Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[NH:7][C:8](=O)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:39]([O:43][C:44](=[O:51])[N:45]([CH2:47][CH2:48][CH2:49][NH2:50])[CH3:46])([CH3:42])([CH3:41])[CH3:40].N12CCCN=C1CCCCC2>CN(C=O)C.C(#N)C>[C:39]([O:43][C:44](=[O:51])[N:45]([CH2:47][CH2:48][CH2:49][NH:50][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH3:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=c1ccc2ncc(Br)n2[nH]1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN(CCCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C

Procedure:
Acetonitrile (16.0 mL) was added to a mixture of 3-bromo-imidazo[1,2-b]pyridazin-6-one (344.3 mg, 1.6 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) [56602-33-6], the mixture allowed to stir to effect dissolution. A solution of (3-amino-propyl)-methyl-carbamic acid tert-butyl ester [150349-36-3] (0.8 g, 3.98 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [6674-22-2] (2.4 mL, 2.4 mmol) in DMF (4.0 mL) was added and the reaction allowed to stir at ambient temperature for 3d. The reaction solution was partitioned between brine and ethyl acetate, dried (MgSO4), and flash chromatographed (silica gel, eluted with 10% (v/v) 2-propanol/ethyl acetate) to provide [3-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid tert-butyl ester as 0.4 g of clear yellow oil. LRMS (ESI) m/z 384.1/386.1 [(M+H)]+, calc'd for C16H22BrN6O2: 384.28.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:22][C:23]1[C:24]([CH2:29]Br)=[CH:25][CH:26]=[CH:27][CH:28]=1.O>CN(C=O)C.[H-].[Na+]>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:29][C:24]5[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide 21 (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 ml mol) at room temperature under N2. The mixture was heated to 65 C for 3 hours. α,α'-dibromoxylene (2.43 g, 9.2 inmol) was added and the resulting mixture was heated at 70° C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2,45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 . m.p. 184°-185° C.
Reaction SMILES: Cl[C:2]1C=C(NC2C=CC(N3CCN(C)CC3)=CN=2)C2N(C=CN=2)C=1.Br[C:26]1[C:27]2[N:28]([CH:33]=[CH:34][N:35]=2)[N:29]=[C:30]([Cl:32])[CH:31]=1.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[Cl:32][C:30]1[CH:31]=[C:26]([NH:36][C:37]2[N:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][C@@H:44]3[CH3:2])=[CH:39][CH:38]=2)[C:27]2[N:28]([CH:33]=[CH:34][N:35]=2)[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)cn4ccnc34)nc2)CC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn3ccnc23)nc1
Yield: 80 %

Procedure:
Following the procedure for 101b and starting with 8-bromo-6-chloroimidazo[1,2-b]pyridazine 104a (1.44 g, 6.2 mmol), and 115b (905 mg, 3.1 mmol) afforded 115c as a yellow solid (2.2 g, 80%). MS-ESI: [M+H]+ 444.2
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].[ClH:28]>C(O)C>[ClH:28].[ClH:28].[C:2]1([C:1](=[N:23][NH:24][C:25](=[NH:26])[NH2:27])[CH2:9][CH2:10][C:11](=[N:23][NH:24][C:25](=[NH:27])[NH2:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)c1ccccc1)c1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Product: N=C(N)NN=C(CCC(=NNC(=N)N)c1ccccc1)c1ccccc1

Procedure:
1,2-dibenzoylethane (4.76 g), aminoguanidine bicarbonate (5.45 g), and concentrated hydrochloric acid (3.33 mL) were heated in 50% ethanol (60 mL) for 24 hr. Cooling, concentration and filtration gave 4.3 g of 2,2'-(1,4-diphenyl-1,4-butanediylidene)bis(hydrazinecarboximidamide) dihydrochloride, mp 285-6° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][N:13]([CH3:15])[CH3:14]>CC(C)=O.O1CCCC1>[Cl-:1].[CH3:12][N+:13]([CH3:15])([CH3:14])[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: CN(C)C
Reactant: COc1nc(Cl)nc(OC)n1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc(OC)nc([N+](C)(C)C)n1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25.0 g of the product from Example 1 in 340 ml dry acetone and 140 ml dry tetrahydrofuran was treated at 0° C. with 21.5 ml of liquid trimethylamine, added over a period of 10 minutes. The resulting thick white reaction mixture was stirred at room temperature for 3 hours. Filtration under nitrogen and drying in vacuo gave 30.4 g of trimethyl(4,6-dimethoxy-1,3,5-triazin-2-yl)ammonium chloride as a white powder, m.p. 130°-134° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)Cc1cnc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Yield: 88.6 %

Procedure:
5.00 g of 4,6-dichloropyridine-3-carboxyamide synthesized according to the method described in US 2006/0217417 was dissolved in 50 mL of ethanol, to which 3.37 g of benzylamine and 4.40 g of N,N-diisopropylethylamine were added, and heated at reflux for 12 hours. After cooling, the solvent was evaporated, and 100 mL of water was added to the residue. After cooling with ice, the deposited crystals were filtered, washed with water and hexane, and air-dried. It was further dried under reduced pressure (100° C., 2 hours) to obtain the title compound (5.96 g, 87%) as light yellow needle crystals.
Reaction SMILES: [C:1]([Li])(C)(C)[CH3:2].[C:6]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=O)[C:10]=2[CH:9]=1)#[N:7]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.CCCCCC>[C:6]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[CH:1][CH3:2])[C:10]=2[CH:9]=1)#[N:7]
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: [Li]C(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=C1c2ccccc2COc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
Suspent 23.6 gm of ethyl triphenylphosphonium bromide in 200 ml of dry tetrahydrofuran add dropwise 2.4 ml of t-butyllithium in hexane with stirring at room temperature under a nitrogen atmosphere. Continue stirring for 3 hours and then cool to -70° C. in a dry ice bath. Add 10 gm. of 2-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin in 75 ml of dry tetrahydrofuran dropwise over 30 minutes. Continue stirring at -70° C. for 30 minutes, warm to room temperature and continue stirring overnight under a nitrogen atmosphere. Pour the mixture into 400 ml. of ether, filter and wash the filtrate with saturated aqueous sodium chloride solution. Dry over anhydrous magnesium sulfate and strip to dryness. Chromatograph the residue over silica gel, eluting with 5% ethyl acetate in hexane to obtain the final product (5.73 gm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.C.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH2:13]
Reactant: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CO
Product: CCCS(=O)c1ccc(N)c(N)c1

Procedure:
1.07 G. of 1-amino-2-nitro-4-n-propylsulfinylbenzene and 1 g. of 5% palladized charcoal in 100 ml. methanol are treated with hydrogen at atmospheric pressure until the theoretical uptake of hydrogen has occured (about 1 hour). The mixture is filtered and the filtrate evaporated to give 1,2-diamino-4-n-propylsulfinylbenzene. This is treated, in 20 ml. acetone, with 2.5 g. methoxy carbonyl isothiocyanate. The mixture is kept at room temperature overnight and then concentrated under vacuum. The residue is triturated with ether and recrystallized from acetone, yielding 1,2-bis-(3-carbomethoxy-2-thioureido)-4-n-propylsulfinylbenzene.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH:24]=[CH:25]1)[C@@H:20]([CH3:33])[CH2:19]3.O[C@H:35]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C=C1)CC3>>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH2:24][C@@H:25]1[CH3:35])[C@@H:20]([CH3:33])[CH2:19]3
Reactant: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(CO)C=CC(=O)C=C12
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CO)[C@@H]1CC[C@@H]2O
Solvent: CCC(=O)O
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@]2(CO)C1=CC(=O)C[C@@H]2C

Procedure:
Substituting 17β,19-dihydroxy-17α-methyl-1,4-androstadien-3-one dipropionate and 17β,19-dihydroxy-6α-methyl-1,4-androstadien-3-one dipropionate for 17β,19-dihydroxy-1,4-androstadien-3-one in the above procedure results in the formation of 17β,19-dihydroxy-1α,17α-dimethyl-4-androsten-3-one dipropionate and 17β,19-dihydroxy-1α,6α-dimethyl-4-androsten-3-one dipropionate.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[N:11])([O-])=O.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C)C=O>[CH2:12]([S:19][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[N:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1SCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture consisting 2-nitrobenzenenitrile (5.0 g, 33.75 mmol) in 30 mL of anhydrous dimethylformamide (DMF) was cooled in an ice water bath (0° C.) and placed under N2 atmosphere. Benzylmercaptan (4.0 mL, 33.75 mmol) was added followed by the dropwise addition of an aqueous potassium hydroxide solution (3.40 g, 60.75 mmol in 10 mL of water). The reaction mixture was stirred at 0° C. for thirty minutes then allowed to warm to room temperature. After four hours the reaction appeared complete by thin layer chromatography (TLC). To the reaction mixture ice water (100 mL) was added. The solution was extracted with dichloromethane (200 mL) and washed with brine (100 mL). The organic layer was dried over sodium sulfate (Na2SO4) and then concentrated under reduced pressure to afford a red oil. The product was purified by flash silica column chromatography. Elution through an 80-g Silicycle® flash silica cartridge with 5% ethyl acetate in heptanes afforded the title compound as a bright yellow solid (6.08 g, 80%) Rf of 0.24″ with 95:5 v/v heptanes: ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 7.62 (dd, 1H), 7.47-7.42 (dt, 1H), 7.38 (dd, 1H), 7.32-7.25 (m, 6H); MS (ESI−) m/z 224.1 (Mz−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>C1COCC1.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.[Cu](I)I>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 3-hydroxy-4-iodobenzoate (1 eq.) in dry THF were added trimethylsilylacetylene (5 eq.), tetrakis(triphenylphosphine)palladium (0.03 eq.), copper iodide (0.02 eq.) and diisopropylamine (2.1 eq.) under argon. The reaction mixture was stirred at 60° C. for 15 h, cooled to 20° C. and the solvents removed under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1) to afford methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>C(O)C.C(O)(=O)C>[CH2:15]([NH:22][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CCN1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCN1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Then, ethyl 3-(4-oxopiperidino)propionate (1.29 g, 6.47 mol) and benzylamine (0.85 ml, 7.78 mmol) were dissolved in ethanol (40 ml). A solution of sodium cyanoborohydride (256 mg, 4.22 mmol) dissolved in ethanol (20 ml) was added at room temperature and acetic acid (1 ml) was further added to adjust its pH to 6-7. The mixture was stirred at room temperature for 18 hours and added with concentrated hydrochloric acid (3 ml) to adjust the pH to 1-2. The resulting precipitate was collected by filtration and a saturated aqueous sodium hydrogencarbonate solution (150 ml) was added to adjust the mixture to pH 8-9. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 1.39 g of ethyl 3-(4-benzylaminopiperidino)propionate as a colorless oil (74%). This oil (1.11 g, 3.82 mmol) was dissolved in ethanol (120 ml) and 10% palladium-carbon (320 mg) was added. The mixture was refluxed under heating for 5 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to give 617 mg of ethyl 3-(4-aminopiperidino)propionate as a colorless oil (81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1I.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C)c(I)c(C)c1
Reactant: Sc1ccccc1
Product: Cc1cc(C)c(Sc2ccccc2)c(C)c1

Procedure:
The general procedure was used to convert 2,4,6-trimethyliodobenzene and thiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (444 mg, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 2H; Hb, Hb′), 7.09 (m, 3H; Hc, Hc′, Hd), 6.96 (m, 2H; Ha, Ha′) 2.44 (s, 6H; ortho methyl protons), 2.37 (s, 3H, para methyl protons). 13C NMR (75 MHz, CDCl3) δ 143.67 (C2, C6), 139.21 (C4), 138.35 (C1), 129.29 (C10), 128.81 (C11, C15), 127.20 (C12, C14), 125.39 (C3, C5), 124.41 (C13), 21.67 (C7, C8), 21.10 (C9). Anal. Calcd. for C15H16S: C, 78.90; H, 7.06; S, 14.04; Found C, 78.76; H, 7.23; S, 14.10.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:30])([F:32])[F:31])=[N:18][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 93 %

Procedure:
(R)-[3-Oxo-3-[1-(3-oxo-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 19a (0.14 g, 0.22 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-4-{7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperazin-2-one hydrochloride 19 (0.12 g, yield 93%) as a white solid.
Reaction SMILES: [C:1]1([Mg]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[C:10](#N)C.C(=O)=O.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][CH2:27][C@H:28]2[O:30][CH2:29]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[OH:30][C@@H:28]([CH2:29][CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:27][O:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: C[Mg]c1ccccc1
Agent: O=C=O
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCc2ccccc2)cc1
Temperature: -35 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Add phenyl methyl magnesium bromide (14 mL, 14 mmol, 1 M in tetrahydrofuran) to a solution of lithium tetrachlorocuprate (5.5 mL, 0.55 mmol, 0.1 M in tetrahydrofuran) in dry tetrahydrofuran (10 mL) and stir at −35° C. (acetonitrile/dry ice bath) for 15 minutes (J. Med. Chem., 41, 2451-2460, (1998); JOC, 54, 1295-1304, (1989)). Cool to −35° C. a solution of (2S)-(+)-glycidyl tosylate (2.51 g, 11.0 mmol) in dry tetrahydrofuran (4 mL) and transfer rapidly via cannula to the Grignard solution. Stir for 1 hour at −35° C., quench with a saturated aqueous ammonium chloride solution and dilute with diethyl ether. Wash the organic layer with saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 35:65 ethyl acetate:hexanes) to give the desired compound as a colorless oil (1.77 g, 50%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of 5-bromo-2-chloro-benzoic acid (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added and the mixture was stirred for 20 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 5-bromo-2-chloro-benzoate (2.4 g, 91% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1.CCOCC>C1(C)C=CC=CC=1>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=3)[CH:4]=2)[CH:36]=1
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CBr)c2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Yield: 88.6 %

Procedure:
A mixture of 3.6 g of N-[3-(bromomethyl)-phenyl]-4-(tetradecyloxy)benzeneacetamide and 3.46 g of 5-methylthiazole in 25 ml of toluene is refluxed under inert gas for 1.5 hours, cooled and poured into 200 ml of ether. The organic layer is decanted and the solid washed with ether and collected to give 3.8 g of the desired product as a white solid, m.p. 173°-175° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]=C)=[N:16][C:15]=23)[CH:2]=1.[O:39]1CCOCC1.N1C(C)=CC=CC=1C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]1[N:14]2[N:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:15]2[N:16]=[C:17]([CH:37]=[O:39])[CH:18]=1
Reactant: C1COCCO1
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6000 %

Procedure:
To 3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (0.7 g, 1.3 mmol) in 1,4-dioxide (10 mL) was added 2.5 wt % OsO4 in 1,4-dioxane (1.0 g, 0.02 mmol), 2,6-lutidine (0.6 mL, 5.2 mmol) and H2O (2 mL), and the resulting mixture was stirred at room temperature for 20 minutes. NaIO4 (0.8 g, 3.81 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. LC/MS analysis at that time showed the diol intermediate still present. Therefore, more NaIO4 (0.3 g, 1.3 mmol) was added, and the reaction mixture was stirred for 12 hours for full conversion to the product. Saturated Na2S2O3 solution (10 mL) was added and the mixture was stirred for 10 minutes. Organics were then extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde as a yellow solid (0.6 g, 1.2 mmol, 92%). LCMS: 2.67 mins, m/z=550.0 (MH+).