Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.C(O)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of ethanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.5 parts of 1,4-diaminoanthraquinone-2-carboxylic acid. Recrystallisation from alcohol yields an analytically pure sample with a melting point of about 352° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[S:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[OH:21][CH2:20][C:18]1[N:19]=[C:15]([C:14]#[C:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:16][CH:17]=1
Reactant: COc1cc(C#Cc2nc(C(=O)O)cs2)cc(OC)c1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C#Cc2nc(CO)cs2)cc(OC)c1OC
Reaction time: 0.25 h

Procedure:
2-(3,4,5-Trimethoxyphenylethynyl)thiazole-4-carboxylic acid (133 mg) was dissolved in THF (8 mL), and to the solution triethylamine (44 mg) was added, and ethyl chloroformate (48 mg) was then added at 0° C. to stir the mixture for 15 minutes. The reaction mixture was filtered, an aqueous solution (2 mL) of sodium borohydride (16 mg) was added to the filtrate, and the resultant mixture was stirred for 30 minutes. Water was added to the reaction mixture, the resultant mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:32][C:31]1[C:23]([F:22])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:33])=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCc1ccccc1
Yield: 38.2 %

Procedure:
A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.39 g, 1.3 mmol), (EP1153920 production examples 28-30), 4-fluoro-5-hydroxy-2-methylindole (0.24 g, 1.43 mmol) and cesium carbonate (1.2 g, 4 mmol) in DMF (4 ml) was stirred at 95° C. for 45 minutes. After cooling, the mixture was filtered and the filtrate was evaporated under vacuum The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (0.213 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: Clc1ccncc1
Agent: Cl
Product: COC(=O)c1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloropyridine hydrochloride (0.22 g, 1.5 mmol) afforded, after purification by ion-exchange chromatography (SCX), 260 mg (73%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.C(Br)(=O)C([Br:23])=O>CN(C=O)C.ClCCCl>[Br:23][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Br)C(=O)Br
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) were placed in a vial (20 ml). To the resulting suspension was added carefully oxalyl bromide (0.53 ml, 1.24 g, 5.75 mmol). A foam was formed during the addition, and as the foam was settling down the stirring was started. DMF (3 drops) was added and the vial was sealed and the mixture was stirred overnight. Another portion of oxalyl bromide (0.2 ml, 0.46 g, 2.23 mmol) and DMF (3 drops) was added and the reaction was run for another 24 h. The mixture was partitioned between is DCM (20 ml) and water (20 ml) and the organic phase was dried. Filtration and evaporation gave a crude product, which was purified on silica, affording 3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one (0.59 g, 93%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1N1CCN(Cc2ccccc2)CC1

Procedure:
3.4 g of methyl 2-chloronicotinate, 5.5 g of potassium carbonate and 3.5 g of N-benzylpiperazine were reacted in 75 ml of DMF analogously to Example 1a, 6.2 g (100%) of the product being obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:24][CH2:25]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1coc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1coc(N2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-furyl)piperazine (4.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.0 g compound (I-43) with a yield of 71.3%. ESI-MS [M+H]+: m/z 325.2.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[CH:7][CH:6]=1>O.O1CCOCC1>[OH:3][NH:2][S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:26]([F:29])([F:28])[F:27])=[N:14]2)=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: NO
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NO)cc2)cc1
Yield: 74 %

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (2.74 g, 40 mmol) in dioxane (25 ml) sodium acetate (3.25 g, 40 mmol) in water (15 ml) was added dropwise at room temperature, followed by dropwise addition of 4-(5-p-methylphenyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonyl chloride (4.11 g, 10 mmol) in dioxane (40 ml). The obtained reaction mixture was poured into water (100 ml), extracted with ethyl acetate (2×50 ml), the organic layers were washed with water (3×50 ml) and brine (1×50 ml), dried over MgSO4, filtered and concentrated in vacuo. The obtained oil was crystallized from 75% aqueous ethanol (75 ml) to yield 2.94 g (75%) of the title compound as white crystals. Mp: 203° C.
Reaction SMILES: Br[C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCO.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>[C:7]([C:6]1[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:3]([C:15]([O:17][CH3:18])=[O:16])[S:4][C:5]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Br
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: COCCOC
Solvent: CCO
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of methyl 3-bromo-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.040 g, 0.12 mmol), p-tolylboronic acid (0.020 g, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.004), 2M aqueous K2CO3 solution (0.120 mL, 0.24 mmol) in 1,2-dimethoxyethane/EtOH (8/2) (2 mL) was subjected to MWI at 110° C. for 10 min. The reaction mixture was concentrated; the residue was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography and triturated with cold MeOH to give methyl 4-cyano-3-(4-methylphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.030 g, 83%). LCMS: (AA) ES+ 343.1. 1H NMR (400 MHz, CDCl3) δ: 7.24-7.27 (m, 4H), 3.87-3.89 (m, 4H), 3.69 (s, 3H), 3.60-3.62 (m, 4H) and 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>>[CH2:1]([N:4]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:5]1)[CH2:2][CH3:3]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CCCNN
Product: CCCn1ncc2c1CCCC2=O

Procedure:
Prepared analogously to Example 1 starting from propylhydrazine and 2-(dimethylaminomethylene)-cyclohexane- 1,3-dione.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:37]1[C:36]([CH3:42])=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from [2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M129) (0.32 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (180 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[NH3:14].[OH-].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:14][CH2:12]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: [NH4+]
Agent: [OH-]
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (0.157 g, 0.510 mmol) was suspended in ammonia (2M solution in MeOH, 0.255 mL, 1.784 mmol). Ammonium hydroxide (0.517 mL, 7.65 mmol) was added and the mixture was stirred at RT overnight. A resulting white solid was collected by vacuum filtration, washed with water, and dried under high vacuum overnight to give the title compound as a white solid (0.066 g, 61%). 1H NMR (500 MHz, CDCl3) δ ppm 4.45 (s, 2 H), 6.35 (br s, 1 H), 7.60-7.68 (m, 2 H), 7.74 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 212.3.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.O.[C:6]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(OCC)(=O)C>[CH:1]1([NH:4][S:20]([C:16]2[CH:15]=[C:14]([S:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5 ml of cyclopropylamine and 10 ml of water was added to a solution of 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to an oil which crystallized from isopropyl ether to give 839 mg of the titled compound as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:38](=[NH:43])(OCC)[CH3:39]>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH:31][C:38](=[NH:43])[CH3:39])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CN
Reactant: CCOC(C)=N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=N)NCC(=O)N(CCc1ccccc1)[C@@H](CCCN)C(=O)NCCCc1ccccc1

Procedure:
Glycyl-Nα-(phenethyl)ornithine 3-phenylpropylamide trifluoroacetate was treated with ethyl acetimidate in ethanol at pH9 and the product was purified by HPLC: 1H NMR (400 MHz, D2O) δ1.6-2.0 (m, 6H), 2.3 (s, 3H), 2.7 (t, J=6.4 Hz, 2H), 2.9-3.1 (m, 4H), 3.2-3.4 (m, 2H), 3.5-3.7 (m, 2H), 4.1-4.3 (m, 2H), 4.7-4.8 (m, 1H), and 7.2-7.5 (m, 10H); mass spectrum, m/e 453 (M+), 354, 300, 247, and 219.
Reaction SMILES: O[CH2:2][CH:3]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:55].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:55][CH2:2][CH:3]([CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: O=c1ccn(CCC(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1ccn(CCC(CBr)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of compound 36 (33 g, 0.073 mol) in dry DMF (200 mL) was added triphenylphosphine (29 g, 0.11 mol) with vigorous stirring at RT. The reaction mixture was cooled to 0° C., added CBr4 (36 g, 0.11 mol) portion wise over a period of 30 min and allowed to stir at RT for 24 h. The reaction mixture was cooled to 0° C., added saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (4×150 mL). The combined organic layer was dried, concentrated under vacuum and the crude product was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to give the title compound (22 g, 57%). TLC: 100% EtOAc, Rf=0.7
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)CSc1ccc(Cl)c(Cl)c1
Reactant: OO
Solvent: CC(=O)O
Product: NS(=O)(=O)CS(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 7 h

Procedure:
To a solution of 0.50 g. (0.0018 mol.) of 1-((3,4-dichlorophenyl)thio)methanesulfonamide in 25 ml. of glacial acetic acid is added 0.10 g. of 30% hydrogen peroxide, and the reaction mixture is heated at 65° to 70° C. The progress of the reaction is followed by nuclear magnetic resonance spectroscopy, and over a period of 7 hours an additional 0.37 g. of 30% hydrogen peroxide is added in small incremental amounts. After the 7 hour reaction period, the acetic acid solution is allowed to cool, and the title compound separates as fluffy, white crystals. The crystals are filtered, washed with ether, and dried to give 0.37 g. of 1-((3,4-dichlorophenyl)sulfinyl)methanesulfonamide, m.p. 205°-207° C.
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(P(=[CH:43][C:44]([O:46][CH3:47])=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:47][O:46][C:44](=[O:45])[CH:43]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCNc1cc(F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCNc1cc(F)ccc1C=CC(=O)OC
Temperature: -35 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
To a solution of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide (0.33 g, 1.37 mmol) in THF (4 mL) was added dropwise LiAlH4 (1 M in THF, 0.7 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. and then quenched by adding saturated aqueous KHSO4 solution. The mixture was diluted with EtOAc, washed with 3 N HCl, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was reacted with methyl (triphenylphosphoranylidene)acetate (0.5 g, 1.5 mmol) in toluene (4 mL) overnight at 100° C. The mixture was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.23 g, 69%) after purification by column chromatography (EtOAc:hexane=1:10).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH2:20])[C@H:7]2[S:6]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH:20][C:42]([C:41]3[C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])=[N:38][O:39][C:40]=3[CH3:45])=[O:43])[C@H:7]2[S:6]1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC1(CCBr)S[C@@H]2C(N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CCBr)S[C@H]12
Reaction time: 33 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g) and triethylamine (3.0 g) in dried methylene chloride (100 ml) was cooled at -25° C. To this solution was added dropwise a solution of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (4.5 g) in dried methylene chloride (30 ml), and the mixture was stirred for 33 hours at the same temperature. After the reaction was completed, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (6.75 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[CH:7]1[N:11]=[CH:10][N:9]([C:12](N2C=NC=C2)=[O:13])[CH:8]=1>O1CCCC1>[N:9]1([C:12]([O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:13])[CH:8]=[CH:7][N:11]=[CH:10]1
Reactant: O[C@@H]1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCOC1)n1ccnc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol, 1.00 equiv) and CDI (2 g, 12.33 mmol, 2.17 equiv) in tetrahydrofuran (50 mL) was stirred overnight under nitrogen at 60° C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 30 mL of DCM and washed with 1×50 mL of H2O. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to yield 0.95 g (92%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3OC)nc2n(CC)c1=O
Yield: 23.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 2-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 990 mg (yield 24%) of Compound 157 as yellow grains.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 458.0 (M+H)+.