Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[CH:14][N:15]=[C:8]1[C:7]([N:16](C#C[Si](C)(C)C)[CH2:17][CH2:18][CH2:19][OH:20])=[N:6]2.[N+:29](=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N-:30].[F-].[Cs+].[CH2:39]1COC[CH2:40]1>>[CH2:35]([O:34][C:32]([C:31]1[CH:40]=[C:39]([C:13]2[N:9]3[C:10]4[C:5]([N:6]=[C:7]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:8]3=[N:15][CH:14]=2)=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:12][CH:11]=4)[NH:30][N:29]=1)=[O:33])[CH3:36]
Reactant: C[Si](C)(C)C#CN(CCCO)c1nc2cc(C(F)(F)F)ccc2n2ccnc12
Reactant: C1CCOC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Yield: 35 %

Procedure:
A mixture of 3-(7-Trifluoromethyl-1-trimethylsilanylethynyl-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (0.37 mmol; 150 mg), ethyl diazoacetate (0.93 mmol; 0.10 mL), and CsF (0.55 mmol; 84 mg), in THF (0.2 mL) under argon was stirred at 85° C. for 20 hr. After concentration in vacuo, the residue was purified by preparative TLC (dichloromethane/methanol) to yield the title compound as a white powder (58 mg; 0.13 mmol; 35%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1.C(OCC)(=O)C.O>C(O)(=O)C>[Br:1][C:6]1[C:7]([OH:10])=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=1
Reactant: BrBr
Reactant: Oc1ccc(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
At room temperature, bromine (1.2 mL, 24 mmol) was added dropwise to a solution of 5-chloro-2-pyridinol (2.9 g, 20 mmol) in glacial acetic acid (25 mL). After stirred at room temperature overnight, ethyl acetate and water were added. The organic layer was washed with water, dried and concentrated. The residue was triturated with diethyl ether and the precipitate was filtered and dried to give the title compound (1.5 g).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[S:23](Cl)(=[O:25])=[O:24]>>[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH:11][S:23]([C:15]1[S:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)(=[O:24])=[O:25])[CH3:4]
Reactant: CCOC(=O)[C@H](C)NCCN
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Agent: Cl
Product: CCOC(=O)[C@H](C)NCCNS(=O)(=O)c1nc2ccccc2s1

Procedure:
N-(2-Aminoethyl)-alanine ethylester 2HCl, prepared as described by Puschl (A. Puschl et al., Tetrahedron, 1998, 39, 4707.), was reacted with benzothiazole-2-sulfonyl chloride as per the procedure of Example 1 to give the title compound. 1H NMR (500 MHz DMSO-d6) δ 8.27 (d, 1H), 8.18 (d, 1H), 7.69-7.62 (m, 2H), 4.01 (q, 2H), 3.17 (q, 1H), 3.13 (t, 2H), 2.61 (m, 1H), 2.49 (m, 1H), 1.13 (t, 3H), 1.06 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:27])[CH:3]=1.C(N1C2C(OC3C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[S:48])=CC=3F)=NC=NC=2C=C1)C>>[C:22]([N:19]1[CH2:20][CH:21]=[C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:25]=[CH:26][C:2]([NH:1][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[S:48])=[CH:3][C:4]=3[F:27])[CH:13]=2)[CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: CCn1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reactant: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)CC1
Yield: 70 %

Procedure:
Starting from compound 391 and following the procedure described for compound 31b (Scheme 5, step 4, example 28); title compound 385 was obtained in 70% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 11.83 (s, 1H), 8.49 (dd, J=5.5 Hz, J=0.8 Hz, 1H), 8.00 (d, J=11.9 Hz, 1H), 7.58-7.49 (m, 3H), 7.41-7.35 (m, 2H), 7.21-7.13 (m, 2H), 6.65 (dd, J=5.5, 1 Hz, 1H), 6.50 (m, 1H), 4.2 (m, 1H), 4.15 (m, 1H), 3.83 (s, 2H), 3.70-3.67 (m, 2H), 2.68 (m, 1H), 2.59 (m, 1H), 2.09 (s, 1.5H), 2.04 (s, 1.5H). LCMS: 579.2 (M+H).
Reaction SMILES: [NH2:1][C:2](=S)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][NH2:10].C1COCC1>C(O)C>[NH2:1][C:2](=[N:9][NH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)=S
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(N)=NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-2-thioxoacetate (5) (5 g, 37.5 mmol) was dissolved in ethanol and cooled to 0° C. Hydrazine in THF (1M, 37.5 mmol) was added dropwise and stirred at ambient temperature for 1 h. The reaction mixture was concentrated, white flakes of ethyl 2-amino-2-hydrazonoacetate were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.S(Cl)([Cl:24])(=O)=O>C1(C)C=CC=CC=1.C(N)(C)(C)C.S(Cl)(Cl)(=O)=O>[Cl:24][C:3]1[C:2]([OH:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]2[CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: CCOC(=O)c1cc2c(Cl)c(O)ccc2n1CC(F)(F)F
Reaction time: 0.02 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.7 g, 2.44 mmol) in toluene (30 mL) was added tert-butyl amine (0.014 g, 0.2 mmol) and the mixture was set in an oil bath preheated at 70° C. After 1 min, a solution of sulfuryl chloride (0.37 g, 2.49 mmol) in toluene (1 mL) was added. The reaction was followed by TLC (60% CH2Cl2-hexanes) and additional reagents were added accordingly. After 30 min, more tert-butylamine (0.014 g, 0.2 mmol) and sulfuryl chloride (0.06 g, 0.37 mmol) were added. After another 30 min additional tert-butylamine (0.014 g, 0.2 mmol) and sulfuryl chloride (0.019 g, 0.12 mmol) were added and heating was continued for 30 min. Upon cooling, the mixture was partitioned between EtOAc and 0.2N HCl. The organic phase was washed with 0.2N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% CH2Cl2-hexanes gradient) to afford the title compound (0.72 g, 92% yield, 95% purity): MS (ES) m/z 322 (M+1).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2([C:18]([F:21])([F:20])[F:19])[O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1OCCOCCOCCOCCOCCOC1.CC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:6]([C:5]#[C:4][CH:1]3[CH2:3][CH2:2]3)([C:18]([F:20])([F:21])[F:19])[C:7]=2[CH:16]=1)[CH3:36]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1Nc2ccc(O)cc2C(C#CC2CC2)(C(F)(F)F)O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Temperature: 56 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To 120 mg (0.40 mmol) of 9 were added 12 mL of anhydrous acetone, 120 mg (0.86 mmol) of anhydrous potassium carbonate, 2 mg of 18-crown-6 and 40 μL (0.28 mmol) of ethyl 4-bromobutyrate. The reaction mixture was allowed to stir at 56° C. for 3 hours and was concentrated under reduced pressure. To the residue 20 mL of water were added followed by 1 mL of 1N HCl. The aqueous layer was extracted with 4×20 mL of dichloromethane. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 2 mm thickness, E. Merck) using 1% methanol in dichloromethane to give 45 mg (0.11 mmol, 27%) of 10 as a colorless thick oil [LC-MS; M+H 412.1].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a round bottom flask was added chloroacetyl chloride (2.0 mL, 25.0 mmol, 1.0 eq.) and CH2Cl2 (100 mL). The solution was cooled to 0° C. before a mixture of 5-amino-2-chloro-benzotrifluoride (4.88 g, 25.0 mmol, 1.0 eq.) and triethyl amine (3.56 mL, 27.5 mmol, 1.1 eq.) in CH2Cl2 (5.0 mL) was added dropwise. The reaction was then stirred at 0° C. for 1.5 h before quenching with H2O (50 mL). The organic layer was then separated, washed with brine, and dried with Na2SO4. Concentration via rotary evaporation gave acetamide 21 as a yellow solid (5.72 g, 84.7% yield). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.79 (br s, 1H), 8.20 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 4.36 (s, 2H) ppm.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:13]([OH:23])[CH:14]([NH2:22])CC1C=CC=CC=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1.O>C(O)C.ClCCl>[C:1]([NH:11][C@@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@H:13]([OH:23])[CH2:14][N:22]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:34](=[O:35])[CH2:33][C:32](=[O:36])[CH3:31])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NC(Cc1ccccc1)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
The Cbz protected amino alcohol (IX) (0.080 g, 0.19 mmol) was dissolved in 2 ml of ethanol and to this diketene (23 μL, 0.29 mmol) was added dropwise. The reaction mixture was then stirred for 1 hour and diluted with 4 ml dichloromethane. It was then poured into water and the organic layer was separated, and dried (Na2SO4). It was then subjected to silica gel chromatography with 2:1 hexane/ethyl acetate as an eluent to give the keto-amide (XI) as oil. 100 mg (98% yield) 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.52-4.87 (m, 2H), 3.75-4.00 (m, 2H), 3.28-3.51 (m, 1H), 2.75-2.94 (m, 2H), 2.43 (s, 2H), 2.05 (s, 3H). 13CNMR (125 MHz, CDCl3) 201.2, 168.4, 155.85, 140.91, 140.36, 138.22, 129.15, 128.68, 128.56, 128.37, 128.10, 127.72, 127.41, 127.64, 126.75, 80.23, 60.18, 54.14, 50.15, 7.99, 43.6, 37.43, 25.7.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O.[NH2:18][NH2:19]>CCO>[N:1]1([C:6]2[CH:16]=[CH:15][C:9]([C:10]([NH:18][NH2:19])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CCOC(=O)c1ccc(-n2cccn2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(-n2cccn2)cc1
Reaction time: 144 h

Procedure:
To a solution of ethyl 4-(1H-pyrazol-1-yl)benzoate (711 mg, 3.29 mmol) in absolute EtOH (50 mL) was added hydrazine monohydrate (1.6 mL, 32.9 mmol) at room temperature. The reaction mixture was heated to reflux and stirred for 6 d, then concentrated under reduced pressure. The residue was suspended in H2O (30 mL), filtered, washed with H2O (2×20 mL) and EtOH (2×20 mL) to provide the title compound as an off white solid (101 mg, 15%): 1H NMR (400 MHz, CDCl3, δ in ppm) 9.84 (s, 1H), 8.62-8.59 (m, 1H), 7.98-7.90 (m, 4H), 7.81-7.78 (m, 1H), 6.61-6.57 (m, 1H), 4.51 (br d, J=3.3 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(OC([NH:39][C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:39][C:40]1([C:43]([N:29]2[CH2:30][CH2:31][N:26]([CH2:25][C:4]3[S:5][C:6]4[C:11]([N:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)=[N:10][C:9]([C:18]5[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=5)=[N:8][C:7]=4[C:3]=3[CH3:2])[CH2:27][CH2:28]2)=[O:44])[CH2:42][CH2:41]1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)C3(N)CC3)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 100.8 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 70 mg 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 89.1 mg of 351 after reverse phase HPLC purification. MS (Q1) 510.3 (M)+.
Reaction SMILES: [BH4-].[Na+].[C:3]12([C:13](=[O:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C@H:27]5[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>O1CCCC1.C(O)C>[C:3]12([CH:13]([OH:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([C@H:27]5[CH2:28][CH2:29][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(=O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (38 mg, 0.1 mmol) was added to a solution of the product from Example 1F (25 mg, 0.05 mmol) in tetrahydrofuran (3 mL) and ethanol (3 mL) maintained at 0° C. The reaction was allowed to warm to room temperature over 30 min and then stirred at room temperature for 1 hour. After this time the reaction was quenched by addition of water (5 mL) and extracted with ethyl acetate. The organic extracts were combined and washed with water, brine, dried (MgSO4), filtered and concentrated to a brown oil which was purified via flash column (eluting with 15% ethyl acetate in hexanes) to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.19 (t, J=7.32 Hz, 3H), 1.42-1.99 (m, 22H), 2.22 (d, J=6.71 Hz, 2H), 2.47 (m, 1H), 3.89 (dd, J1=10.38 Hz, J2=7.94 Hz, 1H), 4.02 (m, 1H), 4.06 (q, J=7.32 Hz, 2H), 4.24 (dd, J1=10.37 Hz, J2=2.74 Hz, 1H), 4.71 (s, 1H), 6.07 (s, 1H), 7.28 (d, J=8.24 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 12.21 (br s 1H); MS (ESI) m/z 507.4 [M+H]+.
Reaction SMILES: O=C1O[N:5]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:19][CH:18]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)[O:17][C:16]3=[O:32])[CH2:9][CH2:8]2)[NH:3]1.N1(CCC(OC)=O)CCNCC1.O=C1ON=C(N2CCN(CCN3CC(CS(C)(=O)=O)OC3=O)CC2)N1.C(OCC)(=O)C>CO>[C:4]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:26]3)[O:17][C:16]2=[O:32])[CH2:11][CH2:12]1)(=[NH:3])[NH2:5]
Reactant: O=C(O)CCN1CCN(CC2CN(CCN3CCN(c4noc(=O)[nH]4)CC3)C(=O)O2)CC1
Agent: COC(=O)CCN1CCNCC1
Agent: CS(=O)(=O)CC1CN(CCN2CCN(c3noc(=O)[nH]3)CC2)C(=O)O1
Solvent: CCOC(C)=O
Solvent: CO
Product: N=C(N)N1CCN(CCN2CC(CN3CCN(CCC(=O)O)CC3)OC2=O)CC1

Procedure:
1.13 g of 3-[2-(1-(5-oxo-1,2,4-oxadiazolin-3-yl)-4-piperazinyl)ethyl]-5-[4-(2-carboxyethyl)piperazino]methyloxazolidin-2-one [obtainable according to Ex. 1 by reaction of methyl 3-piperazinopropanoate with 3-[2-(1-(5-oxo-1,2,4-oxadiazolin-3-yl)-4-piperazinyl)ethyl]-5-methanesulfonylmethyloxazolidin-2-one and subsequent hydrolysis of the product] are dissolved in 50 ml of methanol and hydrogenated on Raney Nickel. The reaction mixture is then filtered and the filtrate is concentrated in vacuo. The product obtained is treated with 20 ml of ethyl acetate in the presence of heat and filtered off with suction after cooling. 3-[2-(1-Amidino-4-piperazinyl)ethyl]-5-[4-(2-carboxyethyl)piperazino]methyloxazolidin-2-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:23][CH:22]=1.C(O)C.II>COCCOC.C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:18]2[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:33][CH:34]=2)=[CH:11][CH:12]=1
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Nc1cccnc1NCc1ccc(Cl)cc1
Agent: II
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(Cl)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 1.20 g of 3-amino-2-(4-chlorobenzyl)aminopyridine (prepared as described in Preparation 53), 1.36 g of 5-[4-(2-oxoethoxy)benzyl]-thiazolidine-2,4-dione (prepared as described in Preparation 47), 3 ml of ethanol, 3 ml of acetic acid, 1.69 g of iodine and 25 ml of 1,2-dimethoxyethane were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 0.40 g of the title compound, melting at 211-213° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC([N+]([O-])=O)=CC=3)=[C:12]([O:27][CH3:28])[CH:11]=2)S[C:6]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:3])[CH3:2]>[Ni].CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[CH2:6][CH:5]([CH2:9][CH2:8][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:27][CH3:28])[CH:11]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(OCc3ccc([N+](=O)[O-])cc3)c(OC)c2)cc1NC(C)=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)CC(CCc1ccc(O)c(OC)c1)NC(C)=O
Yield: 59.9 %

Procedure:
Methyl 3-acetamido-5-[3-methoxy-4-(4-nitrobenzyloxy)phenyl]thiophene-2-carboxylate (1.4481 g, 3.17 mmol) was reductively desulfurized using Raney nickel. The filtered solution was taken up in hot EtOAc then washed with 0.5 N HCl (2×30 mL) and H2O. The organic layer was dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (0.5620 g, 1.90 mmol, 60.0%); TLC: Rf=0.80 (Solvent L); IR (cm−1): 3498 (OH), 2905 (CH aliphatic), 1743 (ester C═O), 1663 (amide C═O), 726 (═CH); 1H nmr (CDCl3): δ 6.82 (d, 1H, J=7.9 Hz), 6.67 (m, 2H), 6.10 (br d, 1H, J=8.6 Hz), 5.56 (br s, 1H), 4.28 (m, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 2.60 (d, 2H, J=8.4 Hz), 2.55 (t, 2H, J=2.2 Hz), 1.97 (s, 3H), 1.85 (m, 2H).
Reaction SMILES: [Na].[BH4-].[Cl:3]C(C)C(O)=O.[CH:9]1[CH:14]=CC=C[CH:10]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:38])[C:22]2[O:28][C:27]3[C:29]([Cl:34])=[CH:30][C:31]([NH2:33])=[CH:32][C:26]=3[CH2:25][S:24](=[O:36])(=[O:35])[C:23]=2[CH:37]=1)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:38])[C:22]2[O:28][C:27]3[C:29]([Cl:34])=[CH:30][C:31]([NH:33][CH2:10][CH2:9][CH2:14][Cl:3])=[CH:32][C:26]=3[CH2:25][S:24](=[O:36])(=[O:35])[C:23]=2[CH:37]=1)=[O:18]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: c1ccccc1
Reactant: CC(Cl)C(=O)O
Agent: [BH4-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCCl)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium-borohydride (0.93 g, 24 mmol) was added in portions at 0° C., to a solution of chloropropionic acid (5.32 g, 49 mmol) in THF (13 mL), and benzene (210 mL). Reaction mixture was warmed to room temperature and stirred for 1 h, and compound of Example 1 (3.0 g, 8.17 mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixture was cooled and quenched using sodium bicarbonate solution, and extracted with ethylacetate. Organic layer was washed with water (100 mL) and brine (50 mL). The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet. ether) to obtain the title compound. Yield: 3.7 g (99%); 1H NMR (DMSO-d6, 300 MHz): δ 1.96 (q, 2H, CH2), 2.62 (s, 3H, CH3), 3.11 (q, 2H, CH2), 3.72 (t, 2H, CH2), 3.85 (s, 3H, OCH3), 5.12 (s, 2H, CH2), 6.29 (s, 1H, Ar), 6.31 (s, 1H, Ar), 8.07 (s, 1H, Ar), 8.13 (s, 1H, Ar); MS: m/e (EI) 443 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:15](=O)[CH3:16])=[CH:5][C:6]1[C:11]2=[N:12][O:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[CH:19]([O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26])([CH3:21])[CH3:20]>C(O)C>[CH3:16][C:15]1[NH:27][C:25]([CH3:26])=[C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:28])[CH:5]([C:6]2[C:11]3=[N:12][O:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Temperature: 26.5 °C
Reaction time: 5 h

Procedure:
Dissolved the purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester obtained in example—3 (25 g, 0.10 mol) in absolute ethanol (375 ml) and added in to the solution isopropyl-β-aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28° C. for 5 hr. Removed sample from the reaction mixture and analysed the sample by qualitative HPLC. Distilled ethanol from the reaction mixture under vacuum at 50° C. Dissolved the residue in ethyl acetate (235 ml) and washed twice with water (90 ml). Dried the organic layer over sodium sulphate and distillation under vacuum at 50° C. Dissolved the concentrate in ethanol (65 ml at 70° C. and slowly cooled to 5° C. to get the product crystallised. Filtered the product and washed with pre cooled ethanol (25 ml and dried at 70° C. under vacuum to obtain 30 g Isradipine (purity=99.4%, Impurity III=0.22%, and Impurity IV=0.11% by HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O.C(OCC)(=O)C.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.0 g) in concentrated sulphuric acid (10 ml) at 0° C. was treated with fuming nitric acid (9 ml) during 15 minutes, keeping the temperature at 5°-15° C. After 30 minutes the mixture was poured onto excess ice, and the precipitated solid was filtered off and dissolved in ethyl acetate. After drying over anhydrous magnesium sulphate, filtration, and evaporation in vacuo a brown oil was obtained. This oil was dissolved in the minimum of ethyl acetate and diluted with hexane. A pale yellow solid crystallized and this was discarded. The filtrate was evaporated in vacuo to give a solid which was recrystallized from toluene-hexane to furnish a yellow solid. One further recrystallization from the same solvent pair gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-3-trifluoromethylpyrazole as white crystals, m.p. 214°-215° C.