Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][OH:5].Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.Cl>CS(C)=O>[CH2:4]([O:5][C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1)[CH3:3]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 71 %

Procedure:
Potassium hydroxide powder (0.373 g, 12.005 mmol) and EtOH (0.3 mL, 6.002 mmol) were added to a solution of 6-chloropyridine-3-carboxylic acid (0.473 g, 3.001 mmol) in DMSO (12 mL) at room temperature. The reaction mixture was heated at 100 C for 21 h, and cooled to room temperature. A 1M aqueous solution of HCl was added. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (356 mg, 71%). Method B HPLC-MS: MH+ requires m/z=168. Found: m/z=168, Rt=1.50 min (95%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:30][CH2:31][CH2:32][CH2:33][CH2:34]I>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C@H:11]([CH2:34][CH2:33][CH2:32][CH2:31][I:30])[C:12]([O:14][CH3:15])=[O:13])[C:16]([O:18][CH3:19])=[O:17])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: ICCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCCI)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
5.51 g (20 mmol) of dimethyl Boc-glutamate were dissolved in 60 ml of tetrahydrofuran and cooled to −70° C. Over a period of one hour, 44 ml (44 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise at this temperature, and the mixture was stirred at −70° C. for 2 hours. 18.60 g (60 mmol) of 1,4-diiodobutane were then added dropwise, and after 2 h at this temperature the cooling bath is removed and 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@H:14]3[OH:22])[C:6]2=[N:5][C:4]=1[CH3:23])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@H:14]3[OH:22])[C:6]2=[N:5][C:4]=1[CH3:23]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1CO

Procedure:
1 g of 3-formyl-8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-imidazo[1,2-a]pyridine is dissolved in 150 ml methanol, and excess sodium boro hydride is added in small portions at room temperature. After reduction has been completed, 150 ml icewater is added. The volatile components are evaporated in the rotary evaporator in vacuo. Subsequently extraction is carried out 3×with 40 ml ethyl acetate each time. The combined extracts are stripped off in vacuo of solvents, and the crystalline residue is recrystallized from methanol. The title compound of 192°-193° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1NCCC1(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the product from Example 25B (0.76 g, 2.5 mmol) in tetrahydrofuran (40 mL) was added a solution of potassium t-butoxide (1.0 M in tetrahydrofuran, 2.6 mL, 2.6 mmol). After stirring for 30 minutes at room temperature a pale yellow homogeneous solution resulted. To the reaction was added ethyl bromoacetate (0.42 g, 2.5 mmol) and stirring was continued overnight at room temperature. The reaction was concentrated, diluted with ethyl acetate (100 mL), washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in minimal amount of dichloromethane and loaded onto a silica gel column. The product was eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]1)#[CH:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([CH3:24])=[CH:19][N:18]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.CCN(C(C)C)C(C)C>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[N:22]=[C:21]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[C:20]([CH3:24])=[CH:19][N:18]=1
Reactant: C#Cc1ccccc1C1(C(=O)OC)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Cl)ncc2C)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 1-(2-ethynylphenyl)cyclopropanecarboxylate K2 (1.34 g, 6.67 mmol), 2,4,-dichloro-5-methylpyrimidine (1.41 g, 8.67 mmol), CuI (0.063 g, 0.33 mmol), PdCl2(PPh3)2 (0.234 g, 0.333 mmol) and tri-t-butylphosphonium tetrafluoroborate (0.097 g, 0.33 mmol) in 1,4-dioxane (15 mL) was bubbled with N2 for 10 minutes. DIPEA (3.48 mL, 20.0 mmol) was added and the reaction mixture was stirred under N2 at 80° C. for 3 hours. The reaction mixture was cooled and the volatiles were removed in vacuo to give a black residue that was purified by column chromatography (Biotage Isolera, 2×40 g SiO2 cartridges, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the impure title compound A41 as a yellow oil (estimated 80% purity, 1.352 g, 50%). LCMS-A: rt 6.79 min; m/z 327 [M+H]+.
Reaction SMILES: [CH2:1]([NH: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][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][O:40][CH2:39]1>C1(C)C=CC=CC=1>[N:19]([C:42]([CH2:41][O:40][CH2:39][C:38]([OH:45])=[O:44])=[O:43])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=C1COCC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Yield: 87.4 %

Procedure:
A solution of dioctadecylamine (2.0 g, 3.8 mmol) and diglycolic anhydride (0.44 g, 3.8 mmol) was refluxed in toluene (50 mL) for 48 h. The solvent was then evaporated and the crude product recrystallized form CHCl3 to give (C18H37)2NCOCH2OCH2COOH as a white solid (2.12 g, 87%), mp 80–81° C. 1H-NMR (300 MHz, δ, CDCl3): 0.87 (6H, t, J=6.9 Hz), 1.25 (64H, m), 1.55 (4H, bs), 3.07 (2H, t, J=7.8 Hz), 3.34 (2H, t, J=7.8 Hz), 4.21 (2H, s), 4.38 (2H, s). 13C-NMR (75 MHz, δ, CDCl3): 14.2, 22.8, 26.9, 27.0, 27.5, 28.7, 29.4, 29.5, 29.6, 29.7, 29.8, 32.0, 47.0, 71.4, 73.2, 171.0, 172.2. IR (KBr, cm−1): 1748 (CO), 1602 (CO).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[N:12][C:13]([Br:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCN(c2cccnc2)CC1
Product: CC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
1-Acetyl-4-(6-bromopyridin-3-yl)piperazine was synthesized from above-mentioned 1-acetyl-4-pyridin-3-ylpiperazine by brominating with N-bromosuccinimide by a method similar to Production Example 86, step 2,
Reaction SMILES: B([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:14])(O)O.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(=O)c1ccc(B(O)O)c(Cl)c1
Reactant: FC(F)(F)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(Cl)c1

Procedure:
A mixture of methyl 4-borono-3-chlorobenzoate (Combi-Blocks BB-3530, 1.5 g, 7.0 mmol), 2-bromobenzotrifluoride (1.9 g, 8.4 mmol), cesium fluoride (3.2 g; 21.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (98 mg, 0.14 mmol) was prepared in dioxane (15 mL) and water (7.5 mL) under nitrogen atmosphere, and then heated at 90° C. for 30 minutes. The reaction mixture was diluted with MTBE (30 mL) and washed with water and brine. The aqueous layers were extracted with MTBE (30 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum. After two purifications by flash chromatography (silica, heptane/DCM, then heptane/EtOAc), the title compound was obtained as a yellow oil. HPLC (Method A) Rt 5.3 min (Purity: 99.7%).
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14][CH2:15][O:16][P:17]([O:27]CC2C=CC=CC=2)([O:19]CC2C=CC=CC=2)=[O:18])=[C:12]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[N:11]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:10]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])C1C=CC=CC=1>CO.[Pd]>[CH3:38][N:36]([CH3:37])[C:35]([C:12]1[N:11]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:10]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:9]([OH:8])[C:13]=1[O:14][CH2:15][O:16][P:17]([OH:19])([OH:27])=[O:18])=[O:39]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(OCOP(=O)(O)O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1

Procedure:
A solution of ethyl 3-(benzyloxy)-4-(((bis(benzyloxy)phosphoryl)oxy)methoxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (42) (2.17 g, 2.99 mmol) in MeOH (20 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo, the residue was taken up in water (50 mL) and washed with EtOAc (50 mL), the organic layer was washed with water (2×50 mL) and the combined aqueous layers were freeze-dried to afford ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-((phosphonooxy)methoxy)-1H-pyrrole-2-carboxylate (UL1-109) (720 mg, 52%) as a white solid: m/z 459 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.14-7.05 (m, 2H), 6.93-6.85 (m, 2H), 5.35-5.23 (br m, 2H), 3.99 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H), 1.02 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=[O:3])[CH3:2].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(OC)(=O)=O>O1CCCC1.Cl.O>[C:1]([S:4][CH2:5][S:6][C:7]1[N:8]([CH3:12])[N:9]=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)SCSc1c[nH]nn1
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SCSc1cnnn1C
Reaction time: 0.08 h

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (6 g : 31.75 mMol.) in tetrahydrofuran (30 ml) is added dropwise at -78° C. a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (35 ml : 35 mMol.), and the mixture is stirred at the same temperature for 5 minutes and added methyl trifluoromethanesulfonate (4.0 ml : 35 mMol.). After stirring at the same temperature for 2 hours, the reaction mixture is diluted with 10% hydrochloric acid (26 ml) and water, and extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (n-hexane : ethyl acetate=1:2) to give 4-acetylthiomethylthio-3-methyl-1,2,3-triazole 2.22 g; NMR δ (CDCl3) ppm: 2.32(s, 3H). 4.13(s, 5H). 7.77(s, 1H).IR ν (CHCl3) cm-1 : 1698, 1429, 1355, 1263, 1226, 1205, 1127, 1100, 957. mp. 37°-38° C. Yield: 34%, 4-acetylthiomethylthio-1-methyl-1,2,3- triazole [884 mg; NMR δ (CDC13) ppm: 2.35(s, 3H), 4.11(s, 3H), 4.33(s, 2H), 7.59(s, 1H).IR (CHC13) cm-1 : 1691, 1434, 1354, 1285, 1131, 1106, 1048, 1031, 956.mp. 71°-72° C. Yield: 14%], and 4-acetylthiomethylthio-2-methyl-1,2,3-triazole [175 mg; NMR δ (CDC13) ppm: 2.35 (s, 3H), 4.20(s, 3H), 4.30(s,2H), 7.56(s, 1H).IR (CHCl3) cm-1 : 1691, 1446, 1369, 1130, 1006, 990, 956.Oil. Yield: 3%].
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.[N+:13]([C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:13]([C:16]1[NH:17][CH:18]=[C:19]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=2)[N:20]=1)([O-:15])=[O:14]
Reactant: OB(O)c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nc(CCc2ccc(B(O)O)cc2)c[nH]1
Reaction time: 48 h
Yield: 14.1 %

Procedure:
4-(2-Bromoethyl)phenyl boronic acid (0.525 g, 2.72 mmol) and 2-nitroimidazole (0.3 g, 2.72 mmol) were heated in dry dimethylformamide (15 ml) in presence of anhydrous potassium carbonate (1.38 g, 10 mmol) under nitrogen with stirring at 60°-70° C. for 48 hours. Dimethylformamide was removed under reduced pressure and the resulting gum was dissolved in a minimum amount of water and acidified with 2N hydrochloric acid. The precipitated solid was filtered off and washed with water. The combined aqueous portion was again extracted with ethyl acetate (5×50 ml). The organic layer was dried, concentrated and combined with the previously precipitated solid and chromatographed (silica gel). Elution with 1:1 ethyl acetate/hexane yielded some unreacted starting bromide (0.1 g); continued elution with 2:1 ethyl acetate/hexane provided the required boronic acid as a pale yellow crystalline solid. The product was recrystallized from tetrahydrofuran/hexane. Yield: 0.25 g (36%), m.p. 229°-231° C., M.S. (M+H)+ 262.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: COC(=O)CCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Initially charge 715 mg (3.2 mmol) of 4-(2-nitrophenyl)butanoic acid methyl ester in 1.5 ml of ethanol, add 34 mg of palladium on activated carbon (10%) under argon and stir under a hydrogen atmosphere (standard pressure) at RT overnight. In order to complete the reaction, add more palladium on activated carbon and stir at RT under a hydrogen atmosphere for a further 24 h. Filter the catalyst off and concentrate the solution under reduced pressure. 229 mg (37.1% of theory) of the target product are obtained.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[N:36][CH:35]=[C:34]([NH2:38])[N:33]=2)[CH2:28][CH2:27]1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:34]3[N:33]=[C:32]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[CH:37]=[N:36][CH:35]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCN(c2cncc(N)n2)CC1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Product: CN1CCN(c2cncc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)n2)CC1

Procedure:
N-Methyl-N-(2-{[2-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (130 mg, 0.36 mmol) and 4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine (92.159 mg, 0.47689 mmol in a manner analogous to Example 2d. Product was isolated as an off-white foam (28.64 mg, 1.8%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.71 (s, 1H), 8.80 (s, 1H), 7.98 (d, J=6.7 Hz, 1H), 7.81 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 3H), 6.79-6.66 (m, 2H), 6.22 (d, J=8.6 Hz, 1H), 4.63 (s, 2H), 3.55 (s, 4H), 3.26 (s, 3H), 3.12 (s, 3H), 2.41 (s, 4H), 2.22 (s, 3H). MS=523 (MH)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl[C:12]1[N:17]2[N:18]=[CH:19][CH:20]=[C:16]2[N:15]=[C:14]([S:21][CH3:22])[N:13]=1.O>O1CCOCC1>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([S:21][CH3:22])[N:13]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CSc1nc(Cl)n2nccc2n1
Reactant: CCOc1ccc(N)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(Nc2nc(SC)nc3ccnn23)cc1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
p-Phenetidine (3.09 g, 22.51 mmol) was added to a mixture of 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (300 mg, 1.5 mmol) from 1d in 1,4-dioxane (6 mL). The mixture was heated to 100° C. for ½ hour. Water (15 mL) was then added to the reaction mixture and the resulting precipitate was collected by vacuum filtration, washed with cold water and hexane, and then air dried to give 360 mg (80%) of N-(4-ethoxyphenyl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]4)[C:10]=3[N:9]=2)=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCC4CCCN(C(=O)OC(C)(C)C)C4)cccc32)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCC4CCCNC4)cccc32)C1

Procedure:
The title product is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[[1-(t-butoxycarbonyl)piperidin-3-yl]methoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole using a standard trifluoroacetic acid deprotection protocol.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:27]([N:29]1[CH2:33][CH2:32][S:31][CH2:30]1)=[O:28])=O)(C)(C)C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[S:31]1[CH2:32][CH2:33][N:29]([C:27]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:22]([OH:24])=[O:23])[CH2:10]2)=[O:28])[CH2:30]1
Reactant: COC(=O)c1cccc(C(=O)NC[C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 18A (100 mg) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) was added 2 M NaOH (1 mL) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was adjusted to a pH 2-3 by the addition of 1 M HCl, extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (15 mL), dried (Na2SO4), filtered and concentrated to provide a white solid which was processed as described in Example 18 to provide the titled compound as a pale yellow solid. MS (ESI) m/e 364 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 1.82 (m, 1H), 2.74 (m, 1H), 2.83 (m, 1H), 3.09 (m, 1H), 3.17 (q, 1H), 3.24 (dd, 1H), 3.33 (m, 1H), 3.55 (m, 2H), 3.64 (m, 1H), 3.75 (m, 1H), 3.88 (m, 1H), 4.52 (m, 1H), 4.66 (m, 2H), 7.60 (m, 1H), 8.06 (t, 1H), 8.20 (d, 1H), 8.49 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]1([NH2:15])[CH2:14][CH2:13][CH2:12]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.[OH-].[Na+].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:15][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NC1CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(CNC2CCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.8 %

Procedure:
4-Methoxybenzaldehyde (5.63 mL, 46.4 mmol) and cyclobutanamine (3.3 g, 46.4 mmol) in dichloromethane (40 mL) were stirred at room temperature. After 45 min., magnesium perchlorate (0.231 g, 2.320 mmol) was added, and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was treated with Na2SO4 (2 g) and stirred at room temperature for 2 hours, filtered and concentrated to dryness. The reaction mixture was dissolved in methanol (40 mL), cooled to 0° C., and NaBH4 (1.6 g, 69.6 mmol) was added. After 15 min., the reaction mixture was warmed to room temperature. After 2 hours, the reaction mixture was diluted with 1N NaOH (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to isolate 4A (8.5 g, 82% yield) as a clear oil. HPLC: Rt=0.82 min (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min gradient, flow rate=5 mL/min, detection at 254 nm). MS (ES): m/z=192.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:29][CH2:30][CH2:31]Br.BrCCCCOC1C=CC(N2N=C(C3C=CC(OC)=C(OC)C=3)[C@@H]3[C@@H](CC=CC3)C2=O)=CC=1>>[Br:29][CH2:30][CH2:31][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14]2=[O:21])=[CH:27][CH:26]=1
Reactant: BrCCBr
Reactant: COc1ccc(C2=NN(c3ccc(O)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: COc1ccc(C2=NN(c3ccc(OCCCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc(OCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound 6b and 1,2-dibromoethane as described for compound 6a. M. p. 40-45° C.