Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([O:32][CH3:33])[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:34][CH3:35])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][N:29]=1)[C:24]([NH:23][C:20]1[S:21][C:22]2[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=[C:17]([O:34][CH3:35])[C:18]=2[N:19]=1)=[O:25]
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c3s2)ccn1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCNCC4)c3s2)ccn1
Yield: 94.1 %

Procedure:
0.10 g (0.20 mMol) 4-{4-methoxy-2-[(2-methoxy-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 2 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 3 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 0.075 g (86%) 2-methoxy-N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-isonicotinamide 1:2 hydrochloride as a yellow solid. F.p.: 305-310° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:12][OH:13].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:9]([O:8][CH3:7])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: COc1cc(COCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred suspension of finely powdered cesium carbonate (8.0 g, 24.5 mmol) was added 3-methoxy-4-nitrobenzyl alcohol (1.5 g, 8.18 mmol), followed by benzyl bromide, (2 mL, 16.4 mmol). After stirring at room temperature for 18 h, the suspension diluted with 100 mL diethyl ether, and washed with 3×50 mL water, then 50 mL brine. The organic phase was dried over MgSO4, filtered through a plug of silica, and concentrated. The resulting orange oil was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to give 1.87 g, (84%) of the benzyl ether. 1H NMR (400 MHz, CDCl3): δ7.85 (d, J=8.2 Hz, 1H) 7.3-7.4 (m, 5H), 7.26 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 4.59(s, 2H), 3.96 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1.COCCOC>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2cccc(C(F)(F)F)c2)c(C)cc2cc(OC)ccc12
Yield: 99 %

Procedure:
2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.5 g, 1.61 mmol), 3-trifluoromethylbenzeneboronic acid (0.61 g, 3.21 mmol), tetrakis(triphenylphosphino)palladium (0) (0.186 g, 0.161 mmol), 2 M sodium carbonate (15 mL) and ethylene glycol dimethyl ether (15 mL) were added in a sealed tube and reacted as described above to give 0.60 g (99%) of the title compound (208) as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 2.21 (s, 3H), 3.01 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H), 7.09 (m, 1H), 7.12-7.15 (dd, J1=2.5 Hz, J2=9.1 Hz, 1H), 7.45 (s, 1H), 7.55-7.65 (m, 4H), 7.98 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([Si](C)(C)C)#[CH:2].Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1>C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)#[CH:2]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
In a 1 Liter, round-bottom, three neck flask, a solution of 50 mL (0.51 Mol) ethynyltrimethylsilane, 1.5 g of palladium[II]acetate, 2.0 g of copper[I] iodide, 3.0 g of triphenylphosphine and 58 mL (0.52 Mol) of 4-bromofluorobenzene in 500 mL of de-aerated triethylamine were heated to 80° C. with stirring under an argon blanket for 2 hr. A white precipitate started to form after approximately 30 min. The reaction mixture was then cooled to 50° C. and stirred for an additional 2 h and then allowed to cool to room temperature with stirring overnight. The orange reaction mixture was filtered and a white precipitate of triethylamine hydrobromide was removed. The filtrate was concentrated by removal of the solvent. The residue was dissolved in 200 mL of dichloromethane and the resulting solution washed with water (3×150 mL), 5% HCl (3×150 mL), saturated sodium bicarbonate solution (3×150 mL), brine and then dried over sodium sulfate. After removal of the solvent, a clear oil was obtained 42.3 g (93%). The clear oil was further purified by dissolving the oil in 200 mL of methanol, to which 2 g of potassium carbonate was added with stirring. The stirring was continued overnight at ambient temperature. Upon distillation, 22.8 g, (0.19 Mol, 82%) of 1-ethynyl-4-fluorobenzene was obtained as a clear colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([OH:36])=O)[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[S:50][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:52][CH:53]=1>>[C:60]([C:57]1[CH:56]=[CH:55][C:54]([C:51]2[S:50][C:49]([CH2:48][C@H:47]([NH:62][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:8][CH:9]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH3:27])=[O:36])[C:46]([OH:63])=[O:45])=[CH:53][CH:52]=2)=[CH:59][CH:58]=1)#[N:61]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)s1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)s1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) was coupled with (S)-2-amino-3-[5-(4-cyano-phenyl)-thiophen-2-yl]-propionic acid methyl ester hydrochloride according to General Procedure L. The resulting ester (25 mg) was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 861.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:35][C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cn1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-methoxypyridin-3-yl)terephthalamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[CH2:13]=O.[OH-].[Na+]>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH3:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C2CCCN2)cn1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Cc1ccc(C2CCCN2C)cn1
Yield: 92 %

Procedure:
Into a round bottom flask was placed XVI (2.0 g), and formaldehyde (37% w/v in water, 20 mL) and formic acid (95-97% w/v, 45 mL), both a 0° C., were added. The mixture then was refluxed under nitrogen for 8 hr. The cooled reaction mixture was basified with aqueous sodium hydroxide (50% w/v) to pH 8-9, and the solution extracted with chloroform (5×25 mL). The combined organic liquors were dried over anhydrous sodium sulfate, filtered and evaporated; and the resulting oil distilled under reduced pressure to afford XVII as a clear odorless oil (b.p. 107° C. at 3 mm Hg, 92% yield).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 4.56 g 2,3,5-trichloropyridine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 8 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 7.45 g of the resultant residue was subjected to silica gel column chromatography, to obtain 7.08 g of diethyl (3,5-dichloro-2-pyridyl)malonate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)[CH:3]=1)(=[O:6])[NH2:7]
Reactant: Cc1ccc(C(N)=O)cc1Br
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2cc(NC(=O)c3ccsc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
3-bromo-4-methylbenzamide (22.7 mg, 0.106 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (62.5 mg, 0.165 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.1 mg), and K2CO3 (2 M in water, 0.24 ml, 0.48 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 10 minutes and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), extracted with dichloromethane (3×10 ml), diluted with 1,4-dioxane (10 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (3.2 mg, 8%). MS (ESI pos. ion) m/z: 387 (M+H). Calc'd Exact Mass for C23H18N2O2S: 386.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].NCCC[C:22]1(C)[NH:26]C(=O)NC1=O.CSC(=N)[NH2:33]>[OH-].[Ba+2].[OH-]>[NH2:33][N:26]=[CH:22][NH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16]
Reactant: CC1(CCCN)NC(=O)NC1=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Product: CC1(CCCNC=NN)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
The compound 5-(3-aminopropyl)-5-methyl-2,4-imidazolidinedione hemisulfate (229 mg, 1 mmol) was dissolved in 0.418 N aqueous barium hydroxide (3.5 ml.) and S-methylisothiourea (153.1 mg, 1.1 mol) was added. The suspension was shaken at room temperature for 6 1/4 hours and 0.418 N aqueous barium hydroxide (1 ml.) was added, followed by another 0.5 ml. of the aforementioned barium hydroxide solution 18 hours later. After 4 hours, S-methylisothiourea (70 mg., 0.5 mmol) was added and shaking of the suspension was continued for 66 hours. At that time only traces of 5-(3-aminopropyl)-5-methyl-2,4-imidazolidinedione hemisulfate could be detected. Barium sulfate was filtered off and washed with water, filtrate and washings were applied to a column containing 5 ml. of sulfonated polystyrene ion exchange resin, the column was washed consecutively with water (50 ml.) 10% by volume aqueous pyridine (25 ml.) and 2.5 M aqueous ammonium hydroxide solution (25 ml). Concentration of the ammoniacal effluent gave a colorless syrup from which crystalline 5-(3-[(aminoiminomethyl) amino]propyl)-5-methyl-2,4-imidazolidinedione was deposited on standing (207 mg., 0.97 mmol, 97%). Recrystallization from water afforded 5-(3-[(amino-iminomethyl)amino]propyl)-5-methyl-2,4-imidazolidienedione as fine needles, m.p. 294°-295° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]2([OH:35])[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)=[C:25]([O:38][CH3:39])[CH:24]=1.C1(O)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]5([OH:35])[CH2:30][C:31]([F:34])([F:33])[CH2:32]5)=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: Oc1ccccc1
Solvent: CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Temperature: 137.5 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of (E)-methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)thiophene-2-carboxylate (33.9 g, 105 mmol) prepared in Example 1 Part E and 1-((4-amino-2-methoxy-phenoxy)methyl)-3,3-difluorocyclobutanol (27.2 g, 105 mmol) prepared in Part C and phenol (200 g) was heated at 135-140° C. for 45 min while the reaction being monitored by LC. The mixture was diluted with methanol (700 mL), stirred at RT for 15 min and allowed to stand at RT overnight. The precipitated product was isolated by filtration, washed with chilled methanol and dried under vacuum to yield 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (37 g, 73.3 mmol, 69.8% yield) as a white solid. Dilution of the mother liquor with Et2O and hexane precipitated more solid which was triturated with MeOH to yield 1.8 g of a second crop of the desired product. MP 198-199° C. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2 H, d, J=8.56 Hz), 7.08 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=2.27 Hz), 6.95 (1 H, dd, J=8.31, 2.27 Hz), 4.14 (2 H, s), 3.89 (3 H, s), 2.72-2.93 (4 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 157.3, 156.7, 151.8, 150.4, 148.60 (1C, s), 148.0, 135.7, 131.4, 131.4, 129.4, 127.6, 123.1, 120.8, 119.4, 115.7, 117.6 (dd, J=282, 269. Hz), 111.4, 75.5, 64.6 (dd, J=18, 8 Hz), 56.0, 46.0 (t, J=22.89 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:4].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A solution of 2-chloro-N-[3,4-bis(phenylmethoxy)phenyl]acetamide (8.98 g, 23.5 mmol) and sodium iodide (3.53 g, 23.5 mmol) in acetone (75 ml) was refluxed for two hours and allowed to stand overnight at room temperature. The reaction was filtered hot to remove the sodium iodide and a precipitate formed in the cold filtrate which was collected and washed with cold acetone to give, upon drying, 6.71 g (14.2 mmol) of the title compound. A second crop was obtained from cold acetone (1.0 g).
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18]OC)=[N:15][C:14]=3[CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)[Br:30]>ClCCl>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][Br:30])=[N:15][C:14]=3[CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(COC)nc2c1)c1ccccc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CBr)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.05 g (5.14 mmol) of 2-methoxymethylbenzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and 5.7 ml (5.7 mmol) of a 1M solution of boron tribromide in dichloromethane was dissolved in a further 60 ml of dichloromethane and stirred for 16 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulfate, and the solvent was distilled off. The crude 2-bromomethylbenzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide thus obtained (2.4 g) was taken up in 5.0 ml of N,N-diisopropylethylamine and mixed with 0.64 g (5.4 mmol) of 4-aminobenzonitrile. After 1 hour's heating to 130° C., the solvent was distilled off in vacuo and the crude product obtained was purified by flash chromatography (silica gel; gradient: ethyl acetate/petroleum ether=1:3 to 1:1), whilst an orange foam was obtained when the eluates were evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O-])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH2:21][CH2:22][O:23][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2ccc(Br)cc2)C1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient solution of Example 54C (0.450 g, 1.17 mmol), triethylamine (0.178 mL, 1.28 mmol), and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) in dichloromethane (3 mL) was added p-toluenesulfonate chloride (0.224 g, 1.17 mmol). The reaction was stirred at room temperature for 8 h and was then partitioned between water (10 mL) and diethyl ether (10 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 25% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 541 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[C:30]([N:31]=[C:32]=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1>O1CCCC1>[CH3:25][C:26]1[C:30]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(C)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2.5 ml) was added 3,5-dimethylisoxazol-4-yl isocyanate (168 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 214 mg (68.6%) of the desired product as a solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])[NH:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[CH2:18]([N:20]([CH2:23][C:24]1[S:28][C:27]([C:29](O)=O)=[CH:26][C:25]=1[CH3:32])[CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:23][C:24]1[S:28][C:27]([C:29]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH:11][CH2:12][CH2:13][OH:14])(=[O:16])=[O:15])=[CH:6][CH:5]=3)[N:17]=2)=[CH:26][C:25]=1[CH3:32])[CH2:21][CH3:22])[CH3:19]
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCCO)cc3)no2)cc1C
Yield: 9.1 %

Procedure:
Starting from N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine (201 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol), the title compound (29 mg) is obtained as a yellow oil according to Method A; LC-MS: tR=0.49 min; [M+1]+=451.02; 1H NMR (CDCl3): δ1.27 (t, J=7.3 Hz, 6H), 2.34 (s, 3H), 2.91 (q, J=7.3 Hz, 4H), 3.17-3.22 (m, 2H), 3.73-3.77 (m, 2H), 4.11 (s, 2H), 7.74 (s, 1H), 8.01-8.04 (m, 2H), 8.24 (s br, 1H), 8.30-8.33 (m, 2H).