Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1C(C1C=CC(Cl)=CC=1)O)=[O:5])[CH3:2].[F:24][C:25]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]=1[N:27]([C:26]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=1[F:24])[C:28]1[CH:26]=[CH:25][C:31]([Cl:32])=[CH:30][CH:29]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1cccc(Cl)c1F
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1cccc(Cl)c1F

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 2-fluoro-3-chloro-aniline as starting materials; 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.46 (d, 2H), 7.30 (d, 2H), 6.98 (dd, 1H), 6.82 (d, 1H), 6.73-6.69 (m, 2H), 4.82 (sep (1H), 4.26 (q, 2H), 1.45 (d, 3H), 1.24 (t, 3H), 1.17 (d, 3H).
Reaction SMILES: II.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:50])[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[NH:24][C:23]=2[N:22]=[C:21]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3([C:46]([F:49])([F:48])[F:47])[NH:45][NH:44]3)[CH:38]=2)[N:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>C(Cl)Cl>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:50])[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[NH:24][C:23]=2[N:22]=[C:21]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3([C:46]([F:47])([F:48])[F:49])[N:44]=[N:45]3)[CH:38]=2)[N:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)NN4)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)N=N4)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
Iodine (27.8 mg, 0.110 mmol) was added to a 5 mL round-bottomed flask protected from light and pre-charged with methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(3-(trifluoromethyl)diaziridin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (70 mg, 0.104 mmol) and triethylamine (43.6 μL, 0.313 mmol) in DCM (2 mL) to give a light yellow solution. After stirring at 20° C. for 15 minutes, the solvent was evaporated and the residue purified by flash chromatography to give methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (65 mg, 0.097 mmol, 93% yield) as a light yellow foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.53 (dt, J=13.8, 7.0 Hz, 2H) 1.70-1.82 (m, 2H) 2.15 (br. s., 3H) 2.24-2.34 (m, 2H) 2.34-2.42 (m, 2H) 2.87-2.98 (m, 2H) 3.55-3.66 (m, 2H) 3.88 (s, 3H) 4.10 (s, 2H) 6.76 (br. s., 1H) 7.14 (d, J=8.2 Hz, 1H) 7.27 (s, 1H) 7.43 (t, J=7.8 Hz, 1H) 7.49-7.58 (m, 2H) 7.83 (dd, J=8.2, 1.4 Hz, 1H) 7.99 (d, J=1.4 Hz, 1H) 8.27 (d, J=8.2 Hz, 1H) 12.06 (s, 1H); MS m/z 669.2 (M+H)+; HPLC 97.6% @ 220 nm and 97.3% @ 254 nm, RT=2.18 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(CC)C.Cl[C:27](=[O:42])[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Cl)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of 5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.338 g, 1.09 mmol, Adesis) in THF (5.5 mL) at about −78° C. was added sec-butyllithium (1.015 mL, 1.421 mmol) drop-wise. The reaction mixture was stirred at about −78° C. for about 1 h then a suspension of tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (0.429 g, 1.64 mmol, Preparation #WWWW.1) in THF (2 mL) was added. The reaction mixture was stirred at about −78° C. for about 1 h then allowed to reach ambient temperature. Water (5 mL) was added and the product was extracted into DCM (3×10 mL). The combined organic extracts were washed with brine and dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to afford tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (0.147 g, 25%) as a colorless oil: LC/MS (Table 1, Method r) Rt=3.97 min; MS m/z: 534/536 (M+H)+
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.[CH2:27]=[O:28]>C1COCC1>[Br:19][C:20]1[N:21]=[C:22]([F:26])[C:23]([CH2:27][OH:28])=[CH:24][CH:25]=1
Reactant: Fc1cccc(Br)n1
Reactant: C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCc1ccc(Br)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To Diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) at 0° C. was added N-Butyllithium (2.5 mol/L) in Hexane (24.001 mmol; 9.6 mL). The reaction was stirred at 0° C. for 0.5 h, and then cooled to −78° C. 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 2.5 h. Paraformaldehyde (40.002 mmol; 3603.3 mg) was added rapidly. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and the residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to afford (6-bromo-2-fluoro-3-pyridyl)methanol (1.4888 g, 36%).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6](#[N:8])[CH3:7].O1P2[O:15][P:16]3[O:18]P(O2)OP1[O:17]3>C(O)C.O.C(O)(=O)C.C(#N)C.C(O)(=O)C>[NH2:8][C:6]([P:16]([OH:15])(=[O:17])[OH:18])([P:16]([OH:18])(=[O:15])[OH:17])[CH3:7]
Reactant: CC#N
Reactant: O1P2OP3OP1OP(O2)O3
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 66 %

Procedure:
48.8 g (0.63 mol) ammonium acetate was suspended in 68 g (1.66 mols) acetonitrile in a flask which was scavenged with nitrogen, provided with an agitator and had a fractionating column mounted thereon, and the suspension was heated to about 80° C. under reflux. Next, 46.4 g (0.21 mol) molten P4O6 was added dropwise to the boiling mixture, the temperature being maintained at 80°-90° C. While the temperature was gradually increased to 160° C., 85.1 g distillate containing 91.5% acetonitrile and 8.2% acetic acid, corresponding to 77.9 g (0.190 mol)acetonitrile and 7.0 g (0.24 mol) acetic acid, was removed through a short column at a head temperature of 84°-89° C. After deduction of the acetonitrile feed material, 11.9 g (0.24 mol) acetonitrile was found to have been obtained as by-product. The acetonitrile/acetic acid mixture was recycled, after conversion of the acetic acid to ammonium acetate. The colorless residue retained in the flask was boiled for a short while in an ethanol/water-mixture (4:1) and 57.1 g 1-aminoethane-1,1-diphosphonic acid was obtained in a yield of 66%.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(O)c1cccc(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a methanol (20 ml) solution of 2-amino-3′-tritylaminomethyl-5-chlorobenzophenone (2 g) was added sodium borohydride (227 mg). The mixture was stirred for 3 hours at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and then dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the-object 2-amino-5-chloro-α-(3-tritylaminomethylphenyl)benzyl alcohol (2.0 g) as a colorless oily product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[OH2:22].[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][S:18](=[O:22])[CH2:19][CH2:20]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN1CCN(C)C1=Nc1ccccc1N1CCSCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCN(C)C1=Nc1ccccc1N1CCS(=O)CC1

Procedure:
Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10° C. yielded 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]thiamorpholine-1-oxide monohydrate (m.p. 103°-105° C.) which was recrystallised from a 1:1 mixture of 1,2-dimethoxyethane and hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Cl>CC(C)=O>[Cl-:1].[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29][N+:8]1[CH:9]=[CH:10][N:6]([CH2:5][CH:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:3]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=2[Cl:1])[CH:7]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Solvent: CC(C)=O
Product: Clc1ccc(COC(Cn2cc[n+](Cc3ccc(Cl)cc3Cl)c2)c2ccc(Cl)cc2Cl)c(Cl)c1
Product: [Cl-]

Procedure:
15 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole and 60 parts of 2,4-dichlorobenzyl chloride are mixed together in 120 parts of acetone as solvent and the resulting mixture is stirred at reflux temperature for 40 hours. At the end of this period, the mixture is warmed to evaporate off most of the solvent and the residue is poured onto diisopropyl ether, whereupon the 1-(2,4-dichlorobenzyl)-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazolium chloride product separates as an oil. The ether is decanted off and the oily residue is washed with warm xylene and thereafter triturated in 2-propanol whereupon the oily product solidified. The solid product is filtered off, washed with 2-propanol and dried to obtain a purified product, 1-(2,4-dichlorobenzyl)-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazolium chloride, m.p. 178.9° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH2:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:39](=[O:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C(Cl)Cl>[C:39]([C:35]1[CH:34]=[C:33]([NH:30][C:31]([NH:18][C:5]2[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:16])([F:17])[F:15])[N:7]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)=[O:32])[CH:38]=[CH:37][CH:36]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: Nc1cc(C(F)(F)F)nn1-c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)Nc2cc(C(F)(F)F)nn2-c2ccccc2C(F)(F)F)c1
Yield: 26.3 %

Procedure:
To a solution of 5-trifluoromethyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine (97 mg, 0.33 mmol) and DIEA (57 μL, 0.33 mmol) in DCM (2 mL) was added 3′-isocyanato-acetophenone (41 μL, 0.30 mmol). After 15 h the reaction mixture was concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to yield the title compound (36 mg). 1H-NMR (DMSO-d6): δ 9.67 (1H, s), 8.24 (1H, m), 7.99 (1H, d), 7.94-7.80 (3H, m), 7.69 (1H, d), 7.62 (1H, d), 7.48 (1H, t), 6.31 (2H, s), 2.57 (3H, s); MS (ES): 457 [M+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH3:12].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[N:30]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][CH:23]=2)[N:18]([CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=2)[CH:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: BrCc1cccc(Br)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.3 %

Procedure:
25.6 mL of potassium hexamethyldisilazane (12.91 mmol, 0.5 M in tolene) was added to 2.5 g (10.76 mmol) of 7-Methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester dissolved in 22 mL of tetrahydrofuran and was stirred at room temperature for 15 minutes. 3.24 g (12.91 mmol) of 2-Bromo-6-bromomethyl-pyridine was added and stirred at room temperature for 2.5 h. Water and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and dried in vacuo. The crude product was purified on silica gel eluting with 50/50 ethyl acetate/hexane to yield 0.620 g of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[NH:10][NH:9][C:8]1=[O:13].COC(N1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24])=O>C([O-])(O)=O.[Na+]>[O:23]=[C:22]1[CH:21]=[CH:20][C:19](=[O:24])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:13])[NH:9][NH:10][C:11]1=[O:12]
Reactant: NCCCCn1c(=O)[nH][nH]c1=O
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1C=CC(=O)N1CCCCn1c(=O)[nH][nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To 4-(4-aminobutyl)-1,2,4-triazolidine-3,5-dione hydrochloride (I-14a: 42 mg, 0.201 mmol) in NaHCO3 sat aqueous solution (1.006 mL) at 0° C. was added N-methoxycarbonylmaleimide (31.2 mg, 0.201 mmol). The mixture was stirred at 0° C. for 1 h, and then at room temperature for 2 h. The mixture was purified by preparative hplc (0-60% CH3CN/(0.1% TFA in H2O)), and then lyophilized, giving 4-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-1,2,4-triazolidine-3,5-dione (I-14b: 10 mg, 20%) a white solid. LC-MS (M+1) 253.3, t=0.89 minute. 1H NMR (400 MHz, CD3CN) δ ppm 1.51-1.62 (m, 4H) 3.45 (t, J=6.44 Hz, 2H) 3.49 (t, J=6.44 Hz, 2 H) 6.76 (s, 2 H) 7.52 (br. s., 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](OC(C)C)(C)[CH3:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:27]=[CH2:28])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: CC(C)OC(C)C
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)CC2

Procedure:
The compound is obtained by following the procedure described in Preparation I step b) but starting from the product obtained in step b) above. Yield: 7 g. M.p. 89°-91° C. (isopropyl ether). [α]D20 =+40° (c=0.3%, CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[CH:34][N:33]=1)=[O:31].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH:38][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][N:33]=1)=[O:31]
Reactant: COC(=O)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 196.4 mg, 0.59 mmol) in methylene chloride (3 mL) was cooled to 0° C. The reaction mixture was then treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (109 μL, 1.25 mmol). The reaction mixture was stirred at 0° C. for 15 min and then at 25° C. for 2 h. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (1 mL) and cooled to 0° C. To this solution was added a suspension of 5-amino-pyrazine-2-carboxylic acid methyl ester (100.0 mg, 0.65 mmol) and pyridine (53 μL, 0.6529 mmol) in warm methylene chloride (2 mL). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was then concentrated in vacuo. The reaction material was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (100 mL), a saturated aqueous sodium chloride solution (100 mL), a 1N aqueous hydrochloric acid solution (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 ethyl acetate/hexanes) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl ester (225.9 mg, 82%) as a white foam: mp 94–97° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H24ClN3O5S (M+H)+466.1198, found 466.1204.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:11][F:12])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.C([O-])(=O)C.[Na+].BrBr.[F:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)(=O)C.C(#N)C>[CH3:1][C:2]([CH3:13])([CH2:11][F:12])[C:3](=[O:10])[CH:4]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[N:27]=1)[N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Reactant: Oc1cccc(F)n1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(CF)C(=O)C(Oc1cccc(F)n1)n1cncn1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
18.5 g (0.1 mole) of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one were dissolved in 150 ml of glacial acetic acid, and, after adding 8.2 g (0.1 mole) of sodium acetate, 16 g (0.1 mole) of bromine were added dropwise at 45° C., until the mixture was completely decolorized. The mixture was then poured into ice-water and extracted with chloroform. The combined chloroform extracts were washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The oily 1-bromo-3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-butan-2-one which remained was dissolved in 50 ml of acetonitrile, and 11.3 g (0.1 mole) of 6-fluoro-2-hydroxy-pyridine and 10.5 g (0.1 mole) of triethylamine, both dissolved in 120 ml of acetonitrile, were added, while stirring. The mixture was stirred under reflux for 1 hour. It was then concentrated by distilling off the solvent in vacuo, and the residue was stirred with water. The crystalline precipitate formed was filtered off and recrystallized from cyclohexane. 20 g (68% of theory) of 3,3-dimethyl-4-fluoro-1-(6-fluoro-pyridin-2-yl-oxy)-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 116° C. were obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[K].CN(C)C=O.[CH2:21]([N:23]([CH2:26][CH2:27]Cl)[CH2:24][CH3:25])[CH3:22]>O>[CH2:21]([N:23]([CH2:26][CH2:27][O:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:24][CH3:25])[CH3:22]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCN(CC)CCCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1NC(C)=O
Temperature: 60 °C

Procedure:
117 g (0.5 mol) of 2-acetylamino-4-nitrophenol, in the form of the potassium salt, are introduced into 350 ml of dimethylformamide and the mixture is then heated to 60° C., whilst stirring. 88.2 g (0.65 mol) of diethylaminoethyl chloride are then added; the reaction medium is heated at 95° C. for 150 minutes and is then poured into 1,500 ml of iced water; the expected product precipitates. This product is filtered off and washed with a 0.5 N sodium carbonate solution and then with water. After filtration, the product is finally dried in vacuo at 45° C. It melts at 117° C.
Reaction SMILES: C1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24](COC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)CCCCC1.C1(N[C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][O:49][C:50]3[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=3)[CH2:44][CH2:43]2)CCCCC1.C([O:59][C:60](=[O:70])[CH:61](SC1SC(N)=NC=1)C)C>>[CH:21]1([N:7]([C@H:42]2[CH2:43][CH2:44][C@H:45]([CH2:48][O:49][C:50]3[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=3)[CH2:46][CH2:47]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:61][C:60]([OH:70])=[O:59])=[CH:13][N:14]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Fc1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccc(F)cc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-[trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH2:11](Br)[CH:12]=[CH2:13].[Li+].CC([N-]C(C)C)C.C(OCC)(=O)C>C1COCC1.O>[CH2:1]([C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Cc1noc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCCc1noc2ccccc12
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
3.0 mL dry THF was added to an oven-dried 25 mL flask and cooled to −78° C. on a dry ice/isopropanol bath. Diisopropylamine (840 μl, 6.0 mmol) was added followed by n-BuLi (3.8 mL, 1.6 M, 6.0 mmol). The LDA-solution that was obtained was left at room temperature. Compound 25 (666 mg, 5.0 mmol) was dissolved in 10 mL dry THF and added to an oven-dried 50 mL flask followed by allylbromide (476 μl, 5.5 mmol). The freshly prepared LDA-solution was slowly added at −78° C. and the mixture was left at room temperature for 30 min. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 893 mg of a light brown oil. Crude product was purified by column chromatography (heptane:ethyl acetate; 9:1; isocratic) to produce pure 26 (355 mg, 41%).