Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH:66]([CH3:68])[CH3:67])[C:64](=[O:65])[C:39]=12)C1C=CC=CC=1>>[OH:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:61][CH2:62][N:63]([CH:66]([CH3:68])[CH3:67])[C:64](=[O:65])[C:39]=12
Reactant: CC(C)N1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: CC(C)N1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
This compound was prepared following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 9-(benzyloxy)-2-isopropyl-6-((1-(naphthalen-1-yl)cyclopentyl)methyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (512).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.[Mg].Cl>CO>[CH3:1][O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[NH:7]1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: COC(=O)C1Cc2cc(OC)ccc2N1
Temperature: 20 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To 5-methoxy-1H-indole-2-carboxylic acid ethyl ester (5 g, 22.8 mmol) in MeOH (150 ml) was added magnesium turnings (2.2 g, 91.6 mmol, 4eq.) and the mixture vigorously mechanically stirred (10-30° C.) for 2 hr. 4N HCl was added (to pH1-2), then 25% NH4OH (to pH 7), and the mixture extracted with EtOAc (4×100 ml). The combined extracts were then washed with satd. NaCl solution (50 ml), dried (Na2SO4) filtered and evaporated. The crude green oil was chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-nHexane (1:3) to afford the title compound (3.21g, 15.5 mmol, 68%) as a yellow solid Mp. 59-61° C., MS: m/e=207.1 (M+).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[N:9]=[CH:10]N(C)C)=O.C(N(CC)CC)C.[N+:25]([CH3:28])([O-:27])=[O:26]>>[N+:25]([C:28]1[CH:10]=[N:9][C:8]2[N:7]([CH3:14])[C:6](=[O:15])[N:5]([CH3:16])[C:4](=[O:17])[C:3]=2[CH:1]=1)([O-:27])=[O:26]
Reactant: CN(C)C=Nc1c(C=O)c(=O)n(C)c(=O)n1C
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2cc([N+](=O)[O-])cnc2n(C)c1=O
Temperature: 80 °C
Yield: 58.8 %

Procedure:
0.24 g of 5-formyl-6-dimethylaminomethyleneamino-1,3-dimethyluracil and 0.5 g of triethylamine were added to 10 ml of nitromethane, and the mixture was heated for 2.5 hr at 80° C. After the solvent was distilled off under reduced pressure, ether was added to the residue. The resulting crude crystals were separated by filtration and recrystallized from ether to give 0.14 g of 6-nitro-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 16).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1COCC1.[CH3:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[OH:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[N:7][CH:6]=2)=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1O
Temperature: 85 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.35 g) in a mixed solvent of THF (8.40 mL)-water (2.80 mL) were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53 g), potassium carbonate (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (0.14 g), and the mixture was stirred overnight at 85° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.35 g).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:39])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:45])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 68 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 68% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C29H32N6O3 (512.6) ##EQU17##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([N+:15]([O-])=O)[C:10]([C:13]#[N:14])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.CC[O:20]C(C)=O>>[NH2:15][C:9]1[C:10]([C:13]([NH2:14])=[O:20])=[N:11][CH:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ncc(N2CCOCC2)cc1[N+](=O)[O-]
Product: NC(=O)c1ncc(N2CCOCC2)cc1N

Procedure:
To a stirred solution of 5-morpholino-3-nitropicolinonitrile (100 mg, 0.43 mmol) in EtOAc (5 mL) was added stannous chloride, dihydrate (0.41 g, 2.13 mmol). The reaction was heated at reflux for 15 min. After this time a white solid precipitates. The suspension was filtered and the resulting solid was washed with 1.0M NaOH (10 mL) and brine (10 mL) and dried under vacuum to give 3-amino-5-morpholinopicolinamide. Mass Spectrum (ESI) m/e=223.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[OH-].[K+]>C(Cl)Cl.O.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[CH:12]/[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)[C:6]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1OC
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/n2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1OC
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 6.3 %

Procedure:
To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(3,4-dimethoxyphenyl)ethanol (300 mg, 0.722 mmol) in DCM (5 mL), triethylamine (0.15 mL, 1.077 mmol) were added and stirred for 10 min., methane sulfonyl chloride (0.062 mL, 0.795 mmol) was added slowly at 0° C. and stirred at the same temperature for 1 h, then at RT for 2 h. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography. The pure product was dissolved in NMP (2.0 mL), KOH powder (283 mg, 5.06 mmol) was added at RT and heated at 90° C. for 14 h. Product was detected by LCMS. The reaction mixture was diluted with methanol, filtered and evaporated. Crude product was purified by reverse phase chromatography to get 18 mg of pure product as TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.80-7.60 (m, 2H), 7.35 (s, 1H), 7.30-7.20 (d, 1H), 7.20-7.15 (d, 1H), 7.00-6.90 (d, 1H), 6.80-6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.80-3.60 (m, 2H), 2.95 (s, 3H), 2.90-2.80 (m, 2H), 2.60-2.30 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]([C:14](=[O:30])[C@H:15]([CH:27]([CH3:29])[CH3:28])[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[K+]>C(O)C>[C:17]([NH:16][C@H:15]([C:14]([N:6]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:5][C:4]([OH:31])=[O:3])=[O:30])[CH:27]([CH3:28])[CH3:29])([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1CCCCCC1
Yield: 62 %

Procedure:
N-CBZ-L-Valyl-N-(cycloheptyl)glycine ethyl ester (11.2 g, 0.0259 mol) was dissolved in ethanol (300 mL) and treated with 1N KOH (27 mL) in portions of 5.0 mL at 0°-5° C. After the mixture was allowed to stir at room temperature over night the ethanol was removed under vacuum, and the residue treated with water. The residue was extracted three times with ethyl acetate and afterwards the aqueous layer was acidified with 2N HCl. The product was extracted into ethyl acetate and washed with saturated aqueous sodium chloride. After drying over MgSO4, filtration and evaporation under reduced pressure isolated the product as a white semisolid (6.5 g) melting at 48°-51° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.CC[O:14]C(C)=O>>[CH3:10][C:9]([N:8]=[C:5]1[N:6]([OH:14])[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4]1)=[O:11]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc(Br)cn1
Product: CC(=O)N=c1ccc(Br)cn1O

Procedure:
Prepared according to the procedure described in EXAMPLE 9, Step 4, but using N-(5-bromo-pyridin-2-yl)-acetamide from Step 1 as starting material. Flash chromatography (EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[NH:11][CH2:10][CH2:9][O:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C1COCC1>[NH:1]1[C:2]2=[CH:3][CH:4]=[CH:5][C:6]3=[C:12]2[N:11]([CH2:10][CH2:9][O:8][C:7]3=[O:13])[C:14]1=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1NCCOC2=O
Solvent: C1CCOC1
Product: O=C1OCCn2c(=O)[nH]c3cccc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.9 %

Procedure:
To a solution of 200 mg (1.13 mmol) of 9-amino-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 20 mL of THF was added 280 mg (2 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture was stirred overnight at room temperature. The reaction mixture was heated at 50° C. for 4 h and allowed to cool to room temperature. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate/n-hexane (1:1) and washed with water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 286 mg (1.40 mmol, 70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12](=[N:15][C:16](=O)[O:17]C)[S:13][CH3:14].C[O-].[Na+].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[NH:15][CH:12]([S:13][CH3:14])[NH:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)N=C(N)SC
Reactant: Cc1ccc(N=C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CSC1NC(=O)N(c2ccc(C)cc2)C(=O)N1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
4-Methylphenylisocyanate (19.0 g.) was added during 10 minutes to a solution of methyl N-[1-amino-1-(methylthio)methylene]carbamate (21.2 g.) in methylene chloride (200 ml.). After 2 hours of stirring, sodium methoxide [obtained by dissolving sodium (3.5 g.) in methanol (30 ml.)] was added at 15°-20° C. The subsequent mixture was stirred at that temperature for 18 hours and the resultant solid collected by filtration and dissolved in water (200 ml.). The solution obtained was acidified with concentrated hydrochloric acid and the solid which formed was collected by filtration, washed well with water and dried to give 3-(4-methylphenyl)-6-methylthiotetrahydro-1,3,5-triazine-2,4-dione (29 g., 81%), m.p. 276°-278° C.
Reaction SMILES: [Cr](O)(O)(=O)=O.[C:6]1([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CC(C)=O>[C:6]1([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCCCC#Cc1ccccc1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCC#Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
Brown's chromic acid reagent (133 mL, 88 mmol, 0.66 M) was added slowly in drops to a magnetically stirred solution of 7-phenylhept-6-yn-1-ol (6) (7.53 g, 40 mmol) in acetone (400 mL) at 0° C. After the chromic acid had been added, the reaction mixture was stirred for 1 hour at 0° C. and then at room temperature until all the base material has been converted as indicated by TLC. Water (300 mL) was added and the aqueous phase was then extracted with petroleum ether (boiling point 40-60° C.)/Et2O 1:1 (6×50 mL). The combined organic phases were washed with water (2×25 mL) and dried (MgSO4). Distillation on a rotary evaporator yielded 7.3 g (90%) of a pale yellow viscous oil, which crystallized when left to rest. TLC and NMR indicated a pure product.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]([CH2:29][CH:30]3[O:32][CH2:31]3)[C:25]([O:27]C)=[O:26])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.CCN(CC)CC.[SH:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1>C1C=CC=CC=1.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:23][CH:24]([CH2:29][CH:30]([OH:32])[CH2:31][S:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nccs1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nccs3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-[2-oxo-5-(thiazol-2-yl)thio]methyl]-tetrahydrofuran: To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.7 g, 1.79 mmol) in benzene (5 mL) and Et3N (0.33 mL, 2.3 mmol) at room temperature is added slowly 2-mercaptothiazole (0.52 g, 4.48 mmol). The reaction mixture is stirred for 4 h at room temperature. The resulting mixture is diluted with water, and the mixture is then extracted three times with EtOAc. The combined EtOAc layer is consecutively washed with water, and brine, dried over MgSO4 and concentrated to an oil under reduced pressure. Purification is accomplished by column chromatography with hexane/EtOAc (4:1 to 7:3 to 6:4) eluent to give the desired product.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([O:9][C:10]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:20]CC)=O)=[O:11])[CH3:8].C(O)(=O)C>C1COCC1>[O:20]=[C:18]1[CH2:17][O:16][CH2:15][CH2:14][O:13][CH:12]1[C:10]([O:9][CH2:7][CH3:8])=[O:11]
Reactant: CCOC(=O)COCCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1OCCOCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixing was carried out under a protective nitrogen gas atmosphere. 7.93 g (80.0 mmol) sodium-tert-butoxide were placed in 150 ml THF and heated to boiling point. At this temperature 8.50 g (36.3 mmol) ethyl (2-ethoxycarbonylmethoxy-ethoxy)-acetate (prepared analogously to Canadian Journal of Chemistry; 74; 8; 1996; 1437-1446) in 100 ml THF were added dropwise within 3 h. After the addition had ended the mixture was refluxed for 1 h and then stirred overnight at RT. Then the reaction mixture was adjusted to pH 5 with glacial acetic acid and concentrated by rotary evaporation. The residue was mixed with water and extracted with ethyl acetate. The organic phases were combined, dried and the solvent was eliminated under reduced pressure and with gentle heating.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(F)cc(OC)c2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2cc(F)cc(OC)c2)cc1C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A mixture of 3-[4-(3-fluoro-5-methoxy-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (0.98 g, 2.96 mmol) and 10% Pd/C (0.50 g) in ethyl acetate (50 mL) is purged with N2, and then with H2. The mixture is stirred under a hydrogen balloon for three hours. The reaction is filtered through hyflo, and the solvent is removed in vacuo to afford 0.715 g (73%) of the title compound. Rf=0.53 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C19H21O4F 332, found 333 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[O:15](S(C(F)(F)F)(=O)=O)[S:16]([C:19]([F:22])([F:21])[F:20])(=O)=[O:17]>ClCCl.N1C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[S:16]([O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:13])[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2)(=[O:17])=[O:15]
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-2,7-dimethylquinolin-6-ol (1.04 g, 3.1 mmol) in dichloromethane (50 mL) and pyridine (10 mL) was added Tf2O (1.1 mL, 6.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slowly addition of NaHCO3 solution at 0° C. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the desired product. Column purification gave pure product. LCMS-ESI+: calc'd for C12H9BrF3NO3S: 383.9 (M+H+); Found: 383.9 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[NH:5][N:4]=[CH:3]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[NH:5]1)[CH3:14]
Reactant: CC1C=NNC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cc(C)c(=O)[nH]1
Yield: 16 %

Procedure:
As described for example 320a, 4-methyl-2-pyrazolin-5-one was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound as a white solid (yield: 16%). MS: m/e=185.0 [M+H]+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([NH:37][NH2:38])=[CH:29][CH:28]=1>>[CH3:25][N:23]([CH3:24])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:37]([C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:27]=[CH:28][CH:29]=4)[N:38]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=473.3 (M+H)+
Reaction SMILES: Cl[S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3].C[Si](C)(C)[NH:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=1[Cl:27].CS(C)=O>CC#N>[Cl:27][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(Cl)c(N[Si](C)(C)C)c1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution consisting of 106.8 mg (0.433 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine, 0.5 ml of CH3CN, and 252 μl (1.30 mmole) of N-trimethylsilyl-3-methyl-2,6-dichloroaniline was stirred at room temperature and 10 μl (0.14 mmole) of dimethyl sulfoxide (DMSO) added dropwise. The solution was stirred for 2 hours during which time a precipitate formed. The CH3CN was removed under nitrogen and the residual solid treated with 1 ml of 1N HCl. The mixture was stirred for 10 min, filtered, and the precipitate washed with acetone to obtain 136 mg of N-(2,6-dichloro-3-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide product as an off-white solid. The solid was washed with methanol and dried to give 120 mg (0.310 mmole, 71.6 percent yield) of product as a white solid, m.p. 286.5°-288° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:22]1([C:28]([NH2:33])([CH2:31][CH3:32])[CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O.CCOC(C)=O>[NH2:33][C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:31][CH3:32])[CH2:29][NH:30][C:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[O:2][CH3:1])=[O:15]
Reactant: CCC(N)(CN)c1ccccc1
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(N)(CNC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
A mixture of 3-methoxy-2-phenylquinoline-4-carboxylic acid (3.0 g), and the compound of step 2 (3.0 g), BOP (5.7 g) and TEA (2.0 g) in 25 mL of anhydrous DMF is stirred at ambient temperature overnight. The mixture is diluted with water and EtOAc. The organic layer is separated, washed with water and concentrated under vacuum. The residue is purified on a silica gel column, eluting with EtOAc and Hexane (1:1) to afford the title compound as white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH2:11][OH:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]>CN(C=O)C.O=[Mn]=O>[NH2:1][C:2]1[C:3]([O:13][CH2:14][CH3:15])=[CH:4][C:5]([CH:11]=[O:12])=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1cc(CO)cc(OCC)c1N
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of (4-amino-3,5-diethoxy-phenyl)-methanol (0.79 g, 3.74 mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO2 (1.63 g, 18.70 mmol, 5.0 equiv). The reaction mixture was stirred for 24 h at rt, filtered through Hyflo Super Cel, the filtrate was extracted with ethyl acetate (3×50 mL), and the combined organic phase was washed with water, dried over MgSO4 and evaporated to dryness providing thereby 0.69 g (88%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.46 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.50 (br s, 2H), 7.04 (s, 2H), 9.70 (s, 1H). MS (ISP): 210.0 [M+H]+.