Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=1)=[O:24])[NH2:22]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 110 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
1-[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (38.0 mg, 0.14 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (27.9 mg, 0.14 mmol) were dissolved in dimethylformamide (2.0 mL) and stirred at 110° C. for 12 hours. After cooling, the solvent was evaporated, and ethyl acetate was added to the resulting crude product. The precipitated solid was recovered by filtration to give 20.0 mg of the desired product as a pale yellow solid (yield 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][OH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][O:18][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1ccc(Br)c(CO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 7-methoxy-2-naphthol (26.92 g, 0.15 moles), 2-bromo-5-methoxybenzyl alcohol (33.58 g, 0.15 moles), and triphenylphosphine (39.3 g, 0.15 moles) in anhydrous THF (500 mls) was added a solution of DEAD (26.10 g, 0.15 moles) in THF (100 mL) dropwise over 0.5 hr. The solution was stirred at room temperature overnight and, upon evaporation of half the volume, the product precipitated in good purity. The solid was filtered and rinsed with THF, then dried to yield 32.96 g (59%) of a white solid: mp 156-157° C.; 1H NMR (DMSO-d6): δ 3.77 (3H, s), 3.86 (3H, s), 5.18 (2H, s), 6.92 (1H, dd, J=3.2 Hz, J=8.7 Hz), 7.00 (1H, dd, J=2.4 Hz, J=8.7 Hz), 7.09 (1H, dd, J=2.4 Hz, J=8.9 Hz), 7.22 (1H, d, J=3.2 Hz), 7.25 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=8.7 Hz); MS m/z 373/375 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([C:29]([N:19]2[CH2:20][CH2:21][C:11]3([NH:10][C:9]4[CH:8]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:15][C:14]=4[C:13](=[O:16])[NH:12]3)[CH2:17][CH2:18]2)=[O:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC2(CCN(C(=O)c3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
A stirred solution of 6′-(pyridin-4-yl)-1′H-spiro [piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.0500 g, 0.170 mmol) and triethylamine (0.070 mL, 0.51 mmol) in tetrahydrofuran (4 mL) was cooled to 0° C. in an ice bath. A solution of benzoyl chloride (0.0260 g, 0.190 mmol) in tetrahydrofuran (0.1 mL) was added, and the reaction was allowed to warm to room temperature overnight. Then, the solvent was removed and the obtained residue was diluted with methanol (25 mL) and the mixture was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solids were removed by filtration. The filtrate was concentrated to give a yellow solid, which was triturated with water and collected by filtration. This solid product was recrystallized from hot methanol/hexanes to give the title compound (0.0315 g, 45%) as a yellow solid:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (1.65 g, 6.65 mmol) in CH2Cl2 (200 mL) was added Et3N (1.35 g, 13.3 mmol), followed by acetyl chloride (0.573 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 5 minutes, washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated, to afford ethyl 4-(4-acetamidopiperidin-1-yl)benzoate as a white solid (1.9 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[N:8][N:7]=1)=[O:5])[CH3:2].[Na].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)c1nnn[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium tetrazole-5-carboxylic acid ethyl ester (2 g, 12.19 mmol) in DMF (8 mL) is added 4-methoxybenzyl bromide (3.68 g, 18.28 mmol) followed by the addition of triethylamine (5.10 mL). The resulting mixture is stirred at room temperature overnight then ice/water is added. The mixture is extracted with EtOAc and the combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography to afford 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid ethyl ester; HPLC Retention time 1.37 minutes (condition C): MS 263.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1C=CC=[CH:4][CH:3]=1.C(=O)(O[CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC.N1CCCC1>C1COCC1>[C:16]1([CH:15]([N:8]2[CH2:1][CH2:2][CH2:3][CH2:4]2)[CH:14]=[CH2:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)OCC=Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: C=CC(c1ccccc1)N1CCCC1
Reaction time: 16 h
Yield: 61 %

Procedure:
A stock solution containing [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) and L1 (10.8 mg, 0.0200 mmol) in 1.0 mL of THF was prepared. By the procedure for reaction of benzylamine with methyl cinnamyl carbonate, the reaction of pyrrolidine (85.0 mg, 1.19 mmol) and methyl cinnamyl carbonate (201.5 mg, 1.049 mmol) was conducted at room temperature for 16 h. 1H NMR analysis of the crude mixture showed the ratio of branched to linear product to be 99/1. After purification, 121 mg of the title compound (61%) was isolated and HPLC analysis as described above indicated that the enantiomeric excess of the major product was 97%.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH3:18])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>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.O1CCOCC1>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:3]=3[O:17][CH3:18])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COc1c(Br)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: C1COCCO1
Product: COc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 97.7 %

Procedure:
Under argon atmosphere, bis(triphenylphosphine)palladium(II) dichloride (777 mg, 1.11 mmol) was added to a 1,4-dioxane (110 ml) solution of 6-bromo-2-cyclopropyl-7-methoxy-5-methyl-1,3-benzoxazole-4-carbonitrile (I-83) (3.40 g, 11.1 mmol), tributylphenyltin (5.28 g, 14.4 mmol) and 2,6-di-tert-butylcresol (488 mg, 2.21 mmol), followed by stirring in an oil bath at 100° C. for 15 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was washed with diethyl ether to obtain the entitled compound (3.30 g, 98%) as a pale gray solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21](C(Cl)(Cl)Cl)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[CH3:28][NH2:29]>CN(C)C=O.O>[CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[NH:22][C:21](=[N:29][CH3:28])[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: CN
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(Cl)(Cl)Cl)n3)cc2C)on1
Solvent: CN(C)C=O
Solvent: O
Product: CN=c1[nH]c(-c2cc(C)c(OCCCc3cc(C)no3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
The product of Example 12 (1.00 g, 2.32 mmol) was added to 5 ml of 40% aqueous methylamine in dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue (0.54 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride and then with 50% ethyl acetate in hexanes) to give 300 mg (37.5%) of pure title compound as a yellow solid, mp 126.5°-127° C. (ethanol).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(2-methanesulfonyloxyethyl)pyrrolidine (5.35 g) in N,N-dimethylformamide (54 ml) were added imidazole (1.18 g) and potassium t-butoxide (1.78 g) with stirring under ice-cooling. The mixture was stirred at 40°-45° C. for 40 minutes. The reaction mixture was poured into water (100 ml) and extracted with dichloromethane (80 ml). The extract was washed in turn with water (50 ml) and 10% aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-methanesulfonyloxypyrrolidine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][S:46]([NH:49][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)=[CH:11][CH:12]=1)(=[O:48])=[O:47]
Reactant: O=C(O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.2 %

Procedure:
To a solution of 4-(3-(trifluoromethyl)phenylamino)benzoic acid (150 mg, 0.533 mmol) in DMF (4 mL) were added HATU (243 mg, 0.640 mmol), methanesulfonamide (152 mg, 1.60 mmol) and DIPEA (0.296 mL) and the reaction stirred at room temperature for 16 hours. Methanesulfonamide (152 mg, 1.60 mmol) was added and the reaction stirred at room temperature for 72 hours. After this time the reaction was quenched by the addition of potassium hydrogen sulfate (20 mL) and the aqueous extracted with dichlormethane (3×20 mL). The combined organics were washed with brine (40 mL), filtered through a phase separation cartridge and then the solvent was removed under reduced pressure to give an oil (325 mg). The crude was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: COc1cccc(NN)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-methoxyphenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a Solution of 50% pyridine in ethanol. The resulting solid was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.38 t (3H); 2.50 s (3H); 2.52 s (3H); 3.84 s (3H); 4.32 q (2H); 6.96 m (3H); 7.3 st (1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)(O)[O-].[K+]>O1CCCC1>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:15]=2)[N:8]=[CH:7]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NCCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCc2c[nH]cn2)nc1

Procedure:
0.5 g (4.5 mmol) of histamine and 0.77 g (4.5 mmol) of 6-chloro-3-carbomethoxypyridine are stirred with potassium bicarbonate in 20 ml of tetrahydrofuran at 21° C. for 24 h and then heated at reflux for 24 h. The mixture is evaporated and the white solid residue is chromatographed through silica gel, using a chloroform/methanol (4/1) mixture as eluent. The fractions containing the pure product are combined and evaporated and the resulting oily residue is treated with a methanol solution of oxalic acid. Addition of ether provides the title compound in the form of the oxalate salt, M.p.: 209°-210° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN=[N+]=[N-]
Temperature: 25 °C

Procedure:
Sodium azide (14.7 g) was added to a solution of 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (22.8 g prepared according to the method of Part F) in N,N-dimethylformamide (75 mL). The reaction mixture was heated at reflux for several hours and then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (100 ml) and then extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum to provide crude 1-(2-azidoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an oil.
Reaction SMILES: [CH:1]1([CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][CH2:2]1.C([O-])(O)=[O:16].[Na+].ClC(OC1C=CC=CC=1)=O>C1COCC1.O>[CH:1]1([CH2:9][C:10]2[NH:11][C:12](=[O:16])[NH:13][CH:14]=2)[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][CH2:2]1
Reactant: c1nc(CC2CCC3=C2CCC3)c[nH]1
Reactant: O=C([O-])O
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]cc(CC2CCC3=C2CCC3)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(1,2,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1H-imidazole; fumarate salt (Intermediate A5 as described in Example A, 340 mg, 1.81 mmol) in THF (15 mL) and water (15 mL) was treated with NaHCO3 (1.52 g, 18 mmol) at rt for 30 m. Phenyl chloroformate (600 mL, 4.7 mmol) was added and stirring was continued for 1 h at 65° C. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The organic portions were combined and freed of solvent. The residue was dissolved in EtOH (15 mL): water (15 mL) and treated with Na2CO3 (500 mg) for 1.5 h at 95° C. The mixture was cooled to rt and the product was collected on a glass frit to give a white solid (˜50%) 4-(1,2,3,4,5,6-Hexahydro-pentalen-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 41).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[C:24]3=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C@@H:19]3[C:24]4=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]4[CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc([C@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (1.34 g), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (500 mg), diacetoxycopper (648 mg), triethylamine (1.24 ml), and powdered 4A MS (1.50 g) in DMF (20 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-IPE to give the title compound (53.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](O)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][OH:13]>O=[Mn]=O>[CH2:1]([C:5]1[NH:6][C:7]([CH:12]=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCc1nc(Cl)c(O)[nH]1
Agent: O=[Mn]=O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-butyl-4-chloro-5-hydroxyimdazole (5.0 g, 26,5 mMol) in methanol (300 ml) were added MnO2 (57.6 g, 0.663 mol) and 3A° powdered molecular sieves (oven dried in vacuo) (4.5 g), and the mixture was stirred at room temperature for 20 h. The reaction was filtered through a pad of celite. The filterate was evaporated in vacuo to give the pure desired aldehyde (purity checked on TIC using EtOAc-Hexane 1:3) in quantitative yield (4.9 g, white solid). This material was used directly in the subsequent steps as described below.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:9]2[S:18][N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccncc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-hydroxy-3-phenyl-7-pyridin-4-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 407.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH:15](C)[C:14]=2[C:13]=1[C:23]([O:25]C)=[O:24])(=[O:10])=[O:9].[F:27][C:28]([F:46])([F:45])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:36]2)[N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O>[F:46][C:28]([F:27])([F:45])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][NH:44][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([NH:11][C:12]3[CH:21]=[CH:20][C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[C:23]([OH:25])=[O:24])(=[O:9])=[O:10])[CH2:37][CH2:36]2)[N:30]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)CCC2
Reactant: NCCCN1CCN(c2nccc(C(F)(F)F)n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCCN2CCN(c3nccc(C(F)(F)F)n3)CC2)ccc2c1CCCC2
Temperature: 160 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of Example 275F (100 mg, 0.275 mmol) in 1.0 mL of N-methylpyrrolidinone was treated with 151 mg of 3-[4-(4-trifluoromethylpyrimidin-2-yl)-piperazin-1-yl]-propylamine and 58 mg of potassium phosphate, warmed to 160° C., stirred for 16 hours, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (63 mg, 36%). MS (ESI) m/e 619 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=4.80 Hz, 1H), 7.52 (dd, J=7.96, 1.51 Hz, 1H), 7.34 (m, 1H), 7.24 (d, J=8.37 Hz, 1H), 7.03 (d, J=4.94 Hz, 1H), 6.97 (d, J=8.37 Hz, 1H), 6.80 (d, J=7.68 Hz, 1H), 6.57-6.61 (m, 1H), 3.75-4.25 (m, 4H), 3.25-3.40 (m, 8H), 2.65-2.76 (m, 4H), 2.03-2.10 (m, 2H), 1.65-1.69 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O.C1(C)C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16]
Reactant: [H][H]
Reactant: O=C(OCCCCl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OCCCCl)c(N)c1
Yield: 100.4 %

Procedure:
A two liter autoclave was charged with 142 g of (3-chloropropyl)-2,4-dinitrobenzoate, 1275 ml of toluene and 4.5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi hydrogen pressure while maintaining the temperature below 100° C. with cooling. The mixture was cooled and 350 ml of tetrahydrofuran was added to dissolve the solid that had precipitated from the toluene. The resulting solution was filtered to remove the catalyst and the solvents removed at reduced pressure to give 113 g of (3-chloropropyl)-2,4-diaminobenzoate, a white solid, mp 97° C.