Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Product: Cc1ccc(Sc2ccc(OS(C)(=O)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (80 mg, 0.195 mmol) was reacted with the methanesulfonyl chloride (22.3 mg, 0.195 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (36 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.88 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.46 Hz, 1H) 7.45-7.51 (m, 1H) 7.35-7.42 (m, 2H) 7.26 (d, 2H) 7.19 (d, 2H) 6.33 (d, J=6.99 Hz, 1H) 3.34 (s, 3H) 2.75 (s, 3H) 2.40 (s, 3H); MS (DCI NH3+) m/z 452 (M+H)+.
Reaction SMILES: [CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=2)[C:17]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:16][C:15]=1[Cl:31])/[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([O:35][C:36]1[C:37](=[O:54])[C:38](=[O:53])[C:39]=1[Sn](CCCC)(CCCC)CCCC)([CH3:34])[CH3:33]>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.CN(C)C=O>[CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:39]3[C:38](=[O:53])[C:37](=[O:54])[C:36]=3[O:35][CH:32]([CH3:34])[CH3:33])=[CH:22][CH:21]=2)[C:17]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:16][C:15]=1[Cl:31])/[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.9 %

Procedure:
A mixture of the product of Example 30 (c) (0.8 g), 3-isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.9 g), tetrakis(triphenylphosphine)palladium(0) (0.2 g), cuprous iodide (0.1 g) and dry dimethylformamide (5 ml) was stirred at ambient temperature under a nitrogen atmosphere for approximately 17 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in diethyl ether (150 ml). The solution obtained was washed with saturated aqueous ammonium chloride solution (50 ml), then with saturated aqueous potassium fluoride solution (2×50 ml) and then dried over magnesium sulphate. The solvent was evaporated and the residue obtained was purified by flash chromatography on silica gel (eluting with dichloromethane/methanol (50:1)) to give the intermediate compound (E)-methyl 2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl]propenoate as an oil (0.4 g).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C1(C)C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1>C(O)C.O>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[N+:33]=[N-:34])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
3.0 g of the cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)methane prepared in (2), was put into a flask, and 100 mL of ethanol was added thereto, followed by stirring. Further, to this solution, 8.0 g of a 5 wt % ethanol solution of sodium hydroxide was added, followed by stirring. This reaction solution was cooled to from -5° C. to -10° C., and 35 mL of pure water was added thereto. Then, 10 mL of the ethanol solution containing 2.0 g of p-toluenesulfonylazide obtained in Reference Example 2, was dropwise added thereto over a period of 5 minutes, and the mixture was stirred for 3 hours and left to stand overnight. Then, the precipitate was collected by filtration to obtain crude crystals. The crude crystals were re-crystallized from ethanol to obtain cyclohexylsulfonyl-(4-methoxyphenylsulfonyl)diazomethane.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]=2[CH3:1])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1
Yield: 69.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-phenylpyrazole-4-carboxylic acid (0.5 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.7 g), the title compound (0.8 g) was obtained, melting point: 227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][NH:75]2)[CH2:71][CH2:70]1>CN(C=O)C>[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][N:75]2[C:32](=[O:34])[CH2:31][CH2:30][C:26]2[C:25]([CH3:35])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:71][CH2:70]1
Reactant: C1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol) and DIPEA (45 mg, 1.9 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.). After stirring for another 3 hours, to the mixture was added cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (29 mg, 1.1 eq.). After stirring for 72 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16]([O:19][CH2:20][CH2:21]Cl)[CH2:17][Cl:18]>C(OCCCC)CCC>[Cl:18][CH2:17][CH2:16][O:19][CH2:20][CH2:21][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: ClCCOCCN(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of sodium hydride (0.70 g, 0.023 mol, 80% oil dispersion) and diphenylamine (3.4 g, 0.020 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 1 h under an atmosphere of nitrogen. The reaction mixture was cooled to 50° C. and 2,2'-dichlorodiethylether (10 ml) was added and the mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled, filtered and the volatile components were removed in vacuo leaving 4.6 g of crude 2-chloro-1-(2-(diphenylamino)ethoxy)ethane as an oil. This oil was dissolved in dry dibutylether (10 ml) and ethyl (R)-3-piperidinecarboxylate (3.7 g, 0.024 mol) and potassium carbonate (3.3 g, 0.024 mol) were added. The mixture was heated at reflux temperature for 2 h under an atmosphere of nitrogen and then stirred overnight at room temperature. Ethyl acetate (50 ml) was added, the mixture was filtered and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (150 g) using a mixture of n-heptane and THF (4:1) as eluent. This provided 3.8 g (48% calculated from diphenylamine) of the title compound as an oil. TLC: rf=0.22 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:25]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Br)c2)c(N)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1c(C(=O)c2cccc(Br)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from ethyl 3-amino-2-(3-bromobenzoyl)-6-chloro-1H-indole-1-carboxylate (step 1) and methanesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2>C(O)(=O)C.CN(C=O)C>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][NH:7][C:8]2=[O:12]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)[nH]ccc2c1N
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A suspension of 6-methyl-5-nitroisoquinolin-1(2H)-one (40 g, 196 mmol) in glacial acetic acid (1 L) was purged with N2. The suspension was treated with 10% Pd/C (10 g) and the reaction vessel was purged with H2. The mixture was stirred at room temperature under H2 (1 atm) until starting material consumed, approximately 100 h. The reaction mixture was purged with N2, then filtered through a pad of Celite. The pad was washed with MeOH (400 mL) and the combined filtrate was treated wtih water (80 mL) and concentrated in vacuo to ˜200 mL. The dark mixture was diluted with 200 mL MeOH and added in a thin stream to ice water (1.5 L) stirred in a large beaker. The resulting fine precipitate was collected by suction filtration. The greenish-grey powder was suspended in water (500 mL) and satd NaHCO3 (100 mL) and sonicated for 1 min. The solid was collected by suction filtration, washed with water (2×100 mL), Et2O (100 mL), and air-dried overnight to afford 28 g as a grey powder. The powder was dissolved in hot DMF (200 mL) and treated with decolorizing carbon (˜10 g). The hot suspension was filtered through Celite. The filter cake was washed with MeOH (200 mL) and the filtrate was concnetraed in vacuo to ˜200 mL. The dark brown solution was added to water (1.2 L) to afford a fine crystalline precipitate. The solid was collected by suction filtration on a medium-sintered glass frit and washed wtih water (500 mL). A second crop precipiated in the filtrate and was colected by suction filtration, washed with water (100 mL) and added to the first crop. The combined material was washed with Et2O (400 mL), and dried on the sintered glass funnel under a stream of N2, with suction, for 16 h to afford 5-amino-6-methylisoquinolin-1(2H)-one (22 g, 64% yield) as a tan crystalline solid. MS (M+H)+ 175.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH:14](O)=O>[Zn]>[S:1]1[C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=[CH:14]1
Reactant: O=C(O)c1ccc(S)c([N+](=O)[O-])c1
Reactant: O=CO
Agent: [Zn]
Product: O=C(O)c1ccc2scnc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-mercapto-3-nitrobenzoic acid (1 eq.) and zinc dust (0.35 eq) in formic acid was refluxed for 6 h. The mixture was allowed to cool to room temperature, filtered and concentrated under reduced pressure. The residue was diluted with water, adjusted to pH=6.5 with aqueous NaOH (2N) and extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford benzothiazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10]([Cl:22])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: CC(Oc1ccc(Cl)nc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(Cl)nc1Cl)C(=O)Cl

Procedure:
23.6 g (0.1 mole) of 2-[(2,6-dichloro-3-pyridyl)oxy]-propionic acid, 150 ml of chloroform and 1.5 ml of dimethylformamide are heated with stirring to 55°, and in the course of 1 hour a solution of 18 g (0.15 mole) of thionyl chloride in 40 ml of chloroform is added dropwise. The reaction mixture is subsequently refluxed for 16 hours and is afterwards concentrated in vacuo. The product obtained is used directly for further reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of 21 g of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and 17 g of benzyl chloroformate. The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:22]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][C:27]([NH2:29])=[O:28])[CH2:24][CH2:23]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: NC(=O)CCN1CCNCC1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)CCN1CCN(C2Cc3cc(Cl)ccc3Sc3cc(F)ccc32)CC1
Reaction time: 8 h

Procedure:
A mixture of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo(b,f)-thiepin (2.8 g), 3-(1-piperazinyl)propionamide (3.2 g) and chloroform (10 ml) is refluxed with stirring for 8 hours. The solvent is than evaporated under reduced pressure, and the residue is extracted by shaking with a two-phase system consisting of benzene (30 ml) and a solution of methanesulfonic acid (4 g) in water (50 ml). The clear aqueous solution is separated and then made alkaline with aqueous ammonia (10 ml). The so-formed suspension of the amorphous base is diluted with ethanol (100 ml), and the mixture is briefly warmed to boiling. The resultant clear solution is then allowed to crystallize at room temperature for 6 hours. The crystalline product is separated, washed with a small amount of ethanol, and then dried in vacuo. The obtained base (2.35 g, 60% of theory) melts at 179°-182° C.; it can be purified by crystallization from ethanol to give the title compound having a m.p. of 182°-184° C. and which is identical with the product of the preceding example 1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=2[F:10])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: NCc1ccc(Br)cc1F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Br)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-2-fluorobenzylamine (2.3 g) and triethylamine (1.55 ml) in chloroform (40 ml) was added dropwise a solution of 4-bromo-2-nitrobenzoyl chloride (2.69 g) in chloroform (10 ml) at 0° C. with stirring and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed in turn with diluted aqueous hydrochloric acid and water, and then dried. Evaporation of the solvent followed by recrystallization from diethyl ether gave 4-bromo-N-(4-bromo-2-fluorobenzyl)-2-nitrobenzamide (3.60 g).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([NH2:25])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g, 10.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine, followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 45 minutes and 1 mL of concentrated ammonium hydroxide then is added. After 10 minutes, the reaction mixture is diluted with 50 mL water and the resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C.,<1 mm) to afford 2.46 g (84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp 224-226° C.; 1H NMR (DMSO-d6, 250 MHz)δ 7.79 (s, 4H, Ar), 7.71 (br s, 1H, CONH2), 7.32 (br s, 1H, CONH2), 7.20-7.02 (m. 5H, Ar), 5.06-4.98 (m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d6, 250 MHz) d: 169.6, 168.0, 137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal. Calculated for C17H14N2O3. Theoretical: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.37; H, 4.73; N, 9.43.
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36]O)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1.[CH2:40]([N:42](CC)[CH2:43][CH3:44])[CH3:41].O>ClCCl>[CH:6]1([NH:9][C:10](=[O:39])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH2:35][CH2:36][N:42]4[CH2:43][CH2:44][CH2:41][CH2:40]4)[CH2:26][CH3:27])[C:19]3=[O:38])[CH:12]=2)[CH2:8][CH2:7]1
Reactant: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.21 mL) was added to a stirred solution of N-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0° C. The mixture was stirred for 1 h at 0° C. and 1 h at room temperature. Water was added and the organic phase was separated, (Na2SO4), filtered and concentrated in vacuo. The residue was treated with dichloromethane (10 mL) and pyrrolidine (0.73 mL) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacu. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (147 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][C:21]#[N:22])SC)[N:8]=1.[CH3:26][NH2:27]>C(O)C>[F:25][C:2]([F:1])([F:24])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:27][CH3:26])=[N:20][C:21]#[N:22])[N:8]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1nsc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nsc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
A solution of 5-[2-(2,2,2-trifluoroethyl)-guanidino]-3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-1,2,4-thiadiazole in 33% w/v methylamine in ethanol (4 ml.) was kept at 20° for 18 hours. Volatile material was evaporated in vacuo and the crude material was fractionated on a silica column (26 cm.×1 cm. diameter) eluted with a methanol/ethyl acetate 1:50 v/v to give 5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-1,2,4-thiadiazole. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethyl silane as an internal standard (δ=0) had the following resonances (δ): 4.2 (2H, quartet); 3.8 (2H, singlet); 3.3 (2H, multiplet); 2.7 (2H, triplet).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9]OS(C)(=O)=O)=[O:4].[C-:23]#[N:24].[Na+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9][C:23]#[N:24])=[O:4]
Reactant: [C-]#N
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCC#N
Temperature: 80 °C
Yield: 93 %

Procedure:
To 1-tert-butoxycarbonylamino-2 (2-methanesulfonyloxy-1-ethyl)-cyclopropanecarboxylic acid methyl ester (400 mg, 1.19 mmol) from example 109 in DMF (6 mL) was added NaCN (350 mg, 7.14 mmol) and NaI (178 mg, 1.19 mmol). The reaction mixture was heated at 80° C. for 2 h then diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica (20→50% EtOAc/Hexanes) to afford 1-tert-butoxycarbonylamino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester (297 mg, 93%). 1H NMR (300 MHz, CDCl3): δ 5.13 (br s, 1H), 2.44 (m, 2H), 2.05 (m, 2H), 1.70-1.53 (m, 1H), 1.53-1.37 (m, 4H) 1.45 (s, 9H). LCMS found 290.9 [M+Na]+. To this intermediate (297 mg, 1.10 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxanes (2 mL). Ater stirring at room temperature for 2 h the reaction was concentrated to afford 225 mg (100%) of the HCl salt of 1-amino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester, which was used in the next step without further purification.