Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([S:9]C)=S)[CH:2]=1.Cl.[NH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[S:9])[NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=1
Reactant: COC(=O)CN
Reactant: CSC(=S)c1cccnc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=S)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a dry 50 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, bleach scrubber, thermometer, and addition funnel, was charged methyl pyridine-3-carbodithioate (2.0 g, 11.82 mmol), methyl 2-aminoacetate hydrochloride (1.48 g; 11.82 mmol) and 20 ml of methanol. Triethylamine (1.20 g, 11.82 mmol) in methanol (5 mls) was added, dropwise. The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into 200 ml of water, and the aqueous mixture was extracted with 3×50 ml of ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was then dissolved in dichloromethane and chromatographed on silica gel (80 g ISCO cartridge) with a gradient of 100% hexanes to 100% ethyl acetate over 20 minutes. The pure fractions were combined and then solvent evaporated under vacuum to afford the title compound as a thick yellow oil (1.6 g, 64%): 1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J=2.4, 0.8 Hz, 1H), 8.68 (dd, J=4.8, 1.7 Hz, 1H), 8.47 (bs, 1H), 8.16 (ddd, J=8.0, 2.4, 1.7 Hz, 1H), 7.35 (ddd, J=8.0, 4.8, 0.9 Hz, 1H), 4.59 (d, J=4.7 Hz, 2H), 3.86 (s, 3H); ESIMS m/z 209.17 ([M-H]−). Step 2: Preparation of N-ethyl-2-(pyridin-3-carbothioamido)acetamide:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[NH:3][C:2]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19]>CC(C)=O>[CH2:21]([O:20][P:18]([O:11][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: O=c1[nH]c2c(s1)CCCCC2
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCCCC2
Yield: 37.2 %

Procedure:
A mixture of 8.5 g of 2,3,5,6,7,8-hexahydro-4H-cycloheptathiazoline-2-one, 7 g of potassium carbonate and 200 ml of acetone was refluxed for 1 hour and after addition of 9.5 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed 24 hours. The mixture was filtered to remove mineral salts and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 cyclohexane-ethyl acetate mixture gave 6 g of 2-(diethoxythiophosphoryloxy)-5,6,7,8-tetrahydro-4H-cycloheptathiazole with a refractive index of nD19 = 1.5246.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].C(I)[I:20].[N+]([O-])([O-])=O>>[I:20][C:9]1[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=1
Reactant: ICI
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: O=[N+]([O-])[O-]
Product: Cc1ccc(-c2cc(I)cc(C(=O)O)c2)cc1

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 5, to afford 5-iodo-4′-methyl-biphenyl-3-carboxylic acid, MS (M+H)=353.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:19]1([NH:18][C:15]([CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cc2cc(Cl)ncc2[nH]1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid (EXAMPLE 40, 30 mg, 0.12 mmol) in DMF (2 mL) was added aniline (12 μL, 0.13 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (41 μL, 0.24 mmol). After 5 min, EDCI (29 mg, 0.15 mmol) was added, and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the solid partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. m/z (ES+)=329 [M+H]+; RT=3.17 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([N:14]([CH3:16])[CH3:15])[N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][N:14]([CH3:16])[C:6]1[N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nc2nc(Cl)c(-c3ccccc3)c(N(C)C)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)c(N(C)C)n2n1
Temperature: 130 °C

Procedure:
To a mixture of 370 mg 5-chloro-N,N,2-trimethyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine and 231 mg 4-formylphenylboronic acid in 7 ml 1,2-dimethoxyethane are added 2.5 ml of a 10% w/w sodium carbonate solution and 47 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The resulting mixture is heated to 130° C. by microwave irradiation under a inert gas atmosphere for 1 hour. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and the solvent is evaporated. The crude product is purified by chromatography on silica gel (dichloromethane/methanol) to yield the desired product.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH3:11]Br>O1CCCC1>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CBr
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with methyl bromide yielding para-methoxyphenol. The para-methoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-methoxytosyloxybenzene. The para-methoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-methoxy-3-iodo-1-tosyloxybenzene. The 4-methoxy-3-iodo-1-tosyloxybenzene can be extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-methoxy-3-iodophenol. The 4-methoxy-3-iodophenol can be extracted and exposed to resin-bound triphenylphosphine (PPh3) in a solution of azopyridine and ethanol (CH3CH2OH) in a salt bath at 0° C., yielding 4-ethoxy-2-iodomethoxybenzene. The 4-ethoxy-2-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-ethoxy-4-iodo-5-methoxybenzaldehyde. The 2-ethoxy-4-iodo-5-methoxybenzaldehyde can be added to lithium aluminum hydride (LiAlH4) and methanesulfonyl chloride (CH3SO2Cl) dissolved in pyridine, and then sodium iodide (NaI) and triethyl phosphite (P(OCH2CH3)3) can be added to the reaction mixture, yielding diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing acetic anhydride (60 mL) was slowly added 2-amino-5-fluorobenzoic acid (7.68 g, 0.05 mol) over 20 minutes and continued to stir over 2 hours at room temperature. The product was collected by filtration and allowed to dry to give 2-acetamido-5-fluorobenzoic acid (8.03 g, 82) as an off white solid.: m.p. 168°-170°; 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 3H), 7.46 (dt, 1H), 7.65 (dd, 1H), 8.41 (dd, 1H), 10.83 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 25.3, 117.1, 117.4, 119.3, 121.2, 121.4, 122.9, 137.6, 156.0, 158.4, 168.7, 168.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH:12]([CH2:16][CH2:17]Br)[C:13](Cl)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[Br:11][CH:12]1[CH2:16][CH2:17][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[C:13]1=[O:14]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: COc1cc(N)ccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCC(Br)C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
To a stirred solution of 4-chloro-3-methoxybenzeneamine (4.7 g, 29.6 mmol) in methylene chloride (100 mL) at ˜0° C. was slowly added 2,4dibromobutyryl chloride (5.1 mL, 39 mmol). After the addition, the reaction mixture was stirred for ˜5 minutes and triethylamine (24.7 mL, 178 mmol) was then added. The resulting reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 5 days. Water (˜100 mL) was then added to the reaction mixture. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, ˜33% ethyl acetate/˜67% hexanes) to give the title compound as a yellow solid (3.9 g) melting at 113–115° C.
Reaction SMILES: [BH4-].[Li+].CC(C)(OC([CH2:9][NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18](OCC)=[O:19])[CH:14]=[CH:13][CH:12]=1)=O)C.O.C(OCC)(=O)C>O1CCCC1>[CH3:9][NH:10][C:11]1[N:16]=[C:15]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1cccc(NCC(=O)OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNc1cccc(CCO)n1
Temperature: 66 °C
Yield: 58 %

Procedure:
A clean dry 2 L 3 necked flask was fitted with reflux condenser, addition funnel, stir bar, nitrogen inlet and outlet, temperature sensor, and heating mantle. The flask was purged using a stream of nitrogen. Lithium borohydride (4.36 g, 200 mmol) was added all at once. Tetrahydrofuran (THF, 150 mL) was charged into the addition funnel and was added to the solid with stirring over a 10-minute period. After dissolution, the mixture was heated to 66° C. Ethyl 6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate (110 g, 374 mmol) was dissolved in THF (400 ml) and charged into the addition funnel. The ethyl 6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate solution was added to the LiBH4 solution in as dropwise manner over a period of 25 minutes. The addition rate was controlled so as to maintain a gentle reflux. The mixture was heated to reflux for 5 h, the heat was turned off, and the reaction was allowed to stir overnight at 23° C. The reaction mixture was cooled to 10° C. and was treated with water (250 mL) in a dropwise manner. The mixture was stirred for 30 min and ethyl acetate (250 mL) was added. The mixture was stirred for 5 minutes and the layers were allowed to separate. The organic layer was washed with 2×250 mL saturated sodium chloride. The organic layers were stripped to thick oil in a 2 L round bottom flask. The residue was dissolved in ethyl acetate (200 mL) and was extracted with 1 N HCl (2×250 mL). The organic layer was discarded and the acid layer was placed in a 2 L 3 neck round bottom flask. The flask was heated to 50° C. for 1 h. The mixture was cooled to 10° C. and the solution was treated with 4 N NaOH (˜350 mL) to a pH of 10. The basic solution was extracted with ethyl acetate (3×150 mL). Care was taken to keep the pH of the aqueous phase above pH=9. The ethyl acetate extracts were combined, washed with water (150 mL) and concentrated to provide the title compound as a thin yellow oil, 33.5 g, yield=58%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:26][C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][CH:23]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1cccc(S)c1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2cccc(C)c2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 3-methylbenzenethiol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 2.36 (s, 3H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.86-7.96 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'd for C20H17N3OS 347.11. found 348.2 (M+H)+.
Reaction SMILES: O=C1N(C)C(=O)N(C)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:13][C:12]=2[OH:27])N1C.[OH-:29].[Na+]>O>[C:21]1([S:18]([NH:17][C:14]2[CH:13]=[C:12]([OH:27])[C:11](=[CH:16][CH:15]=2)[CH:4]=[O:29])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: CN1C(=O)N(C)C(c2ccc(NS(=O)(=O)c3ccccc3)cc2O)N(C)C1=O
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1O
Yield: 98.8 %

Procedure:
432 g (1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-[2-hydroxy-4-benzenesulphonamido-phenyl]-s-triazine (93.5% pure product) are introduced into a solution of 280 g (7 mols) of sodium hydroxide in 600 ml of water. The mixture is boiled under reflux for 6 hours, under nitrogen. A pale brown solution is formed, from which individual small crystals separate out. The contents of the flask are then poured onto a mixture of 700 ml of concentrated hydrochloric acid and 2 kg of ice and the yellow product which has separated out is filtered off. After washing with water and drying at 80° C, 274 g of 4-benzenesulphonamidosalicylaldehyde with a melting point of 150° to 157° C are obtained. According to the oxime titration, the aldehyde is 94.8% pure and the yield is thus 93.6%. After redissolving in xylene (1 : 10), the aldehyde is obtained as colorless crystals with a melting point of 160° to 163° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[NH2:8][C@@H:9]([CH3:12])[CH2:10][OH:11]>ClCCl>[O:4]1[CH2:5][CH2:6][N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: C[C@H](N)CO
Reactant: BrCCOCCBr
Solvent: ClCCl
Product: C[C@@H](CO)N1CCOCC1
Reaction time: 0.32 h
Yield: 87.5 %

Procedure:
Bis(2-bromoethyl) ether (2.3 g, 10 mmol) was added to (S)-2-aminopropan-1-ol (3.8 g, 50 mmol) at rt with vigorous stirring. The reaction slowly exothermed, and the internal temperature peaked at 42° C. after 19 min. After 24 h, the reaction was diluted with dichloromethane (10 mL) and quenched with sat'd potassium carbonate solution (10 mL). Water (˜2.5 mL) was added to the heterogeneous mixture until the solids dissolved. The layers were separated, and the aqueous layer was extracted with dichloromethane (10 mL×2). The organic layers were combined, dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give 1.27 g of (S)-2-morpholinopropan-1-ol. 1H NMR (DMSO-d6): δ 4.29 (dd, 1H), 3.54 (t, 4H), 3.45 (ddd, 1H), 3.25 (ddd, 1H), 2.54-2.40 (m, 5H), 0.92 (d, 3H); MS: 146.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12]Cl>O>[Cl:12][NH:11][C:9]([NH:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: CC1(NC(N)=O)CCCCC1
Reactant: ClCl
Solvent: O
Product: CC1(NC(=O)NCl)CCCCC1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a rapidly stirred slurry of 7.5 g (.048m) of N-(1-methylcyclohexyl)urea in 75 ml. water at 15°C was added 3.36g. (.048 m) of chlorine at 0.5 g/minute. The reaction mixture was stirred an additional 1/2 hour at 15°C and filtered. The filter cake was washed with cold water until free of acid and air dried overnight. The white solid weighed 6.0 g (66% yield) and contained 18.9% active chlorine (calculated value for 1-chloro-3-(1-methylcyclohexyl)urea = 18.5% active chlorine).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cn1cc(N)cn1
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)c2ccc(Br)cc2)cn1
Yield: 87 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (m396 g, 1.55 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (424 mg, 1.34 mmol, 87%). δH (D-6 DMSO, 300K) 9.80 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.61 (2H, d J 8.7 Hz), 7.48 (1H, s), 7.05 (1H, s), 3.71 (3H, s). m/z (ES+, 70V) 318.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:34][CH2:33][CH:29]3[CH2:30][CH2:31][CH2:32][O:28]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NCC1CCCO1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: N=C(NCC1CCCO1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with (tetrahydrofuran-2-yl)methanamine (23 μl, 0.23 mmol) via procedure W to afford 76 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofuran-2-yl)methyl)carbamimidoyl)benzamide. MS (Q1) 435 (M)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH3:38])([CH3:37])[CH2:7][CH:8]=[CH:9][C:10]1[CH2:17][S:16][CH:15]2[N:12]([C:13](=[O:33])[CH:14]2[NH:18][C:19](=[O:32])[CH2:20][S:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:11]=1[C:34]([Cl:36])=[O:35].Cl.[N:40]1(C(=N)N)[CH:44]=[N:43]C=N1.CN(C)C(=N)N(C)C>CS(C)=O>[ClH:36].[NH:2]([CH2:3][CH2:4][CH2:5][N+:6]([CH3:38])([CH3:37])[CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH2:17][S:16][C@H:15]2[N:12]([C:13](=[O:33])[C@H:14]2[NH:18][C:19](=[O:32])[CH2:20][S:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:11]=1[C:34]([Cl:36])=[O:35])[C:44]([NH2:43])=[NH:40]
Reactant: N=C(N)n1cncn1
Reactant: C[N+](C)(CC=CC1=C(C(=O)Cl)N2C(=O)C(NC(=O)CSc3ccc4ccccc4c3)C2SC1)CCCN
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Product: C[N+](C)(C/C=C/C1=C(C(=O)Cl)N2C(=O)[C@@H](NC(=O)CSc3ccc4ccccc4c3)[C@H]2SC1)CCCNC(=N)N
Reaction time: 2 h

Procedure:
To a stirred suspension of 122 mg of (E)-(6R,7R)-3-[3-[(3-amino-propyl)-dimethyl-ammonio]-propenyl-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid chloride monohydrochloride in 2 ml of dimethylsulfoxide was added 60 mg of 1H-1,2,4-triazole-1-carboximidamide monohydrochloride followed by 0.05 ml of tetramethylguanidine. The mixture was stirred for 2 h at 20° and then subjected to chromatographic purification on MCI gel CHP20P using a gradient of 0-30% aqueous acetonitrile for elution. The product-containing fractions were concentrated in vacuo and freeze-dried, and the remaining amorphous material was triturated with 10 ml of a 0.4 N solution of hydrochloric acid in diethyl ether. The white solid was isolated by filtration, washed with 20 ml of diethyl ether and dried to give 48 mg of (E)-(6R,7R)-3-[3-[(3-guanidino-propyl)-dimethyl-ammonio]-propenyl]-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid chloride monohydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:24][CH3:25])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: CCI
Product: CCn1ccc(-n2c(C)nc(C#Cc3cccc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=352.2, 354.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21]([OH:23])=O)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.[NH:50]1[CH2:56][CH2:55][CH2:54][C@@H:51]1[CH2:52][OH:53].FC(F)(F)C(O)=O.ClCl>C(#N)C.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:50]3[CH2:56][CH2:55][CH2:54][C@@H:51]3[CH2:52][OH:53])=[O:23])=[N:10][C:11]=2[CH:16]=1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@@H]2CO)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 67 %

Procedure:
Prepared analogously to Example 1g from (1S)—N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin 1-ylcarbonyl)benzamide, TB TU, diisopropylethyl amine, (R)-prolinol in acetonitrile, and subsequent reaction with trifluoroacetic acid analogously to Example 17. Yield: 67%; Rf value: 0.30 (silica gel; ethyl acetate/ethanol=85:15); C29H34ClN5O4 (552.07); mass spectrum: (M+H)+=552/554 (chlorine isotope).
Reaction SMILES: [C:1]([NH:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[C:1]([NH:6][C:7](=[O:12])[CH:8]([Cl:16])[C:9]([CH3:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)NC(=O)CC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)NC(=O)C(Cl)C(C)=O
Yield: 99.8 %

Procedure:
The N-carbethoxyacetoacetamide (12.7 g from above reaction) was dissolved in methylene chloride (50 ml) and cooled in an ice bath. Sulfuryl chloride (10.0 g) was added dropwise to the reaction mixture. After refluxing for 45 minutes the solvent was evaporated under reduced pressure. The resulting colorless oil crystallized over night to give 15.2 g (99%) colorless product. An analytical sample recrystallized from CHCl3 /cyclohexane had mp 69.5°-70.0°; ir (Nujol) 3200, 1760 (broad), 1540 cm-1 ; nmr (CDCl3) 1.35 (t, 3H, J=7), 2.45 (s, 3H), 4.30 (q, 2H, J=7), 5.75 (s, 1H), 9.0 (s, 1H),; and mass spectrum m/e 43 (100%) and 207 (M+).