Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:13])[NH:8][N:9]=[CH:10][C:11]=1[Cl:12].[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1.C(=O)([O-])O.[K+].C(OCC)(=O)C>CC(C)=O.C(N(CC)CC)C>[Cl:12][C:11]1[CH:10]=[N:9][NH:8][C:7](=[O:13])[C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][N:15]([CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:14]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=c1[nH]ncc(Cl)c1NCCCBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C)CCCNc2c(Cl)cn[nH]c2=O)cc1OC
Yield: 59.1 %

Procedure:
A mixture of 10.66 g (0.04 mole) of 4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone (II), 10.0 g (0.05 mole) of N-methyl-homoveratryl amine (VI) and 8 g of potassium hydrogen carbonate is suspended in 80 cm3 of acetone. The reaction mixture is refluxed for 8 to 12 hours. The reaction is followed by TLC (eluent: ethyl acetate: acetone:triethylamine==10:10:0.5 (II Rf=0.76), (VI Rf=0.14), (I Rf=0.47)). The mixture is filtered while hot, washed with acetone and the mother liquor is evaporated in vacuo. To the residue 50 cm3 of ethyl acetate are added. The possibly separated inorganic substance is filtered off and the filtrate is evaporated again. The residual viscous, oily product (14 to 15 g) is triturated twice with 50 cm3 of hot water in order to remove the unreacted starting substance of the formula (VI). The warm aqueous solution is decanted. The oily residue is dissolved in methanol and dried over magnesium sulfate. Upon adding a small amount of diisopropyl ether and cooling the mixture white porous substance separates. Thus 9 g (59.0%) of crude product are obtained. M.p.: 89-90° C. After recrystallization from diisopropyl ether 7.0 g (46.0%) of the title compound are obtained.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[O:23][CH3:24])(C)C)(C)(C)C.[NH2:25][C:26]1[S:27][C:28]([C:38]([NH2:40])=[O:39])=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([C:29]2[N:30]=[C:26]([NH:25][C:17]3[CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([O:23][CH3:24])=[CH:15][C:16]=3[N+:20]([O-:22])=[O:21])[S:27][C:28]=2[C:38]([NH2:40])=[O:39])[CH:36]=[CH:35][CH:34]=1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1OCCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCCO
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A mixture of 0.469 g (1.31 mmole) of tert-butyl-[3-(5-fluoro-2-methoxy-4-nitro-phenoxy)-propoxy]-dimethyl-silane (IV.42), 0.331 g (1.31 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 1.28 g (3.93 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 70 degrees for 3 hours. The mixture was cooled and 3 mL of 6M hydrochloric acid was added dropwise. Stirring was continued for 15 minutes. The mixture was poured into 50 mL of water, and the precipitated orange solid was collected by filtration, washed with water, and air-dried to give 0.535 g of 4-(3-chloro-phenyl)-2-[5-(3-hydroxy-propoxy)-4-methoxy-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.42).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.Cl[C:10]1[CH:18]=[C:17]2[C:13]([C:14](=[O:20])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.S(O)(C(F)(F)F)(=O)=O>>[I:1][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:10]=1)[NH:16][C:15](=[O:19])[C:14]2=[O:20]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1Nc2ccc(I)cc2C1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.6 %

Procedure:
N-Iodosuccinimide (8.68 g, 38.6 mmol) was added to a stirred mixture of 6-chloro-isatin (6.98 g, 38.6 mmol) and TfOH (120 g) at 0° C. under N2. Ice-bath was removed and stirring at room temperature was continued for 19 h. The mixture was poured to ice-water. The precipitate was collected by filtration, washed with water (until pH˜7), and dried to give 6-chloro, 5-iodo-isatine (10.5 g) as a 95% pure (1H NMR, 400 MHz), orange solid: 1H NMR (DMSO-d6) 7.10 (s, 1 H), 7.96 (s, 1 H), 11.21 (s, 1 H); ms 305.9 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].B.O1CCCC1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][OH:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)O)ccc32)cc1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(CO)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of 4-(5-carboxy-3-cyanoindol-1yl)benzoic acid ethyl ester (0.057 g) in tetrahydrofuran (2 mL) was added borane-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution 0.2 mL) at 0° C. and this mixture was stirred at room temperature for 2 hours. To this reaction mixture was added a saturated aqueous sodium bicarbonate solution, this mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give the title compound (0.032 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7])[CH3:2].CC(O[Na])=O.O.[Cl-].[C:19]1([N+:25]#[N:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4](=[O:9])[C:5](=[N:26][NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6](=[O:8])[CH3:7])[CH3:11]
Reactant: N#[N+]c1ccccc1
Reactant: CCN(CC)C(=O)CC(C)=O
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Temperature: 10 °C

Procedure:
15.7 g (0.1 mol) of N,N-diethyl-3-oxobutyramide were mixed with 12 g (0.14 mol) of CH3COONa, 20 ml of water and 75 ml of ethanol. The solution obtained was cooled to 10° C. and 0.1 mol of freshly prepared solution of phenyldiazonium chloride [Organic Reactions, R. Adams Ed; Wiley, New York, 10, 32-33, (1951-1959)] were added dropwise. The precipitated solid was filtered, dried in vacuo yielding 22.6 g of the title compound. M.p.=63°-65° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]([CH3:34])[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])=[O:14])(C)(C)C.[CH2:35]([C:38]([O-:40])=[O:39])[CH2:36][CH3:37]>ClC(Cl)C>[C:13]([CH2:15][N:16]([CH3:34])[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])([OH:14])=[O:12].[CH2:35]([C:38]([O-:40])=[O:39])[CH2:36][CH3:37]
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCCC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Trifluoroacetic acid (1 mL) is added slowly to a solution of 95 mg (0.2 mmol) of 8-(tert-butoxycarbonylmethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate dissolved in 9 mL of dichloroethane. The solution is stirred at room temperature for 5 hours then the solvents are evaporated. The residue is taken up and triturated in acetonitrile then in diisopropyl ether to give 76 mg (90%) of 8-(carboxymethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].[OH-].[K+]>CO.O.C1COCC1>[C:13]([NH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])(=[O:16])[CH:14]=[CH2:15]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 56 %

Procedure:
1-Amino-1-deoxy-D-sorbitol (D-glucamine) 10 (5.0 g, 28 mmol) was dissolved in a mixture of CH3OH (120 mL) and H2O (15 mL) and cooled in an ice bath. Acryloyl chloride (30 mL of a 2.35 M solution in THF, 71 mmol) was added dropwise to. the above solution, while the pH of the reaction mixture was maintained between 8 and 9 by periodic addition of 2M aqueous KOH. After an additional 1-h period on ice, the volatiles were evaporated under reduced pressure and the residue was subjected to silica gel chromatography with a gradient of 5-15% CH2Cl2 in MeOH to give 3.6 g (56%) compound 3 as a white solid; mp 122-123° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3]OC1C=CC(C(OC)=O)=CC=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:26]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:3][CH2:2][CH2:1][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNCCCC
Reactant: COC(=O)c1ccc(OCCCOc2ccc(C(=O)OC)cc2)cc1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)OC)cc1
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A solution of the mixture of methyl 4-(3-bromopropoxy)benzoate [17a] methyl 4,4′-[1,3-propanediylbis(oxy)]bisbenzoate [20] previous step (19.12 g) and dibutylamine (27.14 g, 35.7 mL, 210 mmol) in toluene (50.0 mL) was stirred under reflux conditions for 3 hours, cooled and extracted with 15% hydrochloric acid (3×40 mL). The combined aqueous layers were washed with of toluene (50 mL), basified to pH 8.5 with sodium bicarbonate and extracted with toluene (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure at 60° C. (water bath). The residue was dissolved in hexane and passed through thin layer of silica gel. The solvent was evaporated under reduced pressure at 50-60° C. (water bath) to give 14.71 g (61.1% yield from 2 steps) of methyl 4-(3-dibutylaminopropoxy)benzoate [18a] as an oil.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:18]=[C:17]([NH:19]C(OC(C)(C)C)=O)[S:16][N:15]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:18]=[C:17]([NH2:19])[S:16][N:15]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1nsc(N)n1)C(=O)O
Yield: 52.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (114 mg, 0.173 mmol), DCM (1.7 mL) and TFA (800 μl, 10.4 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (46 mg, 46%) as a white powder. LCMS: Rt=0.42 min, m/z=504.0 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J=8.6 Hz, 1H), 8.65 (s, 1H), 8.21 (br s, 2H), 8.10 (s, 1H), 5.22 (dd, J=8.6, 5.5 Hz, 1H), 4.67-4.58 (m, 1H), 4.56-4.47 (m, 1H), 4.28 (q, J=5.5 Hz, 1H), 1.39 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13](=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]([N:36]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:37]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:38]=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:47]([N:36]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@@H:37]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:38]([CH:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[O:18])[OH:39])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: O=CC(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
Treat a solution of 4-benzyloxycarbonyl-1-methylpiperazin-2-one (1.4 g, 5.7 mmol) in THF (4 mL) cooled at −78° C. with lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 5.7 mL, 5.7 mmol) dropwise and stir 30 min. Add 2-(dibenzylamino)-3-phenylpropanal (1 g, 3.1 mmol) in THF (2 mL) and stir at −78° C. for 45 min. Quench with saturated aqueous ammonium chloride solution. Separate organic layer and wash with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate) to provide the title compound as a mixture of four diastereoisomers which are separated by HPLC (normal phase, eluting with 85:15 hexanes:isopropanol) (828 mg, 45% total yield).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
Trimethylaluminium (5.75 mL, 11.50 mmol) was added to 5-chloropyridin-2-amine (1.285 g, 10.00 mmol) in toluene (50 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes, (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (2.894 g, 10.00 mmol) in toluene (20 mL) was added, the reaction allowed to warm to room temperature and then heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated in vacuo and the residue neutralised with 1M citric acid (30 mL), diluted with water (25 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford crude product which was purified by flash silica chromatography with EtOAc as eluent to afford the product (2.5 g, 65%). 1H NMR (400 MHz, DMSO) δ 0.01 (6H, s), 0.84 (9H, m), 2.65-2.70 (2H, m), 2.76-2.83 (2H, m), 3.56-3.59 (2H, m), 4.07-4.10 (1, m), 4.28-4.34 (1H, m), 5.78 (1H, s), 7.92 (1H, dd), 8.12 (1H, dd), 8.36-8.37 (1H, m), 9.87 (1H, s); m/z (ESI+) (M+H)+=386; HPLC tR=1.64 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[K+].[Cl-].[NH4+]>C(O)C.CO.O>[N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][C:9]=1[NH2:15])([O-:3])=[O:2]
Reactant: NO
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1c([N+](=O)[O-])ccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-dinitrotoluene (28 g, 0.15 mol) and hydroxylamine hydrochloride (28 g, 0.15 mol) was stirred in ethanol (700 mL) until completely dissolved. 2N potassium hydroxide solution in methanol (275 mL) was added all at once and the resulting mixture allowed to stir overnight at room temperature. After this time a solution of ammonium chloride (36 g) in water (175 mL) was added and the mixture stirred for an additional hour. The reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (300 mL) and saturated brine (250 mL). The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography of the residue (ethyl acetate/hexane (2:1)) afforded the desired product. 1H NMR (400 MHz) (CDCl3) δ 7.98 (d, J=9.4 Hz, 1H); 6.73 (d, J=9.4 Hz, 1H); 5.50 (bs, 2H); 2.59 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)[CH:8]=[CH:7][C:6]=1[CH3:35])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:35][C:6]1[CH:7]=[CH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:10][C:5]=1[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)c1cc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(=O)O
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid ethyl ester (3.31 g, 6.41 mmol), potassium carbonate (1.77 g, 12.82 mmol), methanol (25 mL) and water (6 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 2.95 g (94%) (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([CH3:12])[CH3:11])[C:6]([O:13][CH3:14])=[CH:5][N:4]=1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>O.C(O)(C)C>[CH:10]([O:9][C:7]1[C:6]([O:13][CH3:14])=[CH:5][N:4]=[C:3]([C:2]([OH:16])=[O:1])[CH:8]=1)([CH3:11])[CH3:12]
Reactant: COc1cnc(CO)cc1OC(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC(C)C
Temperature: 70 °C
Yield: 94.2 %

Procedure:
To a stirred and heated (50° C.) solution of the product of step 1 (0.410 g, 2.08 mmol) in water (12 mL) was added, portionwise over 30 minutes, solid potassium permanganate (0.680 g, 4.30 mmol). Following the addition, reaction temperature was increased to 70° C. After 45 minutes the reaction was cooled to room temperature and treated with a solution of potassium hydroxide (0.230 g, 4.10 mmol) in water (6 mL) followed by a few drops of isopropanol. The mixture was stirred for about 5 minutes before filtering through Celite. The filtrate was concentrated to dryness under a nitrogen current. The resulting brown residue was dissolved in water (10 mL), adjusted to pH 2 with concentrated hydrochloric acid and extracted repeatedly with chloroform. The combined extracts were dried (sodium sulfate) and concentrated to afford 0.414 g (94%) of product as a pink-gray foam: 1H NMR (DMSO-d6) δ 8.23 (s, 1H), 7.5 8 (s, 1H), 4.81 (sept, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.29 (d, J=6.0 Hz, 6H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([O:24]CC)=[O:23])=[N:16]1)=[O:8].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([OH:24])=[O:23])=[N:16]1)=[O:8]
Reactant: CCOC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reaction time: 0.33 h

Procedure:
To a solution of 3.0 g. of ethyl 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate in 40 ml. of ethanol is added 9 ml. of 1N-sodium hydroxide solution with stirring at room temperature. After strirring for 20 minutes, the solvent is evaporated by distillation, and neutralized with 9 ml. of 1N-hydrochloric acid. The precipitated crystals are collected by filtration, washed successively with water, ethanol and ether and then dried to give 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as crystals. Recrystallization from ethanol gives colorless prisms, melting at 204° to 206° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:3]=NC(Cl)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.NN.C1N=C[N:27]([C:30]([N:32]2[CH:36]=[N:35]C=C2)=[O:31])C=1.C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[C:36]2[N:32]([C:30](=[O:31])[NH:27][N:35]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccncc2)cc1
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (0.69 g, 2.1 mmol) in ethanol (10 ml) was added hydrazine monohydrate (1.2 ml, 24.7 mmol). The reaction was stirred at 80° C. for 1 h. After this time, the reaction mixture was concentrated under reduced pressure. The crude product was then suspended in THF and CDI (1.36 g, 8.4 mmol) was added. The reaction turned to brownish clear solution, then to a suspension again. After stirring for 20 min, ethyl acetate was added. The resulting solution was washed with water and saturated NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 5%-10% methanol-dichloromethane to give 6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a brown sold (0.52 g) and 6-chloro-8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as light brown solid (0.27 g).
Reaction SMILES: [NH2:1][C@@:2]1([N:28]2[CH2:36][C:34](C(OC)C3C=CC=CC=3)([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH:7](C(OC)C2C=CC=CC=2)[OH:8])[C@@:4](C(OC)C2C=CC=CC=2)([OH:5])[CH2:3]1>[Pd].C(O)C>[NH2:1][C@@:2]1([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[O:18][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: COC(c1ccccc1)C(O)[C@H]1O[C@@](N)(N2CC(C)(C(OC)c3ccccc3)C(=O)NC2=O)C[C@@]1(O)C(OC)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn([C@@]2(N)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 24 h

Procedure:
A suspension of 1′-amino-3′,5′,5-tris(methoxybenzyl)thymidine and 10% palladium on charcoal in ethanol is shaken in a hydrogenation apparatus under hydrogen pressure of 50 psi for 24 h. The solid is filtered and the filtrate concentrated. The crude is purified by recrystallization.