Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CN(C)C=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2cc(Cl)ccc12
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2cc(Cl)ccc12)C(=O)OCC
Temperature: 150 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A mixture of 4-amino-7-chloroquinazoline (1.3 g) and diethyl ethoxymethylenepropanedioate (1.72 g) in N,N-dimethylformamide (6 ml) was stirred for 2 hours at 150° C. The resultant mixture was cooled to ambient temperature and poured into ice-water to give crystals, which were separated by filtration, washed with water and recrystallized from ethanol to give a mixture (1.65 g) of diethyl [(7-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl 9-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate. The mixture was subjected to a column chromatography using silica gel (developing solvent: a mixture of benzene and ethyl acetate (10:1)) to give purified crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:12]([C:5]5[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][N:3]([CH2:1][CH3:2])[CH:4]=5)=[O:14])[CH:48]=[CH:47][CH:46]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)c1
Yield: 73.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid (268 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (238 mg, 74%) was obtained as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:7])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of L-cysteine ethyl ester hydrochloride (18.6 g, 0.1 mole) in 200 mL TFA was added triphenylmethanol (52 g, 0.2 mole). The resulting dark brown solution was allowed to stir for 2 h at room temperature under nitrogen. The solvent was removed in vacuo and ethanol (100 mL) added to the residue. A 1 M solution of sodium ethoxide (50 mL) was added to the ethanolic solution and stirred for 90 min. during which time the solution turned cloudy. The mixture was filtered, the filtrated was concentrated in vacuo to give an oily residue. Flash column chromatography using ethyl acetate:hexane (1:3) and ethyl acetate gave the desired product (containing some ethyl acetate which is difficult to remove) which was stored under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].C(Cl)(=O)C([Cl:25])=O.CN(C)C=O.O>C(Cl)Cl>[Cl:25][C:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:17][C:2]=1[Cl:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(Cl)CCCC2=O)c(Cl)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
2-(2-Chloro-4-methanesulfonylbenzoyl)-cyclohexane -1,3-dione [9.8 grams (g.), 30 millimole (mmol)] was dissolved in 100 milliliters (ml) methylene chloride and stirred at room temperature. To this solution was added oxalyl chloride (5.7 g., 45 mmol) followed by dimethylformamide (0.5 ml) in portions small enough to control effervescence. The resulting solution was stirred for 4 hours and then poured into water and extracted with methylene chloride. The organic layer was washed again with water, saturated K2CO3 solution and then dried with MgSO4 and the solvent evaporated to yield 3-chloro-2(2-chloro-4-methanesulfonylbenzoyl) cyclohex-2-enone (7.3 g., 70%) as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.[NH3:14]>C1COCC1>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:14])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexanecarbonyl chloride (17.3 g, 80.6 mmol) and THF (150 mL) is added dropwise at 15° C. to conc. NH3 (400 mL). The reaction mixture is stirred for 15 min, concentrated and the precipitate is filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.CCOCC.O>C(Cl)Cl>[CH3:21][C:2]1([CH3:1])[O:30][CH:3]1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)NCCOc1ccc(OCC2OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}carbamate (0.46 g, 1.6 mmol) in 10 ml of methylene chloride at 5° is added m-chloroperbenzoic acid (0.29 g, 1.7 mmol) in portions over 15 min. The mixture is stirred at 5° for 1 hour, then allowed to warm to RT and stirred for 1.5 hours longer. Ether is added to the reaction mixture and it is poured into water and washed with 10% sodium sulfite, with saturated sodium bicarbonate, with water until neutral and with brine. The organic layer is dried over calcium sulfate, filtered and rotoevaporated and the residue is purified by column chromatography to give ethyl N-{2-[4-(3-methyl-2,3-epoxybutoxy)phenoxy]ethyl}carbamate (compound 27, Table A).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[F:25][C:26]1[CH:27]=[C:28]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:29]=[C:30]([F:34])[C:31]=1[CH2:32]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:32][C:31]3[C:26]([F:25])=[CH:27][C:28]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][C:30]=3[F:34])[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1ccccc1-c1cc(F)c(CO)c(F)c1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 3′,5′-difluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (1.6 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.5 g, 76%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[F:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.O>[F:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([S:20][CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]3)[NH:19][C:15]=2[CH:14]=1
Reactant: Fc1ccc2nc(S)[nH]c2c1
Reactant: O=CN1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Temperature: 92 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (1.20 g, 7.6 mmol), 5-fluoro-2-mercaptobenzimidazole (1.28 g, 7.6 mmol), and diisopropylethylamine (3.93 g, 30.4 mmol) was dissolved in propionitrile (50 mL), and cyanomethyltrimethylphosphonium iodide (7.39 g, 30.4 mmol) was added to the mixture, followed by stirring for one hour at 92° C. under argon. The reaction mixture was allowed to cool and then poured into water (100 mL), followed by extraction with chloroform (100 mL×3) The resultant organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The crude product was crystallized from acetone-ether, to thereby yield 1-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.87 g, yield 80%) as a brown crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12](I)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:13]=[CH2:12]
Reactant: C=CCI
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (5.0 g, 32.9 mmol) in DMF (20 mL) was added allyl iodide (6.62 g, 39.4 mmol) followed by sodium hydride (60% oil dispersion, 0.95 g, 39.4 mmol). After stirring at rt for 5 h, the reaction mixture was quenched with H2O, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 200 mg (0.55 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 109.4 mg (1.1 mmol) of 2-aminothiazole. Yield: 3.3 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([NH:24][C:19]3[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Reactant: O=C(O)c1ccc2c(Br)c[nH]c2c1
Product: O=C(Nc1ccccc1NC(=O)c1ccc2c(Br)c[nH]c2c1)OCC1CCN(c2ccncc2)CC1

Procedure:
Using the procedure described in Example 23, Part C, and purifying with preparative RPHPLC method A, N2-[1-(4-Pyridyl)-piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine(326 mg, 1.0 mmol) and 3-bromoindole-6-carboxylic acid (240 mg, 1.0 mmol) yielded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5])[CH3:2].Cl[CH:21]([O:23]C(Cl)Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:21]=[O:23])[CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A stirred, cooled (ice bath) solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treated with titanium tetrachloride (0.4 mL, 3.26 mmol) followed by ∀,∀-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowed to warm to ambient temperature over 2 days, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography to afford the title compound (0.11 g, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:14]([C@@H:13]2[CH2:17][C@@H:18]([O:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:26][CH:25]=2)=[O:11])=[O:15])[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
343 mg of N,N'-carbonyldiimidazole were added to a solution of 674 mg of trans-1(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline in 14 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 275 mg of 1-(2-hydroxyethyl)piperazine in 1 ml of dry acetonitrile was then added to the mixture, and the mixture was stirred overnight at room temperature. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the concentrate was mixed with an aqueous solution of sodium chloride. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 574 mg of (2S,4R)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-trimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine as an oil. The whole of the compound thus obtained was dissolved in 5.7 ml of methylene chloride, and 170 mg of 4-dimethylaminopyridine and 300 mg of 4-nitrobenzyl chloroformate were added to the solution, whilst ice-cooling. The resulting mixture was stirred at room temperature for 1 hour and then the solvent was removed by distillation under reduced pressure. 15 ml of 1N aqueous hydrochloric acid were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then made slightly alkaline by the addition of an aqueous solution of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. Following the procedure described in step 90(b)(i') above, the residue was purified to give 348 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(i) above.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[CH:32](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[O:13]=[S:10]1(=[O:12])[C:11]2[C:2]3[N:1]=[CH:32][O:31][C:3]=3[CH:4]=[CH:5][C:6]=2[NH:7][C:8]([C:14]2[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]3[C:22]([C:23]=2[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4ocnc34)N2)c(O)c2ccccc21
Yield: 22 %

Procedure:
A solution of Example 354 (0.036 g, 0.081 mmol) in dimethylformamide (2 mL) was treated with trimethyl orthoformate (1 mL) and a catalytic amount of para-toluenesulfonic acid at room temperature for 20 hours. The solvent was removed under a stream of warm nitrogen and the residue was triturated with 1:1 ethyl acetate: tetrahydrofuran, filtered, and dried to yield the title compound (8 mg, 22%). MS (ESI−) m/z 452 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, J=6.62 Hz, 6 H) 1.93 (m, 1 H) 2.78 (m, 2 H) 6.33 (m, 1 H) 7.45 (t, J=7.54 Hz, 1 H) 7.73 (d, J=8.82 Hz, 1 H) 7.92 (t, J=7.72 Hz, 1 H) 8.00 (m, 1 H) 8.21 (m, 2 H) 9.04 (s, 1 H) 14.28 (s, 1 H).
Reaction SMILES: [Ag:1]=O.[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Ag+:1].[Ag+:1].[Ag+:1]
Reactant: O=[Ag]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Ag+]

Procedure:
As one non-limiting example, the trisilver citrate may be prepared for use in the invention using a “sodium hydroxide route” in which aqueous silver nitrate is reacted with aqueous sodium hydroxide to produce silver oxide as a precipitate, and in which the silver oxide precipitate is reacted with aqueous citric acid to produce trisilver citrate as a precipitate.
Reaction SMILES: [CH3:1][Mg]Br.[I-].[CH3:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N+:7]=1[CH3:16]>C1COCC1>[CH3:5][C:6]1([CH3:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[CH3:16]
Reactant: C[Mg]Br
Reactant: CC1=[N+](C)CCc2ccccc21
Agent: [I-]
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (4.5 ml, 3M in Et2O) was added to a stirred suspension of 1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.3 g) in dry THF (20 ml) at −70° C. under argon. After 1 h, the mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was quenched by cautious addition of water and extracted with ethyl acetate. The extract was washed with water, brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a pink oil (730 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34].CO.C(Cl)Cl.N>[Pd].CO.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 52.7 %

Procedure:
A round bottom flask containing tert-butyl 2-hydroxyethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (220 mg, 0.574 mmol) under argon was charged with palladium on activated carbon (10% wt; 61.0 mg, 0.057 mmol). The mixture was purged with argon prior to the addition of EtOH (20 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 3 hours. The hydrogen balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (327 mg, 1.147 mmol) was added to the reaction. The suspension was stirred at room temperature for 17 hours (overnight). After this time, the mixture was filtered through a pad of Celite, which was then rinsed with MeOH (10 mL). The filtrate was concentrated, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH/CH2Cl2 followed by 3.5:96.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (140 mg, 52.7%). 1H-NMR (DMSO-d6) δ 7.69 (brd, J=3.0 Hz, 1H), 7.57 (d, J=−5.1 Hz, 1H), 7.07 (dd, J=3.9, 4.8 Hz, 1H), 6.82-6.75 (m, 1H), 6.53-6.42 (m, 2H), 6.32 (brs, 2H), 4.73 (t, J=5.4 Hz, 1H), 3.54 (brs, 2H), 3.50-3.42 (m, 2H), 3.38 (brs, 4H, overlap with solvent peak), 3.27-3.19 (m, 2H), 3.08-2.96 (m, 2H), 1.41 (brs, 9H); ESI-MS (m/z, %): 463 (MH+, 100), 398 (60); HPLC purity: 96.4% a/a.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4](=[O:17])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=O>N1C=CC=CC=1>[CH3:30][C:29]1[C:24]([C:22]2[N:1]=[C:2]3[NH:6][N:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=4)[C:4](=[O:17])[C:3]3=[CH:20][CH:21]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Reactant: Cc1cccnc1C(=O)C=CN(C)C
Solvent: c1ccncc1
Product: Cc1cccnc1-c1ccc2c(=O)n(-c3ccc(C(F)(F)F)cc3)[nH]c2n1
Yield: 23.4 %

Procedure:
A mixture of the product of Step 1 (1.68 g, 0.0074 mol) and 3-(dimethylamino)-1-(3-methyl-2-pyridinyl)-2-propen-1-one (EP-A-0233461) (1.4 g, 0.0074 mol) in pyridine (20 mL) was heated at reflux for 3 h. The mixture was concentrated and then triturated to give a solid which was recrystallised from iPrOH to give 0.64 g (23% yield) of product as a yellow powder. 1H NMR (360 MHz, DMSO): 2.6 (3H, s), 7.45-7.55 (1H, m), 7.55-7.65 (1H, m), 7.85-7.95 (3H, m), 8.20 (2H, d, J 8.5 Hz), 8.39 (1H, d, J 8.0 Hz), 8.61 (1H, d, J 4.6 Hz).