Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:33]([C:35]#[N:36])=[CH2:34])=[C:21]([CH:32]=1)[CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:15])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:33]2([C:35]#[N:36])[CH2:4][CH2:34]2)=[C:21]([CH:32]=1)[CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: C=C(C#N)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1C1(C#N)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a suspension of sodium hydride (0.019 g, 0.795 mmol) in DMSO (2 mL), was added trimethylsulfoxonium iodide (0.191 g, 0.867 mmol). The mixture was stirred at rt for 2 h. To the resultant clear solution was added to a solution of 36F (0.280 g, 0.723 mmol) in DMSO (2 mL) to give a yellow solution. The mixture was stirred at rt for 1 h, then at 60° C. for 5 h. Reaction mixture was quenched with sat. NH4Cl (10 mL), extracted with EtOAc (4×25 mL). Combined organic phase was washed with water (2×25 mL), brine (1×25 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give 36G (0.144 g, 0.359 mmol, 49.6% yield) as a colorless syrup. MS (ESI) m/z: 402.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.33-7.58 (1H, m), 7.23 (1H, d, J=8.28 Hz), 6.91-7.11 (1H, m), 6.60-6.79 (1H, m), 4.71 (2H, br. s.), 2.82-2.98 (3H, m), 1.66 (2H, br. s.), 1.37-1.58 (18H, m), 1.19-1.32 (2H, m).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].CC1(C)[O:32][CH:31]([CH:33]2[O:35][CH2:34]2)[CH2:30][O:29]1>O.O1CCOCC1>[OH:35][CH:33]([CH:31]([OH:32])[CH2:30][OH:29])[CH2:34][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC1(C)OCC(C2CO2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(O)CO)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) is dissolved in 40 ml of water, and the pH is set at 13 with 5N sodium hydroxide solution. A solution of 6.24 g (43.30 mmol) of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide (DE 3,150,917) in 10 ml of dioxane is added thereto, and the mixture is stirred for 24 hours at room temperature. The mixture is diluted with 60 ml of water and extracted three times with 50 ml of ether. The aqueous phase is brought to pH 2 with 10% strength hydrochloric acid and evaporated. The residue is dissolved in a small amount of water and passed to a cation exchange column (IR 120). After flushing with water, the ligand is eluted with 0.5-normal aqueous ammonia solution.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:22])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=[CH:16][C:17](OCC)=[O:18])[CH2:9]1>CCOCC>[CH3:7][C:8]1([CH3:22])[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10](=[CH:16][CH2:17][OH:18])[CH2:9]1
Reactant: CCOC(=O)C=C1CC(C)(C)CC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)CC(=CCO)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a stirred solution of LiAlH4 (1.7 g, 45 mmol) in dry ether (60 ml) a solution of acetate 2 (3.2 g, 15 mmol) in ether (20 ml) was added dropwise while cooling with ice water. Stirring was continued for 1 h and the residual LiAlH4 was destroyed with water. The aqueous layer was separated and twice extracted with ether (30 ml). The combined extracts were washed with brine (50 ml) and dried over MgSO4. After concentration in vacuo an oily residue was purified by Kugelrohr short path distillation (150-170° C., 11 mm Hg) to give 3 (2.3 g, 89%) as an oil. 1H NMR (CDCl3, TMS): 0.92 (6H, s, 3,5-CH3); 1.10 (1H, br s, OH); 1.28 (2H, s, 4-CH2); 1.87 and 1.94 (total 4H, both s, 2,6-CH2); 4.16 (2H, d, 7 Hz, CH2O) and 5.50 ppm (1H, t, 7 Hz, ═C—H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl.[NH2:20][OH:21]>CO>[OH:21][NH:20][C:11]([C:9]1[CH:8]=[C:7]([CH3:13])[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)=[NH:12]
Reactant: NO
Reactant: Cc1cc(C#N)nc(NC(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.2 %

Procedure:
2-Isopropylamino-6-methyl-pyrimidine-4-carbonitrile (2.8 g, 16.0 mmol) is added to a suspension of NaHCO3 (4.71 g, 56.1 mmol) and hydroxylamine hydrochloride (3.34 g, 48.1 mmol) in MeOH (20 mL). The reaction mixture is stirred at rt for 1 day and is filtered and evaporated. The residue is dissolved in DCM, washed with water followed by brine and dried to give N-hydroxy-2-isopropylamino-6-methyl-pyrimidine-4-carboxamidine as a yellow oil (1.38 g); LC-MS: tR=0.55; [M+H]+=209.96.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=O)[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:34][NH2:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:35][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-(2,4-dibenzyloxyphenyl)-2,4-dioxobutanoate (3.23 g) in ethanol (10 mL) is treated with hydrazine hydrate (0.4 mL), refluxed for 2 hours and then cooled to room temperature. The mixture is filtered to yield ethyl 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylate as a solid (1.5 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([NH2:18])[N:12]=1)[NH:5]C(=O)C.[ClH:20]>>[ClH:20].[ClH:20].[NH2:18][C:13]1[N:12]=[C:11]([CH2:10][CH2:9][CH:4]([C:3]([OH:19])=[O:2])[NH2:5])[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: COC(=O)C(CCc1cc(C)cc(N)n1)NC(C)=O
Agent: Cl
Product: Cc1cc(N)nc(CCC(N)C(=O)O)c1
Yield: 58 %

Procedure:
N-Acetyl-α-(2-(6-amino-4-methylpyrid-2-yl)ethyl)glycine methyl ester (200 mg, 0.75 mmol) was heated in 6.0 mL of refluxing 2 N aqueous hydrochloric acid for 2.5 h. The solution was cooled and evaporated. The residue was dissolved in 2.75 mL of warm methanol and the solution was concentrated to a volume of 1-1.5 mL. Ethyl acetate (1.0 mL) and seed crystals were added. The crystals were separated using a Craig tube and recrystallized again to give 122 mg (58% yield) of α-(2-(6-amino-4-methylpyrid-2-yl)ethyl)glycine dihydrochloride as white crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.O.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1CCCc2sccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
In a 500 mL round bottomed flask was placed 6,7-dihydro-4-benzo[b]thiophenone (8.3 g, 54 mmol) and then dissolved in acetic acid (30 mL). To the mixture was added water (30 mL) and the solution was stirred for 30 min at rt. To the mixture was dropwise added freshly prepared solution of bromine (9.4 g, 59 mmol) in acetic acid (50 mL) over 10 min. After addition of the Br2, the mixture was stirred for 1.5 h at the same temperature. The mixture was concentrated under reduced pressure and the residue was diluted with ether (150 mL), which was washed with 1N NaOH aq (100 mL). The aqueous phase was extracted with ether (100 mL) and the combined organic phase was washed with brine (100 mL), dried over anhydrous MgSO4 and then decolorized with activated carbon. Insoluble materials were removed by filtration through Celite pad and the filtrate was concentrated under reduced pressure. The residue was suspended in 50 mL of MeOH and then stirred for 15 min for washing. The precipitate was collected by filtration to obtain the title compound (5.65 g; 45%) as a yellowish crystalline solid. From the mother liquid, 2nd crop of the title compound (6.66 g; 53%) has been obtained. LCMS: (FA) ES+ 231, 233. 1H NMR (300 MHz, d1-chloroform) δ: 7.35 (s, 1H), 2.95 (t, 2H), 2.52-2.56 (m, 2H), 2.17-2.25 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH2:8]([C:3]1[N:4]([CH3:7])[N:5]=[CH:6][C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cn1ncc(Br)c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Br)c1Cc1ccccc1
Temperature: 50 °C

Procedure:
(4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol (0.50 g; 1.87 mmol) was treated with 3.0 ml TFA and Triethylsilane (1.49 ml; 9.36 mmol) and heated to 50° C. for 16 hours. The product was purified via reversed phase chromatography under acid conditions.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=1)[CH:3]=[C:2]2[NH:1][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Product: CNc1nccc(-c2cc(NC3CCCNC3)c3cc(OC)ccc3c2)n1

Procedure:
4-(6-methoxy-4-(piperidin-3-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 152 was synthesized according to General Procedure E except compound 33 was used a starting material and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopiperidine-1-carboxylate. 1H NMR (DMSO) 400 MHz δ 9.64 (bs, 1H), 9.42 (bs, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.81-7.70 (m, 2H), 7.47 (bs, 1H), 7.24 (dd, JA=8.8 Hz, JB=2.0 Hz, 1H), 4.24-4.16 (m, 1H), 3.98 (s, 3H), 3.51-3.44 (m, 1H), 3.29-3.22 (m, 1H), 3.09 (bs, 3H), 3.00-2.87 (m, 2H), 2.13-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.93-1.76 (m, 2H); LCMS: 364 [M+H]. Calc. for C21H25N5O 3.1 Hydrochloric Acid 0.85 Dichloromethane 0.4 Ethyl Acetate: C, 51.45; H, 5.89; N, 12.79; Found C 51.58, H 5.71, N 12.79.
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[C:9]3[N:10]([N:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:22][Al](C)C>ClCCl>[OH:19][C:8]1([CH3:22])[CH2:7][O:6][C:5]2[CH:20]=[CH:21][C:2]([I:1])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:9]12
Reactant: C[Al](C)C
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)O
Temperature: -10 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution ethyl 9-iodo-4-oxo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (3 g, 7.53 mmol, 1.00 equiv) in dichloromethane (50 mL) was added trimethylalumane (2.0M in toluene) (4.5 mL, 1.20 equiv) at −10° C. After being stirred for 2 hours at −10° C. the resulting solution was diluted with 20 mL of dichloromethane, washed with saturated ammonia chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:2) to give 2.4 g (77%) of the titled compound as a light yellow solid; LC-MS (ES, m/z): 415 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH3:17]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:17]
Reactant: CCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1C#N

Procedure:
25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[Br:20][C:21]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[N:30]([CH2:46][CH3:47])[C:31]1[N:36]=[C:35]([C:37]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:34]=[C:33]([CH3:45])[N:32]=1.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[Br:20][C:21]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[N:30]([CH2:46][CH3:47])[C:31]1[N:36]=[C:35]([CH:37]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][C:44]=2[C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[O:8][CH3:9])[OH:38])[CH:34]=[C:33]([CH3:45])[N:32]=1
Reactant: CCN(c1nc(C)cc(C(=O)c2cccnc2)n1)c1ccc(C(C)C)cc1Br
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(O)c2cnccc2-c2ccccc2OC)n1)c1ccc(C(C)C)cc1Br
Temperature: -78 °C
Yield: 31.1 %

Procedure:
A solution of 4-bromoanisole (0.2 g, 1.1 mmol) in anhydrous THF (10 mL) was cooled with stirring to −78° C. under a nitrogen atmosphere. A solution of t-butyl lithium in pentane (1.7 M, 1.4 mL, 2.4 mmol) was added dropwise and the reaction mixture was stirred for 0.5 h. A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridyl-carbonyl)-6-methylpyrimidinamine (0.45 g, 1 mmol) in anhydrous THF (10 mL) was added dropwise and the reaction mixture was warmed gradually to ambient temperature over 18 h. The reaction mixture was poured onto a saturated NH4Cl solution and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Column chromatography (ethyl acetate:hexanes::4:1) afforded the title product as a pale brown glass (170 mg, 31% yield, Rf0.2): mp 68-70° C.; NMR (CDCl3, 300 MHz): 8.6-8.4 (m, 2H), 7.7-7.5 (m, 1H), 7.5 (s, 1H), 7.25-7.05 (m, 6H), 6.95-6.75 (m, 2H), 6.25-6.2 (m, 1H), 5.85-5.7 (m, 1H), 4.25-4.05 (m, 1H), 3.8 (br s, 3H), 3.95-3.75 (m, 1H), 3.00-2.8. (m, 1H), 2.45-2.1 (br s, 3H), 1.35-1.15 (m, 9H); CI-HRMS: Calcd(C29H31BrN4O2): 547.1709 (M+H), Found: 547.1709.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH:28]C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH2:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][C:7]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CN(c1ccc(Oc2ccccc2)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(c1ccc(Oc2ccccc2)cc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-phenoxyphenyl)glycine methyl ester (0.375 g, 0.69 mmol) in 6 mL TFA/DCM (1:1) is stirred at ambient temperature for 20 min. The solvent is removed under reduced pressure. Methylene chloride is added to the residue and removed under reduced pressure. The resulting oil is purified by flash chromatography using 10% EtOAc/DCM to elute N-sulfamoyl-N-(2-benzyloxy-4-phenoxyphenyl)glycine methyl ester as an oil: 1H NMR (CDCl3) δ 7.44 (d, J=8.59 Hz, 1H), 7.33-7.26 (m, 7H), 7.09 (t, 1H), 6.97-6.93 (m, 2H), 6.60 (d, J=2.52 Hz, 1H), 6.43 (dd, J=8.59, 2.53 Hz, 1H), 4.96 (s, 2H), 4.26 (s, 2H), 3.62 (s, 3H); MS (M−H)−=441.
Reaction SMILES: ClC1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19]C1C=NC=CC=1.C1C=C(C=O)N=CC=1>>[N:19]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:3]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cccnc1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3cccnc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, but using 3-amino pyridine (565 mg, 6.0 mmol) and 2-pyridyl carboxaldehyde (642 mg, 6.0 mmol), 2-(2-pyridin-3-yl-2H-tetrazol-5-yl)pyridine was obtained as an off white solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH:14]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[CH:20][C:19]=1[O:29][CH3:30])[CH3:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:26]([NH:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:17]([NH:16][CH:14]([CH3:15])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:32])=[O:31])=[C:19]([O:29][CH3:30])[CH:20]=1)(=[O:28])[CH3:27]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)O

Procedure:
Prepared from 96c by treatment with TFA/CH2Cl2. After complete reaction, the solvent is removed in vacuo and the residue repeatedly concentrated from toluene. The resulting residue was dried under vacuum to a constant weight
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[C:19]([O:21]C)=[O:20])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+:24]>CO.O>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH:7]2[C:19]([O-:21])=[O:20])=[O:5])[CH2:3][CH2:2]1.[Na+:24]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)C(C(=O)[O-])C1
Reaction time: 24 h
Yield: 106.9 %

Procedure:
To a solution of 11.5 g (36.8 mmol) of 1-tert-butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in 127.5 ml of methanol are added 1.77 g of sodium hydroxide dissolved in 22.5 ml of water. The mixture is stirred for 24 hours and the reaction medium is then concentrated under reduced pressure and the residue co-evaporated with toluene, to give 12.6 g of sodium 1-tert-butyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in the form of a white powder after drying, and is used as obtained in the rest of the synthesis.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O>CCO>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2c[nH]cn2)cc1
Solvent: CCO
Product: Nc1ccc(Cc2c[nH]cn2)cc1

Procedure:
Prepared by catalytic hydrogenation of 4-(4-nitro-benzyl)-1H-imidazole in EtOH on palladium/charcoal (10%) (20° C., 3.5 bar, 45 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][O:8][C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:27]1[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])=[CH:29][CH:28]=1.CNCCNC>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[C:10](=[O:15])[N:11]([C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])=[CH:29][CH:28]=3)[CH:12]=[CH:13][N:14]=2)=[CH:16][CH:17]=1
Reactant: O=c1[nH]ccnc1OCCc1ccc(Cl)cc1
Reactant: CC(C)(O)COc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(O)COc1ccc(-n2ccnc(OCCc3ccc(Cl)cc3)c2=O)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A mixture of 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (25 mg, 0.100 mmol), K3PO4 (63.5 mg, 0.299 mmol), copper (1) iodide (18.99 mg, 0.100 mmol), 1-(4-bromophenoxy)-2-methylpropan-2-ol and N,N′-dimethylethylenediamine (0.032 mL, 0.299 mmol) in dioxane (1.0 mL) was stirred at 110° C. for 60 min. After removal of the precipitate by filtration, the filtrate was concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (CH2Cl2 to 10% MeOH/CH2Cl2) to elute 3-(4-chlorophenethoxy)-1-(4-(2-hydroxy-2-methylpropoxy)phenyl)pyrazin-2(1H)-one (31.82 mg, 0.073 mmol, 73.1% yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.32 (2H, d), 7.23-7.29 (4 H, m), 7.02 (2H, d), 6.84 (2H, s), 4.51 (2H, t, J=7.29 Hz), 3.83 (2H, s), 3.13 (2H, t, J=7.15 Hz), 1.36 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([N:11]1[CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:21]1=[O:22])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@H](NCc1ccccc1N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)OC(C)(C)C)N1Cc2ccccc2NC1=O
Yield: 38.5 %

Procedure:
To a solution of (2S)-2-(2-amino-benzylamino)-3-methyl-butyric acid tert-butyl ester (1.573 g, 5.65 mmol) in THF (20 mL) was added carbonyldiimidazol (1.008 g, 6.21 mmol) and the reaction was stirred under reflux overnight. The solvent was evaporated and the residue purified by flash chromatography (hexane/ethyl acetate, 50/50) to afford the sub-title compound as a yellow solid (662 mg, 38%). 1H NMR (400 MHz CDCl3) δ 0.95 (3H, d), 1.08 (3H, d), 1.49 (9H, s), 2.32 (1H, m), 4.39 (1H, d), 4.60 (1H, d), 4.72 (1H, d), 6.81 (1H, d), 6.94 (1H, t), 7.07 (1H, d), 7.18 (1H, t), 8.68 (1H, s).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]1[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[C:25]([O:24][C:22]([N:21]1[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]=[C:17]1[N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[C:9]([OH:10])=[O:8])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1c(N2CCCC[C@H]2C(=O)OCc2ccccc2)nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(N2CCCC[C@H]2C(=O)O)nc2ccccc21
Reaction time: 18 h
Yield: 98.1 %

Procedure:
10% w/w Palladium on carbon (300 mg) was added to a solution of tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate (900 mg) [see Preparation 47] in ethanol (30 ml). The reaction mixture was hydrogenated at 103.5 kPa (15 psi) at room temperature for 18 hours. The catalyst was then filtered off and the solvent removed under reduced pressure to afford (2S)-1-[1-(tert-butoxycarbonyl)-1H-1,3-benzimidazol-2-yl]-2-piperidinecarboxylic acid (700 mg) as a white foam.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CC(O)=O.O.[Pd]>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 96.8 %

Procedure:
To a solution of 2-(1-hydroxy-1-methyl-ethyl)-4-methoxy-phenol (50.57 g, 278 mmol) in 550 ml AcOH was added 10% Pd/C (as a slurry in 20 ml H2O). Ammonium formate (87.52 g, 1388 mmol) was added in portions. The mixture was warmed to 100° C. for 1 hour, cooled and filtered through a pad of celite. The celite pad was washed with ethyl acetate. The mother liquor was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-isopropyl-4-methoxy-phenol (44.74 g, 97%) as a pale yellow oil.