 mmol) sodium triacetoxyborohydride and 5.7 ml (100 mmol) acetic acid in THF (100 ml) was stirred for 24 h at RT. Subsequently, a further 10.6 g (50 mmol) sodium triacetoxyborohydride and 2.85 ml (50 mmol) acetic acid were added and stirring took place for a further 2 d at RT. The solvent was removed in vacuo and the residue was taken up by chloroform and washed a plurality of times with 10% aq. NaOH soln and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, Chloroform/EtOH 20:1) was carried out on the residue, yielding 712 mg (2.5 mmol, 25%) tert-butyl-4-(thiazol-2-ylamino)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C:10]1([F:16])[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15])=[O:9]>N1C=CC=CC=1>[CH3:6][O:7][C:8]([C:10]1([F:16])[CH2:14][CH2:13][CH2:12][CH:11]1[O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:9]
Reactant: COC(=O)C1(F)CCCC1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)C1(F)CCCC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
0.36 g (3 mmol) of methanesulfonyl chloride was added under ice cooling to a mixture of 0.5 g (3 mmol) of 1-fluoro-2-hydroxy-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1 and 2 ml of pyridine, and the mixture was stirred at 0° C. for 5 hours. The reaction solution was poured into a ice water and extracted with ether, and the ether layer was washed with cold water. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to obtain 0.59 g (yield: 80%) of the desired 2-methanesulfonyloxy-1-fluoro-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 5a).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)Nc2ccc(Cl)cc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-chloroaniline the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=301 and 303.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2S[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22]1(S(C=C)=O)C=CC=C[CH:23]=1.C(#N)C>C1(C)C(C)=CC=CC=1>[C:16]1([C:4]2[C:3](=[O:2])[N:7]3[C:6](=[CH:22][CH:23]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CS(=O)c1ccccc1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Agent: [OH-]
Solvent: CC#N
Solvent: Cc1ccccc1C
Product: O=c1c(-c2ccccc2)ccc2n1CCc1ccccc1-2

Procedure:
be) from 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and phenylvinyl sulfoxide in xylene there was obtained 6,7-dihydro-3-phenyl-4H-benzo[a]quinolizine-4-one of m.p. 139.5°-140.5° (from acetonitrile):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20].Cl>C(#N)C>[OH:8][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1ccc(F)cc1O
Yield: 72 %

Procedure:
To the mixture of 3-fluorophenol (10 mL, 102 mmole), anhydrous magnesium chloride (28.2 g, 744.6 mmole) in 500 mL of anhydrous acetonitrile was added anhydrous triethylamine (67 mL, 382.5 mmole) and paraformaldehyde (22.3 g, 744.6 mmole). The mixture was then heated to reflux for five hours. After cooling to r.t, 500 mL of 5% aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed with 5% hydrochloric acid (×3), brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was a light pink solid. 11 g, yield 72%. M.P: 67.5-69.0° C. ESHRMS m/z 139.0211(M−H, C7H4FO2 calc'd 139.0201). 1H NMR (CDCl3/300 MHz) 11.40 (s, 1H), 9.86 (s, 1H), 7.62-7.57 (m, 1H ), 6.79-6.67 (m, 2H). 3C (CDCl3/300 MH) 195.4, 168.3 (d, J=258 Hz), 164.4 (d, J=14.9 Hz), 136.3 (d, J=12.6 Hz), 118.2 (d, J=2.0 Hz), 108.5 (d, J=23.3 Hz), 104.9 (d, J=24.4 Hz). 19F (CDCl3/400 MHz) −97.9 (m).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.[CH3:13][C:14]1([C:17]([O:19]C)=O)[CH2:16][CH2:15]1>C1COCC1>[CH3:13][C:14]1([C:17](=[O:19])[CH2:2][C:1]#[N:4])[CH2:16][CH2:15]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1(C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (7.43 mL, 52.6 mmol) in 60 mL of THF was added n-BuLi (2.5M) (21.03 mL, 52.6 mmol) at −78° C. The reaction was stirred at −78° C. for 30 min, then acetononitrile (2.76 mL, 52.6 mmol) was added at −78° C. and the reaction was stirred for 30 min, then methyl 1-methylcyclopropanecarboxylate (3 g, 52.6 mmol) was added at −78° C. The reaction was stirred at −78° C. for 1 h and then allowed to warm up at rt overnight. The solvent was evaporated and the solid dissolved in water. The aqueous layer was washed with ether and then acidified with 6N HCl to pH 2-3. The aqueous layer was extracted with ether. The organic layer was dried with MgSO4 and concentrated to afford the title compound (2.89 g, 89%). MS (DCI/NH3) m/z 124 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](N(C)OC)=[O:11])=[CH:8][CH:7]=1.[CH:22]([Mg]Br)=[CH2:23]>C1COCC1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:11])[CH:22]=[CH2:23])=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2F)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: -78 °C
Yield: 91 %

Procedure:
4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3, 6.0 g, 20.7 mmol) was dissolved in THF (100 mL) and cooled to −78° C. A 1.0 M solution of vinyl magnesium bromide in THF (31 mL, 31 mmol) was added and the cold bath was removed. Upon warming to 20-25° C., the mixture was poured into a vigorously stirred solution of 1 M HCl. The resulting mixture was extracted twice with CH2Cl2. The combined organic layers were then washed with 1 M HCl, then with a saturated NaHCO3 solution, dried over Na2SO4, and concentrated to a thick residue. The product was purified by flash column chromatography eluting with 0→40% acetone hexanes (gradient). Concentration of the fractions containing 4 gave an oil that crystallized upon standing (4.83 g, 91% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:4])=[CH:15][CH:16]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(C(=O)COc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirring solution of 2-bromo-3′-methoxyacetophenone (3.00 g, 13.1 mmol; Supplier=Kalexsyn; Lot=803-TTP-145) in acetone (30 ml) was added 4-hydroxybenzylalcohol (1.69 g, 13.6 mmol) and potassium carbonate (1.88 g, 13.6 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The product was analyzed on a large Biotage column eluting with 50% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 2.98 g of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:19]=[C:20](\[CH3:28])/[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:19]=[C:20](\[CH3:28])/[C:21]([OH:23])=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C/C(=C\c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C\c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
The tert-butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-methyl-2-propenoate (70 mg) obtained in (A) was dissolved in trifluoroacetic acid (1 ml) and stirred at room temperature for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (21 mg).
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC

Procedure:
The above aminodiester was alternatively prepared in the following manner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C. with stirring, and set aside at room temperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioate as a colourless oil, δ2.3(4H, multiplet, --CH2 --CO2Et and NCH2CH2CO--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for 31/2 hours at room temperature, and concentrated at 40° C. in vacuo. The residue, dissolved in water, was brought to pH5 with N-hydrochloric acid and extracted thoroughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Without further purification, the latter was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) followed by p-toluenesulphonic acid (6.72 g) in portions, and set aside at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate then water, dried, and evaporated, and the residue was purified by column chromatography on silica in 1:4 hexane/ether, giving diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical (n.m.r., i.r. mixed t.l.c.) with that prepared previously.
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: COc1ccccc1
Reactant: C=CC(=O)N1Cc2cc(OC)ccc2SC(Cl)C1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1Cc2cc(OC)ccc2SC(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
The above-mentioned 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.3 g) and anisole (1.1 g) were dissolved in methylene chloride (50 ml) and stannic chloride (2.8 g) was added thereto and agitated at room temperature for 2 hours. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-[4-methoxyphenyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.7 g).
Reaction SMILES: P(Cl)(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]([O-])[CH:13]=1)([O-:7])=[O:6]>ClCCCl>[N+:5]([C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][CH:13]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Solvent: ClCCCl
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
88.8 g (0.648 mol) of phosphorus trichloride were added in the course of 30 minutes while stirring at 25° C. to a mixture of 92 g (0.324 mol) of the above N-oxide and 300 ml of 1,2-dichloroethane. After stirring at 25° C. for 12 hours, the reaction mixture was concentrated in vacuo, the residue was taken up again in methylene chloride and the solution was poured into 2.5 l of ice-water. After phase separation, the aqueous phase was extracted with methylene chloride. The organic extract was washed with water, saturated sodium hydrogencarbonate and sodium chloride solution, dried over magnesium sulfate and filtered off with suction through neutral alumina and silica gel. After concentrating, 58.2 g (67% of theory) of the title compound were obtained as a yellowish syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following the procedure for the synthesis of Preparation XVI,) N-[(1R)-1-[(4- chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide was prepared from tert-butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 1) (1.42 g, 2.04 mmol) and 50 mL of EtOAc satd with HCl. The crude product was purified by preparative HPLC (AcOH buffer) yielding the desired product as the acetate salt (250 mg). MS (ESI, pos. ion) m/z: 596 (M+H), (ESI, neg. ion) m/z: 594 (M−H). Calc'd for C30H34ClN5O4S: 595. Anal. Calcd for C30H34ClN5O4S—C2H4O2H2O: C, 57.01; H, 5.98; N, 10.39; Cl, 5.26. Found C, 56.83; H, 6.05; N, 10.25; Cl, 5.25.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(O)(=O)C.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCOCC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl) butan-1-amine obtained in step VI of example I in tetrahydrofuran was added acetic acid (1 eq.) and tetrahydro-pyran-4-one (1.1 eq.). Resulting reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (2.2 eq.) was added to reaction mixture over a period of 1 hrs and resulting suspension was then stirred for 4-5 hrs. Reaction was then quenched with methanol and concentrated to dryness. Reaction mixture was basified using aq.sodium hydroxide solution and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky solid. Product was then purified by silica gel column chromatography to afford N-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-amine.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].[CH2:7]([O:9][CH2:10][CH2:11]Br)[CH3:8]>>[CH2:7]([O:9][CH2:10][CH2:11][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH3:8]
Reactant: CCOCCBr
Reactant: C#CC(C)(C)O
Product: C#CC(C)(C)OCCOCC
Yield: 63.8 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, and using 34.5 g of 3-methyl-1-butyn-3-ol and 69.0 g of 2-bromoethyl ethyl ether, 40.9 g of 3-(2-ethoxyethoxy)-3-methyl-1-butyne was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH:20](C3C=CC(F)=CC=3)[CH2:21][CH:16]2[CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][CH:14]1[O:18][CH:17]2[O:19][CH2:20][CH2:21][CH:16]2[CH2:15]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCC1CC2CC(c3ccc(F)cc3)OC2O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1NCCC1CC2CCOC2O1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
4Chloro-3-nitropyridine (160 mg, 1.0 mmol) is added to a stirred solution of 5-(2-aminoethyl)-2-(4-fluorophenyl)hexahydrofuro[2,3-b]furan (200 mg, 0.8 mmol) and triethylamine (1.0 ml) in chloroform (15 ml) at ambient temperature. The reaction mixture is stirred overnight, then washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to leave an orange oil. This is purified by chromatography over silica (1:1 ethyl acetate/hexane) to give 2-(4-fluorophenyl)-5-(2-(N-3-nitropyrid-4-ylaminoethyl)hexahydrofuro[2,3-b]furan (175 mg, 59%) as a yellow amorphous solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=[O:4])=[O:3].[F:41][C:42]1[CH:51]=[CH:50][C:45]2B(O)[O:47][CH2:48][C:44]=2[CH:43]=1>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>[F:41][C:42]1[CH:51]=[CH:50][C:45]([C:11]2[C:12]([C:16](=[O:32])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:19][CH:18]=3)=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]3)=[C:44]([CH2:48][OH:47])[CH:43]=1
Reactant: OB1OCc2cc(F)ccc21
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3CO)ccc2c1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Charge a 100 mL round bottom flask with trifluoro-methanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.3 g, 3.8 mmol), 5-fluoro-3H-benzo[c][1,2]oxaborol-1-ol (1.16 g, 7.6 mmol) and Pd(PPh3)4 (220 mg, 0.19 mmol) and purge with nitrogen. Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath and stir overnight. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Wash the organic layer with water and dry with sodium sulfate. Filter and concentrate to an amber foam. Purify the crude material on silica gel (1% to 6% methanol in methylene chloride) to yield 1.6 g (73%) of the title compound as a tan foam. 1H NMR (CDCl3) δ7.98 (d, J=8.4 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H), 7.60 (bs, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (bs, 11), 6.90-6.70 (m, 4H), 4.40-4.25 (m, 2H), 4.12 (m, 2H), 3.23 (s, 3H), 2.76 (t, J=5.4 Hz, 2H), 2.49 (bs, 4H), 1.59 (m, 5H), 1.45 (m, 1H).
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[C:6]1([NH:12][C:13]2[C:22]([NH2:23])=[C:21]3[C:16](C=CC=N3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([N:12]2[C:13]3=[C:14]4[C:15](=[CH:16][CH:21]=[C:22]3[NH:23][S:1]2(=[O:3])=[O:2])[CH:8]=[CH:7][CH:6]=[N:12]4)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1c(Nc2ccccc2)ccc2cccnc12
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccc3cccnc3c2N1c1ccccc1
Temperature: 115 °C
Yield: 36 %

Procedure:
Sulfamide (34 mg, 0.35 mmol) was added to a solution of N*7*-phenyl-quinoline-7,8-diamine 576 (56 mg, 0.23 mmol) in pyridine (2 ml) and the mixture was heated in a microwave at 115° C. for 2 h. After cooling, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 solution (30 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography DCM/MeOH/TEA (98:2:0.5-90:10:0.5 gradient) followed by preparative HPLC (acidic conditions 1) to give the title compound (12.3 mg, 17%).