Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][C:8]=2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>ClCCCl>[C:26]1([C:22]2[N:9]3[CH:10]=[N:11][N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]3=[N:13][C:23]=2[OH:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnnc1-c1ccccc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
To a solution of 6-phenyl-[1,2,4]triazin-5-ylamine (1.1 g, 6.4 mmol) and triethylamine (891 μl, 6.4 mmol) in anhydrous 1,2-dichloroethane (75 ml) under an atmosphere of nitrogen was added dropwise 2-chloro-2-phenylacetyl chloride (1.01 ml, 6.4 mmol). The reaction mixture was stirred at 0° C. for 90 min, then triethylamine (891 μl, 6.4 mmol) was added, and the resulting mixture heated under reflux for 30 min. The cooled reaction mixture was partitioned between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The solid residue was triturated with a 1:1 mixture of CH2Cl2 and MeOH (10 ml), filtered and dried to give 780 mg (2.7 mmol, 42%) of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol as a pale yellow solid. δH (360 MHz; DMSO-d6) 7.41 (1H, t, J 7.3 and 7.2, aromatic), 7.50-7.63 (5H, m, aromatics), 7.82 (2H, d, J 7.8, aromatics), 8.57 (2H, m, aromatics), 9.65 (1H, s, imidazotriazine H5), 11.72 (1H, br s, OH); m/z (ES+) 289 (M++H, 100%).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:37])[C@@H:21]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])[N:22]1[C:33](=[O:36])[CH2:34][NH:35][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(CC(SC(C)=O)C(=O)O)cc1
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(OC)cc1)SC(C)=O
Yield: 50 %

Procedure:
Condensation of 2-acetylthio-3-(para-methoxyphenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 4:6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:18])[CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C.NC(O)C.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][N:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:21](=[O:22])[CH2:20][O:18]2)=[CH:6][CH:7]=1
Reactant: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Reactant: O=C(Cl)CCl
Agent: CC(N)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CO[C@@H](c2ccc(F)cc2)CN1Cc1ccccc1
Temperature: 2 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a suspension of (1S)-1-(4-fluorophenyl)-2-(benzylamino)ethanol (22.0 g, 89.69 mmol) in toluene (100 mL) was added dropwise over 1 hr a solution of chloroacetyl chloride (9.3 mL, 116.6 mmol) in toluene (30 mL) at 5-15° C. After stirring for 2 hrs, a solution of triethylamine (17.4 mL, 123.7 mmol) in toluene (20 mL) was added dropwise over 15 min to the mixture at 10-15° C. The mixture was stirred for 17 hrs at room temperature. After HPLC analysis to confirm a disappearance of the aminoethanol, the mixture was cooled to 2° C., and sodium methoxide (52 g, 269.07 mmol, 28% methanol solution) was added dropwise over 15 min. The mixture was stirred at 2-5° C. for 9 hrs, and water (60 mL) was added. The organic layer was separated and washed successively with 0.5N hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution. The solvent was evaporated under reduced pressure to give (6S)-6-(4-fluorophenyl)-4-(benzyl)morpholin-3-one (27.78 g) as a yellow oil.
Reaction SMILES: CC1NC2C[CH:9]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:11](=[O:12])[C:5]=2C(C2C=CC=C(O)C=2)C=1C(OCCOC)=O.C(O)(=O)C.N.COC1C=CC=CC=1C=O.C(OCC)(=O)CC([O-])=O>CC(C)=O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:9]=[CH:10][C:11](=[O:12])[CH3:5]
Reactant: COCCOC(=O)C1=C(C)NC2=C(C(=O)CC(c3ccccc3OC)C2)C1c1cccc(O)c1
Agent: CCOC(=O)CC(=O)[O-]
Agent: COc1ccccc1C=O
Agent: N
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccccc1C=CC(C)=O

Procedure:
Synthesis of HPIs of the disclosure can be performed by any means by one of skill in the art. However, an example of synthesis of HPI-1 is provided. HPI-1 can be readily prepared in a one-pot synthesis using the Hantzsch reaction (Loev et al., J. Pharm. Pharmacol. (1972) 24:917-918) (see also FIG. 10 panel A-B). This synthetic transformation generates the dihydropyridyl pharmacophore from an aldehyde, two 1,3-diones, and ammonia acetate in high yields. First, one of the 1,3-diones was prepared in two synthetic steps (FIG. 10, panel A). 4-(2-methoxyphenyl)but-3-en-2-one was synthesized by an aldol condensation of 2-methoxybenzaldehyde and acetone, followed by dehydration. Reaction of the α,β-unsaturated ketone product with ethyl malonate generated an ester intermediate, which yielded the desired aryl-substituted 1,3-dione upon decarboxylation. HPI-1 was then synthesized by heating a mixture of the aryl-substituted 1,3-dione, 3-hydroxybenzaldehyde, 2-methoxyethyl acetoacetate, ammonium acetate, and the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM.BF4) (FIG. 10, panel B). Purification by silica gel chromatography yielded the final product as a mixture of four diastereomers in 63% overall yield. Using this procedure, it is possible to synthesize gram quantities of HPI-1, which would be sufficient for both research and clinical applications. HPI-1 derivatives set forth in Table II were similarly prepared.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[CH:5]([OH:7])[CH3:6].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: CC(O)/C=C/[Si](C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)/C=C/[Si](C)(C)C

Procedure:
Referring to Flowchart II, 3-butyn-2-ol (formula 21) is treated in step H with sodium hydride in ether at -20° C. and then with 2.0 n-butyllithium in hexane, followed by chlorotrimethylsilane, to produce (+)-4-trimethylsilyl-3-butyn-2-ol (formula 22), which is then reacted in step I with lithium aluminum hydride in ether at reflux for several hours, basified and distilled, to produce (±)-trans-4-(trimethylsilyl)-3-buten-2-ol (formula 23). The reaction in step J of (23) in ether with a mixture of sodium dichromate hydrate and sulfuric acid at <5° C. or below produces trans-4-(trimethylsilyl)-3-buten-2-one (formula 24), which upon distillation with selected solvents gives trans-4-(trimethylsilyl)-2-acetoxy-1,3-butadiene (formula 25).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:34].C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (5.85 g, 12.5 mmol) (obtained as described in Reference Example 2(1)) in benzene (290 ml) was added a solution of 0.67M ammonium chloride-trimethylaluminium in benzene (56.4 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (40° C.) for 17 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (50 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1→1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (4.97 g, yield 91%) as a pale brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH:27][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccc(Cl)c(Cl)c4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 3,4-dichlorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=95%, [M+H]+=445.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[OH:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1.NC1C=CC=CC=1.Cl>N1C=CC=CC=1>[CH:11]1[C:12](/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6])=[CH:15][CH:16]=[C:9]([OH:8])[CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: Nc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 7.5 h
Yield: 80 %

Procedure:
Malonic acid, 813 g, was added to p-hydroxy benzaldehyde, 472 g, in pyridine, 957 ml. The mixture was heated to 65° C. and aniline, 28 ml, was added. The reaction was stirred at 65° C. for 7.5 hours and then cooled to room temperature. HCl, 2.75 L, 2N HCl, was then added dropwise while the reaction stirred A creamy precipitate formed. The reaction was stirred for an additional 10 minutes. The precipitate was collected by filtration and dried under reduced pressure. The solid was identified as coumaric acid by IR spectroscopy. The yield was ≥80%.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([C:33]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=2)=[CH:9][C:10]#[N:11])[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OCC)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(OCC)c2)ccc1OC
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (7.0 mL, 44.4 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 44.4 mL, 44.4 mmol) at 0° C. and stirred for 30 min followed by addition of bis-(3-ethoxy-4-methoxy-phenyl)-methanone (7.34 g, 22.2 mmol) and refluxed for 3 h. The reaction mixture was poured into water (100 mL), extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as a white solid (3.92 g, 50% yield): 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 6H, 2CH2CH3), 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.94-4.04 (two q, J=7 Hz, 4H, 2CH2CH3), 6.11 (s, 1H, CH), 6.77-7.09 (m, 6H, Ar); 13C NMR (DMSO-d6) δ 14.6, 14.6, 55.5, 55.5, 63.8, 92.6, 111.3, 111.5, 112.3, 113.8, 118.9, 122.3, 122.4, 129.3, 130.6, 147.3, 147.8, 150.1, 151.0, 161.4; Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.42; H, 6.42; N, 3.97.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-])=O>[Cu]>[C:2]1([N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:20]3[CH:19]=[CH:18][C:17]([N:14]([C:2]4[CH:7]=[CH:6][C:5]([C:2]5([C:20]6[CH:19]=[CH:18][C:17]([N:14]([C:2]7[CH:7]=[CH:6][C:5]([C:20]8[CH:19]=[CH:18][C:17]([N:14]([C:2]9[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=9)[C:2]9[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=9)=[CH:22][CH:21]=8)=[CH:4][CH:3]=7)[C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)=[CH:22][CH:21]=6)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[CH:4][CH:3]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:22][CH:21]=3)=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(C5(c6ccc(N(c7ccccc7)c7ccc(-c8ccc(N(c9ccccc9)c9ccccc9)cc8)cc7)cc6)CCCCC5)cc4)cc3)cc2)cc1
Yield: 48.9 %

Procedure:
9.05 g (0.01 mol) of 1,1-bis[p-[N-(4'-anilino-4-biphenylyl)anilino]phenyl]cyclohexane thus obtained, 4.49 g (0.022 mol) of iodobenzene, 2.90 g (0.021 mol) of anhydrous potassium carbonate, 0.32 g (0.005 mol) of copper powder, and 15 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 198° C. to 213° C. for 19 hours. The reaction product was then extracted with 150 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated. To the concentrate was then added 110 ml of n-hexane to recover a crude crystal. The crude crystal thus recovered was then purified by column chromatography (carrier: silica gel; elute: 2/3 mixture of toluene and n-hexane) to obtain 5.17 g (yield: 48.9%) of 1,1-bis[p-[N-(4'-diphenylamino-4-biphenylyl)anilino]phenyl]cyclohexane. The melting point of the product was indefinite.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12][C:13]2[C:14]3[CH:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:18][C:15]=3[S:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:26]I>C1COCC1>[C:6]1([S:12][C:13]2[C:14]3[CH:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:18][C:15]=3[S:16][C:17]=2[I:26])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: II
Reactant: c1ccc(Sc2csc3cc4ccccc4cc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1sc2cc3ccccc3cc2c1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under nitrogen atmosphere, n-butyl lithium (1.63 M (solvent: hexane), 0.46 ml, 0.75 mmol) was dripped into a THF solution (5 ml) of 3-(phenylsulfenyl)naphtho[2,3-b]thiophene (146 mg, 0.5 mmol) at 0° C. After the mixture was stirred for 1 hour at room temperature, iodine (190 mg, 0.75 mmol) was added thereto at 0° C. and the mixture was stirred for further 6 hours at room temperature. Subsequently an aqueous solution of Na2S2O5 was added thereto, and the mixture was extracted with CH2Cl2 (50 ml×3) and washed with saline (15 ml×3). The extract liquid was dried with magnesium sulfate, and concentrated. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that 3-(phenylsulfenyl)-2-iodonaphtho[2,3-b]thiophene was produced as an orange solid (138 mg, 0.3 mmol, yield: 66%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]#[CH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[CH:18]([NH:20][NH2:21])=O.CN(C)C=O>O>[C:11]1([C:6]2[N:5]=[C:4]([NH2:17])[N:3]3[CH:18]=[N:20][N:21]=[C:2]3[C:7]=2[CH2:8][C:9]#[CH:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: NNC=O
Solvent: O
Solvent: CN(C)C=O
Product: C#CCc1c(-c2ccccc2)nc(N)n2cnnc12

Procedure:
1.7 Parts of 4-chloro-6-phenyl-5-(2-propynyl)pyrimidin-2-amine and 0.84 part of formylhydrazine are added to 20 parts by volume dimethylformamide containing 2.0 parts of molecular sieve 3A and refluxed under nitrogen for two hours. The solution is allowed to cool and is poured into cold water. The crystalline product is filtered out, washed with water and dried. The product is chromatographed to give 7-phenyl-8-(2-propynyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-amine having the formula: ##STR6##
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18](=[O:19])[N:14]2[CH2:15][CH2:16][O:17][C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[C:7]=1[OH:20])=[O:5])C.Br>C(O)(=O)C>[C:4]([C:6]1[C:18](=[O:19])[N:14]2[CH2:15][CH2:16][O:17][C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[C:7]=1[OH:20])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1c(O)c2cccc3c2n(c1=O)CCO3
Temperature: 75 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.28 g) and hydrobromic acid (47%; 0.44 ml) in acetic acid (1.5 ml) was stirred at 75° C. for 1 hour. The mixture was cooled in ice-water. The precipitates were collected, washed with water, and dried in vacuo at 60° C. to give pale brown crystals of 2,3-dihydro-6-carboxy-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.19 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:11]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1nc(C2CC2)c2cc[nH]c2n1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 0.452 g, 2.94 mmol), cyclopropylmagnesium bromide (17, 31.4 mL, 0.50 M in tetrahydrofuran, 15.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.240 g, 0.294 mmol) are combined with 15.4 mL of toluene. The reaction is heated at 60° C. overnight, then quenched with 1 M aqueous hydrochloric acid to pH 4 and filtered through a bed of celite. The layers of the filtrate are separated and the aqueous layer extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (18, 0.465 g). MS (ESI) [M+H+]+=160.1. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 19.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([NH2:23])[N:15]=2)=[N:6]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.ClC(Cl)(Cl)S(O[CH2:52][C:53]([F:56])([F:55])[F:54])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH2:52][C:53]([F:56])([F:55])[F:54])=[C:16]([NH2:23])[N:15]=2)=[N:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]cnc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1ncn2CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
100 mg (0.278 mmol) of the compound from example 58 and 76 mg (0.278 mmol) of BEMP were initially charged in 3 ml of dimethylformamide, a solution of 78 mg (0.266 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min and the mixture was stirred at RT for 20 min The product was precipitated by adding water, filtered off with suction and purified by means of preparative HPLC (eluent: acetonitrile/water with 0.05% trifluoroacetic acid, gradient 20:80→50:50). 53 mg of the title compound were obtained (43% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26]2[N:30](COCCOC)[N:29]=[CH:28][CH:27]=2)=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.CO>[Cl:1][C:2]1[C:3]([O:19][C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26]2[NH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COCCOCn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Agent: Cl
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CCCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 79.7 %

Procedure:
A solution of the 5-chloro-2-fluoro-4-{[(1S,2R)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.222 mmol) prepared in Example 158d in 6 M HCl (5.0 mL) and methanol (4.0 mL) was stirred for 5 hours under heated reflux. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=85:15) to yield the title compound (80.0 mg, 80%) as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH3:13])[C:10]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:10]1([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[O:15])[CH:11]([CH3:13])[CH2:12][N:8]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:9]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(Cc3ccccc3)CC2C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)CC2C)cc1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of (4-methoxyphenyl)methyl (3RS,4SR)-1-benzyl-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylate obtained in Example 2g (18 g, 39.7 mmol) in dichloromethane (85.7 ml) was adjusted to an internal temperature of 10 to 20° C., and benzyl chloroformate (11.9 ml, 79.4 mmol) was added thereto. After returning to mom temperature and stirring for 0.5 hour, the reaction mixture was concentrated directly. The resulting crude product was purified by column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (12.89 g, yield: 65.3%).