Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(OCC)C.[Li]CCCC.[CH:16]([C:18]1[N:23]2[CH:24]=[N:25][N:26]=[C:22]2[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:20][CH:19]=1)=[O:17]>C(Cl)Cl>[OH:17][CH:16]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:18]1[N:23]2[CH:24]=[N:25][N:26]=[C:22]2[C:21]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:20][CH:19]=1
Reactant: c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)n3cnnc23)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)c3cccs3)n3cnnc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 250 mL 3-necked round bottom flask was charged with thiophene (0.63 g, 7.5 mmol) and dry ethyl ether (10 mL). To the above was added dropwise nBuLi solution (2.5 M in hexane, 3 mL, 7.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, and was then cooled to −78° C. A solution of tert-butyl 4-(5-formyl-[1,2,4]-triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in dry CH2Cl2 (10 mL) was added dropwise at that temperature. The resulting mixture was stirred at −78° C. for 0.5 h, and then quenched by slow addition of methanol (10 mL). The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with ethyl ether (100 mL×2). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 1% MeOH in CH2Cl2, to afford 0.90 g (72%) of the product as a white solid. MS m/z: 417 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[C:4]([CH3:30])[CH:3]=1.CN1CCOCC1.[Si](I)(C)(C)C>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:30])[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[C:23]([CH3:29])[CH:24]=1
Reactant: Cc1cc(Cl)ccc1C(c1ccc(Cl)cc1C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(c1ccc(Cl)cc1C)N1CCNCC1
Temperature: 0 °C

Procedure:
A round bottom flask was charged with tert-butyl 4-(bis(4-chloro-2-methylphenyl)methyl)piperazine-1-carboxylate (184 mg, 409 mmol), CH2Cl2 (5 mL), and NMM (90 μL, 0.819 mmol). Cooled to 0° C. and added TMSI (70 μL, 0.491 mmol) dropwise. After 15 min at 4° C. the reaction was quenched with sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 6% 2M NH3 in MeOH) and 1-(bis(4-chloro-2-methylphenyl)methyl)piperazine (143 mg, 70%). 1H NMR 400 MHz (CDCl3) δ 7.47 (dd, J=8.4, 1.1 Hz, 2H), 7.16-7.11 (m, 1H), 7.11-7.06 (m, 2H), 4.64 (s, 1H), 2.88-2.80 (m, 4H), 2.44-2.33 (m, 5H), 2.28 (s, 7H). LCMS (ESI, m/z): 349 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].Cl>CN(C)C=O>[Si:25]([O:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]12
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3 g (12.5 mmol) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran4-carboxylate was dissoved in 50 ml of dimethylformamide and 1.9 ml (13.8 mmol) of triethylamine was added thereto under nitrogen atmosphere. The reaction solution was stirred for one hour and then 2.07 g (13.8 mmol) of t-butyldimethylsilylchloride dissolved in 10 ml of dimethylformamide was added dropwise thereto. After stirring for 3 hours, 1N-aqueous hydrochloric acid solution was added in order to stop the reaction. Organic layer was extracted by the addition of diethylether and then it was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4.16 g (Yield 94%) of methyl (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1 -methoxy-1,4a,5,7a-tetrahydrocyclo penta[c]pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12]>O1CCCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)CCN
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Add 24.4 g (0.154 mol) of p-fluorobenzoyl chloride in 100 mL of tetrahydrofuran dropwise to 17.88 g (0.154 mol) of N,N-diethylethylenediamine in 150 mL of tetrahydrofuran at 0° C. Stir at 0° C. for about 2 hr then at room temperature for about 17 hr. Concentrate the resultant solution and treat the residue with 1N NaOH until about pH=10. Extract the resultant solution with methylene chloride (2×100 mL). Dry the extract with Na2SO4 amd evaporate the solvent to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH2:26][CH2:27][OH:28])[CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCOCC>[CH3:29][S:30]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][O:8][Si:9]([C:22]([CH3:24])([CH3:23])[CH3:25])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCC(CCO)COCCO)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCC(CCOS(C)(=O)=O)COCCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a stirred CH2Cl2 (400 mL) solution of diol, 1-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-3-(tert-butyldiphenylsilyloxy)-propane (5.48 g, 13.6 mmol) under N2 atmosphere was added TEA (11.2 mL, 78 mmol), followed by dropwise addition of methane sulfonyl chloride (3 mL, 39.00 mmol) in CH2Cl2 (100 mL) over a period of 30 minutes. After 12 hours, the reaction was diluted with ether (500 mL), washed with water (100 mL×3), brine (100 mL), dried, and concentrated under reduced pressure to a residue. The residue was eluted through a short silica gel column with ethyl acetate/hexane (10% to 50% ethyl acetate gradient) and evaporation of the eluting solvent gave the bismesylate, 1-(2-(methylsulfonyloxy)-ethoxy)-2-((methylsulfonyloxy)ethyl)-3-(tert-butyldiphenylsilyloxy)-propane (7.40 g, 97%). Rf =0.55 (50% ethyl acetate in hexane). NMR. ##STR24##
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]=[C:46]=[S:47]>>[CH3:44][NH:45][C:46]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[S:47]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CN=C=S
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=S)NC)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and methyl isothiocyanate in Step B, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14](C)[C:15](=O)C)[C:8]=2[N:7]=[C:6]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].Cl>O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][CH3:15])[C:8]=2[N:7]=[C:6]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CC(=O)N(C)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Cl
Solvent: O
Product: CNc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 77.6 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)-benzimidazole (Example 96) (0.50 g, 1.17 mmol) suspended in water (9.0 mL) was added HCl (1.0 mL). After 3 h at reflux, the solution was concentrated to dryness, diluted with ethylacetate, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH2Cl2, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylamino)-benzimidazole (0.35 g, 78% yield). M.p. 194-195° C. 1H NMR (200 MHz, CD2Cl2): δ7.52 (m, 1H, H4′), 7.23 (m, 1H, H4″), 7.13 (dd, J=8.3, 8.0 Hz, 1H, H6), 7.07 (m, 2H, H3′,5′), 6.80 (m, 2H, H3″,5″), 6.76 (d, J=8.3 Hz, 1H, H5), 6.36 (d, J=8.0 Hz, 1H, H7), 5.29 (s, 2H, CH2PhF2), 2.96 (s, 3H, NCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.[CH:23]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:25])[CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH2:27]([N:26]([CH:23]([CH3:25])[CH3:24])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1Cl
Reactant: CC(C)NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1Cl
Temperature: 160 °C

Procedure:
In a microwave tube was added 1 eq. of 4-(2-chlorophenyl)-2-morpholino pyrimidine-5-carboxylic acid (80 mg), 1.1 eq. of isopropyl benzylamine (43 mL), 2.5 eq. of triethylamine (80 mL) and 1.2 eq. of BtSO2Me in 4 mL of dioxane. The reaction mixture was heated to 160° C./300 W for 1200 sec. The crude product was purified by prep HPLC. ES+=451.0. NMR confirmed the structure.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:33][CH2:34][NH2:35])[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.[BH4-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CO>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:33][CH2:34][NH:35][CH2:48][C:44]2[NH:45][CH:46]=[CH:47][N:43]=2)[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:20]=1
Reactant: O=Cc1ncc[nH]1
Reactant: NCCN(Cc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)C1CCCc2cccnc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(CCNCc3ncc[nH]3)C3CCCc4cccnc43)cc2)nc1
Reaction time: 17 h
Yield: 40.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (333 mg, 0.57 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (110 mg, 1.14 mmol) and the mixture was stirred for 17 hours. To this solution was added sodium borohydride (110 mg, 2.91 mmol) in one portion and the mixture was stirred for 40 min. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude amine was dissolved in THF (10 mL) and protected with di-t-butyldicarbonate (1.0 g, 4.59 mmol). Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 followed by 9:1) gave the desired product (110 mg, 22%) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:19]([O:22][CH2:23]C)(=[O:21])C.C(N(CC)CC)C>CO>[CH3:23][O:22][C:19]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:21]
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCC2)n1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 50 mL bomb with a glass liner was charged with the 5-bromo-3-cyclobutylmethoxy-2-pyrrolidin-1-yl-pyrazine (2.27 g, 7.3 mmol), ethyl acetate (6 mL, degassed), methanol (7 mL, degassed) and triethylamine (2.0 mL, 14.5 mmol). PdCl2dppfCH2Cl2 (0.29 g, 0.36 mmol) was charged to the bomb; the bomb was sealed and degassed under vacuum. The reaction was purged with carbon monoxide (×5) then pressurized to 5 bar and heated to 100° C. for 1 hour. The reaction mixture was filtered through celite and washed with methanol then ethyl acetate and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester as an orange solid, 2.2 g (75% yield). LC@215 nm; Rt 2.39: 75%, m/z (ES+): 292 (M+H).
Reaction SMILES: [C:1](=[O:30])([O:5][CH2:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])SCC.S(Cl)([Cl:34])(=O)=O>>[CH2:16]([O:15][P:13]([CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][CH2:10][CH2:9][C:8]([O:7][CH2:6][O:5][C:1]([Cl:34])=[O:30])=[O:29])([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(OCC)C(CCCC(=O)OCOC(=O)SCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCCC(=O)OCOC(=O)Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 56 neat (519.2 mg, 1.054 mmol) was cooled in an ice/water bath and sulfuryl chloride (128 μL, 1.58 mmol) was carefully added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. After removal of the excess sulfuryl chloride in vacuo, the crude acid chloride 57 was used directly in the next step without further purification. 1HNMR (400 MHz, CDCl3): δ 1.35 (t, J=7.0, 12H), 1.86-2.06 (m, 4H), 2.28 (tt, J=23.8, 6.2, 1H), 2.45 (t, J=7.0, 2H), 4.14-4.24 (m, 8H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 24.34 (s, 2P)
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:26])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
tert-Butyl methyl[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]carbamate (1.5 g, 3.75 mmol) was dissolved in TFA (5 mL) and DCM (5 mL). The resulting solution was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford N-methyl-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (1.090 g, 97%) as a solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[S:7][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC[C@H]1O[C@H](S)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose (287 mg, 0.79 mmol) in dichloromethane (6 ml) was added cholest-5-en-3β-yl 6-iodohexyl ether (470 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol). After stirring under dry nitrogen atmosphere overnight at room temperature, the solvent was removed at reduced pressure and the residue chromatographed on silica gel eluted with 5-25% ethyl acetate in hexanes to give 6-(cholest-5-en-3β-yloxy)hexyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-mannopyranoside (0.36 g, 55% yield), m.p. 103°-103.5° C. This product was dissolved in 1:1 (v/v) ethanol-tetrahydrofuran (10 ml) and treated with a suspension of Bio-Rad AG-1-X2 OH-- ion-exchange resin (2.5-3 fold excess) in ethanol (5 ml). After stirring a room temperature for 45 minutes, the resin was filtered and washed with warm tetrahydrofuran (3×5 ml), and the combined filtrates concentrated to give 6-(5-cholesten-3 β-yloxy)hexyl 1-thio-α-D-mannopyranoside (250 mg, 91% yield) as needles from warm tetrahydrofuran, m.p. (endothermic transitions) 64-64, 81-82, and 226°-227° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=O.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>C(O)(=O)C.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[N:17]/[CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[C:13]([F:12])([F:22])[F:23]
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: NCc1ccccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1ccccc1C/N=C/c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1.1 g (7.5 mmol) 1H-benzimidazole-2-carbaldehyde (Fluorochem), 1.3 g (7.5 mmol) 2-trifluoromethylbenzylamine and 1 drop glacial acetic acid in 10 ml methanol was stirred at room temperature for 72 hours. The resulted yellow solution was evaporated to c.a. 2–3 ml, cooled to −40° C. and the formed solid filtered. It was washed with methanol/water mixture (1/2) and dried under reduced pressure. Yield—1.96 g (86.4%). 1H NMR (250 MHz, D2-DCM), δ: 5.03 (s, 2H), 7.28–7.69 (m, 8H), 8.46 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Br:21][C:22]1[C:27]([F:28])=[CH:26][C:25](O)=[CH:24][C:23]=1[F:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)=[CH:24][C:23]=1[F:30]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: Oc1cc(F)c(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (1.4 g, 5.05 mmol), 4-bromo-3,5-difluorophenol (1.26 g, 6.06 mmol) and triphenylphosphine (1.98 g, 7.57 mmol) were dissolved in dichloromethane (25 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.53 g, 7.57 mmol) added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with 0.5 N NaOH (50 ml), brine, dried over sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography (50 g SNAP, 10˜40% EtOAc in hexane) to afford 1.86 g (79%) of the titled compound. LC/MS (m/z): 469 (M+H)+. Rf was 0.3 @ 30% EtOAc in hexanes (blue spot on CAM stain)
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 9-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 0.88 mmol) in DCM (20 mL) was added a solution of HCl in EtOAc (20 mL, 80 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (50 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (a solution of NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=1/20/60) to give the title compound as a beige solid (100.2 mg, 32%).