Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1.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:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cn1cccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2cccn2C)cc1
Reaction time: 0.75 h
Yield: 28.5 %

Procedure:
A solution of 5 g (0.06 mole) N-methylpyrrole and 13.3 g (0.078 mole) of 4-methoxybenzoyl chloride in 50 mL of dry toluene was heated under reflux overnight with an argon stream bubbling through the reaction mixture. After cooling, 40 mL of 20% 3-dimethylaminopropylamine in H2O was added and the mixture stirred for 45 minutes. Diethyl ether was added and the organic solution was washed with 1N HCl, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from ethanol to give 3.68 g of product: mp. 66-68° C.; mass spectrum (CH4-Cl) m/z=216 (M+1); NMR (CDCl3) d 7.85 (d, 2H); 6.9-7.1 (d,s, 3H); 6.7 (d, 1H); 6.15 (d, 1H); 4.1 (s, 3H); 3.9 (s, 3H). Anal Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.59; H, 6.06; N. 6.43.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[N:54]=[C:55]([CH:57]([NH:59][CH2:60][CH3:61])[CH3:58])[NH:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([CH:57]([N:59]([CH2:60][CH3:61])[C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CCNC(C)c1nc2ccc(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)C(C)c1nc2cc(Cl)ccc2[nH]1
Yield: 36 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and N-[1-(5-chlorobenzimidazol-2-yl)ethyl]ethylamine in tetrahydrofuran. Yield: 36%; Rf value: 0.45 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O2 (438.96); mass spectrum: (M−H)−=437/439 (chlorine isotope).
Reaction SMILES: [CH3:1]CN(CC)CC.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][N:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>CN(C=O)C>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:1])[CH2:32][CH2:31]2)=[N:28][N:29]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.5 %

Procedure:
Et3N (631 μL, 4.5 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (997 mg) in DMF (15 mL). Then, MeI (106 μL, 1.6 mmol) was slowly added at 0° C. The mixture was stirred at rt for 6 hrs then, the mixture was concentrated and purified by reverse phase column chromatography (gradient elution, 0 to 80% of acetonitrile in water) to give (2S,5R)-6-(benzyloxy)-2-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (202 mg, 34% for two steps) as a yellow solid. ESI-MS (EI+, m/z): 399.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[C:13]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[CH3:14].[H-].[Na+].Cl>C1COCC1>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: CC(=O)OCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCCOCc1cc(Cl)cc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.3 mmol) (A.2.5.1) and 2-hydroxyethyl acetate (1.43 mmol) in 7 mL THF was added NaH (1.95 mmol, 60% suspension in oil). The reaction mixture was stirred at RT overnight and then poured into a 1M HCl solution. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (75/25) gives the desired compound as orange oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(Br)(Br)(Br)[Br:40].[Cl-].[NH4+]>O1CCCC1.C1CCCCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[Br:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1ncn2Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To Compound 13a (6.65 g, 21.2 mmol) obtained in Example 13 was added (R)-phenylalaminol (4.80 g, 31.7 mmol, 1.5 equivalents) and the mixture was stirred with heating at 150° C. for 4 hours. The reaction mixture was directly purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:3) to obtain an adduct (2.66 g, 30%). To the resulting adduct (2.66 g, 6.37 mmol) was added thionyl chloride (5 mL) and the mixture was stirred with heating at 60° C. for 2.5 hours. After the thionyl chloride was evaporated, the residue was neutralized with saturated aqueous sodium hydrogen carbonate and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain (R)-1,8-dibenzyl-7,8-dihydro-4-(n-propyl)-1Himidazo[2,1-i]purin-5(4H)-one (Compound 35a, 1.75 g, 69%). Compound 35a (1.75 g, 4.38 mmol) was dissolved in tetrahydrofuran (30 mL), to the solution was added a 1.54 mol/L solution of lithium diisopropylamide (4.38 mL, 6.75 mmol, 1.5 equivalents) in cyclohexane at −78° C., and the mixture was stirred for 1 hour. To the reaction solution was added a solution (10 mL) of carbon tetrabromide (2.18 g, 6.65 mmol, 1.5 equivalents) in tetrahydrofuran, and the mixture was stirred at −78° C. for 1 hour, then warmed to room temperature and stirred for 2 hours. To the reaction solution was added saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=99.5:0.5), the eluent was concentrated, and to the residue were added acetone and diethyl ether. The deposited crystals were collected by filtration and dried under reduced pressure to obtain the title compound (1.51 g, 72%) as white crystals.
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]=1[CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:16]=1[CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(OC)c2)c1CCOCCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(O)cc(O)c(-c2cccc(OC)c2)c1CCOCCOC
Yield: 46 %

Procedure:
In the same manner as in Example 118, 1-{4,6-bis(methoxycarbonyloxy)-2-[2-(2-methoxyethoxy)ethyl]-3-(3-methoxyphenyl)phenyl}ethanone was obtained from Compound 137 (250 mg, 0.69 mmol) obtained in Example 137, using methyl chlorocarbonate (0.15 mL, 1.9 mmol), triethylamine (0.26 mL, 1.9 mmol) and tetrahydrofuran (5.0 mL); and from the resulting compound, obtained was 4-ethyl-1,5-bis(methoxycarbonyloxy)-3-[2-(2-methoxyethoxy)ethyl]-2-(3-methoxyphenyl)benzene, using sodium borohydride (120 mg, 3.2 mmol), water (3.0 mL) and tetrahydrofuran (5.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 138 (110 mg, 46%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:40])[CH3:39])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][CH2:23][C:24]#[N:25])=O)[CH2:6]1)(=[O:3])[CH3:2].[N-:41]=[N+:42]=[N-:43].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:39])[CH3:40])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]2[N:21]([CH2:22][CH2:23][C:24]#[N:25])[N:43]=[N:42][N:41]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)NCCC#N)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/c2nnnn2CCC#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
The 1-(3-{(E)-3-[(2-cyanoethyl)amino]-3-oxo-1-propenyl}-8-[(E)-2-(4-isopropyl -1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-3-piperidyl acetate (57.3 mg, 0.102 mmol) obtained in (B) was suspended in acetonitrile (3.0 ml), added with sodium azide (13.3 mg, 0.204 mmol) and trifluoromethanesulfonic acid anhydride (25.8 μl, 0.153 mmol) under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was further added with sodium azide (13.3 mg, 0.204 mmol) and trifluoromethanesulfonic acid anhydride (25.8 μl, 0.153 mmol), and stirred for 3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane:ethyl acetate=1:2→1:3→0:1, v/v) to obtain the title compound (26.8 mg, 45%).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH:48]([OH:50])[CH3:49]>CN(C)C=O>[OH:50][CH:48]([CH3:49])[CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(O)CCl
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a) ) was dissolved in dimethylformamide. Sodium iodide (7.5 mg, 0.5 mmol), triethylamine (76 mg, 0.75 mmol) and 3-chloro-2-propanol (48 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 4 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was washed with ether (5×2 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 75 mg (74%) The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]Br)=[CH:4][CH:3]=1.[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1)OC
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A suspension of 3,3-bis(4-fluorophenyl)-1-bromo-2-(tetrazol-1-yl)-2-propene (108 mg, 0.29 mmol) and trimethylphosphite (4 mL, 34 mmol) was heated to reflux under an inert atmosphere for five minutes. After cooling to room temperature, excess trimethylphosphite was evaporated under reduced pressure to give a pale crystalline material. The crude product was crystallized from a 10:1 mixture of hexanes: ethyl acetate to give 98 mg (83%) of the title compound as rhombic, colorless crystals; m.p.=132.8°-133.7° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[CH:10][CH:9]=3)[CH:5]1[CH2:4][NH:3][CH2:2]2.[CH2:29](Br)[CH:30]=[CH2:31].C(N(CC)CC)C>CN(C)C=O>[CH2:31]([N:3]1[CH2:4][C@@H:5]2[C@@H:1]([CH2:7][C@H:6]2[C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:2]1)[CH:30]=[CH2:29]
Reactant: O=S(=O)(Nc1ccc(C2CC3CNCC32)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
100 mg (0.43 mmol) of N-[4-(3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide and 40 μl (0.46 mmol) of allyl bromide were dissolved in 2 ml of N,N-dimethylformamide. 0.18 ml (1.26 mmol) of triethylamine were then added to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 10 μl of allyl bromide were added to the reaction mixture, which was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down give 50 mg of title compound (yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:34](=[O:36])[CH3:35])[C:16]=1[O:20][CH3:21]
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1NC(C)=O
Temperature: 100 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 0.7 mL DMF. After addition of 14 mg of triethylamine (0.14 mmol, 1.0 eq.) and 14 mg of acetic anhydride (0.14 mmol, 1.0 eq.), the resulting reaction mixture was heated for three h at 100° C. For completition of reaction further 4 mg of triethylamine (0.04 mmol, 0.3 eq.) and 4 mg of acetic anhydride (0.04 mmol, 0.3 eq.) were added and the mixture was heated over night at 100° C. After cooling and dilution with water, the crude product was extracted with DCM and was purified by flash chromatography yielding 25 mg (0.063 mmol, 45%) of analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:34](=[O:36])[CH3:35])[CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C)C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.114 g, 0.31 mmol) and triethylamine (0.05 mL, 0.34 mmol) in CH2Cl2 (1.2 mL) was added acetyl chloride (0.02 mL, 0.34 mmol), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH:22]1[CH:23]=[CH:24][N:25]2[CH2:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][C:26]=12.C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.CN(C)C=O>[CH:22]1[CH:23]=[CH:24][N:25]2[CH2:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[CH:15][CH:14]=3)=[O:13])[CH2:27][C:26]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(O)c1ccc(C2=CCCCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(C2=CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
4-Cyclohex-1-en-1-yl-benzoic acid of Step C (0.099 g, 0.489 mmol) and oxalyl chloride (0.065 g, 0.513 mmol) were dissolved in anhydrous methylene chloride (5 mL) and N,N-dimethylformamide (0.00114 mL, 0.0147 mmol) added. The resulting mixture was refluxed for 1 hour, then cooled to room temperature and solvent evaporated. The crude acid chloride thus prepared was combined with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.090 g, 0.489 mmol) and N,N-diisopropyl ethylamine (0.103 mL, 0.589 mmol) in anhydrous dichloromethane (5 mL). After stirring at room temperature for 1.5 hours, 1 N hydrochloric acid (50 mL) was added and the resulting mixture extracted with diethyl ether (50 mL). The organic phase was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane. A slightly orange solid was isolated which was recrystallized from petroleum ether to afford the title compound (0.131 g) as white crystals, m.p. 156° C.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CC(O)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([Br:32])=[CH:34][N:35]=3)=[CH:60][CH:61]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)C(=O)C1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Yield: 51.6 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.283 g, 1.00 mmol), 4-(4-amino-phenyl)-3-oxo-piperazine-1-carboxylic acid ter-t-butyl ester (0.300 g, 1.00 mmol) and N-ethyldiisopropyl-amine (0.20 mL, 1.02 mmol) in 2-propanol (1 mL). Purification of the crude material by silica gel column chromatography eluting with DCM followed by 98:2 DCM:MeOH affords 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.252 g, 51%).