Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH:15]([Cl:19])[C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[C:15]([Cl:19])=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 12 (0.05 g, 0.36 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl-2-chloroacetoacetate (0.096 g, 0.58 mmol) and sodium carbonate (0.070 g, 0.66 mmol) and the reaction mixture was stirred at room temperature for 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]4[CH2:20][C:21]5[S:22][CH:23]=[CH:24][C:25]=5[C:18]=4[N:17](COCC[Si](C)(C)C)[N:16]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[S:22]1[CH:23]=[CH:24][C:25]2[C:18]3[NH:17][N:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[CH:14][CH:13]=4)[C:19]=3[CH2:20][C:21]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3cccc(F)c3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: Fc1cccc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
(3-Fluoro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine (0.24 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding [4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(3-fluoro-phenyl)-amine (0.14 g, 0.40 mmol) as yellow solid in 79% yield.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1)=[O:19]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:22]=[C:23](/[CH:3]=[CH:2]/[C:1]([NH2:5])=[O:4])[CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)/C=C/c1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 25.7 %

Procedure:
A mixture of acrylamide (24.7 mg, 0.347 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-iodophenyl)urea (36.8 mg, 0.087 mmol), and palladium(II) acetate (7.8 mg, 0.035 mmol) in 0.8 mL degassed DMF:triethylamine (1:1) was reacted at 75° C. After 14.5 hours a catalytic amount of palladium(II) acetate was added, the temperature increased to 85° C., and the reaction continued for an additional 3.5 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, dried with anhydrous Na2SO4 and evaporated. The resulting solid was triturated with CHCl3/MeOH to give the title compound as a light tan solid (8.2 mg, 26%). 1H NMR (Acetone-d6) δ: 8.73-8.82 (m, 2H), 8.41 (br. s., 1H), 7.94 (s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.30-7.48 (m, 4H), 7.21-7.27 (m, 1H), 7.10 (br. s., 1H), 6.70 (d, J=15.7 Hz, 1H), 6.41 (br. s., 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.[OH-].[Li+]>CO.O.Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][C:13]([NH:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:24])=[O:2])=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1NC(=O)Cc1ccc(Cl)cc1Cl

Procedure:
To a solution of 400 mg 3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid methyl ester in 5 ml MeOH/H2O 2:1 56 mg lithium hydroxide monohydrate were added and the mixture was stirred over night. The suspension was diluted with 5 ml concentrated HCl to precipitate the acid. After filtration the filter cake was washed twice with water and then dried to yield the acid as a white powder.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=C[Se:15](=O)[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+]>[NH2:13][C:12]1[CH:17]=[CH:18][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[Se:15][Se:15][C:11]1[CH:10]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][C:12]=1[NH2:13]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)[Se](=O)C=N2
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C(=O)c2ccccc2)cc1[Se][Se]c1cc(C(=O)c2ccccc2)ccc1N
Reaction time: 2 h

Procedure:
1.5 g (0.005 mol) of 6-benzoylbenzoselenazolinone are introduced together with 20 cm3 of 10% sodium hydroxide into a ground-necked flask. The mixture is heated to reflux with stirring for two hours. After cooling, the reaction medium is neutralized. The precipitate is drained, washed with water and dried and the product is recrystallized in toluene.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18])(C)(C)C.Cl>CCOCC>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)COCC1=O
Agent: Cl
Solvent: CCOCC
Product: NCCCN1C(=O)COCC1=O
Temperature: 25 °C
Yield: 116 %

Procedure:
To a solution of tert-butyl-3-(3,5-dioxomorpholin-4-yl)propylcarbamate (15 g) in dry ether (150 mL) was added a saturated solution of dry HCl (gas) in diethylether (300 mL) at 0° C. and the solution was then slowly warmed up to r.t. The precipitate obtained was filtered, washed with cold ether and dried under vacuum to give 11 g of the title compound (94%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)[N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]4[N:27]=[C:23]([C:21]([NH:20][C@@H:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])[S:24][CH:25]=4)=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccc2c(c1)CCC2
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 2,3-dihydro-5-isocyanato-1H-indene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.817-8.795 (d, 2H), 8.578 (s, 1H), 8.306 (s, 1H), 8.040-8.011 (d, J=8.7 Hz, 2H), 7.582-7.553 (d, J=8.7 Hz, 2H), 7.401 (s, 1H), 7.170-7.104 (m, 2H), 4.394-4.342 (t, J=7.5, 8.1 Hz, 1H), 3.700 (s, 3H), 2.863-2.773 (m, 4H), 2.343-2.274 (m, 1H), 2.087-1.981 (m, 2H), 1.001-0.953 (t, J=7.2 Hz, 6H); MS (ESI) m/z 491 (M−H), 493 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(I)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=Cc1cccc(I)c1

Procedure:
3-iodobenzaldehyde was prepared by oxidation of 3-iodobenzylalcohol by pyridinium chlorochromate in the presence of sodium acetate as in Example 9.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CN(OC)[C:18]([C:20]1[CH:24]=[CH:23][O:22][C:21]=1[CH3:25])=[O:19]>O1CCCC1.[Cl-].[Na+].O>[CH3:25][C:21]1[O:22][CH:23]=[CH:24][C:20]=1[C:18](=[O:19])[CH2:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)c1ccoc1C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1occc1C(=O)Cc1ccncc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
To a solution of lithium diisopropylamide (2M solution in THF/heptane/ethylbenzene) (12.00 ml, 24.00 mmol) in tetrahydrofuran (20 ml) at −78° C. under argon was added 4-picoline (1.946 ml, 20 mmol). The reaction mixture was stirred at −78° C. for 15 minutes and a solution of N,2-dimethyl-N-(methyloxy)-3-furancarboxamide (3.38 g, 20.00 mmol) in tetrahydrofuran (5 ml) was added dropwise. The solution was allowed to warm to room temperature over 2 hours. Brine was added and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated sodium hydrogen carbonate solution, water and brine, dried and evaporated to give the title compound as a solid (3.72 g, 92%). LC/MS [M+H]+=202.
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])OCC)C.[CH2:11]([C:14]#[N:15])[C:12]#[N:13]>C(OC(=O)C)(=O)C>[CH3:10][CH2:9][O:8][CH:4]=[C:11]([C:14]#[N:15])[C:12]#[N:13]
Reactant: N#CCC#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C#N
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
A two-liter, four necked flask is charged with 1332 g (9 moles) of orthoformic acid triethyl ester, 198 g (3 moles) of malonic acid dinitrile and 4 g of acetic acid anhydride. With vigorous stirring, the solution is heated to ebullition. At about 110° C. sump temperature, alcohol begins to distil out through the top of the column. During the course of the reaction, approximately 8 g of acetic acid anhydride is fed in continuously, and the heating of the reaction mixture and the reflux flow are so regulated that the temperature at the top of the condenser is between 75° and 79° C. The condensed distillate is collected and consists substantially of ethanol, acetic acid ethyl ester, formic acid ethyl ester and a small amount of orthoformic acid triethyl ester. During the reaction the sump temperature rises slowly to 130 to 140 degrees C. After 2 to 3 hours the reaction has ended. The unreacted orthoformic acid triethyl ester is distilled out through the column and is fed back to the next batch. Then ethoxymethylene malonic acid dinitrile is separated from the remainder through a simple distillation bridge at 0.1 to 0.02 Torr. In this manner, 361 g of ethoxymethylene malonic acid dinitrile is obtained, with a melting point of 64° C. and a purity of better than 99%. This corresponds to a yield of 98.7% with respect to the malonic acid dinitrile charged.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[CH:7]=[C:8]([CH:11](O)[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:16])[C:6]=2[CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(O)c1ccc2c(c1)C(C)(C)CO2
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc2c(c1)C(C)(C)CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a cold solution (0° C.) of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-ol (1.97 g, 8.93 mmol) in dry dichloromethane (40 mL) was added triethylsilane (2.85 mL, 17.86 mmol). After 10 minutes, trifluoroacetic acid was added and the reaction mixture stirred at 0° C. for 30 minutes. Water was poured into the reaction mixture and the layers separated. The organic layer was further washed with water, aqueous NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (0% to 5% ethyl acetate in hexane) to give 1.6 g of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (87%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6H), 1.32 (s, 6H), 1.79 (m, 1H), 2.40 (d, J=6.9 Hz, 2H), 4.20 (s, 2H), 6.68 (dd, J=1.2 Hz and 7.5 Hz, 1H), 6.87 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.CN([CH:16]=[O:17])C>CCOC(C)=O>[C:1]([C:5]1[O:9][N:8]([CH2:2][C@H:1]2[CH2:5][CH2:6][CH2:16][O:17]2)[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cc(=N)n(C[C@H]2CCCO2)o1
Temperature: 85 °C
Reaction time: 70 h
Yield: 17 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (1 g, 7.1 mmol) and a solution of Example 39A (1.7 g, 6.8 mmol) in 1.5 mL DMF was warmed to 85° C. and was allowed to stir for 70 hours at 85° C. The mixture was cooled to ambient temperature, concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50% hexanes in EtOAc then 10% CH3OH in EtOAc) to afford the title compound (0.48 g, 1.2 mmol, 17% yield). MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]([N:18]([CH2:28]C(O)=O)[C:19]1C=[CH:26][CH:25]=[CH:24][C:20]=1C(O)=O)(=[O:17])[CH3:16]>O>[C:15]([N:18]1[C:19]2[C:6](=[CH:26][CH:25]=[CH:24][CH:20]=2)[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:28]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N(CC(=O)O)c1ccccc1C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirred mixture of acetic anhydride (46.29 g, 0.45 mol) and triethylamine (13.77 g, 0.14 mol), 2-(N-acetylcarboxymethylamino)benzoic acid of Example 1b (11.36 g, 0.048 mol) was added at room temperature. The mixture was refluxed for 20 min and concentrated in vacuum to give an oily residue. Water (350 mL) was added under vigorous stirring, and the mixture was refrigerated overnight. The solid product was collected, washed with water and air-dried to give 9.0 g (86%) of the product which was used in the next step without purification.
Reaction SMILES: [C:1]1([C:7]2([C:10](Cl)=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12>>[NH2:13][C:14]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:10]([C:7]3([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:9][CH2:8]3)=[O:11])=[CH:24][CH:25]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3ccccc3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-Phenyl-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 371 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([OH:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:12]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:6][CH2:5][OH:17])=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CCO)c([N+](=O)[O-])cc1OC
Temperature: -10 °C
Reaction time: 0.1 h
Yield: 56 %

Procedure:
For 6 min, conc. HNO3 (4.8 ml, 65%, d=1.4) was added dropwise to a mixture of homoveratryl alcohol (3.02 g, 16.6 mmol) in glacial acetic acid (30 ml) under stirring, this mixture having been cooled to -10° C. (common salt/ice) It was then allowed to warm up to 23° C. in 30 min. After being stirred for 1 h at this temperature, the mixture was diluted with H2O, neutralized with NaHCO3 and extracted with EtOAc (3×30 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue (3.25 g) was purified by column chromatography (90 g SiO2 toluene/EtOAc 4:1 500 ml, toluene/EtOAc 3:1 400 ml, toluene/EtOAc 2:1 300 ml). 2-(4,5-dimethoxy-2-nitrophenyl)ethanol (2.13 g, 56%) was obtained as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[Cl:18][CH:19]([CH3:35])[C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=2[Cl:32])[CH:23]=1)=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:18].[ClH:1].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH:19]([C:20]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=4[Cl:32])[CH:23]=3)=[O:21])[CH3:35])[CH2:12][CH2:11]2)=[CH:16][CH:17]=1
Reactant: COc1ccc2cc(C(=O)C(C)Cl)ccc2c1Cl
Reactant: COc1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(C(C)C(=O)c3ccc4c(Cl)c(OC)ccc4c3)CC2)cc1
Yield: 58.5 %

Procedure:
A mixture of N-(4-methoxybenzyl)piperazine dihydrochloride (0.35 g, 1.3 mmol), 2-chloro-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (0.44 g, 1.57 mmol) and K2CO3 (0.65 g, 4.6 mmol) in 20 ml of DMF was treated according to general preparation 2 to give 0.4 g of compound (IV-31), yield 57%, mp 222-224° C. M+ 452.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[CH3:1][O:2][C:3]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][C:25](=[O:27])[CH3:26])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(C)c(OC)c(Cc2ccc(O)c(C(=O)O)c2)c1C
Solvent: O
Product: COc1c(C)c(C)c(OC)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
5-(2,5-Dimethoxy-3,4,6-trimethylbenzyl)-2-hydroxybenzoic acid (0.150 g, 0.455 mmol) was dissolved in acetic anhydride (3 ml) and the resulting solution was stirred at 80° C. for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.170 g, 0.454 mmol, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[N:5]=[N:6][C:7]=1[NH2:8].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[C:7]2[N:6]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=2)[N:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nnc(Cl)cc1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2nc(Cl)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-bromo-3-chloro-6-aminopyridazine (15.7 g, 75.3 mmol) in dry DMF (80 mL) was added ethyl bromopyruvate (21.0 mL, 151 mmol) via a syringe. The resulting mixture was stirred at rt for 20 h. The reaction mixture was poured into ice water (300 mL), and the precipitated solid was isolated by filtration, and washed with water (2×50 mL) and Et2O (3×50 mL). The residual solvents in the solid were removed under reduced pressure to give compound 5a as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.50 (s, 1H), 7.47 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.[OH-].[K+]>C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(-c2ccco2)cc1
Reactant: Cc1cc(CCCCCBr)on1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(-c3ccco3)cc2)on1

Procedure:
5-{5-[4-(2-Furanyl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =H, Het=2-furanyl] was prepared from 3.6 g 4-(2-furanyl)phenol (m.p. 128-129° C., King and Walton, Synthesis 1976, p. 40), 5.4 g 5-(5-bromopentyl)-3-methylisoxazole and 1.5 g potassium hydroxide in acetonitrile according to the procedure of Example 1, part (c), and was obtained (4.2 g) as a light-tan solid, m.p. 86-88° C. when recrystallized from isopropyl acetate.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[CH:41]1([B-](F)(F)F)[CH2:43][CH2:42]1.[K+].Cl[C:50]1[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]2[C:59]=1[S:58][CH2:57][CH2:56][C:55]2([CH3:61])[CH3:60]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:41]1([C:50]2[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]3[C:59]=2[S:58][CH2:57][CH2:56][C:55]3([CH3:60])[CH3:61])[CH2:43][CH2:42]1
Reactant: CC1(C)CCSc2c(Cl)cc(C=O)cc21
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC1(C)CCSc2c(C3CC3)cc(C=O)cc21

Procedure:
Using essentially the same procedure as Example 5-22, Step 4, Pd(OAc)2 (5.18 mg, 0.02 mmol), X-Phos (22.0 mg, 0.05 mmol), potassium carbonate (319 mg, 2.30 mmol), potassium cyclopropyltrifluoroborate (125 mg, 0.84 mmol), and 8-chloro-4,4-dimethyl-3,4-dihydro-2H-thiochromene-6-carbaldehyde (185 mg, 0.77 mmol, Example 5-29, Step 3) afforded the desired product as a yellow oil.
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:35]=1)[C:22]1[CH:21]=[C:20]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:13][CH:14]=1)(C)(C)C.Br>>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:8][S:7][C:6]([NH2:5])=[N:35]3)[C:22]=2[CH:21]=1)[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)COc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: Br
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with a solution of N-tert-butyl-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (0.033 g, 0.068 mmol) in 48% HBr (1.00 mL, 18.42 mmol) was heated to 80° C. After 3 hrs, the solution was cooled and evaporated to dryness with a stream of N2. The residue was treated with CH2Cl2 (2 mL) and TEA (0.1 mL). The solution was loaded onto a silica gel column and purified with 1-5% MeOH:CH2Cl2 w/1% NH4OH (Rf=0.5 in 10% MeOH:CH2Cl2 w/1% NH4OH) to afford racemic material that was resolved by chiral chromatography to give both (R) and (S)-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine MS Found: MH+=433.2.
Reaction SMILES: C([NH:4][C:5]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:6]=1[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH3:20])=[O:8])(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:6]=1[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH3:20])=[O:8]
Reactant: COc1cc(OC)c(C(=O)c2cc(Cl)ccc2NC(C)=O)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)c(C(=O)c2cc(Cl)ccc2N)c(OC)c1
Yield: 90.2 %

Procedure:
A mixture of 4.7 g of 2-acetylamino-5-chloro-2',4',6'-trimethoxybenzophenone, 50 ml of 6N hydrochloric acid and 50 ml of ethanol was refluxed for 1 hour while heating. After the solvent was distilled off, the residue was basefied with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed, and the residue was subjected to silica gel column chromatography to yield 3.75 g of a crystal.