Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7].[I-:19].[Na+].CCCCCC>CC(C)=O>[I:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(CCCCCl)Nc1ccc(C(F)(F)F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(CCCCI)Nc1ccc(C(F)(F)F)cc1

Procedure:
5--Chloro-N-[4--(trifluoromethyl)phenyl]-pentanamide (2.795 g) and sodium iodide (3.32 g) were stirred in acetone (20 ml) at 22° C. for 3d, then heated at reflux for 16h, all under nitrogen. The cooled reaction mixture was chromatographed with 50:50 ethyl acetate:hexane to isolate product with Rf =0.30 in 35:65 ethyl acetate:hexane by addition of hexane and evaporation of solvent under a stream of nitrogen afforded, after suction filtration, a white solid (2.8 87 g). The product iodide contained ca. 5% starting chloride and was used without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g of N-chlorosuccinimide was added thereto. The resulting mixture was stirred at room temperature for five hours. 2200 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hour. The white precipitate was collected by filtration, and the white solid was washed with water and, with t-butyl methyl ether. Thus, 117 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:3]([OH:15])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:3]([O:15][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-hydroxybutylcarbamate (0.18 g, 0.54 mmol) in anhydrous CH2Cl2 (1.5 mL) at 0° C., triethylamine (0.41 mL, 2.70 mmol) was added, followed by chlorotrimethylsilane (176 mg, 1.62 mmol). The resulting white mixture was warmed to rt slowly, and stirred at rt for another 40 min. Solvent was removed under vacuum, and the residue was redissolved in anhydrous CH2Cl2 (1 mL), and evaporated to dryness under vacuum to give 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate (quant.) as a white solid; MS m/z 403 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.Cl.[NH2:37][C:38]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([NH2:42])=[O:41].C(O)(C)C>N1C=CC=CC=1.CN(C=O)C>[NH2:37][C:38]1[C:39]([C:40](=[O:41])[NH2:42])=[CH:43][CH:44]=[CH:45][C:46]=1[NH:47][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(N)=O)c3N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (1 g) in pyridine (3 mL) and DMF (3 mL) at 40° C. was stirred for 30 minutes, treated with carbonyl diimidazole (CDI, 0.55 g), stirred for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, 0.73 g), stirred for 1 hour at ambient temperature, treated with isopropanol, (10 mL), cooled for 18 hours at 0° C. and filtered. The filtrant was dissolved in water (10 mL), treated with 50% aqueous NaOH (0.26 mL), stirred for 3 hours at ambient temperature and filtered.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.O>CN1CCCC1=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(OCC2CCCO2)ccc1C=O
Temperature: 80 °C
Reaction time: 22 h
Yield: 62.3 %

Procedure:
In 160 mL of N-methylpyrrolidone was dissolved 24.5 g (161 mmol) of 4-hydroxy-2-methoxybenzaldehyde. To this solution were added 63 g (0.19 mol) of cesium carbonate and 40 g (0.24 mol) of tetrahydrofurfuryl bromide at room temperature and the mixture was stirred at 80° C. for 22 hours. Water (800 mL) was added to the resulting reaction mixture under ice-cooling, and extraction with diethyl ether (500 mL×3 times) was performed. The combined organic layer was washed with water and then with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting crude product was purified on basic alumina (hexane/ethyl acetate=50/50 to 0/100) to give 23.7 g (62% yield) of the title compound as a light yellow powder with the following properties.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]([CH3:16])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:22]1([NH:28][C:29]([NH2:31])=[NH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:28]([C:29]1[N:31]=[C:5]([C:7]2[N:11]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[C:10]([CH3:16])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Reactant: N=C(N)Nc1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C1CCC1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37; 466 mg, 2 mmol), phenylguanidine hydrogen carbonate (434 g, 2.2 mmol) and sodium methoxide (238 mg, 4.4 mmol) were suspended in anhydrous DMA (5 ml) and the mixture heated at 160° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (205 mg, 35%) as a brown solid. NMR: 1.63 (m, 2H), 2.35 (m, 4H), 2.53 (s, 3H), 5.5 (m, 1H), 6.96 (d, 2H), 7.28 (m, 4H), 7.70 (d, 2H), 8.39 (d, 1H), 9/45 (s, 1H); m/z 306.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][S:12][CH3:13].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[C:3]([CH2:11][S:12][CH3:13])=[C:4]2[C:5]([CH:14]=[CH:15][NH:8]2)=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CSCc1c(F)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSCc1c(F)ccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 11.42 g (56.7 mmol) of the compound from Example 2A in 127 ml of tetrahydrofuran was slowly added dropwise to 284 ml (283.7 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran under argon at −78° C., and the solution was then stirred at −78° C. for 2 h. The reaction mixture was added to an ice-cold, saturated aqueous ammonium chloride solution, some ethyl acetate was added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. Washing of the combined organic phases with saturated aqueous sodium chloride solution was followed by drying over sodium sulfate, filtration and removal of the solvents in vacuo. Purification of the residue by flash chromatography (mobile phase: cyclohexane/toluene/dichloromethane 10/10/1) afforded 6.31 g (57% of theory) of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](O)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>>[C:1]([C:6]1[CH:16]=[C:15]([C:17]([CH2:20][CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([Cl:24])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Product: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1

Procedure:
2-(2,4-Di-t-pentylphenoxy)ethanoic acid (CAS Registry Number 13402-96-5) (11.05 g, 0.038 mol) and thionyl chloride (50 ml) were heated under reflux on a steam-bath for 1.5 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure. The residue was dissolved in 60-80 petroleum-ether (200 ml) and the solution was distilled under reduced pressure to remove volatiles, leaving 2-(2,4-di-t-pentylphenoxy)ethanoyl chloride as a red oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34](I)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:23][C:24](=[O:38])[CH2:25][S:26][C:27]1[NH:31][C:30]2[CH:32]=[C:33]([Cl:37])[C:34]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:18])[CH:11]=3)=[CH:35][C:29]=2[N:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CSc1nc2cc(-c3ccc(OCc4ccccc4)c(F)c3)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A 4 mL vial with a septum cap and a stirring bar was charged with 4-benzyloxy-3-fluoro-phenylboronic acid (14.8 mg, 0.060 mmol) and Pd(PPh3)4 (5.8 mg, 5 mol %) and was purged briefly with N2. A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 21.4 mg, 0.050 mmol) in toluene (200 uL) was added to the vial, followed by a solution K2CO3 (21.4 mg, 0.050 mmol) in water (100 uL). The resulting mixture was stirred at 80° C. for 14 h. The mixture was allowed to cool down to rt, and was partitioned with EtOAc (1 mL) and 10% aqueous AcOH (1 mL). The organic layer was separated evaporated to dryness in vacuo. LR-MS (API-ES) of the residue confirmed the presence of the title compound: calculated for C26H24ClFN2O3S 498.1, observed m/e 499.0 (M+H)+ (Rt 3.54 min). The crude product was used in the next step without further purification.
Reaction SMILES: C([O:5]O)(C)(C)C.C([Li])CCC.[CH:12]1([NH:15][C:16](=[O:22])/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[CH:12]1([NH:15][C:16]([CH:17]2[CH:18]([CH2:19][CH2:20][CH3:21])[O:5]2)=[O:22])[CH2:14][CH2:13]1
Reactant: CCC/C=C/C(=O)NC1CC1
Reactant: CC(C)(C)OO
Agent: O=S([O-])S(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1OC1C(=O)NC1CC1
Temperature: -20 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with tert-butyl hydrogen peroxide (TBHP; 95 mL, 5.5 M, 522 mmol) and tetrahydrofuran (THF; 200 mL). The reaction was cooled to −20±5° C. and n-butyl lithium (n-BuLi; 235 mL, 2.5 M, 587 mmol) was charged to the addition funnel and slowly added, keeping the reaction temperature below −5±5° C. Upon completion of addition the reaction was warmed to 0±5° C. and the amide of Example 4 (19.80 g, 130 mmol) in THF (20 mL) was added maintaining the temperature at 0±5° C. after which the temperature was increased to 25±5° C. and the reaction stirred for 12 hours. After this time IPAc (200 mL) and saturated aqueous sodium hydrosulfite (200 mL) were added and the reaction stirred for 60 min. The layers were separated and the aqueous layer extracted with IPAc (twice, 75 mL each). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (21.87 g, 99%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O.[OH-].[Na+].Cl>CO.O>[C:1]1([CH:7]2[O:25][CH:8]2[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(C(=O)C3OC3c3ccccc3)cc2)S1
Yield: 79.2 %

Procedure:
To a solution of title product of Example 39 (0.5 g, 1.5 mmol) in methanol (4 ml), cooled to 0° C., was added 30% H2O2 (0.5 ml, 4.8 mmol), followed by 2N NaOH (1.6 ml, 3.2 mmol). After 30 minutes at 0° C. the solution was acidified with 2N HCl, diluted with water (15 ml) and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo, leaving present title product as an oil (420 mg, 80%). HRMS (C19H15NO4S). Calc.: 353.0721. Found: 353.0755.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:24])([F:23])[CH2:14]OS(C(F)(F)F)(=O)=O>O>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:14][C:13]([F:24])([F:23])[F:12])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 2,2,2-trifluoroethylamine was prepared as follows. Into a flask were placed diethylamine (5.5 g) and potassium carbonate (10.0 g). 2,2,2-Trifluoroethyl-trifluoromethanesulfonate (12 g) was slowly added to the flask. Heat was evolved. After addition, the reaction mixture was stirred at room temperature overnight. Approximately 100 mL of water was added and the organic layer was separated and dried over MgSO4. The organic liquid was distilled to receive a fraction (a clear liquid 7.25 g) at 88-89° C. under normal pressure. The clear liquid was sampled and analyzed by 1H and 19F NMR. 1H NMR: δ3.56 (q, 2H, J=9 Hz), 2.65 (q, 2H, J=7 Hz), 1.10 (t, 3H, J=7H); ·F NMR: δ−68.13 (t, 3F, J=9 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[C:42]([C:43](Cl)=[O:44])=[CH:41][N:40]=[C:39]2[CH:46]=[CH:47][S:48][C:38]=12.O>ClCCl>[Cl:36][C:37]1[C:42]([C:43]([N:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[C@H:5]2[CH2:10][C@@H:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:6]2)=[O:44])=[CH:41][N:40]=[C:39]2[CH:46]=[CH:47][S:48][C:38]=12
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1cnc2ccsc2c1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc2ccsc2c1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
tert-Butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) and diisopropylethylamine (0.095 ml) were dissolved in dichloromethane (3 ml), a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonyl chloride (70 mg) in dichloromethane (2 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (120 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH2:25])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH:25][C:27](=[O:34])[C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5c(N)cccc45)[nH]c3c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5c(NC(=O)c6ccccc6)cccc45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
The 3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine of Example 743 is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[C:48]([CH2:49]O)=[CH:47][N:46]=[CH:45]1>O1CCCC1>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:48]2[S:44][CH:45]=[N:46][CH:47]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: OCc1cncs1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cncs2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylazodicarboxylate (4.0 g) was dissolved in a little anhydrous tetrahydrofuran (about 10 ml) and added dropwise to a stirred solution of triphenylphosphine (5.2 g) in anhydrous tetrahydrofuran (150 ml) at 0° C. under nitrogen. After stirring at 0 C. for 15 minutes, during which time a white precipitate formed, a mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (2.0 g) and thiazole-5-methanol (2.3 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise whilst maintaining the temperature at or below 5° C. The reaction mixture was stirred in the cooling bath for a further 2 hours then allowed to warm slowly to room temperature. After standing at room temperature overnight the reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the organic phase washed with water (100 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (1:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound as a pale yellow solid (2.0 g).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:28][C:29]([F:40])([F:39])[CH:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:36]([CH:33]2[CH2:32][CH2:31][CH:30]([C:29]([F:28])([F:39])[F:40])[CH2:35][CH2:34]2)=[O:37])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)C2CCC(C(F)(F)F)CC2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with 4-(trifluoromethyl)-cyclohexane carboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-1-(4-trifluoromethyl-cyclohexanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow oil. MS: 566.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:46])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:29]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][C@@H:30]2[C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[O:28])=[CH:22][CH:21]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@H:11]1[CH2:15][C:14]([F:16])([F:17])[CH2:13][N:12]1[C:18](=[O:46])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:29]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][C@@H:30]2[C:36]([OH:38])=[O:37])=[O:28])=[CH:24][CH:25]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1CC(F)(F)CN1C(=O)Cc1ccc(CC(=O)N2CC(F)(F)C[C@@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CC(F)(F)CN1C(=O)Cc1ccc(CC(=O)N2CC(F)(F)C[C@@H]2C(=O)O)cc1
Yield: 60.8 %

Procedure:
0.64 g (0.001 mol) (R)-1-[[4-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxlic acid benzyl ester in 20 ml ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.13 g 5% palladium/carbon. After completion of the reaction the catalyst was filtered off, the solvent was distilled off, and the residue was dissolved in dichloromethane. Evaporation gave 0.28 g (61%) (R)-1-[[4-[2-[(R)-2-carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethyl]-phenyl]-acetyl]-4,4-difluoropyrrolidine-2-carboxylic acid as a light yellow foam. ISP-MS: 478 (MNH4)+; [α]D=+50.3° (c=0.33% in dimethylsulfoxide).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>C(Cl)Cl.Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][NH:11][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)C(=O)Cl
Reactant: NCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)NCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Nitro-phenoxy)ethylamine (0.27 g) was dissolved in dry DCM (8.5 ml) and dry pyridine (0.15 ml) and isobutyryl chloride (0.12 ml) were then added. After stirring for 1 h at room temperature, the reaction mixture was then diluted with HCl 3 N (50 ml) and extracted with ethyl acetate (50 ml), then the organic phase was washed with brine (50 ml). The organic layer was separated, dried, filtered and evaporated under vacuum to give a crude product which was crystallized (diethyl ether, 7 ml) to give the title compound (0.11 g) as a yellow solid. m.p. 102-103°.