Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9](CC2C=CC(OC)=CC=2OC)[CH:10]=[O:11])[CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1>C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH:10]=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Solvent: O=CO
Solvent: COc1ccccc1
Product: O=CNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-((6-Bromopyridin-2-yl)methyl)-N-(2,4-dimethoxybenzyl)formamide obtained in Reference Example 20 (830 mg) and anisole (1.0 mL) were dissolved in formic acid (20 mL), and the solution was stirred at 100% for 8 hr. The mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to azeotropy with toluene, to the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (279 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[N:14][C:13]([N+:16]([O-:18])=[O:17])=[N:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:19]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:16]([C:13]1[N:14]=[CH:15][N:11]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:19])=[CH:10][C:7]=2[C:8]#[N:9])[N:12]=1)([O-:18])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cnc([N+](=O)[O-])n2)c(C#N)c1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]−); IR (thin film) 2240, 1514, 1312 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]#[N:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(CC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(CC)cc2)cc1

Procedure:
A solution of 2,3-bis(4-ethylphenyl)quinoxaline-6-carbonitrile (200 mg, 0.55 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), NaN3 (179 mg, 2.75 mmol, 5.00 equiv), and NH4Cl (146 mg, 2.75 mmol, 5.00 equiv) was stirred for 7 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 8×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting solution was concentrated in vacuo, and washed with methanol. This resulted in 98 mg (44%) of 2,3-bis(4-ethylphenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[O:22][N:21]=[C:20]([CH3:23])[CH:19]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Temperature: 80 °C

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C36) (0.100 g, 0.189 mmol), zinc cyanide (0.027 g, 0.227 mmol), tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.110 mmol) and N,N-dimethylformamide (6 mL) were added to an Emrys microwave reaction vial. The vial was sealed and purged with nitrogen gas for 10 minutes with stirring. After that time, the vial was placed on a Biotage microwave processor and heated to 80° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and aqueous layer was extracted further with ethyl acetate (3×50 mL). The combined organics were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 51 mg, 57%. LCMS m/z 477.3 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.09 (br s, 2H), 7.83-7.87 (m, 2H), 7.40-7.59 (m, 4H), 4.97 (d, J=9.2 Hz, 1H), 4.30 (dd, J=11.7, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=12.9, 3.9 Hz, 1H), 2.82 (dd, J=13.2, 3.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])=[O:6])[CH3:3].Cl.[CH3:15][C:16](=[CH2:19])[CH2:17][NH2:18].CN1CCOCC1>>[CH3:9][C@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:10]([NH:18][CH2:17][C:16]([CH3:19])=[CH2:15])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=C(C)CN
Agent: Cl
Solvent: CN1CCOCC1
Product: C=C(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a cooled (0° C.) mixture of 18.9 parts of (S)-N-[(1,1,-dimethylethoxy)carbonyl]-alanine, 10.8 parts of 2-methyl-2-propen-1-amine monohydrochloride, 27.0 parts of 1-hydroxy-1H-benzotriazle hydrate and tetaahydrofuran, there were added 10.1 parts of N-methylmorpholine and, after 20 min, 20.6 parts of N,N-methanetetraylbis-[cyclohexanamine] under a nitrogen atmosphere. The whole was kept at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and NaHCO3 (sat.). The organic layer was separated, washed with NaCl (sat), dried, filtered and evaporated, yielding 24.2 parts (99.9%) of (1,1-dimethylethyl) (S)-[1-methyl-2-[(2-methyl-2-propenyl)amino]-2-oxoethyl]carbamate (interm. 63).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CSCC[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CSCC[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
D-Methionine (100 g, 0.67 mol) was dissolved in 600 ml of 10% H2SO4 and cooled to 0°-5° C. A solution of NaNO2 (58 g, 0.84 mol) in 100 ml of H2O, also chilled to 0°-5 ° C., was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture at 10° C. or less by means of an ice water bath. After stirring for 18 hours at room temperature, the mixture was extracted 9×200 ml ethyl acetate. The organic extracts were combined, dried over MgSO4, and stripped to yield 10.1 g of title product as oil; tlc Rf 0.15 (ethyl acetate), 0.08 (1:1 hexane:ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl.C(#N)C>O>[CH3:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH:29]4[CH2:30][O:31]4)=[CH:7][CH:6]=3)=[CH:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A mixture of 7-methoxy-4′-hydroxyisoflavone (1, 0.27 g, 1 mmol), K2CO3 (0.41 g, 3 mmol), epichlorohydrin (0.3 g, 3 mmol) and acetonitrile (30 mL) was refluxed with stirring for 4 hrs (TLC monitoring). The mixture was evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus formed was collected, purified by column chromatography (MeOH/CH2Cl2=1:50), and crystallized from EtOH to give the title compound 3 (0.14 g, 43% yield). M.p.: 153-154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(3,5-difluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.24 mmol) in methylene chloride (5 ml), 2-aminoethanol (0.016 ml, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (0.029 ml, 0.26 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.26 mmol) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (36 mg, 0.07 mmol, 31%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 5 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl] hydrazine carbothioamide and benzoyl isothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9](=[O:12])[C:8]2[CH2:7][O:6][C:5]([C:17]([O:19][CH3:20])=[O:18])([C:13]([O:15][CH3:16])=[O:14])[CH2:4][C:3]1=2.C(O[CH:25]=[CH:26][CH:27]=[CH2:28])(=O)C>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([C:5]1([C:13]([O:15][CH3:16])=[O:14])[O:6][CH2:7][C:8]2[C:9](=[O:12])[C:10]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:4]1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:18]
Reactant: COC(=O)C1(C(=O)OC)CC2=C(CO1)C(=O)C=CC2=O
Reactant: C=CC=COC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,8-dioxo-3,3 bis (methoxycarbonyl)-5,8-dihydroisochroman (50 mg; 0.17 mmol) in toluene (4 ml) at room temperature was added 1-acetoxy-1,3 butadiene (113 μl; 1 mmol). The resulting mixture was stirred at room temperature for 24 hours. Air was then bubbled through for 30 minutes and the mixture was concentrated to a volume of ~1 ml and applied to silica gel column. Elution with 30% ethyl acetate in hexane afforded pure title compound (20 mg; 34%) as a yellow solid; m.p.: 210°-222° C. (dec):
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:5][C:6]=1[CH2:7]P(=O)(OCC)OCC.[H-].[Na+].[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=1[CH3:44])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39](/[CH:40]=[CH:7]/[C:6]2[S:5][C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[N:3][C:2]=2[CH3:1])=[CH:38][C:37]=1[CH3:44])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCOP(=O)(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of diethyl {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methylphosphonate (intermediate 4, 1.4 g) in dry tetrahydrofuran (10 ml) cooled in ice under nitrogen was added sodium hydride (0.12 g, 60% dispersion in mineral oil) and the reaction was stirred for 30 minutes. A solution of 4-benzyloxy-3-methylbenzaldehyde (0.724 g) in dry tetrahydrofuran (10 ml) was added drop-wise, the reaction was allowed to come to room temperature and stirred for 2 hours. The solvent was removed and the residues partitioned between water (50 ml) and chloroform (50 ml). The aqueous phase was extracted with chloroform (20 ml) and the combined organics were washed with water and dried. Removal of solvent gave a solid which was purified by SPE chromatography. Elution with cyclohexane:ethyl acetate (20:1) gave the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]1([C:7]([C:11]2[CH:12]=[C:13]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH2:9][Cl:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)c1cccc(C(=CCO)c2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(=CCCl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a three-necked flask with thermometer and presion-compensated addition funnel, a solution of 14.0 g of methyl 2-[3-(1-phenyl-3-hydroxy-1-propenyl)phenyl]propionate in 20 mL dry methylene chloride was placed and cooled to 0° C. A solution of 3.77 mL of thionyl chloride and 5 mL methylene chloride was added along 30 min, keeping the temperature at 5-10° C. After standing for 1 hour, solvents were removed under vacuum. The resulting residue (13,8 g) was identified as the title compound and it was used in subsequent reaction without any further purification. IR Spectrum (film), cm-1 : 3080-2910, 1740, 1430, 1240, 1200, 1160, 1065, 690.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26](C(Cl)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:26]3[N:22]([C:17]4[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:23]=[C:24]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1
Reactant: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Br)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a suspension of 8-Bromo-6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 18.1 mmol) in acetonitrile (10 mL) was added a solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (6.45 g, 20.8 mmol) in acetonitrile (8 mL). After stirring for 5 min pyridine (10.4 mL) was added dropwise. The reaction was stirred for a further 30 min at room temperature, then heated to 100° C. for 4 h and stirred for a further 16 h at room temperature. The reaction was then cooled in an ice-bath and the resulting white solid filtered and washed with cold acetonitrile to obtain the title compound (5.88 g, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:20]CCCCCC)[N:18]=[CH:19][N:12]2[N:11]=1)[CH3:2].[S:27]([Cl:31])(Cl)(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:31])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:20])[N:18]=[C:19]([CH2:10][CH2:5][CH2:4][CH2:9][CH2:8][CH2:7][CH3:6])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCc1ncn2nc(-c3ccccc3OCC)[nH]c(=O)c12
Product: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:19][C:20]1[C:21]2[CH:22]=[C:23]3[CH:32]([CH2:33][C:34](O)=[O:35])[CH2:31][CH2:30][N:24]3[C:25]=2[CH:26]=[C:27]([F:29])[CH:28]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:34](=[O:35])[CH2:33][CH:32]1[C:23]2=[CH:22][C:21]3[C:20]([Br:19])=[CH:28][C:27]([F:29])=[CH:26][C:25]=3[N:24]2[CH2:30][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CC1CCn2c1cc1c(Br)cc(F)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1CCn2c1cc1c(Br)cc(F)cc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution (S)-(−)-4-benzyl-2-oxazolidinone (7.8 g, 43.8 mmol) in THF (300 mL) at −78° C. was slowly added 1.6M n-butyllithium (27.3 mL, 43.8 mmol). The mixture was stirred for 30 minutes at −78° C. and a mixture of the compound of Step 1 (10.5 g, 33.7 mmol) and 1,1′-carbonyldiimidazole (6 g, 37 mmol) in THF (100 mL) was added. The mixture was stirred for 30 minutes at −78° C. and then warmed to −30° C. and stirred for 2 hours. The reaction was quenched with saturated NH4Cl, the phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 10% EtOAc in Toluene, which permitted the separation of the two diastereomers. Both isomers were obtained as an yellow solid with diastereomeric excess >95%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH3:27].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:18][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:20]([CH3:27])[CH:21]=1)=[O:24]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)Cc1ccccc1Oc1ccc(C=O)cc1C
Yield: 95.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (3.68 mmol) of 4-hydroxy-3-methylbenzaldehyde was alkylated with 0.926 g (4.05 mmol) of methyl 2-bromophenylacetate to afford 1.00 g (96%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:3][CH3:4])=[O:2].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][CH2:22][C:23]([C:13]1[N:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)c1cc2ccccn2c1
Product: COC(=O)c1cc2ccccn2c1C(=O)COCc1ccccc1

Procedure:
Following the procedure of Example 3, 2-carbomethoxyindolizine was reacted with benzyloxyacetyl chloride to give 3-benzyloxyacetyl-2-carbomethoxyindolizine (VII) Cyclization of VII with hydrazine and reaction of the resulting pyridazino[4,5-b]indolizin-1-one with POCl3 gave the corresponding chloro compound (VIII). The reaction of VII with 4-(2-pyrimidinyl)-1-piperizinyl)ethyl amine gave the title compound. Treatment with ethereal HCl in ether gave the product as the trihydrochloride salt: m.p. 140° C.
Reaction SMILES: C(=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C(O)C.[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC>[Cl-].[NH4+]>[CH2:22]([O:21][CH:14]([O:18][CH2:19][CH3:20])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:23]
Reactant: O=Cc1cccc(C=O)c1
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
A mixture of isophthalaldehyde (21.44 g, 160 mmol), ammonium chloride (0.34 g, 6.38 mmol) in anhydrous ethanol (23.2 g, 480 mmol) was cooled to 0° C., then triethyl orthoformate was added drop-wise. After the addition, the mixture was warmed to 40° C. and stirred for two days. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=200:1 to 100:1) to give 3-(diethoxymethyl)benzaldehyde (25.4 g, yield 76%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.23-1.27 (m, 6H), 3.53-3.67 (m, 4H), 5.58 (s, 1H), 7.52-7.56 (t, J=7.6 Hz, 1H), 7.74-7.77 (dd, J1=7.6 Hz, J2=3.6 Hz, 1H), 8.00 (s, 1H), 10.04 (s, 1H); LC-MS (ESI) m/z: 209 (M+1)+.