Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2>C(O)(=O)C.CN(C=O)C>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][NH:7][C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)[nH]ccc2c1N
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A suspension of 6-methyl-5-nitroisoquinolin-1(2H)-one (40 g, 196 mmol) in glacial acetic acid (1 L) was purged with N2. The suspension was treated with 10% Pd/C (10 g) and the reaction vessel was purged with H2. The mixture was stirred at room temperature under H2 (1 atm) until starting material consumed, approximately 100 h. The reaction mixture was purged with N2, then filtered through a pad of Celite. The pad was washed with MeOH (400 mL) and the combined filtrate was treated wtih water (80 mL) and concentrated in vacuo to ˜200 mL. The dark mixture was diluted with 200 mL MeOH and added in a thin stream to ice water (1.5 L) stirred in a large beaker. The resulting fine precipitate was collected by suction filtration. The greenish-grey powder was suspended in water (500 mL) and satd NaHCO3 (100 mL) and sonicated for 1 min. The solid was collected by suction filtration, washed with water (2×100 mL), Et2O (100 mL), and air-dried overnight to afford 28 g as a grey powder. The powder was dissolved in hot DMF (200 mL) and treated with decolorizing carbon (˜10 g). The hot suspension was filtered through Celite. The filter cake was washed with MeOH (200 mL) and the filtrate was concnetraed in vacuo to ˜200 mL. The dark brown solution was added to water (1.2 L) to afford a fine crystalline precipitate. The solid was collected by suction filtration on a medium-sintered glass frit and washed wtih water (500 mL). A second crop precipiated in the filtrate and was colected by suction filtration, washed with water (100 mL) and added to the first crop. The combined material was washed with Et2O (400 mL), and dried on the sintered glass funnel under a stream of N2, with suction, for 16 h to afford 5-amino-6-methylisoquinolin-1(2H)-one (22 g, 64% yield) as a tan crystalline solid. MS (M+H)+ 175.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2Cl)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(F)cc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 2.9 g (0.011 mole) of 3-(2-chloro-4-fluorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4 mL (0.05 mole) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 mL of water. The solid which precipitated was collected by filtration (2.7 g). The crude product was recrystallized from benzene/ligroin yielding 2.4 g (84.3%) of fine white crystals, mp 139°-141° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:24][CH2:25][CH3:26])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19](=[O:22])[NH:20][CH3:21])[CH:16]=[CH:15][C:14]=3[CH3:23])C.[OH-].[Na+]>C1COCC1.CO>[CH3:23][C:14]1[CH:15]=[CH:16][C:17]([C:19](=[O:22])[NH:20][CH3:21])=[C:18]2[C:13]=1[NH:12][C:11]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])([CH2:24][CH2:25][CH3:26])[O:7][CH2:8][CH2:9][C:10]2=1
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of (8-methyl-5-methylcarbamoyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (87 mg, 0.234 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.468 mL, 0.468 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 67 mg (84%) of title compound as a white solid. Mp=89–91° C.; HRMS (ESI) [M+H]+ calculated for C19H25N2O4 345.1809, found 345.1807; 1H NMR (DMSO-d6): 300 MHz δ 10.63 (s, 1H), 8.00 (s, 1H), 6.97 (d, J=6.00 Hz, 1H), 6.84 (d, J=6.00 Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 2.93–2.46 (m, 10H), 2.01 (m, 2H), 1.29 (m, 1H), 0.82 (m, 1H), 0.78 (t, J=5.10 Hz, 3H). LCMS retention time: 1.936 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=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>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:3]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(-c2ccccn2)cccc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (4.8 g, 19 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (XCVII) (7.5 g, 20 mmol, 1.05 eq) and Pd(PPh3)4 (2.1 g, 1.8 mmol, 0.01 eq) in toluene (60 mL) was heated to reflux under nitrogen overnight. Saturated sodium bicarbonate solution (50 mL) was then added to the mixture and it was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by column chromatography on silica gel (EtOAc:PE=1:2→100% EtOAc) to afford N-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (XCVIII) (4.4 g, 17.1 mmol, 92% yield) as a white-off solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.93 (s, 3H), 7.43-7.51 (m, 1H), 7.51-7.65 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.97 (dd, J=7.6 Hz, J=2.4 Hz, 3H), 8.75 (d, J=4.4 Hz, 1H), 10.52 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[C:3]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:4][C:5]([C:18]([F:19])([F:20])[F:21])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 540.1 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:3]1.[CH3:15][NH:16][CH3:17]>N1C=CC=CC=1>[NH2:1][N:2]1[C:7]([N:16]([CH3:17])[CH3:15])=[N:6][C:5](=[O:10])[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:3]1
Reactant: CNC
Reactant: CSc1nc(=O)c(C(C)(C)C)nn1N
Solvent: c1ccncc1
Product: CN(C)c1nc(=O)c(C(C)(C)C)nn1N
Yield: 81 %

Procedure:
2-Amino-3-methylthio-6-t-butyl-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) was added to a mixture of a 40% aqueous solution of dimethylamine (5 ml) and pyridine (10 ml), and the resulting mixture was heated with reflux for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness under reduced pressure to give a crude product. Recrystallization of the crude product from acetone gave 0.8 g of 2-amino-3-dimethylamino-6-t-butyl-5-oxo-2,5-dihydro-1,2,4-triazine in 81% yield. M.P. 168°-169° C.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](F)=[CH:17][CH:16]=1>>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:17][CH:16]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(Br)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)(C)O
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 1.4 ml of tert.-butanol were reacted to obtain 1.43 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+67°±4° (c=0.25% in benzene).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH2:24][CH2:23][CH2:22]1
Reactant: C1CNC1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-methoxyphenyl]acetic acid (1.8 g, 6.61 mmol) was dissolved in DMF (5 ml) and azetidine (0.566 g, 9.92 mmol), DIEA (3.46 ml, 19.8 mmol), and HATU (4.02 g, 10.6 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 312 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:36]([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 59.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (100 mg, 0.30 mmol) in DCM (4 ml) and triethylamine (65.8 μl, 0.90 mmol), was added phenylmethanesulfonyl chloride (68.6 mg, 0.36 mmol). The reaction was stirred at RT for 13 hours. DCM was evaporated, and the crude was taken up with EtOAc and washed 1M Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylmethylsulfonamido)-acetate (74 mg; 59.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C(=O)C>[C:13]1([S:19]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[CH2:10][CH2:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccccc1)N1CCc2cc(Br)cnc21
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a 0° C. stirred solution of 5-bromo-azaindoline 5 (150 mg, 0.75 mmol) in N,N-dimethylacetamide (7 mL) was added in one portion 60% dispersion of NaH in mineral oil (38 mg, 0.94 mmol). After 0.5 h benzenesulfonyl chloride (0.12 mL, 0.94 mmol) in N,N-dimethylacetamide (1 mL) was added dropwise, and the mixture allowed to slowly warm to r.t. After 2 days the mixture was partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (2×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by preparative TLC (PTLC) with CH2Cl2 as eluent to afford the azaindoline 6 (21 mg, 8%) as a solid. 1H NMR (400 MHz; CDCl3) δ 3.04 (t, J=8.6 Hz, 2H), 4.08 (t, J=8.6 Hz, 2H), 7.45-7.51 (m, 3H), 7.56-7.60 (m, 1H), 8.08 (m, 2H), 8.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.[C:27]([O-])(=O)[CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([O:16][CH2:29][C:28]4[CH:27]=[CH:9][C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CCC(=O)[O-]
Reactant: COC(=O)C(C)(C)Cc1cc2c(O)cccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1cc2c(OCc3ccc4ccccc4n3)cccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title product was prepared according to conditions described in Steps D and E of Example 1 substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy indol-2-yl]-2,2-dimethylpropanoate for the propanoate in Example 1 (Step D), m.p. 158°-160° C. Anal. C, H, N: Calc. C 72.20; H 5.45; N 5.61 Found C 72.25; H 5.60; N 5.75.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:14]([O-])=[O:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.C(OC(Cl)=O)C>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][OH:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CC(=O)[O-])NC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](CCO)NC(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.05 h

Procedure:
29.23 g of N-[(phenylmethoxy)carbonyl]-D-aspartic acid, 1,1-dimethylethyl ester, prepared as in Example C, in 120 mL dry tetrahydrofuran at -10° C. was treated with 10 mL N-methylmorpholine. The mixture was stirred for 3 min and 8.7 mL ethylchloroformate was added dropwise. The mixture was warmed to 23° C. over 15 min and filtered. The filtrate was added dropwise over 30 min to a vigorously stirred mixture of 7.7 g sodium borohydride in 60 mL water at 3° C. The cooling bath was removed, the mixture stirred at 21° C. for 3 h, then cooled to 0° C. and acidified to pH2 with concentrated HCl. The mixture was extracted with 3×200 mL ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to furnish a clear oil. Purification by silica chromatography using methylene chloride-acetone (9:1) as eluent gave the title compound as a clear oil; 21.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:21][CH2:20][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(F)c(F)cc1Cl
Reactant: NCC1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cc(F)c(NCC2CCOCC2)cc1Cl
Reaction time: 36 h

Procedure:
2-Chloro-4,5-difluorobenzenesulfonamide (0.683 g), (tetrahydro-2H-pyran-4-yl)methanamine (0.346 g), N,N-diisopropylethylamine (0.681 ml) and dioxane (10 ml) were heated at 65° C. for 2.5 days. Additional (tetrahydro-2H-pyran-4-yl)methanamine (0.346 g) and N,N-diisopropylethylamine (0.681 ml) were added and heating was continued at 70° C. for 1.5 days. The reaction mixture was concentrated and column chromatographed on silica gel with 0-3% methanol in dichloromethane as eluent. The obtained solid was triturated with dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:10]([O:13][CH2:14][CH2:15]Br)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:10]([O:13][CH2:14][CH2:15][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(SCCOC(C)=O)cc1
Yield: 84.8 %

Procedure:
4-methoxybenzene-1-thiol (15.7 g, 0.11 mol), 2-bromoethyl acetate (18.8 g, 0.11 mol), and K2CO3 (46.6 g, 0.34 mol) in acetone (200 mL) were stirred at room temperature for 12 h. Then the mixture was filtered. After CH2Cl2 extractive work up and silica gel chromatography chromatography (PE: EA=1:0-10:1) the title compound (21.1 g, 83.3%) was obtained as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 7.40 (dd, J1=6.8 Hz, J2=2.0 Hz, 2H), 6.86 (dd, J1=6.8 Hz, J2=2.0 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.02 (t, J=7.2 Hz, 2H), 2.03 (s, 3H). LCMS: 139.0 (M−87)+
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[N-:18]=[N+:19]=[N-:20].[Na+]>CCO.O>[N:18]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[N+:19]=[N-:20]
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-(2-iodoethoxy)ethoxy)ethylphosphonate (1 eq) in EtOH (0.2 M) was added sodium azide (5 eq) in water (1.4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with EtOAc (3 times). The combined organic layers were washed brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate as colorless oil.
Reaction SMILES: [N+](=[C:3]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[OH:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[O:27]1[CH2:28][CH2:29][CH:24]([O:23][CH:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:25][CH2:26]1
Reactant: OC1CCOCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Methyl 2-diazo-2-(4-tetrahydropyran-4-ylsulfonylphenyl)acetate (4.0 g, 12.34 mmol) was dissolved in DCM (40 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (1.5 g, 14.8 mmol) was added followed by rhodium (II) acetate dimer (0.109 g, 0.24 mmol). Mixture was stirred at 25° C. for 30 min. Reaction mixture was diluted with DCM (10 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product as methyl 2-tetrahydropyran-4-yloxy-2-(4-tetrahydropyran-4-ylsulfonylphenyl)acetate (4.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH:16][CH2:15][CH2:13][OH:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)c(F)c1NCCO
Reaction time: 5 h

Procedure:
A solution of 1,2,3-trifluoro-4-nitrobenzene (5.0 g, 28.2 mmol) and ethanolamine (1.72 g, 28.2 mmol) in 100 ml of ethanol is stirred over night at room temperature then at 70° C. for 5 hours. The reaction is concentrated to dryness and purified by silica gel flash chromatography using a gradient of 80/20 to 20/80 heptane/ethyl acetate providing an orange solid. Yield (3.8 g, 62%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere a mixture of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.06 mmol) and dichloromethane (50 mL) was cooled to 0° C. Phenyl isocyanate was added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (110 g silica gel eluting with 9:1 dichloromethane:methanol). The resulting orange solid was triturated with hexanes, isolated by filtration and then dried. This material was recrystallized from propyl acetate with a small amount of methanol, isolated by filtration, washed with hexanes, and then dried in a vacuum oven at 60° C. for 2 days to provide 0.6 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylurea as an off white powder, m.p. 136–142° C. Analysis: Calculated for C28H36N6O2: % C, 68.83; % H, 7.43; % N, 17.20; Found: % C, 68.27; % H, 7.44; % N, 16.85. 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3. 1.0 Hz, 1H), 7.44–7.35 (m, 3H), 7.29–7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.52 (s, 2H), 6.08 (m, 1H), 4.51 (t, J=7.8 Hz, 2H), 3.82 (m, 2H), 3.29 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 3.05 (m, 2H), 1.81 (m, 2H), 1.42–1.29 (m, 10H);