Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.C.[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:15]=[O:14]
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(N=C=O)c1
Temperature: -20 °C

Procedure:
Methyl 3-isocyanatophenylacetate is prepared as follows: at a temperature in the vicinity of -20° C. and under argon, 8.25 g of methyl 3-aminophenylacetate in solution in 100 cm3 of toluene are added to a suspension of 1 g of charcoal and 6 cm3 of diphosgene in 70 cm3 of toluene. The reaction mixture is stirred and maintained at -20° C. for 15 minutes, then, after returning to a temperature in the vicinity of 20° C., heated under reflux for 2 hours and 30 minutes. The mixture is then degassed by bubbling through argon for 30 minutes, filtered on Celite, rinsed with 50 cm3 of dichloromethane and concentrated under reduced pressure at a temperature in the vicinity of 50° C. 9.30 g of methyl 3-isocyanatophenylacetate are thus obtained in the form of a yellow liquid stored under argon and used as it is in subsequent syntheses.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:21](O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][NH2:25]>CS(C)=O.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH:21]=[N:24][NH:25]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)c1c(F)cccc1N1CCN(Cc2ccccc2)CC1
Solvent: CS(C)=O
Solvent: CCOCC
Product: c1ccc(CN2CCN(c3cccc4[nH]ncc34)CC2)cc1
Reaction time: 8 h
Yield: 53 %

Procedure:
A stirred solution of 4-benzyl-1-(3-fluoro-2-carboxyphenyl)-piperazine (5.96 g, 20.0 mmol) in dimethylsulfoxide (10 mL) and hydrazine (10 mL) is heated at 95° C. under nitrogen for 4 days. The cooled reaction is diluted with ether and washed with a mixture of water and saturated aqueous sodium bicarbonate. The organic layer is further washed sequentially with water and brine dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using ethyl acetate as the eluant. The resulting oil is reconcentrated from ether to give a white foam which is stirred under hexanes/ether overnight. The resulting white powder is isolated by suction filtration and washed with hexane to give the title compound 3.11 g, (53% yield), identified by HNMR.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([O:53]C)=O)=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.N>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([NH2:2])=[O:53])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: N
Product: NC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and ammonia. m/e+ 355 for C17H13F2N6O (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15](OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.O>C1COCC1.[NH4+].[OH-]>[CH2:1]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@@H]2C[C@H]1CN2Cc1ccccc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of (1S,4S)-2-benzyl-5-ethoxycarbonyl-2,5-diazabicyclo(2.2.1)heptane (3.3 g, 0.013 mol) in THF at -10° C., was added dropwise 1M LiAIH4 in ether (26.3 mL, 0.026 mol). The reaction mixture was slowly warmed to room temperature and mixed overnight. Upon cooling to 0° C., 4 mL of 95% THF:H2O was slowly added followed by 4 mL of H2O. The mixture was diluted with NH4OH (40 mL), filtered through a celite pad and concentrated in vacuo. The remaining NH4OH solution was further diluted with NH4OH (15 mL) and extracted with CH2Cl2. The combined organic phases were dried (K2CO3) and concentrated in vacuo to yield (1S,4S)-2-benzyl-5-methyl-2,5diazabicyclo(2.2.1)heptane (2.2 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(N(CC)CC)C>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[C:26]([F:25])([F:36])[F:37])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1.44 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.15 g of triethylamine and 0.300 g (1.44 mmol) of 2-trifluoromethylbenzoyl chloride is stirred at room temperature for 2 hours and then washed with 1N HCl 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give a solid. Crystallization from dichloromethane-hexane gives 0.41 g of crystals, m.p. 191°-193° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:31][CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=5)[C:23]4=[O:34])=[CH:18][C:17]=3[F:35])[CH2:12]2)[O:10][CH2:9][CH2:8]1.C1(S)C=CC=CC=1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[O:10]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:31][CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([OH:32])[CH:28]=5)[C:23]4=[O:34])=[CH:18][C:17]=3[F:35])[CH2:12]2)[O:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CCC4(C3)OCCO4)c(F)c1)C2=O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1c2ccc(O)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Temperature: 200 °C

Procedure:
Potassium carbonate (2.5 g) was added to a mixture of 2-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (7.2 g) and thiophenol (2 g) in NMP (80.2 mL). Small portions of the reaction mixture were each heated for 20 min at 200° C. in a microwave. Then ethyl acetate and water were added to the mixture. The aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 384.41 (C21H21FN2O4); MS (ESI): 385 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:19][C:6]([CH3:20])([CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)[CH2:5][OH:4]
Reactant: CC(=O)OCC(C)(C)Cn1cnc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(CO)Cn1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propyl acetate (20 mg) in methanol was added saturated solution of K2CO3 in metanol (1.5 mL) and the resulting solution was stirred at room temperature for 1 hour. MeOH was evaporated in vacuo and water was added followed by CH2Cl2. The aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound as a slightly yellow oil.
Reaction SMILES: COC1N=C2C(=CC=1)N=CC=C2N1C=C2C(CCC(NCCCC3C=CC=CC=3C)C2)=N1.[CH3:33][O:34][C:35]1[N:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][CH:39]=[C:38]2[N:45]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][CH:50]([NH:54][C:55](=O)[CH2:56][CH2:57][C:58]3[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=3)[CH2:51]2)=[N:46]1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.O>[CH3:33][O:34][C:35]1[N:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][CH:39]=[C:38]2[N:45]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][CH:50]([NH:54][CH2:55][CH2:56][CH2:57][C:58]3[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=3)[CH2:51]2)=[N:46]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NC(=O)CCc3ccc(C)cc3)C4)c2n1
Agent: CC(C)C[AlH]CC(C)C
Agent: COc1ccc2nccc(-n3cc4c(n3)CCC(NCCCc3ccccc3C)C4)c2n1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCCCc3ccc(C)cc3)C4)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(3-o-tolyl-propyl)-amine. A solution of N-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-3-p-tolyl-propionamide (0.020 g, 0.045 mmol) in CH2Cl2 (2 mL) was treated with DIBAL-H (1 M solution in THF, 0.45 mL, 0.45 mmol) at −78° C. for 30 min. The reaction mixture was warmed to 0° C. and stirred for 20 min, then at RT for 1 h. Satd. potassium sodium tartrate solution (5 mL) was added at −30° C. The solution was warmed to RT and stirred for 1 h. Water (10 mL) was added, and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO4), filtered, and concentrated. The crude was purified on SiO2 (0-5% CH3OH/CH2Cl2) to give 10 mg (53%) of the title compound as a clear oil. MS (ESI): exact mass calculated for C26H29N5O, 427.24; m/z found, 428.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.10 (s, 1H), 8.77 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.1, 1H), 7.19 (d, J=9.1, 1H), 7.09 (s, 4H), 4.10 (s, 3H), 3.03-2.95 (m, 3H), 2.84-2.76 (m, 3H), 2.68-2.64 (m, 2H), 2.54-2.50 (m, 1H), 2.31 (s, 3H), 2.15-2.13 (m, 1H), 1.91-1.80 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([N:16](CC)[C:17](=O)[C:18](F)(F)F)=[C:9]([I:25])[CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.C[O-].[Na+].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH2:17][CH3:18])=[C:9]([I:25])[CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCN(C(=O)C(F)(F)F)c1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1c(N)cc(-c2c(C)noc2C)cc1I
Temperature: 25 °C
Yield: 28 %

Procedure:
Crude N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide (1.5 g, 3.1 mmol) was dissolved in 100 mL of methanol. To the mixture was added 1M sodium methoxide in methanol (15.5 mL, 15.5 mmol) and reaction stirred at room temperature until complete. Reaction was then quenched with 15 mL of 1M HCl or until pH is approximately neutral then diluted with aqueous ammonium chloride. Methanol was removed under reduced pressure and then remaining suspension was extracted with EtOAc. The solution was washed with water, brine then dried over sodium sulfate. Solvents were removed under reduced pressure the residue was then dissolved in 20 mL of ethanol and placed in a sealed pressure tube with stannous chloride (2.2 g, 11.62 mmol). The mixture was heated at 120° C. for 1 hour. Reaction mixture was cooled to room temperature. To the mixture was added 1M NaOH (10 mL) and the mixture was stirred at room temperature for 30 minutes. At this point the reaction mixture was diluted with water and extracted with EtOAc (3 times). The solution was washed with water, brine and dried over sodium sulfate. Solvents were removed under reduced pressure and crude product was purified by silica gel chromatography (Hexanes/EtOAc as the eluent) to provide 4-(3,5-dimethylisoxazol-4-yl)-N1-ethyl-6-iodobenzene-1,2-diamine (310 mg, 22%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
A solution of 2.58 g of (RS)-2'-(2-oxoethyl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 1.98 g (67%) of (R)-1-[7'-methoxy-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[CH:18]=[C:17]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:21][CH2:20][CH2:19][C:17]1[S:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([O:9][CH:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:29])[CH3:1])[CH2:4][CH2:5]3)[C:11]=2[CH:18]=1
Reactant: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCC(Oc2ncnc3sc(CCN)cc23)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate (140 mg, 0.33 mmol, 1.00 equiv) in 5 mL of DCM was added CF3COOH (0.5 mL) at room temperature. The resulting solution was stirred for 5 h at ambient temperature and then concentrated under vacuum to give the desired 4-[[6-(2-aminoethyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N,N-dimethylcyclohexan-1-amine trifluoroacetate (100 mg) as a yellow oil which was used directly without further purification. MS (ES): m/z 321 (M+H)+.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15]4[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=4[N:13]=[CH:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CO>[C:21]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([N:11]4[C:15]5[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=5[N:13]=[CH:12]4)[CH:6]=3)[NH:2][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: O=C1CCCCC1
Reactant: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Agent: [Na]
Solvent: CO
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCCCC3)c2c1
Yield: 24.3 %

Procedure:
To a stirred solution of sodium (0.325 g, 14.2 mmol, 7.0 equivalents) in absolute methanol (10 mL) was added 1-(indol-5-yl)-5-methylbenzimidazole (0.500 g, 2.02 mmol) and cyclohexanone (0.84 mL, 8.08 mmol, 4.0 equivalents), and the resulting reaction solution was heated at reflux under nitrogen for 12 hours. The resulting mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and eluted with 20% ethyl acetate in methylene chloride to afford the title compound (0.160 g, 0.49 mmol, 24%) as a pale yellow foam. Mp, 101.0°-102.0° C.; Rf =0.75 in 5% MeOH in methylene chloride; 1H NMR (CD3OD) d 8.25 (s, 1H), 7.88 (s, 1H), 7.53-7.50 (m, 2H), 7.35-7.33 (m, 2H), 7.21 (br d, J=8.5 Hz, 1H), 7.12 (d, J=8.2 Hz, 1Hz), 6.14 (br m, 1H), 4.90 (s, 1 exchangeable H), 2.46 (s, 3H), 2.19 (br m, 2H), 1.86-1.75 (m, 2H), 1.75-1.63 (m, 2H); IR (KBr) 2929, 2859, 1615, 1579, 1494, 1447 cm-1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:42]=3)[C:37](O)=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>>[C:48]([O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@H:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:29]2[C:30]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:37]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])=[O:38])=[CH:46][CH:45]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CN[C@H](C)c1ccccc1)OCC
Product: CCOC(CN(C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C)c1ccccc1)OCC
Yield: 87.7 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (R)-2,2-diethoxy-N-(1-phenylethyl)ethanamine (Compound IX-14) (50.0 g, 210 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (101.1 g, 220 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (125.0 g, 87%).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:34][C:35]([CH3:42])([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:42])([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 440 mg (1.12 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 310 mg (1.22 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 70° C. for 6 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 522 mg of a black powder (yield: 74.3%; mp: 205-207° C.)
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12]I>CC(C)=O>[CH3:12][S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(S)n1
Solvent: CC(C)=O
Product: CCOC(=O)c1c[nH]c(SC)n1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a suspension of ethyl 2-mercapto-1H-imidazole-4-carboxylate (4.00 g, 23.3 mmol) in acetone (30 mL) at room temperature, MeI (6 mL, 96.3 mmol) was added. During first 10 min of stirring, the suspension became clear, then it turned cloudy as product began to precipitate out. After being stirred at room temperature overnight, the precipitate was collected, dried on vacuum to give ethyl 2-(methylthio)-1H-imidazole-4-carboxylate (3.47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18](C3CCN(C(OC(C)(C)C)=O)CC3)=[CH:17][C:15]=2[N:16]=1.F[C:35](F)(F)[C:36](O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH:36]3[CH2:35][CH2:15][NH:16][CH2:12][CH2:3]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3sc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(C4CCNCC4)cc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate (190 mg, 0.38 mmol) dissolved in DCM, cooled to 0° C., trifluoroacetic acid (0.8 ml) was added and stirred the reaction mixture at rt for 3 h. DCM and trifluoroacetic acid was removed on rotavapour to obtain the crude. Crude was washed with petether to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole (190 mg) as an off-white solid. 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole (190 mg, 0.38 mmol) dissolved in DCM (20 ml). To this mixture added TEA (0.3 g, 3 mmol) and stirred the reaction mixture at rt for 30 mins. Reaction mixture cooled to 0° C. and added isopropylchloro formate (92 mg, 0.75 mmol). This mixture was stirred at rt for 30 mins. Work up (DCM/H2O) followed by evaporation of the DCM on rotavapour afforded crude. Crude was triturated with diethyl ether and dried on high vacuum to afford the titled compound (60 mg) as a white solid. M.P.: 163-166° C. 1H-NMR (δ ppm, CDCl3, 400 MHz):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.[NH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:48])[C@@H:36]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:47])=[N:43][N+:44]([O-:46])=[O:45])[NH2:37])=[CH:29][CH:28]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[NH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][NH:34][C:35](=[O:48])[C@@H:36]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:47])=[N:43][N+:44]([O-:46])=[O:45])[NH:37][C:10](=[O:12])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:32]=1)=[O:24]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: COc1ccc(C(C(=O)O)c2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc(C(C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccc(OC)cc2)cc1
Yield: 48 %

Procedure:
Prepared analogously to Example 14c) from bis-(4-methoxyphenyl)-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamidehydrochloride and TBTU in a yield of 48% of theory. Colourless crystals, Mp. 149-151° C. (Acetonitrile).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=3)=[O:29])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccnc(CSc2nc3cc(C(F)(F)F)ccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccnc(CS(=O)c2nc3cc(C(F)(F)F)ccc3[nH]2)c1

Procedure:
0.1 g of the title compound of m.p. 166° C. (with decomposition, recrystallized twice from isopropanol) is obtained, by a method analogous to that in Example 1, starting from 0.3 g (0.92 mole) of 5-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole and 0.3 g of 85% strength m-chloroperoxybenzoic acid.