Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl acrylate (5.4 ml) is added. After stirring at 50° C. for 3 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) to give 3.2 g of (±)-ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)propionate as an oil. (±)-Ethyl 3-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionate (3.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (7.8 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether to give 0.1 g of (±)-3-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)propionic acid as brown crystals, melting point 210°-212° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.Cl.[OH-].[Na+]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850, mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH:4]=C.[OH2:16]>C1COCC1.O.O=[Os](=O)(=O)=O>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH:4]=[O:16])[N:11]=1
Reactant: O
Reactant: C=CCCCc1nccc(C(F)(F)F)n1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=CCCCc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-penten-1-yl)-4-(trifluoromethyl)pyrimidine (P7, 143 mg) in THF/H2O 5/1 (6.5 mL) were added OsO4 (4% in water, 0.2 mL) and NaIO4 (424 mg). The solution was stirred at r.t. for 30 min. Water was then added and the mixture extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give 91 mg of the title compound as an oil, which was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([Si:20](Cl)([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:11][Si:20]([CH3:22])([CH3:21])[C:14]([CH3:16])([CH3:15])[CH:17]([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1

Procedure:
This intermediate (hereinafter "intermediate A") was prepared in two steps. 4-Bromophenylacetic acid underwent diborane (B2H6) reduction. A solution of the resulting alcohol then underwent silylation with sodium hydride (NaH) and thexyl dimethyl silyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[F:11][C:12]1[C:13](=[NH:20])[N:14]([CH3:19])[C:15](=[O:18])[NH:16][CH:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:16]2[CH:17]=[C:12]([F:11])[C:13](=[NH:20])[N:14]([CH3:19])[C:15]2=[O:18])=[S:10])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: Cn1c(=N)c(F)cn(C(=S)Nc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
1-Chloro-4-isothiocyanatobenzene (78 mg, 0.46 mmol) was added to a stirred mixture of 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (60 mg, 0.42 mmol) and DMF (1.0 mL) and stirred at room temperature overnight. The solvent was removed and the residue was purified on normal phase chromatography (gradient, 0 to 10% MeOH-DCM). A second purification (gradient, 2 to 6% [10% NH4OH-MeOH]-DCM) gave the title compound as a yellow gum (68 mg, 52%); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.99 (s, 1H), 7.75 (d, J=39.7 Hz, 2H), 7.48-7.15 (m, 3H), 3.22 (d, J=13.8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) 6148.96, 144.90, 138.17, 136.27, 135.90, 128.51, 124.11, 123.07, 29.88; ESIMS m/z 311 ([M−H]+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:16]=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:16]([I:27])=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C(F)(F)F)nn2cc(C)nc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)c1cc(C(F)(F)F)nn2c(I)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 8-(1-ethyl-propyl)-2-methyl-6-trifluoromethyl-imidazo[1,2-b]pyridazine (0.18 g, 0.67 mmol) in CH3CN (5 mL) is treated with NIS (0.18 g, 0.80 mmol), and stirred at rt overnight. It is diluted with EtOAc (50 mL), washed with 5% Na2SO3 (2×25 mL); dried (Na2SO4), filtered and concentrated to give the title compound (0.26 g, 0.65 mmol, 98%). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 6H), 1.79-1.92 (m, 4H), 2.59 (s, 3H), 3.30-3.43 (m, 1H), 7.09 (s, 1H). ES-MS (m/z): calcd for C13H15F31N3 (M+H)+: 398.2. found: 398.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.C(Cl)Cl.[OH:35][CH:36]([CH2:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:35][CH:36]([C:37]([O:39][CH3:40])=[O:38])[CH2:41][CH3:42])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C[Si](Cl)(C)C.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CO.N1C=CC=CC=1.CN(C)C=O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CCNCC
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 7.8 h
Yield: 88.9 %

Procedure:
2-Hydroxy-2-phenylacetic acid (500 mg, 3.29 mmol) was dissolved in dichloromethane (7.5 mL). To this, pyridine (0.532 mL, 6.58 mmol), DMAP (40 mg, 0.33 mmol) and trimethylsilyl chloride (0.835 mL, 6.58 mmol) were added at room temperature and the mixture was stirred for 7.8 hours. After the reaction mixture was cooled to 0° C., N,N-dimethylformamide (0.050 mL) and oxalyl chloride (0.301 mL, 3.45 mmol) were added thereto, and the mixture was stirred at a temperature of 0° C. to room temperature for 1 hour. After the reaction mixture was cooled to 0° C. again, a pyridine solution (0.878 mL) of diethylamine (0.374 mL, 3.62 mmol) was added thereto, and the mixture was stirred at a temperature of 0° C. to room temperature for 2 hours. Then, a methanol solution (5 mL) of citric acid (695 mg, 3.62 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. After addition of ethyl acetate, the reaction mixture was filtered. One mol/L hydrochloric acid was added to the filtrate, and extraction with ethyl acetate was performed, followed by washing with saturated sodium carbonate and brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby N,N-diethyl-2-hydroxy-2-phenylacetamide (Compound ED) (606 mg, yield: 89%) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]=1[OH:10])[CH:2]=[CH2:3].[I:28]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]2[N:8]([C:9]3[O:10][CH:2]([CH2:3][I:28])[CH2:1][C:4]=3[CH:5]=[N:6]2)[N:11]=1
Reactant: C=CCc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c4c(cnc23)CC(CI)O4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-allyl-3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-15A-1a; 25 mg, 0.063 mmol) in 9:1 methylene chloride/chloroform (0.63 ml) at 0° C. was added N-iodosuccinimide (15 mg, 0.066 mmol), portionwise. The reaction was stirred overnight at room temperature and then extracted from water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo. Purification on a Biotage™ Flash 12S column using 20% ethyl acetate in hexanes as eluant afforded compound 15A-1 (15 mg, 46%) as a solid: +ESI MS (M+1) 522.3; 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.53–7.40 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 5.45–5.41 (m, 1H), 3.81–3.64 (m, 2H), 3.33 (d, J=6.2 Hz, 2H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=O)=CC=1)([O-])=O.C[O:44][C:45](=[O:54])[CH2:46][CH2:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:35])([F:34])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:51]5[CH2:52][CH2:53][CH:48]([CH2:47][CH2:46][C:45]([OH:44])=[O:54])[CH2:49][CH2:50]5)=[O:10])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)CCC1CCNCC1
Product: O=C(O)CCC1CCN(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1

Procedure:
With a procedure similar to above, 3-[1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidin-4-yl]-propionic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-propionic acid methyl ester. LCMS calcd for C31H33F3N4O5 (m/e) 598, obsd 599 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl.C(N(S(C1C=CC(C)=CC=1)(=O)=O)[C@H](C(O)=O)CCCCN)C(C)C.[N+](C1C=CC(S(N[C@H](C(O)=O)CC2C3C(=CC=CC=3)NC=2)(=O)=O)=CC=1)([O-])=O.[CH3:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([N:63]([C@H:68]([C:100]([OH:102])=[O:101])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]([NH:87][S:88]([C:91]2[CH:96]=[CH:95][C:94]([N+:97]([O-])=O)=[CH:93][CH:92]=2)(=[O:90])=[O:89])[CH2:77][C:78]2[C:86]3[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=3)[NH:80][CH:79]=2)=[O:75])[CH2:64][CH:65]([CH3:67])[CH3:66])(=[O:62])=[O:61])=[CH:56][CH:55]=1>>[CH3:53][C:54]1[CH:55]=[CH:56][C:57]([S:60]([N:63]([C@H:68]([C:100]([OH:102])=[O:101])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]([NH:87][S:88]([C:91]2[CH:92]=[CH:93][C:94]([NH2:97])=[CH:95][CH:96]=2)(=[O:89])=[O:90])[CH2:77][C:78]2[C:86]3[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=3)[NH:80][CH:79]=2)=[O:75])[CH2:64][CH:65]([CH3:67])[CH3:66])(=[O:61])=[O:62])=[CH:58][CH:59]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Agent: Cl
Agent: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc(N)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine hydrochloride (200 mg, 0.59 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-nitrobenzenesulfonyl)-L-tryptophan (300 mg, 0.75 mmol) prepared in step A of example 5. The intermediate, Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-nitrobenzenesulfonyl)-L-tryptophanyl]-L-lysine, was reduced following the conditions of general procedure E. The final product was purified by preparative HPLC to yield 266 mg (58%) of the desired material.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[OH:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[CH3:31][C:32]1([CH3:34])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:30][CH:29]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:17]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 1.9 g (4.5 mmol) of N1-(4-hydroxybenzyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 30 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized with 80% aqueous acetonitrile to obtain 0.4 g of colorless crystals having a melting point of 109 to 111° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:24][NH:25][CH2:26][C:27]#[N:28].CCN=C=NCCCN(C)C>C(O)C.ClCCl>[C:27]([CH2:26][N:25]([CH3:24])[C:19]([C:17]1[S:18][C:14]([C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:22])[CH3:23])=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)=[CH:15][CH:16]=1)=[O:20])#[N:28]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(C(=O)O)s3)nc12
Reactant: CNCC#N
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCO
Product: CN(CC#N)C(=O)c1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)s1
Yield: 58.3 %

Procedure:
A solution of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.060 g, 0.18 mmol), methylaminoacetonitrile (0.200 mL, 1.64 mmol) and EDCI (0.315 g, 1.64 mmol) in 3 mL of ethanol and 3 mL of dichloromethane was stirred for 1 h, then concentrated. The resulting residue was partitioned between 30 ml of ethyl acetate and 30 mL of a 10% citric acid solution, and the aqueous layer was extracted 30 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->40% EtOAc/hexanes) afforded 0.040 g (58%) of 5-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid cyanomethyl-methyl-amide as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.17) (178 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a brown solid (176 mg, 69%). MS (ISN) 511.2 [(M+H)+]; mp 290° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[N:6][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)[C:4]2[N:26]=[CH:27][CH:28]=[CH:29][C:3]1=2.[OH-].[K+].Cl>CO>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[N:6][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)[C:4]2[N:26]=[CH:27][CH:28]=[CH:29][C:3]1=2
Reactant: CCOC(=O)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Yield: 17.7 %

Procedure:
Ethyl 4-oxo-1-(3-(pyridin-3-ylthio)phenyl)-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylate (1.2 g, 3 mmol) was dispersed in 100 ml of methanol, KOH (840 mg, 15 mmol) was added, reacted at 40° C. for 4 h. The reaction solution was regulated with hydrochloric acid to pH 7, precipitated out solid, suction filtrated and dried to obtain an object product 200 mg.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][N:17]12.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([C:23]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22][N:17]2[C:18]3[C:14]([CH:15]=[C:16]2[CH2:25][CH2:24]1)=[CH:13][CH:21]=[CH:20][CH:19]=3)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCc2cc3ccccc3n2C1
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)CC1(C(=O)OCC)CCc2cc3ccccc3n2C1
Reaction time: 0.17 h

Procedure:
A stirred solution of 2.52 ml of diisopropylamine in 20 ml of THF was cooled in a bath at -78° C. under an argon atmosphere and treated with 11.25 ml of a 1.6M solution of n-butyllithium in n-hexane. The mixture was treated with a solution of 2.85 g of ethyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-7-carboxylate in 80 ml of THF. After 10 minutes, 1.46 ml of ethyl bromoacetate were added and the cooling bath was removed. The mixture was stirred and then diluted with diethyl ether. The solution was washed in succession with saturated aqueous ammonium chloride, water and sodium chloride solution and then dried. The solvent was removed by evaporation and the residue was subjected to chromatography on silica gel using ethyl acetate/n-hexane (1:9) for the elution to give 2.55 g of ethyl 7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indole-7-acetate.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:17][C:13]1[S:14][CH:15]=[CH:16][C:12]=1[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1ccsc1Br
Temperature: 25 °C
Yield: 94 %

Procedure:
3-decyloxy-thiophene (5.50 g, 0.023 mol) was dissolved in CHCl3 (50 mL) under argon atmosphere. N-Bromosuccinimide (NBS) (4.09 g, 0.023 mol) was added to the solution as one portion. The mixture was reacted under argon and protected from light for 4˜8 hours at room temperature (25° C.). Afterwards it was distilled to remove CHCl3, allowed to cool to room temperature, and diluted with hexane (100 mL). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was applied to silica gel, eluted with 1:9 ethyl acetate/hexane to give 6.97 g (94% yield) of light yellow liquid. Mw=319.30. Element Anal. Calcd. for C14H23BrOS: C, 52.66; H, 7.26; Br, 25.02; 0, 5.01; S, 10.04. Found: C, 52.62; H, 7.25; Br, 24.90; 0, 5.09; S, 10.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Reaction time: 1 h

Procedure:
While cooling with ice, a solution of 3,4-dimethoxyphenylacetyl chloride (485.2 g) in methylene chloride (1.1 liters) is added dropwise at 15°-20° C. to a solution of aminoacetaldehyde dimethyl acetal (246.2 ml) and triethylamine (315 ml) in methylene chloride (2.2 liters) and the mixture is stirred for one hour at 16°-18° C. It is then extracted several times with water, dried over magnesium sulphate and concentrated by evaporation. The oil obtained slowly crystallizes out. Yield: 608 g. Mp: 66°-69° C.