Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH:3]1[CH:20]2[C:7]([OH:25])([C:8]([OH:24])=[C:9]3[CH:18]([CH2:19]2)[S:17][C:16]2[C:11](=[C:12]([OH:22])[CH:13]=[CH:14][C:15]=2Cl)[C:10]3=[O:23])[C:6](=[O:26])[C:5]([C:27]([NH2:29])=[O:28])=[C:4]1[OH:30].C(N(CC)CC)C>CO>[CH3:31][N:2]([C@@H:3]1[C:4](=[O:30])[C:5]([C:27]([NH2:29])=[O:28])=[C:6]([OH:26])[C@:7]2([OH:25])[C@H:20]1[CH2:19][C@@H:18]1[S:17][C:16]3[C:11](=[C:12]([OH:22])[CH:13]=[CH:14][CH:15]=3)[C:10]([OH:23])=[C:9]1[C:8]2=[O:24])[CH3:1]
Reactant: CN(C)C1C(O)=C(C(N)=O)C(=O)C2(O)C(O)=C3C(=O)c4c(O)ccc(Cl)c4SC3CC12
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)cccc4S[C@H]3C[C@@H]12

Procedure:
467 mg of 7-chloro-6-thiatetracycline in 25 ml of methanol are hydrogenated in the presence of 101 mg of triethylamine on 200 mg of 10% Pd-on-charcoal at 20° and normal pressure to give 6-thiatetracycline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(C)CCCN(Cc2ccccc2)C1
Yield: 92.3 %

Procedure:
(S)-3-Methylpiperidine-3-carboxylic acid ethyl ester (1.16 g, 6.8 mmol), benzyl chloride (0.82 ml, 7.1 mmol), K2CO3 (1.22 g, 8.8 mmol) and KI (0.056 g) were stirred and heated in DMF (50 ml) for 2.5 h. The cooled solution was poured into water and extracted with EtOAc (3×50 ml). The combined extracts were washed several times with water and finally with brine. Drying, filtering and evaporation of the solvent gave 1.64 g of the target compound as a yellowish oil.
Reaction SMILES: [Na+].[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:23])=O>>[Cl:23][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:2](=[O:4])[CH3:3])=[CH:7][CH:8]=1)(=[O:15])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
42.9 g 4-Acetoxy-benzenesulfonic acid sodium salt were suspended in 135 ml thionyl chloride. Then 0.5 ml dimethylformamide were added. The reaction mixture was heated under reflux for one hour. The cooled reaction mixture was evaporated in vacuo. The residue was coevaporated with 600 ml toluene twice. The residue was suspended in 500 ml dichloromethane and stirred at room temperature for thirty minutes. The suspension was filtered and the filtrate reduced in vacuo to one fifth of its volume. To this stirred solution 400 ml n-heptane were added dropwise and acetic acid 4-chlorosulfonyl-phenyl ester precipitated as a white solid. The precipitate was filtered off and dried in vacuo to obtain 40.4 g acetic acid 4-chlorosulfonyl-phenyl ester.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10].C1COCC1>CO>[CH3:8][N:9]([CH3:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: CNC
Reactant: C1CCC2OC2C1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)[C@@H]1CCCC[C@H]1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of cyclohexene oxide (3.64 mL, 36.0 mmol) in 30 mL of dry methanol was added dropwise 2.0 M dimethylamine in THF (15.0 mL, 30.0 mmol). The reaction mixture was stirred at 0° C. for 4 h. The solution was then warmed to room temperature and stirred for 18 h. The reaction mixture was then concentrated under reduced pressure to afford 1.11 g (26% crude yield) of the crude product which was used in the following reaction without purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC>[CH2:10]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCNCc1ccccc1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
A solution of 4.89 g. of phenylisocyanate in 100 ml. of hexane was added to a solution of 4.41 g. of N-benzyl-n-butylamine in 150 ml. of hexane and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to yield 1-benzyl-1-(n-butyl)-3-(phenyl)urea.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)indoline (intermediate-26) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29).
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6].[Cl:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][C:36]2[S:40][C:39]([CH:41]=O)=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>CS(C)=O>[Cl:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][C:36]2[S:40][C:39]([CH:41]=[CH:10][CH2:9][CH2:8][CH2:7][C:5]([OH:6])=[O:4])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccc(Cc2ccc(Cl)cc2)s1

Procedure:
This compound is prepared analogously to Example 7b from: 6.3 g of sodium hydride (=7.8 g of 80% strength mineral oil suspension) in 180 ml of dimethylsulphoxide, 57.9 g of 4-hydroxycarbonylbutyl-triphenylphosphonium bromide in 180 ml of dimethylsulphoxide and 25.0 g of 5-(4-chlorobenzyl)-thiophene-2-aldehyde in 20 ml of dimethylsulphoxide.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[H-].[Na+].[F:20]N(CC(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.Cl>C1COCC1.ClCCl>[F:20][C:2]1([CH3:1])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Reactant: CC1C(=O)N(c2ccccc2)c2ncccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(F)C(=O)N(c2ccccc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 1,3-dihydro-3-methyl-1-phenyl-2H-pyrrolo[2,3-b]-pyridin-2-one (H) (3.0 g, 0.013 mole) portionwise to sodium hydride (0.63 g of 60% NaH in oil, 0.015 mole, washed with hexane) in dry THF (35 mL) at 10° C. under a N2 atmosphere. Stir for 30 minutes at room temperature, and then recool to 10° C. Add N-fluoro-N-neopentyl-p-toluenesulfonamide (4.1 g, 0.015 mole) in dry THF (30 mL) dropwise over 10 minutes. Warm reaction mixture up to room temperature slowly, and stir for 16 hours. Pour onto ice/water (100 mL), and neutralize to pH=4 to 5 with 15% aqueous HCl. Separate layers. Dry organic solution with MgSO4, filter, and rotoevaporate to give an oil. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with 30% ethyl acetate-hexane. Combine the appropriate fractions, and concentrate under reduced pressure. Triturate with isopropyl ether-petroleum ether and filter to give the title compound AA as a white solid (1.1 g, m.p. 83°-85° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]3[N:14]=[CH:15][CH:16]=[CH:17][N:12]3[NH:11][C:10]=2[NH2:18])[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>CN(C=O)C>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]3[N:14]=[CH:15][CH:16]=[CH:17][N:12]3[NH:11][C:10]=2[NH2:18])[CH:4]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C2=C(N)NN3C=CC=NC23)ncn1
Solvent: CN(C)C=O
Product: CS(=O)c1cc(C2=C(N)NN3C=CC=NC23)ncn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
3-(6-(Methylthio)pyrimidin-4-yl)-1,3a-dihydropyrazolo[1,5-a]pyrimidin-2-amine (22′, 7.2 g, 27.9 mmol) was suspended/dissolved in 70 mL of DMF and stirred at 0° C. while mCPBA (8.0 g, 34.8 mmol) in 20 mL of DMF was added drop wise over 30 minutes. After addition, the reaction was stirred for an additional hour at ambient temperature. The ppt was isolated via suction filtration, and washed with acetonitrile, and finally ethyl ether and air dried. Isolated 5.1 g of solid (66.7% yield)
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][Si:13]([CH3:24])([CH3:23])[C:14]1[O:22][C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>C(Cl)Cl>[CH3:12][Si:13]([CH3:24])([CH3:23])[C:14]1[O:22][C:21]2[C:16](=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[Si](C)(C)c1cc2ncccc2o1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of m-CPBA (17 g, 0.098 mmol) in DCM (80 ml) is added to a solution of 2-(Trimethylsilyl)furo(3,2-b)pyridine (7.5 g, 0.0392 mol) in dry DCM (50 ml) at 0° C. The reaction mixture is stirred at RT for 4 h and then diluted with DCM (100 ml), washed with saturated sodium bicarbonate (2×100 ml) and saturated brine (50 ml), dried over sodium sulphate and evaporated to afford the title compound as (6 g, 73.5%) light brown oil. TLC: chloroform/methanol (9/1): Rf=0.8; 1H NMR (DMSO-d6, 400 MHz) δ [ppm] 8.21-8.19 (1H, d, J1=6.4 Hz), 7.693-7.671 (1H, d, J1=8.52 Hz), 7.465-7.163 (1H, d, J1=1 Hz), 7.333-7.296 (1H, dd, J1=6.36 Hz, J2=8.48 Hz), 0.372-0.355 (9H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([NH2:26])[S:18][C:19]=1[CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:26][C:17]2[S:18][C:19]([CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24])=[C:15]([CH3:14])[N:16]=2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(C)c(CCO[N+](=O)[O-])s2)cc1
Yield: 44 %

Procedure:
Pet-157 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 4-acetylamino-benzoic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 44%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>ClCCl>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine dihydrochloride salt (2.0 g, 6.09 mmol) in dichloromethane (50 mL). Add triethylamine (3.39 mL, 24.4 mmol), and benzenesulfonylchloride (854 μL, 6.69 mmol). Stir at ambient temperature for 18 hr. Add dichloromethane and aqueous 1 N HCl solution. Separate the organic layer and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry (magnesium sulfate), filter, and concentrate. Purify via SCX chromatography, followed by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate) to give the title preparation (1.88 g, 78%). MS (ES): m/z=396 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1>CN(C=O)C>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:5][CH2:4][CH2:3][OH:6])=[N:15]2)=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: Clc1cnc2ccc(Br)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1cnc2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Suspend sodium hydride (310 mg, 13 mmol) in a solution of ethylene glycol (800 mg, 13 mmol) in DMF (50 mL) at 0° C. After stirring for 30 min at room temperature, 7-bromo-2-chloro-quinoxaline (Preparation 26; 610 mg, 2.5 mmol) is added. Stir for 2 h at room temperature and dilute with 3:1 chloroform/isopropyl alchol. Wash the organic phase with brine and purify by FCC to give the title compound (564 mg, 85%). MS m/e (268, M+1). 1H NMR (400 MHz, CDCl3) δ 8.5 (s, 1H), 8.0 (d, J=2.0 Hz), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H), 4.6 (t, d=4.8 Hz, 2H), 43.9 (t, J=4.8 Hz, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH3:31])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>ClCCl>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:24][CH2:23]1)=[O:46]
Reactant: Cc1ccccc1C1(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)CCNCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 2-methyl-1-(8-{2-[4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole dihydrochloride (0.15 g, 0.31 mmol), triethylamine (0.087 mL, 0.62 mmol) and trimethylacetyl chloride (0.043 mL, 0.34 mmol) in dichloromethane (3 mL) was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 1-((1R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a white solid (0.073 g, 45%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.13-7.31 (m, 7H), 4.62 (m, 1H), 3.86 (m, 2H), 3.48 (m, 2H), 3.24 (m, 2H), 2.56 (m, 6H), 2.34 (m, 4H), 10.93 (m, 8H), 1.60 (m, 4H), 1.27 (s, 9H). HRMS C34H46N4O m/z 527.3750 (M+H)Cal., 527.3749 (M+H)Obs..
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:3][CH:2]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cccc(OCc3ccc(-c4ccccc4)cc3)c2)S1
Yield: 28.5 %

Procedure:
A mixture of the above benzaldehyde (500 g, 17 mmol), 2,4-thiazolidinedione (3.03 g, 26 mmol) and piperidine (0.35 ml, 3.5 mmol) in ethanol (75 ml) was stirred at reflux temperature for 16 h. The reaction mixture was cooled and the precipitated was filtered off and washed thoroughly with ethanol and dried in vacuo at 50° C. The solid was first washed with a mixture of ethyl acetate, heptane and dichloromethane (1:1:6, 40 ml) and then washed with dichloromethane (20 ml). Drying in vacuo at 50° C. afforded 1.88 g (28%) of the title compound as a solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](I)=[C:22]([F:27])[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:18])[N:8]([C@H:5]4[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[C:22]([F:27])[CH:21]=1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCNC2
Reactant: Fc1cc(Br)ccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (1.04 g, 0.00412 mol), 4-bromo-2-fluoro-1-iodobenzene (Aldrich, cat #: 283304) (1.85 g, 0.00615 mol), copper(I) iodide (Aldrich, cat #: 215554) (0.122 g, 0.000640 mol), potassium phosphate (2.63 g, 0.0124 mol) and 1,2-ethanediol (0.48 mL, 0.0086 mol) in 1-butanol (3.90 mL) was heated at 100° C. under nitrogen for 2 d. The reaction was quenched with water, and extracted with ether. The organic layers were combined, washed with water, brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column eluting with 0 to 5% methanol in DCM to yield the desired product (950 mg, 54.2%). LC/MS m/e 425.1/427.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]3[C:21]([C:22]=2[CH3:26])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:12])=[CH:24][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: C1CCOC1
Product: Cc1nc2ncccc2c(C)c1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (150 mg, 0.45 mmol) was dissolved in THF (anh, 8.0 ml) under N2. Methylmagnesium bromide (4.5 ml of a 1M sln) was added dropwise. The mixture was stirred at r.t. for 2.0 h. The reaction was quenched with NH4Cl (sat). The product was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The residue was dissolved in CHCl3 and O2 (94%) was bubbled through the solution for 3.0 h. The mixture was concentrated and purified by flash chromatography CH2Cl2/MeOH (96:4→95:5) yielding 50.0 mg of the title compound (32%). 1H NMR (CDCl3) δ 8.80 (m, 1H), 8.13 (m, 1H), 7.44 (d, 2H), 7.41 (d, 2H), 7.35 (m, 1H), 7.02 (t, 1H), 4.74 (d, 2H), 2.73 (s, 3H), 2.49 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)S(N)(=O)=O
Reactant: OB(O)c1cccnc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)S(N)(=O)=O
Yield: 27.8 %

Procedure:
Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100–140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191–192° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].Cl.O1CCOCC1>O>[Cl:1][C:2]1[C:3]([C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)(=O)C4)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of the compound obtained in Example 114 (200 mg), 10% aqueous hydrochloric acid (3 ml) and dioxane (5 ml) was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure to obtain (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7,7-dioxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]-thieno[2,3-b]pyridin-4-yl}phenoxy)acetic acid (130 mg, 72%). It was recrystallized from acetone-hexane. Colorless prisms. Melting point 260–261° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCN1c2cc(CO)ccc2Sc2nccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCN1c2cc(CN3C(=O)c4ccccc4C3=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of 3.32 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methanol, 2.12 g of phthalimide and 3.77 g of triphenylphosphine in tetrahydrofuran (50 ml) was ice-cooled and 2.24 ml of diethyl azodicarboxylate was dropped thereinto. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and diethyl ether was added to the residue. Then it was subjected to ultrasonication and the crystals thus precipitated were taken up by filtration to thereby give 2.6 g of the title compound as pale yellow crystals.