Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([C:15]3([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with 1-(trifluoromethyl)cyclopropanecarboxylic acid (161 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2Cl2 (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide (229.5 mg, 72% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (br s, 1H), 9.38 (s, 1H), 8.36 (d, 1H), 7.51 (s, 1H), 1.49-1.43 (m, 2H), 1.38-1.33 (m, 2H); LCMS (APCI+) m/z 366, 368 (M+H)+, Retention time=3.32 minutes (Method 3).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:25][CH2:26][CH:27]([NH2:29])[CH3:28]>C(O)C>[CH3:28][CH:27]1[CH2:26][N:25]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:29]1
Reactant: O=C(C(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: CC(N)CN
Solvent: CCO
Product: CC1CN=C(c2ccc(C(F)(F)F)cc2)C(c2ccc(C(F)(F)F)cc2)=N1
Yield: 87 %

Procedure:
First, with 150 mL of dehydrated ethanol as a solvent, 5.07 g of 4,4′-bis(trifluoromethyl)benzil and 1.09 g of 1,2-diaminopropane were mixed, and the mixture was refluxed in a nitrogen atmosphere for four hours. After reaction, a reaction solution was condensed under reduced pressure, and an obtained residue was recrystallized by using ethanol to obtain 2-methyl-5,6-bis(4-trifluoromethylphenyl)-2,3-dihydropyrazine (light yellow crystal, yield: 87%). Further, with 100 mL of dehydrated ethanol as a solvent, 5.05 g of 2-methyl-5,6-bis(4-trifluoromethylphenyl)-2,3-dihydropyrazine that is obtained as described above and 4.26 g of iron (III) chloride were mixed, and the mixture was heated in a nitrogen atmosphere for two hours in a gentle manner. After reaction, water was added into a reaction solution for dilution, and extraction was performed with ether. An extraction solution was dried with magnesium sulfate and filtered, and solvent of filtrate was removed. An obtained residue was recrystallized with ethanol to obtain 5-methyl-2,3-bis(4-trifluoromethylphenyl)pyrazine (CF3DPPR-Me) that is a ligand (white powder, yield: 52%). A synthesis scheme (h-1) relating to the synthesis of Step 1 is shown below.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1>CO.Cl>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Agent: Cl
Solvent: CO
Product: FCCN1CCN(C2CCNCC2)CC1
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinecarboxylate (10.2 g, 32.3 mmol) was dissolved in 40 mL of MeOH and 40 mL of 37% HCl. Reaction was stirred for 1 h, concentrated in vacuo and then a small amount of H2O was added back to solubilize the HCl salt of the product. When everything was in solution, solid K2CO3 was added to neutralize. The mixture was then concentrated in vacuo to remove H2O. Residue taken up in DCM and solids were filtered and washed with 20% MeOH/DCM. Filtrate was concentrated in vacuo and residue taken up in diethyl ether. Solids filtered and washed with diethyl ether several times. Combined filtrates were concentrated in vacuo to give desired product in two crops (2.42 g and 1.85 g) without further purification. Batches were combined together to give the title compound of step D (4.3 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.40-4.58 (m, 2H), 3.15 (s, 1H), 2.91 (d, J=12.1 Hz, 2H), 2.35-2.59 (m, 12H), 2.15 (tt, J=11.36, 3.67 Hz, 1H), 1.63 (d, J=12.10 Hz, 2H), 1.19 (qd, J=11.85, 4.03 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:22][CH2:23][CH2:24][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.63 mL (4.6 mmol) of triethylamine was added and dissolved in a suspension of 0.73 g (4.2 mmol) of ascorbic acid in acetonitrile (9 mL). After the above crude product of (4,8,12-trimethyltridec-3-enyl)tosylate was added at room temperature, the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])=[CH:7][CH:6]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Solvent: ClCCl
Product: O=C(c1ccc(OCCCl)cc1)N1CCOCC1

Procedure:
4-(2-Chloroethoxy)benzoyl chloride (5.0 g) was dissolved in dry methylene chloride and stirred while cooling to 0°. Morpholine (4.0 g) was added dropwise and the mixture was stirred at room temperature for 2 days. The resultant colourless solid was filtered off and the liquors allowed to stand from which the title compound crystallised (5.5 g), m.p. 102°-104°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:21][C:20](=O)[C:11]2[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:21]/[C:20](=[N:27]\[NH:26][C:23]([NH2:25])=[NH:24])/[C:11]2[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: N=C(N)NN
Reactant: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g) and aminoguanidine hydrochloride (49 mg) were ethanol (9 ml) and 6N hydrochloric acid (0.038 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-chlorophenyl)-3-ethoxycarbonyl-4-guanidinoimino-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 56) (90 mg).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1>S(=O)(=O)(O)O.C(O)(=O)C.[Na]>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH2:2][N:3]3[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]3=[O:11])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:21]=2)[CH:18]=1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Cc1ccc(-c2cn3cc(Cl)ccc3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Product: CCCC1CC(=O)N(Cc2c(-c3ccc(C)cc3)nc3ccc(Cl)cn23)C1

Procedure:
To a refluxing solution of acetic acid (8 ml) and sulfuric acid (2 drops) is added, dropwised, a solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (400 mg, 2.54 mmol) in 3 ml of acetic acid. 6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridine x267 (309 mg, 1.27 mmol, 0.5 eq) is then added in once. The reaction mixture is refluxed for 3 days. After cooling, the reaction mixture is slowly poored in 150 ml of concentrated sodium hydroxyde solution (40% wt) and the crude product is extracted by dichloromethane (4×150 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure leading to the crude product which is purified by flash chromatography over silicagel (hexane/ethyl acetate 80/20). 1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one 4 is recrystallized in ethyl acetate.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([S:29](OC3C=CC([N+]([O-])=O)=CC=3)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:29]([C:24]2[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:31])=[O:30])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)cc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.094 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.159 g) in dimethoxyethane (4 ml). The solution was stirred for 10 minutes and then 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.321 g) was added. The solution was allowed to stand for 5 hours and then water (20 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted with ethyl acetate (2×30 ml). The extracts were dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was recrystallised from a mixture of ether and hexane to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-isobutyl-2-biphenylsulphonamide (0.09 g), m.p. 154°-156° C.; 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 3.85 (s,3H), 7.1 (s,4H), 7.3 (d,1H), 7.5-7.7 (m,2H), 7.8 (br s,1H), 8.05 (d,1H), 10.2-10.3 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 478 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:17])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([NH:22][CH2:23][CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:17])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:25][CH2:24][CH2:23][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)NCCN
Reactant: O=C(NC1CCCCC1)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCNC(C(=O)NC1CCCCC1)c1ccccc1
Yield: 38.8 %

Procedure:
A mixture of N-cyclohexyl-α-bromophenylacetamide (2.37 g), N-tert-butylethylenediamine (2.00 g), triethylamine (1.12 ml) and toluene (30 ml) was refluxed for 18 hours. The reaction mixture was concentrated and the residue was purified by means of alumina column chromatography (developing solvent, ethyl acetate) and then distilled under reduced pressure to obtain 1.03 g (38.9%) of title compound as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl>ClCCl.C(OCC)C>[CH3:1][O:2][C:3]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:4][CH2:5][CH:6]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: COC1(Cc2ccccc2C)CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC1(Cc2ccccc2C)CCC(N2CCNCC2)CC1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of EXAMPLE 15D (0.51 g, 1.26 mmol) in dichloromethane (5 mL) at room temperature was treated with 2M HCl in diethyl ether (5 mL), stirred overnight, and concentrated to provide the desired product (0.38 g, 100%). MS (ESI) m/e 303 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[C:10]([Br:12])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2c(Br)c(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10 ml of AcOH was added Br2 (0.12 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl3) to yield 0.27 g (1.2 mmol, 50%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:22][C@@H:21]4[C@@H:19]([CH2:20]4)[N:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:14][CH:13]=1)[CH:6]=[CH:5]2.[C:30]([C:32]1[NH:36][C:35]([C@@H:37]2[CH2:42][C@@H:41]3[C@@H:39]([CH2:40]3)[N:38]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:34][CH:33]=1)#[CH:31].C(N(CC)CC)C>CN(C=O)C.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:46]([O:45][C:43]([N:38]1[C@H:37]([C:35]2[NH:34][CH:33]=[C:32]([C:30]#[C:31][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]3[N:16]=[C:15]([C@@H:17]5[CH2:22][C@@H:21]6[C@@H:19]([CH2:20]6)[N:18]5[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[NH:14][CH:13]=3)[CH:6]=[CH:5]4)[N:36]=2)[CH2:42][C@@H:41]2[C@H:39]1[CH2:40]2)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)[nH]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(C#Cc2ccc3cc(-c4c[nH]c([C@@H]5C[C@H]6C[C@H]6N5C(=O)OC(C)(C)C)n4)ccc3c2)c[nH]1
Temperature: 50 °C
Yield: 104.5 %

Procedure:
Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (400 mg, 0.880 mmol), (1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (313 mg, 1.14 mmol) and Cu(I)I (8.4 mg, 0.044 mmol) in triethylamine (0.37 mL, 2.6 mmol) and DMF (8 mL) for 10 min. Then Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added, nitrogen was bubbled through the reaction mixture for 1 min, and then the flask was sealed and heated at 50° C. for 16 h. The reaction was concentrated to under high vacuum) and the residual solids were triturated with EtOAc (˜5 mL) and collected by filtration (rinsing with EtOAc and hexanes) to yield tert-butyl(1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (595 mg) as a light yellow solid. The material was used without further purification. LC-MS retention time 3.140 min; m/z 647.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 241.9 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc-piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250 ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340).
Reaction SMILES: [CH2:1]([SH:17])[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][CH3:16].[CH2:18]([O:21][CH2:22][C:23]([CH2:34][O:35][CH2:36][CH:37]=[CH2:38])([CH2:29][O:30][CH2:31][CH:32]=[CH2:33])[CH2:24][O:25][CH2:26][CH:27]=[CH2:28])[CH:19]=[CH2:20]>>[CH2:1]([S:17][CH2:38][CH2:37][CH2:36][O:35][CH2:34][C:23]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][S:17][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][CH3:16])([CH2:29][O:30][CH2:31][CH2:32][CH2:33][S:17][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][CH3:16])[CH2:22][O:21][CH2:18][CH2:19][CH2:20][S:17][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][CH3:16])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: C=CCOCC(COCC=C)(COCC=C)COCC=C
Product: CCCCCCCCCCCCCCCCSCCCOCC(COCCCSCCCCCCCCCCCCCCCC)(COCCCSCCCCCCCCCCCCCCCC)COCCCSCCCCCCCCCCCCCCCC

Procedure:
The procedure used was identical to that set forth in Example 4, except that 107 g of hexadecyl mercaptan (0.417 moles) was reacted with 29.64 g of pure pentaerythritol tetraallyl ether (0.1 moles). The crude product was recrystallized three times in 300 ml of hexane yielding 57 g of white solid having a melting point 55°-57° C. The elemental analysis found: C-73.4%, H-11.9%, S-10.0%, calculated for C88H164S4 (theoretical C-73.12%, H-12.4%, S-9.64% and O-4.81%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(CN)c2ccccc21
Reactant: O=C(O)c1ccncc1F
Product: CN1CCC(CNc2cnccc2C(=O)O)c2ccccc21
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from 1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.72 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz), 7.01-7.08 (m, 2H), 6.52-6.62 (m, 2H), 3.45-3.51 (m, 2H), 3.04-3.32 (m, 3H), 2.85 (s, 3H), 1.89-1.95 (m, 2H). [M+H] calc'd for C17H19N3O2, 298. Found 298.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:32])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
tert-Butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (3.21 g, 7.39 mmol) was dissolved in CH2Cl2 (55 ml). TFA (50 ml) was added and the reaction was stirred for 1 hour. After evaporating the solvents in vacuo, the crude material was diluted with CH2Cl2 and neutralized with a 1 N NaOH solution. The layers were separated, and the aqueous layer was extracted three times with CH2Cl2 (30 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated to give 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as a yellow solid (2.06 g, 83%). LC/MS: m/z 335.3 (M+H)+ at 1.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:12][N:11]([C:9](=[O:10])[C@H:8]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][O:6][Si:26]([CH3:28])([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:13][CH3:14]
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
Imidazole (1.8 g, 26.5 mmol) was added to a solution of (R)-benzyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 10.6 mmol) in DMF (dimethyl formamide, 15 mL) followed by TBDMSiCl (tert-butyldimethylsilyl chloride, 2.4 g, 15.95 mmol). The reaction stirred for 12 hrs at room temperature under nitrogen atmosphere and was quenched with aqueous ammonium chloride (100 ml). The aqueous layer was extracted with methylene chloride (200 mL) and ethyl acetate (100 mL) and the organic layers were washed with brine and concentrated. The crude product was purified by column chromatography using 10% EtOAc (ethylacetate)-hexanes to give an oil (3 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ=0 (s, 6H), 0.9 (s, 9H), 3.2 (s, 3H), 3.8 (s, 3H), 3.8-3.9 (m, 2H), 4.8 (broad s, 1H), 5.1 (q, 2H), 5.7 (d, 1H), 7.2-7.4 (m, 5H).