Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50]([O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62]I)=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: ICc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one (Example 46 c)) dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (60 min) with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 44a)) in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1) and crystallisation from ethyl acetate/hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=1>O>[CH3:24][N:23]([CH3:25])[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)[N:22]=1
Reactant: CN(C)c1ccnc(Cl)n1
Reactant: NC1CCN(CCc2ccccc2)CC1
Solvent: O
Product: CN(C)c1ccnc(NC2CCN(CCc3ccccc3)CC2)n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 28.4 %

Procedure:
A mixture of 1-(2-phenylethyl)-4-piperidinamine (8.17 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (6.3 g) was stirred for 20 hours at 120° C. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH(NH3) 96/4). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 3.69 g (28.4%) of N4,N4-dimethyl-N2-[1-(2-phenylethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 11).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](OC)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C2C(=[C:20]([O:25]C)C=CC=2)N=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:25][CH3:20])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: COc1cccc2c(Cl)ccnc12
Product: COc1ccc2nccc(Cl)c2c1

Procedure:
4-Chloro-7-methoxyquinoline and 4-Chloro-8-methoxy-quinoline: Lauer; J. Am. Chem. Soc.; 68; 1946; 1268);
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH2:15])=[C:4]([Br:16])[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([NH:15][C:23](=[O:25])[CH3:24])=[C:4]([Br:16])[CH:3]=1
Reactant: Nc1c(Br)cc(Br)c2c1oc1ccccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1c(Br)cc(Br)c2c1oc1ccccc12
Yield: 70.2 %

Procedure:
In a 2 L round-bottomed flask, 1,3-dibromodibenzo[b,d]furan-4-amine (76 g, 223 mmol) in dichloromethane (800 mL) and pyridine (180 mL, 2229 mmol) were cooled by ice bath. Acetyl chloride (31.7 mL, 446 mmol) was added dropwise while stirring. Then the ice bath was removed. The reaction was stirred at room temperature for 1 h. The residue was collected by filtration and washed by water and dichloromethane to give N-(1,3-dibromodibenzo[b,d]furan-4-yl)acetamide (60 g, 70.3% yield) as brown solid.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH3:12]C(C)=O.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: CC(C)=O
Reactant: O=C(O)C1CCC=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)C1CCC=CCCC1
Reaction time: 8 h

Procedure:
A 50 mL, 3-neck round bottom flask was charged with cyclooct-4-ene carboxylic acid (0.517 g, 3.35 mmol, prepared as described below in Example 35) and 30 mL reagent-grade acetone and vigorously stirred for several minutes. K2CO3 (1.15 g, 8.32 mmol) was then added, followed by an excess of methyl iodide (4 mL). A reflux condenser (water temperature 5° C.) was then fitted to the flask and the reaction was gently refluxed overnight. The mixture was filtered, the filtrate was concentrated using a rotary evaporator, and the residue was purified by flash chromatography on silica (1:9 ethyl acetate:hexanes mobile phase) to give methyl cyclooct-4-ene carboxylate as a single isomer (0.560 g, 99%). A copolymer of methyl cyclooct-4-ene carboxylate and cyclooctene, prepared similarly to polymer 15 at room temperature, would have the following features: The end groups R2 and R3 would be H or CH3. For this polymer, e and f would be derived from methyl cyclooct-4-ene carboxylate and would equal 3 and 4, respectively; d would derive from cyclooctene and would equal 8. The run lengths would therefore be: rHH=(3+3)+8z; rHT=(3+4)+8z; and rTT=(4+4)+8z; therefore rtotal=(6+8z), (7+8z), (8+8z).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1

Procedure:
3-Iodo-5-nitropyridin-2-ol (3.00 g, 0.0113 mol) was heated to reflux in phosphoryl chloride (15 mL, 0.1609 mol) for 4 hours. The reaction was quenched in ice/water and was neutralized with Na2CO3. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo to give the product, which was used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:11])[C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[C:14]([O:13][CH3:12])=[O:15])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 67.6 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.355 g, 1.63 mmol) in THF (16 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.294 g, 1.63 mmol), HBTU (0.929 g, 2.45 mmol), Et3N (0.458 mL, 3.26 mmol) and stirred at room temperature for 65 h, and then quenched with H2O. The organic layer was loaded onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.419 g (68%). LC-MS m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].C1CCN2C(=NCCC2)CC1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH:37]=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][CH2:36][C:35]([F:40])([F:39])[F:34]
Reactant: O=CCC(F)(F)F
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester and DBU were dissolved in dry methylene chloride (50 mL) and the reaction mixture was chilled to −30° C. 3,3,3-Trifluoropropanal (1 eq) was added dropwise to the chilled and stirred solution and the reaction was allowed to stir for an additional hour at −30° C., and then overnight at ambient temperature. Methylene chloride (ca. 100 mL) was added and the organic phase was washed with 1N HCl (ca. 100 mL), then saturated brine (ca. 100 mL). The organic phase was dried over MgSO4, filtered, and concentrated by rotary evaporation. This crude product was purified by silica gel chromatography with a gradient of 10-30% ethyl acetate in hexanes to yield 2-benzyloxycarbonylamino-5,5,5-trifluoro-pent-2-enoic acid methyl ester as a white, crystalline solid.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH2:31][CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 33.1 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (104 mg, 0.75 mmol) and propyl bromide (92 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 33.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.Cl[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>CC(O)C.C(OCC)(=O)C>[NH:29]1[CH2:28][CH2:27][N:26]=[C:25]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: ClC1=NCCN1
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(CCc1ccc(NC2=NCCN2)cc1)c1ccc(F)cc1
Yield: 67.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (1.17 g, 4.81 mmol) and 2-chloro-4,5-dihydro-1H-imidazole sulfate (1.95 g, 9.62 mmol) (prepared according to the procedure described in Trani, A and Bellasio, E., J. Het. Chem. 1974, 11, 257) in 2-propanol (20 mL) was heated under reflux for 15 minutes. The reaction mixture was cooled and diluted with ethyl acetate (150 mL) and washed with 5% sodium hydroxide solution, water, and brine. The organic layer was separated and dried with potassium carbonate, and evaporated in vacuo. Purification by silica gel chromatography, eluting with 10% methanol/dichloromethane containing 1% ammonium hydroxide, gave 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-fluorophenyl)propan-1-one as an oil (1.01 g, 76.5%). The oil was converted to the hydrochloride salt, m.p. 190.2-190.8° C. Analysis for C18H19CIFN3O.0.2H20: Calcd.: C, 61.52; H, 5.56, N, 11.96. Found: C, 61.40; H, 5.47; N, 11.97.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:37]2[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([N:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]4=[O:60])=[N:30][CH:31]=3)=[CH:40][N:39]=[CH:38]2)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(CO)ccc1C#N
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of [2-(2-cyano-5-hydroxymethylphenoxy)-ethyl]-carbamic acid tert-butyl ester from step 3 (248 mg, 0.85 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (450 mg, 0.85 mmol) in CH2Cl2 (4.5 ml) was added DIEA (325 μl, 1.87 mmol) followed immediately by the addition of Tf2O (215 μl, 1.27 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (4.5 ml) and heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography with 0 to 4% MeOH(NH4OH 5%) in CH2Cl2 to yield the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH3:25])=[C:10]3[CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenol (0.300 g, 0.916 mmol) was reacted with K2CO3 (0.152 g, 1.099 mmol) and methyl bromoacetate (0.168 g, 1.099 mmol) in acetone (10 ml) to give the product (0.233 g, 0.583 mmol, 64%) as a purple solid, mp 133-136° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.28 (s, 3H), 3.71 (s, 3H), 4.82 (s, 2H), 5.39 (s, 2H), 6.98 (d, J=8.6 Hz, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.26-7.29 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.62 (s, 1H); [ESI(+)], m/z 400 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Compound 21a (11.8 g, 32.0 mmol) and pyridine (27 ml, 305 mmol) were dissolved in DCM (200 ml) and cooled to 0° C., 4-nitrobenzoyl chloride (6.6 g, 35.6 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was washed with NaHCO3 (aq), aqueous citric acid and brine, dried over MgSO4 and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane: 50:50) to give 11.84 g, 72% of the title compound.
Reaction SMILES: C(OC(C1O[C:8]2[C:13](C(=O)C=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:9]=2[CH:24]=CC)=O)C.I([O-])(=O)(=O)=[O:28].[Na+]>[Os](=O)(=O)(=O)=O>[F:22][C:19]([F:20])([F:21])[C:18]([NH:17][C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=1[CH:24]=[O:28])=[O:23]
Reactant: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Product: O=Cc1ccccc1NC(=O)C(F)(F)F

Procedure:
Compounds of the invention in which R1 is alkyl may be prepared from the 8-propenyl-7-trifluoroacetamido-4-oxo-4H-chromene-2-carboxylic acid ethyl ester described above in accordance with Scheme II. The rearranged olefin (5) is treated with osmium tetroxide and sodium periodate to give the o-trifluoroacetamidobenzaldehyde (8). Condensation with the appropriate triphenylphosphorylidene ketone under Wittig conditions gives the o-trifluoroacetamidostyryl ketone (9), which upon treatment with acid cyclizes to give the 5-oxa-1-aza-phenanthrene ring system of the title compounds (10). Reduction, re-aromatization and tosylation as above gives the 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-methyltosylate. Replacement of the tosylate with the appropriately substituted azaheterocycle as above gives the title compounds of the invention. Substitution of trimethyl phosphonoacetate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by cyclization in acid gives the compounds of the invention in which R1 is hydroxy. Alkylation of this hydroxy derivative by a suitable alkyl halide or tosylate in the presence of base gives the compounds of the invention in which R1 is alkoxy. Treatment of the hydroxy derivative with an inorganic acid chloride such as phosphoryl chloride or bromide gives the compounds of the invention in which R1 is halo. Substitution of diethyl cyanomethylphosphonate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by cyclization in acid gives the compounds of the invention in which R1 is amino.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:4]([CH3:16])[CH:3]=1>C(O)CCC>[CH2:4]([C:5]1[N:7]2[N:6]=[C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[C:4]([CH3:16])=[CH:3][C:2]2=[N:7][N:6]=1)[CH3:3]
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Solvent: CCCCO
Product: CCc1nnc2cc(C)c(-c3ccc(C#N)cc3)nn12

Procedure:
A 30.8 g. portion of the above compound is dissolved in one liter of butyl alcohol (dried over 3-A molecular sieves), then 40.0 g. of p-(6-chloro-4-methyl-3-pyridazinyl)-benzonitrile (prepared as in Example 1) is added and the reaction mixture is allowed to heat at reflux for 18 hours. The reaction mixture is concentrated free of solvent and the concentrate is triturated with petroleum ether, then is filtered. The filter cake is vacuum dried to afford a yellow solid which is then recrystallized from methyl alcohol to give the product of the example, m.p. 192°-195° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])([C:16]([F:24])([F:23])[CH2:17]OS(C)(=O)=O)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]2([N:25]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:17][C:16]2([F:24])[F:23])[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a suspension of sodium hydride (1.7 g, with 40% mineral oil) in N,N-dimethylformamide (428 ml) cooled to 0° C. was added a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (17.1 g) in N,N-dimethylformamide (86 ml), and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (12.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([SH:11])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:12]1COCC1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([S:11][CH3:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CSc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask was added 5-chloro[1,3]thiazolo[5,4-b]pyridine-2-thiol (1-1) (21.4 g, 106 mmol), anhydrous THF (400 mL), potassium carbonate (20.5 g, 148 mmol), followed by methyl iodide (16.9 g, 119 mmol). The reaction vessel was sealed and stirred at room temperature for 5 minutes. The crude reaction mixture was then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 5-chloro-2-(methylthio)[1,3]thiazolo[5,4-b]pyridine (1-2) as a pink solid. HRMS (M+H)+: observed=216.9658, calculated=216.9655.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:15]=1[O:14][CH3:13]
Reactant: COc1cc(N(C)C)ccc1C=O
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: COc1cc(N(C)C)ccc1C=NNC(=S)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.6 mmol) and 2-methoxy-4-dimethylaminobenzaldehyde (97 mg, 0.72 mmol) similar to Example 3 and isolated as a yellow solid (60 mg, 29%). 1H NMR (CDCl3): 9.08 (s, 1H), 8.05 (s, 1H), 7.65 (brs, 1H), 7.45 (brs, 1H), 6.27 (brs, 1H), 6.22 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 6.00 (s, 1H), 4.32 (m, 1H), 3.82 (s, 3H), 3.03 (s, 6H), 2.93 (s, 1H), 1.85 (m, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.41 (m, 1H).