Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([O:22][CH2:23][CH3:24])[CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:23]([O:22][C:8]1[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(OCC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc(CO)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 79.7 %

Procedure:
To the above synthesized 2-ethoxy-4′-trifluoromethyl-biphenyl-4-carboxylic acid ethyl ester (0.515 g, 1.52 mmol), dissolved in 6 ml of abs. THF, was added drop wise at −10° C. DIBAL-H solution in toluene (3.81 ml 1M, 2.5 eq.). After additional 60 Min. at ambient temperature, the reaction mixture was carefully poured onto crashed ice/dil. HCl-solution, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 0.359 g of the title alcohol was isolated as white solid, sufficiently pure for the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CO>ClCCl>[CH3:14][N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=1)[CH2:6][C:2]1[N:3]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:4]=[CH:5][N:1]=1
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
The compound (281 mg) obtained in Example 84-5 was dissolved in dichloromethane (6.0 ml) and added with diisopropylethylamine (310 μl) at room temperature under a nitrogen atmosphere. The solution was added with tritylchloride (310 mg) under ice-cooling and the whole was stirred at room temperature for 4 hours. After completion of the reaction, methanol was added thereto. The solvent was distilled off under reduced pressure and the residue was diluted with chloroform and added with water. The aqueous layer was subjected to extraction with chloroform. The combined organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and evaporated to dryness under reduced pressure and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (217 mg) as a yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1OCCN1CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCN2CCOC2=O)cc1

Procedure:
Pd/C 10% (500 mg) is added to a solution of the compound obtained in Step B (16.6 mmoles) in MeOH (100 ml). The reaction mixture is stirred at 50° C. under 4.5 bars of hydrogen for 4 hours. The catalyst is filtered off and then washed with MeOH. The filtrate is evaporated to dryness and the product obtained is triturated in 10 ml of MeOH. The solid obtained is filtered off and dried in vacuo at 40° C. overnight to yield the title product in the form of a white solid, which is used directly in the next Step.
Reaction SMILES: Cl.[CH3:2][C:3]([NH:6][NH2:7])([CH3:5])[CH3:4].CO[CH:10](OC)[CH2:11][CH:12](OC)OC.Cl>C(O)C.CO>[CH3:2][C:3]([N:6]1[CH:12]=[CH:11][CH:10]=[N:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)(C)NN
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)n1cccn1
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of (1,1-dimethylethyl)hydrazine hydrochloride (1.02 g, 8.19 mmol) (Aldrich), 1,1,3,3-tetrakis(methyloxy)propane (1.344 g, 8.19 mmol) (Aldrich) and hydrochloric acid (0.672 ml, 8.19 mmol) in ethanol (10 ml) was heated under reflux. A solution formed. After 16 h the reaction had gone to completion and so was concentrated in vacuo to yield the crude product. This was dissolved in methanol and passed through an aminopropyl cartridge (20 g), eluting with methanol. The combined filtrates were concentrated in vacuo to yield the title compound as a cream gum (210 mg)
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([OH:21])=[N:8][C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][C:11]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[N:8]=[C:7]([OH:21])[C:6]3[N:5]=[C:1]([SH:2])[O:12][C:11]=3[N:10]=2)=[CH:15][CH:16]=1
Reactant: Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1nc(Cc2ccc(Cl)cc2)nc2oc(S)nc12
Temperature: 5 °C
Reaction time: 2 h

Procedure:
3 ml of thiophosgene were added slowly to a suspension of 9.65 g of 5-amino-2-(4-chloro-benzyl)-pyrimidine-4,6-diol and 5.3 g of potassium carbonate in 75 ml of N-methyl-pyrrolidin-2-one (NMP) while maintaining the temperature below 10° C. The reaction mixture was stirred for 2 h at 0-10° C. Then 300 ml of water were added and the resulting solution was extracted three times with 200 ml of dichloromethane and three times with 200 ml of a mixture of dichloromethane and isopropanol (3:1). The combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield approximately 7 g of 5-(4-chloro-benzyl)-2-mercapto-oxazolo[5,4-d]pyrimidin-7-ol as a solution in NMP. 45 ml of NMP and a solution of 2.38 g of sodium hydroxide in 64 ml of water were added at 0° C., and the mixture was stirred for 30 min at 0° C. while the color changed to brown. Then a solution of 1.5 ml of iodomethane in 1.5 ml of NMP was added dropwise. After stirring at 0° C. for 90 min the reaction was complete. The solution was extracted twice with 80 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield 2.2 g of the title compound as a brown solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: Fc1ccc(C(=CCCCc2ccccc2)c2c[nH]cn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Fc1ccc(C(CCCCc2ccccc2)c2c[nH]cn2)cc1
Yield: 82 %

Procedure:
4-[1-(4-fluorophenyl)-5-phenyl-1-pentenyl]-1H-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount 10% Pd/C is added. The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloride-methanol mixture. Yield 82%.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].Cl[C:5]1[N:10]=[CH:9][NH:8][C:7]2=[N:11][CH:12]=[CH:13][C:6]=12.[Cl-].[NH4+].[CH2:16]1COCC1>>[CH3:16][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C1CCOC1
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Product: Cc1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A 3.00 M solution of magnesium chloride in THF (13.0 mL, 39.0 mmol) was added dropwise to a stirred solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.50 g, 16.3 mmol) and ferric acetylacetonate (700. mg 1.98 mmol) in THF (30.0 mL) under an atmosphere of argon. The resulting reaction mixture was stirred at rt for 8 h. The mixture was poured onto a mixture of ice (100 mL) and ammonium chloride (1.00 g) and the mixture was extracted with chloroform. Volatiles were removed in vacuo, and C-18 column chromatography eluting with a gradient of 0 to 60% AcCN in water with 0.1% AA afforded the title compound (1.50 g, 69%). LC/MS: Rt=0.94 min, ES+ 134 (AA standard).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>[OH-].[Na+].O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(O)CO)cc1C
Temperature: 140 °C
Yield: 57.4 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (2.00 g, 12.2 mmol, 1.0 equiv) and 3-chloropropane-1,2-diol (1.02 mL, 12.2 mmol, 1.0 equiv) in 50% aqueous NaOH solution (20.0 mL) was heated at 140° C. for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2,3-dihydroxypropoxy)-2,6-dimethylphenyl)ethanone (1.66 g, 7.0 mmol) as yellow oil in 57% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2H), 4.10-4.11 (m, 1H), 4.08-4.09 (m, 2H), 4.01-4.02 (m, 1H), 3.74-3.75 (m, 1H), 2.58-2.59 (brs, 1H), 2.45 (s, 3H), 2.23 (s, 6H), 2.05-2.10 (brs, 1H); ESI-MS: m/z 239.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([NH:26][NH:27][C:28]([NH:30][CH3:31])=O)=O)[CH2:7]1)(=[O:4])=[O:3].O.N.[S:34](=O)(=O)(O)O>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]2[S:34][C:28]([NH:30][CH3:31])=[N:27][N:26]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CNC(=O)NNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: O
Product: CNc1nnc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of (2S,4R)-4-methanesulfonyloxy-2-(4-methylsemicarbazidocarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g) in concentrated sulfuric acid (20 ml) was stirred at 0°-5° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml), adjusted to pH 9 with concentrated ammonia water, extracted with dichloromethane (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99,V/V) to give (2S,4R)-4-methanesulfonyloxy-2-{5-(methylamino)-1,3,4-thiadiazol-2-yl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH2:29]([NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C(=O)O)C(=O)NCc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=455.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-benzyl-malonamic acid.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[C:18]([O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[C:18]([O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:2][C:3]2[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=2)=[CH:27][C:28]=1[Cl:29])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
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: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(Cc2cc(F)c(C(=O)NS(C)(=O)=O)cc2F)cc1Cl
Yield: 23.1 %

Procedure:
4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 245, 70 mg, 0.21 mmol), 2-tert-butoxy-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 118, 72.9 mg, 0.234 mmol), tetrakistriphenylphosphinepalladium (24.3 mg, 0.021 mmol), aqueous potassium carbonate solution (1.8 M, 0.35 mL, 0.639 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 5 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (3×20 mL), dried over sodium sulphate, filtered and evaporated to give an oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (21 mg, 23%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][O:11][C:8]3[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)[CH2:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(C2=CCN(CCCl)CC2)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
0.3 g. of p-acetamidophenol are dissolved in a solution of 0.12 g. of sodium in 10 ml. of absolute ethanol and 0.55 g. of 1-(2-chloroethyl)-4 -(p-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride are added thereto all at once. The reaction mixture is heated under reflux conditions for 24 hours, filtered from the precipitated sodium chloride and the filtrate evaporated to dryness. The residue is absorbed on silica gel and eluted with methylene chloride-ether (1:1). The 4'-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethoxy}-acetanilide obtained from the eluate melts at 139°C. after recrystallization from acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])([CH3:4])([CH3:3])[CH3:2].C(OC(NCCCCCCCCCCC[O:49][S:50]([CH3:53])(=O)=[O:51])=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][S:50]([CH3:53])(=[O:51])=[O:49])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCOCCOCCOCCO
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCOS(C)(=O)=O
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCOCCOCCOCCOS(C)(=O)=O

Procedure:
Compound 16 was prepared from compound 4 using methods analogous to the preparation of compound 3 (Example 1, step C). 1H NMR (DMSO-d6) δ 6.95 (t, 1H, J=5.5 Hz), 4.50 (m, 2H), 3.86 (m, 2H), 3.75–3.62 (m, 8H), 3.57 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 3.07 (q, 2H, J=6.0 Hz), 1.70–1.58 (m, 27H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[F:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]([NH:1][CH2:2][C:3]3[NH:4][C:5](=[O:13])[C:6]4[CH2:12][O:11][CH2:10][CH2:9][C:7]=4[N:8]=3)=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:31][CH:32]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a solution of 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.7 g, 9.6 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (2.7 g, 10 mmol) in dichloromethane (50 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g, 11 mmol), 1-hydroxybenzotriazole (1.5 g, 9.6 mmol) and triethylamine (4.0 mL, 29 mmol). The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was washed with ammonium chloride solution, concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol:dichloromethane, 1:99 to 10:90) to provide the title compound (2.2 g, 54% yield). 1H NMR (400 MHz, CDC3) δ 11.12 (s, 1H), 8.07 (s, 1H), 7.99 (dd, J=9.0, 5.5 Hz, 2H), 7.18 (t, J=8.5 Hz, 2H), 4.58 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.22-3.35 (m, 1H), 3.10-3.22 (m, 2H), 2.94-3.07 (m, 2H), 2.66-2.75 (m, 2H), 2.31-2.48 (m, 2H), 1.80-1.99 (m, 4H). HRMS calculated for C22H23N4O4 429.1938. found (ESI, [M+H]+), 429.1925. MS m/z 429.3 (M+1), retention time=1.28 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][CH3:13])[C:4]=2[O:3]1.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]([CH3:13])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)[C:4]=2[O:3]1
Reactant: CNCc1cccc2c1OC(C)(C)C2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1cccc2c1OC(C)(C)C2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 72.8 %

Procedure:
According to the procedure of Example 35g, (2,2-dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (284 mg, 1.48 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (382 mg, 1.50 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (422 mg, 73%) as an orange solid and a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.65-10.64 (m, 1H), 8.35-8.34 (m, 1H), 8.06-8.01 (m, 1H), 7.51-7.44 (m, 1H), 7.37-7.07 (m, 2H), 6.92-6.89 (m, 1H), 6.81-6.73 (m, 1H), 4.65-4.49 (m, 2H), 3.11-2.87 (m, 7H), 2.55-2.53 (m, 2H), 1.42-1.39 (m, 6H); ESI MS m/e 392 [C23H25N3O3+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:12][C:11]1[C:2]([NH:25][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:24])=[O:23])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 150 °C

Procedure:
2,3-Dichloroquinoxaline (26.1 g, 131.1 mmol), m-Nitrobenzene sulfonamide (26.5 g, 131.1 mmol) and potassium carbonate (18.1 g, 131.1) were dissolved in anhydrous DMSO (500 mL). The reaction was heated to 150° C. for 2 h. The reaction mixture was poured into water (400 mL), followed by addition of 2M HCl (60 mL). The product was extracted with EtOAc (3×500 mL). The organic layers were combined and washed water (2×500 mL) and brine (2×500 mL). The product was then dried with sodium sulfate to give N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. MS (EI) for C14H9ClN4O4S: 364.94, 366.97 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.C[CH2:18][N:19]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]([NH:19][CH3:18])=[O:16])[CH:5]=1)([O-:11])=[O:10]
Reactant: COc1ccc([N+](=O)[O-])cc1/C=C/C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1cc([N+](=O)[O-])ccc1OC
Reaction time: 18 h
Yield: 70.9 %

Procedure:
(E)-3-(2-Methoxy-5-nitro-phenyl)-acrylic acid (Egypt. J. Pharm. Sci., (1996), 37, 71-84), (1.0 g) in dimethylformamide (5 ml) was treated with EDC.HCl (0.86 g), N-hydroxybenzotriazole (0.1 g) and methylamine (2M in tetrahydrofuran 3 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane, washed with 2N HCl, sodium hydrogen carbonate and brine. After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.75 g). 1H NMR δ: 2.71 (3H, d, J=4.7Hz), 4.01 (3H, s), 6.71 (1H, d, J=15.9 Hz), 7.30 (1H, d, J=9.2 Hz), 7.62 (1H, d, J=15.9 Hz), 8.09 (1H, m), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.36 (1H, d, J=2.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6](/[CH:7]=[N:8]/[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[H][H]>[Pd].CC(=O)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: COc1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNNC(=O)OC(C)(C)C)cc1
Yield: 104.3 %

Procedure:
Add 10% palladium on carbon (water wet, 20 g) slurried in EA (100 mL) to a sealed pressure reactor via vacuum transfer. Rinse transfer line with a minimal amount of EA. Charge (E)-tert-butyl 2-(4-methoxybenzylidene)hydrazinecarboxylate (320 g, 1.28 mol) dissolved in tetrahydrofuran (THF, 1000 mL) via vacuum transfer and rinse line with a minimal amount of THF. Pressurize the reactor to 50 PSI with H2 and mix the contents of the reactor at 20±10° C. Continue the reaction, maintaining the hydrogen pressure at 50 PSI, until no further hydrogen uptake is observed. Filter the reaction solution to remove the catalyst and wash the catalyst filter-cake with THF (500 mL). Add the wash to the reaction filtrate. Concentrate the solution in vacuo to obtain the title compound (337 g, 86%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.1-8.3 (s, 1H), 7.1-7.3 (d, 2H), 6.8-6.9 (d, 2H), 4.4-4.6 (bs, 1H), 3.7-3.8 (s, 2H), 3.6-3.7 (s, 3H), 1.3-1.5 (s, 9H).