Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[CH2:22]([C:24]1[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]\[C:32]#[N:33])=[N:28][CH:29]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[C:32]([NH2:33])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)=[N:28][CH:29]=1)[CH3:23]
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: CCc1ccc(/C=C\C#N)nc1
Product: CCc1ccc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)nc1

Procedure:
The title compound, MS m/e (%):317 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(5-ethyl-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1>>[CH3:33][C:29]1[N:30]=[C:31]([O:25][C:22]2[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=2)[CH:32]=[CH:27][N:28]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1nccc(Cl)n1
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: Cc1nccc(Oc2ccc(N)cc2)n1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-phenol and 4-chloro-2-methylpyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2cccc(F)c2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
7-fluoro-1,3-dihydro-2H-indol-2-one (8.0 g, 52.9 mmol) was slurried in H2SO4 (conc., 86 ml) and the mixture cooled to −45° C. A solution of fuming nitric acid (>90%, 3.34 g, 52.9 mmol) in H2SO4 (20 ml) was added drop wise, while maintaining the temperature at −45° C. throughout the addition. The mixture was allowed to slowly warm to RT and stirred overnight. The mixture was poured into stirred ice-cold water (1500 ml). A white precipitate resulted, and the slurry was aged at 0° C. for 1 hour. The solid was collected by filtration, triturated with cold water (2×), and dissolved into EtOAc (1 L). This solution was washed with basic brine (containing sodium bicarbonate), dried over Na2SO4, filtered, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[CH:37]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[N:4]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:3]=[C:2]([CH3:1])[C:10]4=[C:9]([O:11][CH3:37])[CH:8]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc(=O)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc2c1c(C)nn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (330 mg, 0.87 mmol, 1.00 equiv) in tetrahydrofuran (15 mL), PPh3 (488 mg, 1.86 mmol, 2.20 equiv), MeOH (36 mg, 1.12 mmol, 1.10 equiv). To the resulting mixture was then added DEAD (237 mg, 1.36 mmol, 2.00 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×3 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (PE-1:100) to yield 4-[4-(4-methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid. MS (m/z): 500 [MH+].
Reaction SMILES: O=[C:2]([CH2:8][C:9](OC)=O)[CH2:3][C:4](OC)=O.BrC[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1CBr.C[O-].[Na+]>C1COCC1.CO>[CH2:2]1[C:8]2=[CH:9][CH:19]=[CH:20][CH:15]=[CH:16][C:17]2=[CH:18][CH:4]=[CH:3]1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: BrCc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C1=CC=C2CC=CC=C2C=C1

Procedure:
Accordingly, compounds of formula (Ca) are prepared, as set forth above in REACTION SCHEME 2B, by first combining a pentane-3-dioate, e.g. dimethyl 3-oxopentanedioate shown, with a 1,2-bismethyl aromatic having a suitable leaving group on each methyl group, e.g., 1,2-bis(bromomethyl)benzene, in a mixed protic/aprotic solvent medium, e.g., THF-MeOH, and a metal alkoxide, e.g., sodium methoxide. The metal alkoxide can be added as such or made in situ via careful addition (e.g., at low temperature) of the appropriate metal to at least the protic solvent, preferably prior to combination with the remaining reactants. The intermediate benzo[7]annulene product so formed can be optionally isolated and may contain one or two carboxy ester groups depending on the reaction conditions, e.g., methyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate, as shown above. The intermediate, dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate, is subjected to basic hydrolysis (saponification) conditions followed by acidification to give compounds of formula (Ca).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: CCN(CC)CCc1ccc(N)cc1Cl
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CCN(CC)CCc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-(2-diethylamino-ethyl)-phenylamine (Z44d). The reaction mixture was poured onto ice water and the aqueous phase was extracted with EtOAc. The org. phase was dried over sodium sulphate and evaporated down i. vac. The residue was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 5:2→1:1).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH3:41][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:4][CH:3]([CH3:41])[C:2]([CH3:1])([CH3:40])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C=O)cc2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 4′-({4-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.97 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.91 mL) at 0° C., and the mixture was stirred for 3 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.72 g, 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([NH:9][C@@H:10]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4]1.[Si]([Cl:36])(C)(C)C>CC(CC)=O>[ClH:36].[ClH:36].[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([NH:9][C@@H:10]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
(S)-2-(4-(dimethylamino)-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-N-methylpropanamide (480 mg, 1.15 mmol, non-polar diastereomer from step 3) was dissolved in ethyl methyl ketone (50 ml) and mixed with Me3SiCl (0.39 ml, 2.8 mmol). The solid was aspirated after 1 h.
Reaction SMILES: [C:1](=[O:57])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:35][C:36]([O:38][C@@H:39]2[C@H:46]3[C@H:42]([O:43][CH2:44][CH2:45]3)[O:41][CH2:40]2)=[O:37])[C@H:15]([OH:34])[CH2:16][N:17]([S:22]([C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:9][CH:8]=1.[OH-].[NH4+:59]>>[NH2:59][C:1]([O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([NH:35][C:36](=[O:37])[O:38][C@@H:39]2[C@H:46]3[C@H:42]([O:43][CH2:44][CH2:45]3)[O:41][CH2:40]2)[C@H:15]([OH:34])[CH2:16][N:17]([S:22]([C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)(=[O:23])=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21])=[CH:11][CH:12]=1)=[O:57]
Reactant: [NH4+]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [OH-]
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
3-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)propyl 4-nitrophenyl carbonate was treated with concentrated ammonium hydroxide as described above to afford the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2-1.3 (1H, m), 1.4 (1H, quintuplet), 1.9-2.0 (3H, m), 2.2 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.0 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.17 (2H, s), 6.4 (2H, br s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.2-7.3 (3H, m); MS: 694 (MH+)
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[NH:17][N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:28]I>>[C:1]12([O:11][CH2:12][C:13]3[N:17]([CH3:28])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CI
Reactant: O=c1c(Br)c(COC23CC4CC(CC(C4)C2)C3)[nH]n1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: Cn1c(COC23CC4CC(CC(C4)C2)C3)c(Br)c(=O)n1C1CCCCC1

Procedure:
The compound was prepared by treating 5-(adamantan-1-yloxymethyl)-4-bromo-2-cyclohexyl-1,2-dihydro-pyrazol-3-one with sodium hydride and methyl iodide as outlined in Reaction Scheme 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)OCC)c1

Procedure:
A mixture of 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267; 110 mg; 0.32 mmol) and ethyl 2-bromobutyrate (50 μl; 0.35 mmol) in DME (2 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and refluxed for 18 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a colorless sticky solid which was not further purified before use.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[H-].[Na+].[C:21]1([C:27]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:28]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=3)=[N:31][N:30]=[N:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:53]1([C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:28]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][C:42]([CH2:45][O:1][C:2]4[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=4[N+:16]([O-:18])=[O:17])[C:5]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[O:6])=[CH:41][CH:40]=3)=[N:31][N:30]=[N:29]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(c1ccc([N+](=O)[O-])c(O)c1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])c(OCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
The compound ([3]-(32)-587) (0.99 g) prepared in Example 36 was dissolved in dry N,N-dimethylformamide (19 ml), and 50% sodium hydride (0.20 g) was added to the solution. The mixture was stirred at room temperature for 15 minutes. A solution of N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (2.19 g) in N,N-dimethylformamide (6.5 ml) was added to the solution. The mixture was stirred at room temperature for 39 hours. The reaction mixture was added to water (50 ml), and extracted with chloroform (100 ml). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated to obtain the compound (2.72 g) as a light yellow solid. The product was purified by silica gel column chromatography (Kieselgel 60=190 g, chloroform/ethyl acetate=7/3) to obtain the compound ([3]-(33)-587) (1.41 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49]>ClCCl.O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][CH:53]=[C:45]([C:44]([F:43])([F:54])[F:55])[CH:46]=2)[N:13]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 203 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 230 mg of 3-trifluoromethyl benzoic acid is added and agitation is carried out for 6 hours and 30 minutes at ambient temperature. Water is added, followed by separating, washing with ether, drying and 307 mg of expected product is collected.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH3:22][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)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>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([CH3:22])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2nc(-c3ccccc3)oc2c1O
Temperature: 130 °C
Yield: 61.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (200 mg, 0.573 mmol), tetramethyltin (0.32 mL, 2.29 mmol), and dichlorobis(triphenylphosphine)palladium(II) (40.2 mg, 0.057 mmol) was suspended in 4.8 mL of anhydrous N,N-dimethylformamide. The reaction mixture was heated at 130° C. for 1 hour, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to give 99.6 mg of the title compound as a white solid. MS: (+) m/z 285.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.[F:19][CH:20]([F:25])[C:21]([NH:23][NH2:24])=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]3[C:21]([CH:20]([F:25])[F:19])=[N:23][N:24]=[C:9]3[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: NNC(=O)C(F)F
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Solvent: Cc1ccccc1C
Product: FC(F)c1nnc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Yield: 22.2 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (0.21 g, 0.654 mmol) and 2,2-difluoroacetohydrazide (0.14 g, 1.3 mmol) in xylene (6 ml) was heated at 150 degree under microwave for 60 min. The reaction solution was concentrated and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phase was concentrated and purified by column (biotage 25 g) eluted with ethyl acetate/cyclohexane (0-60%) to afford product (55 mg). 1H NMR (500 MHz, CDCl3) 8.09 (s, 1H), 7.4-7.55 (m, 5H), 7.06 (t, 1H), 5.66 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH2:11][OH:12])[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH3:1][C:2]1([CH2:11][O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1
Reactant: BrCc1ccccc1
Reactant: CC1(CO)CCC2(CCCO2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(COCc2ccccc2)CCC2(CCCO2)O1
Yield: 54.1 %

Procedure:
A solution of 1.70 g of 2-methyl-1,6-dioxaspiro[4.4]nonane-2-methanol in 20 ml of dimethylformamide was treated sequentially with 0.60 g of 60% sodium hydride-mineral oil dispersion at 15°-25° C. for 1 hour and then with 1.71 g of benzyl bromide at 0°-25° C. for 1 hour. The resulting mixture was poured into 150 ml of water and extracted with diethyl ether. The ether extract was washed with water, dried and distilled to yield 1.40 g of the desired product as a colorless liquid, b.p. 105°-110° C. (0.3 torr.).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26](O)[N:21]2[N:20]=1)(=[O:18])=[O:17]>C(#N)C>[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([Cl:3])[N:21]2[N:20]=1)(=[O:18])=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reaction time: 24 h

Procedure:
A solution of 100 ml of phosphoryl chloride in 400 ml of dry acetonitrile was added to 12.0 g (30.9 mmol) of N-(2,6-dichloro-3-methylphenyl)-7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide and heated to reflux with stirring. After about 24 hours, the mixture became a solution which appeared to contain little or no starting material by thin layer chromatography. The volatiles were largely removed by evaporation under reduced pressure and the residue poured onto about one liter of ice and water with stirring using fresh acetonitrile as a transfer solvent. The solid in the resulting mixture was collected by filtration, washed with water, and dried under reduced pressure at 70° C. overnight. The resulting solid, which was found to be the title compound by NMR analysis, amounted to 8.4 g (67 percent of theory).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.6 %

Procedure:
To 4-hydroxybenzaldehyde (10.0 g, 81.89 mmol) was added 175 mL methylene chloride, 3,4-dihydro-2H-pyran (18.7 mL, 204.97 mmol) and pyridinium p-toluenesulfonate (2.06 g, 8.2 mmol). The reaction mixture was stirred at room temperature for three days. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with a second portion of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, which was then back-extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Silica gel flash chromatography of the residue (10% ether/hexanes to 20% ether/hexanes) afforded 17.32 g of the title compound of Step A. MS 207.4 (M+1)+Step B: [4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine