Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:7]#[CH:8])[CH3:6])[CH:2]=C.F[P-](F)(F)(F)(F)F.[C:22]1(C)C=CC=CC=1>>[CH3:6][C:5]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]([CH:8]=[CH2:22])=[CH:2][CH2:1][O:4]1
Reactant: Cc1ccccc1
Reactant: C#CC(C)(OCC=C)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1=CCOC1(C)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Metathesis under Photo-chemical Irradiation. A solution of 2-allyloxy-2-phenylbut-3-yne (371 mg, 1.99 mmol) and the allenylidene complex (p-cymene)RuCl(PCy3)(═C═C═CPh2)+PF6− (44 mg, 0.0496 mmol, 2.5 mol %) in toluene (10 ml) is irradiated with UV light (Hg lamp, 300 nm) for 30 minutes at room temperature under nitrogen, then stirred for 4 hours at 80° C. without UV irradiation. The solvent is evaporated and the crude product is purified by flash chromatography using ether:pentane (1:10) as the eluent. This affords the title compound as a yellowish liquid (313 mg, 84%), the spectral data of which are identical to those reported above.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[F:9][C:10]1[CH:22]=[C:21](F)[C:20]([F:24])=[CH:19][C:11]=1[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13]>CN(C)C=O>[CH:1]1([CH2:4][CH2:5][O:6][C:21]2[C:20]([F:24])=[CH:19][C:11]([C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])=[C:10]([F:9])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: OCCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(OCCC2CC2)cc1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a mixture of 2-cyclopropylethanol (0.172 g, 2.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 5.0 mmol) at room temperature. The resulting mixture was stirred at 45° C. for 30 min and then cooled to room temperature. 2,4,5-Trifluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1) (0.51 g, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 2% acetic acid) in hexanes as an eluent to afford the title compound as a white solid (0.12 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 12.06 (brs, 1H), 7.58 (dd, J=6.9 Hz & 11.4 Hz, 1H), 7.30 (dd, J=6.9 Hz & 12.1 Hz, 1H), 4.19 (t, J=6.6 Hz, 2H), 3.35 (s, 3H), 1.69-1.62 (m, 2H), 0.88-0.74 (m, 1H), 0.47-0.41 (m, 2H), 0.16-0.11 (m, 2H); MS (ES−) m/z 318.1 (M−1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:6][CH2:7][O:8][CH3:9]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCN(CCOC)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCCN(CCOC)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In acetic acid (200 ml) was dissolved N,N-bis(2-methoxyethyl)-4-nitrobenzylamine (10.5 g), and to the mixture was added reduced iron (11 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give 4-((N,N-bis(2-methoxyethyl)amino)methyl)aniline (6.2 g) as red oil.
Reaction SMILES: [CH2:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH2:4][CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CCCCCC>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: ClCCN1CCCC1
Reactant: C1=CCC2=C(C1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 0.5 h

Procedure:
1.0 g of 1,4,10,11-tetrahydro-5H-dibenzo[a,d]cycloheptene in 20 ml of dry tetrahydrofuran are treated dropwise at between -70° and -60° with 9.0 ml of an about 0.85M solution of n-butyl lithium in hexane. The mixture is stirred at -70° for 60 minutes and at -30° for 30 minutes, a solution of 2.1 g of 2-chloroethylpyrrolidine in 5 ml of dry tetrahydrofuran at -30° is added dropwise thereto and subsequently the mixture is stirred at -30° for an additional 30 minutes, at 0° to 5° for 3 hours and at room temperature for 30 minutes. After evaporation of the mixture, the residue remaining is dissolved in toluene and washed ion-free with water. The organic phase is filtered over aluminum oxide (activity grade II, neutral) using toluene for the elution. Crude 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15].C[Al](C)C.[CH3:28][C@H:29]1[CH2:31][O:30]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.ClC1C=CC=CC=1>[OH:30][C@@H:29]([CH3:31])[CH2:28][N:6]1[C:2]([CH3:1])=[C:3]([C:14]([OH:16])=[O:15])[C:4](=[O:13])[N:5]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1CO1
Reactant: Cc1[nH]n(-c2ccccc2)c(=O)c1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a 500 mL round-bottomed flask was added benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 10 mmol), chlorobenzene (30 mL) and the mixture cooled in an ice bath. The trimethylaluminum (25 ml, 50 mmol) was added and the ice bath removed followed by the addition of (S)-2-methyloxirane (0.87 g, 15 mmol). The mixture stirred 1 h and cooled in an ice bath with the addition of THF (60 mL). Sodium sulfate decahydrate (3g) was added to the mixture cautiously (foaming) and the mixture stirred 1 h. Sodium sulfate (10 g) was added and stirred 1 h. The mixture was filtered through celite, washed with 4:1 chloroform/isopropanol and the filtrate concentrated, diluted with chloroform, washed with 1 N HCl and sat. sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with methanol/chloroform to afford the title compound as a foam (1.5 g). MS (ESI pos. ion) m/z: 367 (MH+). Calc'd exact mass for C21H22N2O4: 366.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])=[CH:22][CH:23]=1
Reactant: Fc1ccc(CNC2CCCC2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CN(C(=S)Nc2ccccc2)C2CCCC2)cc1
Yield: 84 %

Procedure:
6.75 g (0.05 mol) of phenyl isothiocyanate were rapidly added dropwise to a solution of 9.65 g (0.05 mol) of N-4-fluorobenzyl-N-cyclopentylamine in 80 ml of toluene. The mixture was heated to the boil for 30 minutes, the solvent was distilled off in vacuo, and the residue was recrystallized from isopropanol. 13.8 g of N-4-fluorobenzyl-N-cyclopentyl-N'-phenylthiourea of melting point 135° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:18]=[CH:19]/[C:20]([O:22]CC)=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc2cnn(-c3ccc(F)cc3)c2cc1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CCC(=O)O
Reaction time: 16 h
Yield: 99.3 %

Procedure:
(c)(d) (E)-ethyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)acrylate (350 mg, 1.08 mmol) was dissolved in EtOH (30 mL) and hydrogenated over 10% Pd/C (70 mg) at 50 psi H2 for 4 h. The catalyst was filtered off and the solution was treated with 1 M NaOH (30 mL) and stirred for 16 h. The pH was adjusted to 4-5 with conc HCl. Most of the EtOH was removed in vacuo and the solution was extracted with EtOAc and dried over MgSO4, filtered, and conc. Obtained 320 mg (100%) of 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)propanoic acid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.II.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:23](N(OC)C)=[O:24])[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18](=[O:19])[NH:20][C@@H:21]([CH3:22])[C:23]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1)=[O:24])([CH3:16])([CH3:14])[CH3:15]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: CCc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of magnesium turnings (243 mg, 10 mmol) in dry THF (10 ml) was added a solution of 1-bromo-4-ethylbenzene (1.85 g, 10 mmol) in dry THF (10 ml), followed by a small crystal of iodine. The reaction mixture was heated with reflux for 4 h, then cooled to r.t. A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (464 mg, 2 mmol) in dry THF (15 ml) was added dropwise, and the stirring was continued for 5 h at r.t. Then the reaction mixture was quenched with sat. aqueous NH4Cl (25 ml) stirred for 30 min, and the layers were separated. The aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed under reduced pressure to give the subtitle compound as colourless oil, 718 mg, 70% purity (as determined by NMR). Used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13]CC)=O)=[C:5]([O:16][CH2:17][CH2:18][NH:19][C:20](=[O:41])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:4]=1)#[N:2].[OH-].[Na+].O[N:45]1C2C=CC=CC=2N=N1.C(=O)([O-])N.[NH4+].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(O)C.CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:45])=[O:13])=[C:5]([O:16][CH2:17][CH2:18][NH:19][C:20](=[O:41])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3C=CC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (5.33 mmol) of ethyl 3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate was dissolved in 100 ml of ethanol. 15 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature overnight. The solvent was evaporated under reduced pressure. 1 N aqueous hydrochloric acid/ice solution was added to the obtained crude product, and they were treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the crude product. 30 ml of N,N-dimethylformamide, 0.75 g (5.55 mmol) of 1-hydroxybenzotriazole (hydrous), 1.40 g (25.2 mmol) of ammonium carbamate, 2 ml (0.015 mmol) of triethylamine and 2.12 g (11.09 mmol) of 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the crude product, and they were stirred overnight. After the evaporation of the solvent followed by the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]2[C:24]([C:25]3[N:30]=[C:29](S(C)=O)[C:28]([F:34])=[CH:27][N:26]=3)=[CH:23][N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]2=[N:20][CH:21]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:34][C:28]1[C:29]([NH:1][CH:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:30][C:25]([C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([F:15])[CH:17]=3)[N:22]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:23]=2)=[N:26][CH:27]=1
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Temperature: 80 °C

Procedure:
A suspension of ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.20 g, 1.00 mmol), 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 25a (0.54 g, 1.20 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.50 mmol) in THF (14.4 mL) was refluxed at 80° C. overnight. After removing the solvent in vacuo, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 300 mg of the desired product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.99 (d, J=3.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 5.23 (d, J=8.9 Hz, 1H), 4.80 (td, J=9.7, 3.6 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H), 3.91 (q, J=7.1 Hz, 2H), 2.73-2.58 (m, 1H), 2.44 (dd, J=14.7, 9.6 Hz, 1H), 2.33-2.21 (m, 3H), 1.72-1.46 (m, 7H), 1.42-1.31 (m, 1H), 1.28 (t, J=6.1 Hz, 1H), 1.17 (dd, J=13.4, 6.2 Hz, 2H), 0.98 (t, J=7.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.25 minutes (M+H) 584.29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][C:23]3[C:18]([Cl:17])=[N:19][CH:20]=[CH:21][N:22]=3)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: Clc1nccnc1Cl
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1Nc1nccnc1Cl
Temperature: 150 °C
Yield: 19.6 %

Procedure:
A mixture of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg; 0.23 mmol) and 2,3-dichloropyrazine (140 mg; 0.92 mmol) was heated at 150° C. (50 W) for 20 minutes in a CEM Discover™ microwave synthesiser. The crude reaction mixture was purified by flash column chromatography eluting with ethyl acetate/hexane (1:3 then 1:2). Product containing fractions were combined and evaporated to give 15 mg of the title compound as a white solid. (LC/MS: Rt 4.06 M+H]+ 332).
Reaction SMILES: C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[CH3:17][O:18][NH:19][C:20]([NH:22][CH3:23])=[NH:21].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[N:43]=[C:44]=[O:45])[CH3:34].[ClH:46]>O1CCCC1.CO>[ClH:46].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[NH:43][C:44]([NH:21][C:20](=[N:22][CH3:23])[NH:19][O:18][CH3:17])=[O:45])[CH3:34]
Reactant: CNC(=N)NOC
Reactant: CCc1cccc(CC)c1N=C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)NC(=NC)NOC

Procedure:
To a suspension of 10.0 g. (30.0 mmol) of N-methoxy-N'-methyl guanidine picrate in tetrahydrofuran (60 ml.) are added 2.4 g. (30.0 mmol) of fifty percent (w/w) aqueous sodium hydroxide and the mixture stirred for 11/2 hours. Five (5.0) grams of anhydrous sodium sulfate is added and the mixture stirred for an additional one-half hour. To this mixture is added a solution of 4.8 g. (30.0 mmol) of 2,6-diethylphenylisocyanate in tetrahydrofuran (20 ml.) and the mixture stirred over night. The mixture is partitioned between chloroform and water and the layers are separated. The chloroform layer is washed well with dilute aqueous sodium hydroxide until most of the color is removed then dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which is dissolved in methanol and acidified with methanolic hydrochloric acid. The methanol is removed under vacuum to give a gummy foam which is crystallized from methanol/ethyl acetate to give 1-(2,6-diethylphenyl)-3-(N-methoxy-N'-methylamidino)urea hydrochloride, m.p. 159.5°-160.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[OH:17][C:18]1[C:10]2[C:11](=[CH:13][CH:14]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[N:12]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1O

Procedure:
Prepared as in Example 1c from 4-phenoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (41%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=8.0 Hz, 3H), 4.18 (q, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.47 (m, 2H), 7.69 (d, J=12.0 Hz, 1H), 12.39 (bs, 1H). MS 310 (MH+).
Reaction SMILES: C(#N)C.[CH2:4]([OH:7])[C:5]#[CH:6].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:18])[C:16]=1F)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([F:8])[C:16]=1[O:7][CH2:4][C:5]#[CH:6])[CH:12]=[O:13]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1c(F)cc(C=O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 102 %

Procedure:
To 50 ml of acetonitrile were added 12 g of propargyl alcohol, 16 g of 3,4,5-trifluorobenzaldehyde and 15 g of potassium carbonate, and the mixture obtained was stirred at room temperature for 1 day. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 20 g of 3,5-difluoro-4-(2-propynyloxy)benzaldehyde represented by the formula:
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[Br:11][C:12]1[NH:16][CH:15]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=1.O>C(#N)C>[Br:11][C:12]1[NH:16][C:15]([CH:9]=[O:10])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=1
Reactant: COC(=O)c1c[nH]c(Br)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Br)[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
POCl3 (Aldrich; 0.531 mL, 5.70 mmol) was added (dropwise, over 1 min) to DMF (1.32 mL, 17.10 mmol) under argon at 0° C., and the resulting solution was stirred at 0° C. for 15 min. This solution was then added (dropwise, over 1 min) to a dark-brown solution of methyl 5-bromo-1H-pyrrole-3-carboxylate (581 mg, 2.85 mmol) in ACN (6.0 mL) at 23° C., and the resulting solution was stirred under argon at 50° C. for 3 h. The reaction mixture was then poured into 10:1 water/sat. aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-30% EtOAc/hexanes) furnished methyl 5-bromo-2-formyl-1H-pyrrole-3-carboxylate (245 mg, 1.05 mmol, 37% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.09 (1H, s), 9.56 (1H, br. s.), 6.72 (1H, d, J=2.7 Hz), 3.90 (3H, s). m/z (ESI, +ve) 231.9/234.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>CCOCC>[F:1][C:2]([F:22])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCOCC
Product: OCc1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.1 %

Procedure:
LiAH4 (0.039 g, 1.03 mmol) was added to a solution of ester 126 (0.166 g, 0.515 mmol) in Et2O (10 mL) at 0° C. The mixture was stirred at room temperature for 0.5 h, and then cooled to 0° C., quenched with ice, and filtered through Celite. The organic fraction was dried and evaporated, and then column chromatography of the residue, eluting with 95:5 CH2Cl2:MeOH, gave (4-{(E)-2-[4-(trifluoromethoxy)phenyl]ethenyl}phenyl)methanol (127) (0.182 g, 82%) as a white solid: mp 161-163° C.; 1H NMR [(CD3)2SO] δ 7.78 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.31-7.38 (m, 4H), 7.27 (s, 2H), 5.16 (t, J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H). APCI MS m/z 277 [M+H−H2O]+.
Reaction SMILES: [C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:21])(=[O:3])[CH3:2].[Br:22]([O-])(=O)=O.[K+].Br>C(O)(=O)C>[Br:22][CH2:2][C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:21])=[O:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C(C)=O)c(F)c21
Reactant: [O-][Br+2]([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C(=O)CBr)c(F)c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 322.4 %

Procedure:
To 1.12 g (3.80 mmol) of the 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of acetic acid was added 0.18 g of potassium bromate and 1.48 ml of 48% hydrobromic acid. The mixture was stirred at 50° C. for 24 hours. The mixture was concentrated to one-half volume and 20 ml of water was added. The solids were filtered to give 1.3 g of the 7-bromoacetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 213°-215° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][NH:12]1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:10][CH:11]1[CH2:16][NH:15][CH:14]([CH3:17])[CH2:13][N:12]1[C:25](=[O:26])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)Cc2ccccc2)C(C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 178.8 %

Procedure:
Diisopropylethylamine (0.38 ml) was added to a solution of trans-2,5-dimethyl-piperazine (1.50 g), phenyl acetic acid (0.59 g) and HATU (1.55 g) in DMF (10 ml). The reaction mixture was stirred overnight at ambient temperature. The solution was diluted with water, then extracted with ethyl acetate. The organic extracts were dried (MgSO4) then concentrated in vacuo to give the sub-title compound (1.8 g).