Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:13][CH2:12][O:11][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COCCO
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.), 2-methoxyethanol (3.0 equiv.) and triphenylphosphine (3.0 equiv) in THF (0.1 M) was added DIAD (3.0 equiv.). After stirring at rt for 18 hours, the volatiles were removed in vacuo and the residue was purified by SiO2 chromatography to yield 1,3-difluoro-5-(2-methoxyethoxy)benzene in 95% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.41-6.47 m (3H), 4.08 (t, 2H), 3.74 (t, 2H), 3.45 (s, 3H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17](C4C=CC=CN=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26](O)=[O:27].[C:29]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:66]2[N:67]=[CH:68][CH:69]=[CH:70][C:65]=2N=N1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:70]4[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([NH:38][C:36]1[S:37][C:33]([C:29]([CH3:32])([CH3:30])[CH3:31])=[C:34]([CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:35]=1)=[O:27]
Reactant: CC(C)(C)c1sc(N)nc1CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccccn4)ccn23)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1sc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)nc1CN1CCOCC1

Procedure:
Combine [2-fluoro-4-(7-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid, dihydrochloride (0.500 g, 1.19 mmol) and 5-tert-Butyl-4-morpholin-4-ylmethyl-thiazol-2-ylamine (0.334 g, 1.31 mmol) in DMF (6 mL). Add N,N-diisopropyl-ethylamine (0.54 mL, 3.93 mmol), then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.498 g, 1.31 mmol). The reaction mixture is stirred over the weekend under N2. Purify using an SCX cartridge (10 g VARIAN BondElut®), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. Concentrate the latter and purify via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 min). Partition between ethyl acetate and 1 N NaOH. Dry the organic layer over magnesium sulfate, filter, and concentrate to the title compound (0.190 g, 27%). MS(ES), m/z 585 (M+1).
Reaction SMILES: [OH:1]CCOC1C=C(OC)C=CC=1C1C2C(=CC=C(OCCC)C=2)C(C2C=CC3OCOC=3C=2)C1C(O)=O.[C:38]1([CH3:44])C=CC=C[CH:39]=1.O[CH2:46][CH2:47][O:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1[CH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:66]C(C)C)[CH:64]=2)[CH:59]([C:70]2[CH:75]=[CH:74][C:73]3[O:76][CH2:77][O:78][C:72]=3[CH:71]=2)[CH:58]1[C:79]([OH:81])=[O:80].[CH2:82]([NH2:85])[CH2:83][NH2:84]>CC(O)C>[CH2:82]([NH2:85])[CH2:83][NH2:84].[OH:1][CH:47]([O:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1[C@@H:57]1[C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:66][CH2:39][CH2:38][CH3:44])[CH:64]=2)[C@H:59]([C:70]2[CH:75]=[CH:74][C:73]3[O:76][CH2:77][O:78][C:72]=3[CH:71]=2)[C@H:58]1[C:79]([OH:81])=[O:80])[CH3:46]
Reactant: Cc1ccccc1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: COc1ccc(C2c3cc(OC(C)C)ccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c(OCCO)c1
Solvent: NCCN
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OC(C)O)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An analytical sample could be obtained by concentration of the toluene in vacuo and recrystallization from 2-propanol. m.p. 125-127° C. A toluene solution of (+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-2-yloxy)indane-2-carboxylic acid (868.8 g@11.2% wt/wt, 192.5 mmol) was concentrated under reduced pressure to a volume of approximately 200 mL. Distillation was discontinued and 2-propanol (500 mL) added to the concentrate. The organic solution was concentrated again under reduced pressure to a volume of approximately 200 mL. Distillation was discontinued and 2-propanol (500 mL) added to the concentrate. The resulting solution in 2-propanol was allowed to stir at ambient temperature for approximately 15 minutes to obtain a homogeneous mixture then diluted with an additional 1000 mL of 2-propanol. The resulting solution was heated to approximately 60° C. over a period of 15-20 minutes under a gentle purge of nitrogen. Heating was discontinued and ethylene diamine (11.6 g, 99.5+%, 192.5 mmol) was added. The reaction mixture was cooled to 30-35° C. over a period of 4 hours. As the solution cooled to 57° C., precipitation of the title compound occurred. The resulting slurry was stirred at ambient temperature for approximately 12 hours then cooled to 0° C. an additional 3 hours before isolation of the title compound via filtration. The product was washed with 3 portions of 2-propanol (300 mL) followed by hexane's (600 mL) chilled to 0-5° C. The product was dried in the vacuum oven for approximately 16 hours at 20-25° C. to afford 91.6 (87%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:3]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH2:17][OH:18])=[CH:5][CH2:4]1.CC([O:30]O)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(N(C(C)C)CCC1C2C(=CC=CC=2)NC=1)C>[CH3:1][Si:2]([CH3:25])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:3]1[CH2:4][CH:5]2[C:6]([CH2:17][OH:18])([O:30]2)[CH:7]1[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(c1ccccc1)[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Reactant: CC(C)(C)OO
Agent: [Ti+4]
Agent: CC(C)N(CCc1c[nH]c2ccccc12)C(C)C
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[Si](C)(c1ccccc1)C1CC2OC2(CO)C1COCc1ccccc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 162.8 %

Procedure:
To an oven dried, 1-L 3-necked round bottomed flask equipped with a mechanical stirrer, a temperature probe, and an argon line was charged activated molecular sieves (35 g) and DCM (160 mL) under an atmosphere of argon. The solution was cooled to about −30° C. DIPT (2.34 g, 0.01 moles) followed by titanium (IV) isopropoxide (2.36 mL, 0.008 moles) was added to the reaction mixture. The reaction mixture was stirred at −30° C. for about 20 minutes. Crude 76 (42 g, ˜0.1 moles) in DCM (40 mL) was added to the reaction mixture and stirred for about 30 minutes. TBHP (40 mL, 0.2 moles) was added to the reaction mixture at −30° C. After complete addition of TBHP, the reaction mixture was stirred at −30° C. for about 5 hours to complete the reaction. The excess peroxide was quenched with aqueous sodium bisulfite (20 g). The mixture was filtered through a Buchner Funnel with a pad of diatomaceous earth (Hyflo Celite®). The filtrate was washed with saturated NaHCO3, solution (100 mL) and brine (100 mL). The organic layer was concentrated in vacuo to give the crude title compound (60 g, >100% material balance) as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:11]([OH:13])=[O:12].CN(C=O)C.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:11]([O:13][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Oxalyl chloride (4.60 mL), 53.6 mmol) is added to a stirred suspension of 3-fluoro-4-nitrobenzoic acid (5.11 g, 26.8 mmol) in CH2Cl2 (100 mL). DMF (0.1 mL) is added, and the solution stirred for 2 h at room temperature. The solvent is evaporated, and the residue is dissolved in CH2Cl2 (100 mL). Benzyl alcohol (5.54 mL, 53.6 mmol) and pyridine (2 mL) are added and the solution stirred for 16 h. The solvent is removed and the residue purified by filtration through a pad of silica gel, eluting with EtOAc/heptanes (1:9) to afford the title compound (6.8 g, 24.7 mmol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[NH2:26][NH2:27]>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[C:21]([NH:26][NH2:27])=[N:20][S:19](=[O:25])(=[O:24])[N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: NN
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)N=C2NN)o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmoles) in 30 ml of dry methanol was added dropwise over a period of 45 minutes to a well stirred cold (ice-water bath) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 250 ml of methanol. After stirring at 0° for 15 minutes, a solution of anhydrous hydrazine (1.8 g; 56.13 mmoles) in 30 ml of dry methanol was added all at once, and stirring was continued for 30 minutes. The reaction mixture was evaporated under reduced pressure and the solid residue was treated with chloroform and filtered to give 3.28 g of the title compound, mp 170° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-trifluoromethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24][CH2:23]1.[CH3:30][C:31]1([CH3:45])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:38]2[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=2)[O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.O>[CH3:36][C:35]1([CH3:37])[C:31]([CH3:30])([CH3:45])[O:32][B:33]([C:38]2[CH:43]=[CH:42][C:41]([O:29][CH2:28][C@H:25]3[CH2:26][CH2:27][C@H:22]([O:21][CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20][O:15]4)[CH2:23][CH2:24]3)=[CH:40][CH:39]=2)[O:34]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: OC[C@H]1CC[C@H](OC2CCCCO2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) was added to a solution of [trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol (2.05 g, 9.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.3 g, 10.7 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) in THF (150 mL) at 0° C. The reaction was allowed to warm to it and stirred overnight. Water (200 mL) was added and the reaction was extracted with EtOAc (600 mL). The organics were washed with 1 M aq NaOH (4×100 mL), brine, then dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified via flash chromatography using an eluent of 20% EtOAc in hexanes to afford the title compound as a white solid (1.9 g, 48%). MS (APCI) m/z 417.3 (M+1).
Reaction SMILES: C1([C:3](=[CH:5][CH:6]=[CH:7]C=1)[OH:4])O.[C:9](Cl)(=O)[C:10](Cl)=O.[CH2:15](OCC)[CH3:16]>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:15]([O:4][CH2:3][CH2:5][CH2:6][CH3:7])[CH2:16][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCC
Reactant: Oc1ccccc1O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCOCCCC
Temperature: 25 °C

Procedure:
1 mole of pyrocatechol or pyrocatechol derivatives (see Table 1) in a mixture of 500 ml of toluene and 50 ml of dioxane was taken and 1.05 mole of oxalyl chloride were added dropwise at 70° C. Thereafter, the mixture was subsequently stirred until the evolution of gas had ended. After the reaction mixture had cooled to room temperature, it was filtered and the solid product was dried in vacuo. The same results were obtained when diethyl ether or dibutyl ether was used instead of the toluene/dioxane mixture. The starting materials and the results are summarized in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[S:10][CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[O:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[S:10][CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][CH:20]([NH:23][CH2:35][C:32]4[CH:33]=[CH:34][C:28]5[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)[CH2:21][CH2:22]3)[CH2:7][C:6]2=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CS3
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NCc2ccc4c(c2)NC(=O)CO4)CC1)CS3

Procedure:
The titled compound is prepared as a light yellow solid (21 mg, 28% yield) following Scheme 1 and in analogy to Example 2 using 1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (27 mg, 0.14 mmol, 1.0 eq) as starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)[CH2:23][CH2:22]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2CC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), bis(tricyclohexylphosphine)palladium(II)dichloride (396 mg), tripotassium phosphate (12 g) and cyclopropylboronic acid (2.1 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform) to give 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g). The obtained 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (20 mL), and the precipitate was collected by filtration to give the title compound (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C.[NH4+].[OH-]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:21])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 88 %

Procedure:
To 5-Fluoro-2-nitro-benzoic acid (3 g, 16.2 mmol) in 200 mL of methylene chloride was added oxalyl chloride (2.26 g, 17.8 mmol) and a drop of DMF. After stirring for 2 h, the solution was poured into concentrated NH4OH. The partial solution was poured into water, extracted with Ethyl acetate, dried (Na2SO4) and concentrated to give 5-Fluoro-2-nitro-benzamide (2.61 g, 88% yield) used without purification. LCMS m/e 185.1 (M+H) 183.2 (M-H), HPLC tr=2.9 min (100%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>C1(C)C=CC=CC=1.O1CCCC1>[CH:27]([C:6]1[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]([CH2:10][OH:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.2 g (23 mmol) of the compound from Example 3 in 100 ml of dry tetrahydrofuran at -10° C. to -5° C. and the mixture is stirred for 5 h at room temperature. After cooling to 0° C., 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, φ4.5 cm, using ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: O=C1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(=O)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and piperidin-4-one as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([NH:48][NH2:49])=[O:47])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH:48]([C:46]([C:45]1[CH:50]=[CH:51][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:43][CH:44]=1)=[O:47])[NH2:49]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: NNC(=O)c1ccc(N)cc1
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: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)NN)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 67.3 %

Procedure:
To a solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (52.7 mg, 0.113 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), 4-aminobenzhydrazide (33.1 mg, 0.22 mmol, Aldrich) and HATU (72.3 mg, 0.19 mmol). (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 minutes the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by HPLC with acetonitrile and water (with TFA 0.1% VAT) to give chiral (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-phenyl)-amide (45.7 mg., 67.5%) as a white solid. HRMS (ES+) m/z Calcd C30H29Cl2F2N5O2+H [(M+H): 600.1739. Found: 600.1737.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([N:17]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:29][C:30]([NH2:32])=[NH:31])=[N:6][CH:5]=1.[H-].[Na+].[C:35](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=NC=CC=1)([CH3:38])([CH3:37])[CH3:36]>COCCOC>[C:35]([O:20][C:19](=[O:21])[CH2:18][N:17]([S:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:4]([Cl:3])=[CH:5][N:6]=[C:7]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:12][CH:11]=1)(=[O:15])=[O:16])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccnc3)cc12
Reactant: CC(C)(C)OC(=O)CN(Cc1cccnc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1cccnc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine dihydrochloride ##STR26## Guanidine hydrochloride (317 mg, 3.32 mmol was added in one portion to a stirred suspension of NaH (62.3 mg, 80% dispersion by wt in mineral oil, 2.08 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine t-butyl ester (400 mg, 0.83 mmol) in DME (10 mL) was added and the mixture heated at 80° C. for 4 h. The solvents were evaporated in vacuo, the residue was dissolved with EtOAc (200 mL), and washed with aqueous NH4Cl (200 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using (i) pentane-EtOAc (70:30 to 50:50) and then (ii) CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 90:101) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-pyridylmethyl)glycine t-butyl ester (104 mg, 0.21 mmol) as a pale yellow solid.