Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C([O-])(O)=O.[Na+].C1C(=O)N([O:30][C:31]([O:33][CH2:34][CH:35]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]3[C:36]2=[CH:37][CH:38]=[CH:39][CH:40]=3)=O)C(=O)C1.Cl>O1CCOCC1.O>[CH:46]1[C:47]2[CH:35]([CH2:34][O:33][C:31]([NH:8][C@H:7]([C:6]([OH:5])=[O:17])[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[O:30])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.2 %

Procedure:
To a stirring suspension of L-tyrosine O-t-butyl ester (1.00 g, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1,4-dioxane/water (1:1, 20 mL) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 mL followed by the addition of 50 mL of cold 1N HCl. The product was extracted with ethyl acetate (3×). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100%) which was used without purification: 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1, 1H), 4.33 (dd, J=7.1, 10.5, 1H), 4.41-4.53 (m, 2H), 5.01 (bs, 1H), 5.30, (d, J=8.2, 1H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)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>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([N:10]1[C:14]2[CH2:15][C:16](=[CH:19]O)[C:17](=O)[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C:14]2[CH2:15][C:16]3[CH:19]=[N:2][NH:1][C:17]=3[C:13]=2[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C1C(=CO)Cc2c1cnn2Cc1ccccc1
Solvent: CO
Product: c1ccc(Cn2ncc3c2Cc2cn[nH]c2-3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Hydrazine (0.07 ml) was added dropwise to an ice-cold solution of 0.5 g of 1-benzyl-5,6-dihydro-5-hydroxymethylene-4(1H) cyclopentapyrazolone in 25 ml of methanol. The solution was heated at reflux for 2 hours and then cooled to room temperature and stirred for 16 hours. An additional 0.07 ml of hydrazine was added and the solution was heated at reflux for 8 hours. Removal of the solvent under reduced pressure gave 1-benzyl-4,7-dihydro-1H-cyclopenta-[1,2-c:3,4-c']dipyrazole as an orange-red solid (86% yield) melting at about 61°-72° C.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[C:4]#[C:5][CH3:6].[CH2:8]([NH:10][NH2:11])[CH3:9]>C(O)CCC.O>[CH2:8]([N:10]1[C:5]([CH3:6])=[CH:4][C:3]([CH2:2][CH3:1])=[N:11]1)[CH3:9]
Reactant: CCNN
Reactant: CC#CC(=O)CC
Solvent: O
Solvent: CCCCO
Product: CCc1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
A solution of 18.9 g (0.2 mol) of hex-4-yn-3-one (from Step B) in 120 mL of n-butanol was treated with 40 mL (0.227 mol) of ethyl hydrazine, 34% solution in water. The resulting mixture was heated at reflux for 1.5 h, then cooled to rt. The mixture was concentrated to ˜150 μL volume; this was partitioned between 1 L of ether and 250 mL of water. The layers were separated and the organic layer was dried and concentrated to afford the title compound, which was used without further purification. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.37 (t, J=7.2, 3H), 2.23 (s, 3H), 2.59 (q, J=7.6, 2H), 4.01 (q, J=7.2, 2H), 5.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C:35]([O:37]C)=[O:36])=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:29][C@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C:35]([OH:37])=[O:36])=[N:4][CH:5]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][O:27][CH3:28])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: COCc1cc(-c2nc(-c3cnc(N[C@H]4CCC[C@H]4C(=O)OC)c(Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3cnc(N[C@H]4CCC[C@H]4C(=O)O)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 60 °C

Procedure:
A solution of methyl cis-2-(3-chloro-5-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)pyridin-2-ylamino)cyclopentanecarboxylate (0.099 g; 0.19 mmol) in dioxan (2 mL) was added hydrochloric acid (1 mL). The mixture was heated at 60° C. for 24 hours. The solvent was evaporated and the residue purified by preparative HPLC to afford the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.76 (1H, d, J=2.0 Hz), 8.33 (1H, s), 8.23-8.14 (2H, s), 7.45-7.26 (4H, m), 7.18 (1H, d, J=7.4 Hz), 6.86 (1H, s), 4.76-4.66 (1H, m), 4.28-4.16 (2H, m), 3.28 (3H, s), 3.11-3.02 (1H, m), 2.15-1.88 (6H, m), 1.88-1.78 (2H, m), 1.71-1.59 (1H, m). LC/MS: 519 (M+H)+. HPLC (Method F) Rt 9.03 min (Purity: 90.9%).
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([OH:27])[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.C(#N)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:31](=[O:32])[N:30]([CH3:33])[CH2:29][CH2:28][N:11]4[C:12]=3[C:13]([OH:27])=[N:14]2)=[CH:21][CH:22]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-4-hydroxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (23 mg, 0.05 mmol) and Pearlman's catalyst [25 mg, 20% Pd(OH)2 on carbon] in methanol (10 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 45 minutes. The reaction mixture was diluted with acetonitrile and filtered. The filtrate was concentrated under vacuum, and the residue was subjected to purification on reverse phase HPLC. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=1>ClCCl>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][C:23]=1[N+:31]([O-:33])=[O:32])(=[O:28])=[O:29])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCNS(=O)(=O)c1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of N-(2-aminoethyl)-glycine ethyl ester 2HCl (1.10 g, 5.0 mmol), prepared as described by Will (D. W. Will et al., Tetrahedron, 1995, 51, 12069–12802.), in dichloromethane (50 mL) was slowly added triethylamine (2.02 g, 20 mmol) at room temperature. Then 4-methyl-2-nitro-benzenesulfonyl chloride (1.19 g 5.0 mmol) in dichloromethane (10 mL) was added to the reaction mixture at room temperature for 5 min. The resulting reaction mixture was stirred for additional 2 h. at room temperature and washed with water (30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give desired product (1.60 g, 92%) as a solid. 1H-NMR (500 MHz; DMSO-d6) δ 7.87 (d, 1H), 7.81 (s, 1H), 7.66 (d, 1H), 4.06 (q, 2H), 3.24 (s, 2H), 2.91 (t, 2H), 2.57 (t, 2H), 2.44 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:11]1([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:20]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=4[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]3)=[CH:4][CH:5]=2)=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(c1ccc(CBr)cc1)N1CCCC1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 53.8 %

Procedure:
A mixture of 1-{[4-(bromomethyl)phenyl]carbonyl}pyrrolidine (84 mg, 0.31 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (60 mg, 0.32 mmol), and potassium carbonate (87 mg, 0.63 mmol) in N,N-dimethylformamide (2 ml) was stirred at 140° C. in a microwave reactor for 10 minutes. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate and reduced to minimum volume under reduced pressure. The crude product was purified using mass directed auto-prep to give the title compound as a pale yellow oil (63 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH:14]=[CH2:15]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: C=CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: C=CCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 9.25 g. (0.05 mole) of methyl 2-chloro-6-methylnicotinate, 2,85 g. (0.05 mole) of allylamine and 5.3 g. (0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was diluted with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small amount of this oil was dissolved in diethyl ether containing a few drops of ethanol and this solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic acid methyl ester, m.p. 140°-2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c(OC)c1
Yield: 67.3 %

Procedure:
Using 1.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane, 1.80 g of 1-(2,4-dimethoxyphenyl)piperazine dihydrochloride, 1.9 ml of triethylamine and 50 ml of dioxane, reaction and workup were carried out as in Example 1-A. Purification by column chromatography (silica gel, elution with ethyl acetate:hexane =1:0.5) gave 1.96 g of pale red crystals, m.p. 110-112° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH:52][CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:52]([CH:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)[CH3:53])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNC1CCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)C2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with cyclopentyl-methyl-amine (Oakwood) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1>>[F:13][C:12]([F:15])([F:14])[C:11]1[N:6]2[CH:5]=[N:4][C:3]([C:1]#[C:2][C:30]3[CH:29]=[CH:28][C:27]([NH2:26])=[N:32][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.x) (178 mg, 0.5 mmol) and commercially available 6-amino-3-bromo-pyridine (86 mg, 0.5 mmol) according to general procedure II. Obtained as a dark red solid (70 mg, 31%). MS (EI) 448.1 [(M+)]; mp 225° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C([O:28][N:29]=O)CC(C)C>CC(O)(C)C>[OH:28]/[N:29]=[C:14](/[CH3:15])\[C:13]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:16]
Reactant: CCC(=O)c1c(C(C)C)nn2ccccc12
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C/C(=N/O)C(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.4 g (40 mmol) of 2-isopropylpyrazolo[1,5-a]pyridine, 3.7 g (40 mmol) of propionyl chloride and 400 mg of AlCl3 was stirred at RT in 5 ml of CS2 for 3 days. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 5.44 g of crude 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, which was purified on a silica gel column to yield 700 mg of pure intermediate along with 3.53 g of starting material. 700 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was reacted with 600 μl of 1M t-BuOK in t-BuOH at −20° C. for 20 minutes, followed by the addition of 600 μl of isoamylnitrite at 0° C. and stirring at RT overnight. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 1.2 g of crude product, which was purified on a silica gel column to furnish 314 mg of (Z)-2-(hydroxyimino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1083.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=O)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([O:28][C:29]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])[CH3:27]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=[CH:31][C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Solvent: ClCCCl
Product: CCOC(=O)C=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Reaction time: 0.5 h

Procedure:
A solution of 2-((3,4-dichlorophenyl)amino)-4-hydroxy-6-nitroquinazoline-8-carbaldehyde (100 mg) and ethoxycarbonylmethylene triphenylphosphorane (100 mg) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated to an oil, which was purified by preparative high pressure liquid chromatography (21.4 mm i.d.×30 cm Dynamax 300 Å C18 column; 30-90% CH3CN/H2O (+0.1% (v/v) CF3CO2H) gradient over 30 min, then to 100% CH3CN over 5 min; 15.0 mL/min flow; 1.0 min (15 mL) fractions). Fractions containing the desired product, as determined by analytical HPLC, were concentrated to afford the title compound as a crystalline yellow solid which was isolated by filtration and dried. Yield 14.2 mg. 1H NMR (300 MHz, CDCl3): δ8.79 (d, J=2.4 Hz, 1H); 8.61 (d, J=2.4 Hz, 1H), 8.20 (d, J=16.2 Hz, 1H); 7.72-7.52 (m, 3H), 6.98 (d, J=16.2 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H); 1.27 (t, J=7.2 Hz, 3H). HPLC (Method A): 8.45 min. MS (APCI+): m/z 449, 451.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19][C@@H:20]([O:24][C:25]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:34](=[O:43])[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:29][CH2:28]2)=[O:26])[C:21](O)=[O:22])[CH:3]=1.[NH2:44][C:45](=[N:51]O)[C:46]([O:48][CH2:49][CH3:50])=[O:47].Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[O:43]=[C:34]1[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C@@H:20]([C:21]3[O:22][N:51]=[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=3)[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:10]4[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:9]=4)[CH:5]=3)=[O:26])[CH2:32][CH2:31]2)=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CCOC(=O)C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: CCOC(=O)c1noc([C@@H](Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A stirred solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (28.5 mg, 0.0471 mmol) in anhydrous diglyme (2.5 mL) was treated with ethyl 2-amino-2-(hydroxyimino)acetate (6.54 mg, 0.0495 mmol) and 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (0.49 mg, 0.0495 mmol) at room temperature. The mixture was stirred overnight at room temperature and then overnight at 110° C. After cooling to room temperature and removal of the solvent in vacuo, the crude compound was purified using preparative HPLC to afford a tan gum (11.2 mg, 34%). 1H-NMR (CDCl3, 400 MHz) δ 8.0 (s,1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.46 (m, 1H), 7.30 (s,1H), 7.24-7.20 (m, 2H), 6.93 (s,1H), 6.17-6.15 (m, 1H), 5.71 (s, 2H), 4.50-4.48 (m, 2H), 4.29-4.20 (m, 2H), 3.65-3.55 (m, 2H), 3.40-3.38 (m, 2H), 3.20-2.81 (m, 4H), 2.59 (s, 3 h), 2.03-1.72 (m, 4H), 1.44-1.38 (m, 3H), 0.95-0.86 (m, 2H), −0.045 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[S:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@@H:14]([CH3:28])[CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl>[ClH:37].[ClH:37].[NH2:29][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C@H:26]([CH3:27])[S:25][CH2:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C@@H:14]([CH3:28])[CH2:13]1)=[O:11]
Reactant: C[C@@H]1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(F)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)[C@H](N)Cc4ccc(F)cc4)C[C@@H]3C)c21
Yield: 52 %

Procedure:
tert-Butyl (R)-3-(4-fluorophenyl)-1-((S)-3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) afford (R)-2-amino-3-(4-fluorophenyl)-1-((S)-3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (20 mg, 52%). MS (APCI+) [M+H]+ 415.
Reaction SMILES: C1(O[C:8](=[O:32])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:12]([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH:11]=2)C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]C(NC2C=CC(SC(C)C)=C(C=2)CN(C)C(=O)OC(C)(C)C)=O)=[CH:36][CH:35]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[C:12]([CH:11]=2)[CH2:22][N:23]([CH3:24])[C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:32])=[CH:36][CH:35]=1
Reactant: CC(C)Sc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
Using a procedure analogous to that used for preparation of 16G, 18A (0.642 g, 1.20 mmol) was reacted with mCPBA (0.672 g, 3.00 mmol) to give 18B (0.660 g, 97%) as a white solid. MS (ESI) m/z 568.9 (M+H)+.