Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.[I-].[I-].[Sm+2]>O1CCCC1>[F:8][C:2]([F:9])([C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][N:15]=2)=[CH:22][CH:21]=1)([OH:25])[CH3:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(=O)c1ccc(-c2ccc(F)cn2)cc1
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(C)(O)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A solution of ethyl bromo(difluoro)acetate (0.53 mL, 4.1 mmol) and 1-[4-(5-fluoropyridin-2-yl)phenyl]ethanone (800 mg, 3.7 mmol) in tetrahydrofuran (40 mL) was added to a 0.1 M solution of samarium diiodide in tetrahydrofuran (82 mL, 8.2 mmol) at ambient temperature. After stirring at ambient temperature for 3 min, the reaction was cooled and quenched with 1N aqueous hydrochloric acid. Volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded ethyl 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanoate.
Reaction SMILES: [ClH:1].N[C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)(Cl)Cl>[Cl:1][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C)c1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1Cl
Reaction time: 1 h

Procedure:
For a period of 60 minutes, hydrogen chloride gas was bubbled into a solution of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester (12 grams, 0.07 mole) in 75 ml. of chloroform. The reaction mixture set up and nitrosyl chloride was bubbled into the reaction mixture for a period of five minutes. TLC indicated that starting material was still present, therefore, nitrosyl chloride was bubbled into the reaction mixture for an additional five minutes. The solution was heated on a steam bath for five minutes, then cooled and the solvent removed in vacuo, yielding 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester. The identity of the product was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][C:16]#[N:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.N.CO>O1CCCC1.CO.[Co]>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(F)cc2n1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(F)cc2n1)CCC3=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (5-fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)acetonitrile (156 mg, 0.686 mmol) in tetrahydrofuran/methanol (5 mL/5 mL) were added Raney cobalt (1.5 g) and 2M ammonia/methanol solution (2 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (157 mg, yield 99%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=3)=[O:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2cnccc12
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12

Procedure:
Prepared from isoquinolin-5-amine and 4-(trifluoromethyl)phenyl isocyanate according to Description 61. m/z (ES+) 332 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:22])N(OC)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:22])[CH3:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5 g of 4-(N-methoxy-N-methyl-carbamoyl)-piperidine-1-carboxylic acid benzyl ester (S. Nahm and S. W. Weinreb, Tetrahedron Letters, 22:3815–3818(1981)) in 50 mL of anhydrous THF cooled to 0° C., was added dropwise 6 mL of 3M methylmagnesium bromide in ether over 10 minutes. After stirring for 1 h at 0° C., the resulting mixture was quenched with 50 mL of 1N HCl and extracted with 3×50 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure. Drying under vacuum gave 4-Acetyl-piperidine-1-carboxylic acid benzyl ester as a white solid:
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]2=[CH:3]1.O(Cl)[Cl:18].[P+3]>>[Cl:18][C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Alternatively, 3-Oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was heated with 20 mL of phosphorus(III)oxychloride at 100° C. for 4.75 h. The solvent was removed under vacuum. The residue was treated with ice and saturated sodium bicarbonate solution. The solid which formed was filtered off, washed well with water and air-dried to yield the corresponding 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g); 1H NMR (CDCl3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1.O([CH:25]([CH3:27])[CH3:26])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH:25]([CH3:27])[CH3:26])=[CH:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1
Reactant: O=C(Cn1cnnn1)c1ccc(Cl)cc1Cl
Reactant: CC(C)OS(=O)(=O)C(F)(F)F
Product: CC(C)OC(=Cn1cnnn1)c1ccc(Cl)cc1Cl

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-1-yl-ethanone with isopropyl triflate there was obtained 1-[2-(2,4-dichloro-phenyl)-2-isopropoxy-vinyl]-1H-tetrazole as a white powder with m.p. 82° C.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2
Yield: 93.3 %

Procedure:
A solution of intermediate 6, ethyl 3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladium on activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) of the title compound as white needles; mp 172–174° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH3), 4.08 (4H, m, 2×CH2), 4.54 (2H, q, J=7.3 Hz, OCH2), 4.72 (2H, s, OCH2), 10.75 (1H, s, OH). Anal. Calcd for C10H12N2O5: C, 50.00; H, 5.03; N, 11.66. Found: C, 50.01; H, 4.95; N, 11.54.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]#[C:14][CH:15]([NH:17][OH:18])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[N-:21]=[C:22]=[O:23].[K+]>C(OCC)(=O)C.O>[OH:18][N:17]([CH:15]([C:14]#[C:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:16])[C:22]([NH2:21])=[O:23]
Reactant: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)N(O)C(N)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
The N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine prepared in step 3 above was taken up in ethyl acetate (36 kg) and cooled to 5° C. A solution of freshly prepared potassium isocyanate (10 kg) in water (18 kg) was slowly added and the exotherimic reaction was maintained below 10° C. The reaction mixture was agitated for 30 min. The layers were separated and the organic phase was dried over MgSO4 and filtered. The filtrate was diluted with heptane (58 kg) and agitated for one hour. The resulting crude product was filtered, dissolved in 45° C. ethyl acetate (42 kg). PWA carbon (0.5 kg) and Ultra Norit C (0.5 kg) were added and the mixture was agitated for 30 minutes and filtered. The combined filtrate and washings were diluted with heptane (68 kg) and filtered to provide N-hydroxy-N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]urea (2.94 kg). m.p. 139°-40° C.; 1H NMR (d6Me2SO) 1.33 (d, 3, J=7 Hz), 5.10 (q, 1, J=7 Hz), 6.55 (s, 2), 6.87 (m, 1), 7.03 (m, 1), 7.13 (m, 3), 7.25 (t, 2, J=8 Hz), 7.37 (t, 1, J=8 Hz), 9.33 (s, 1) ppm; mass spectrum m/e (rel intensity) 332 (80, M+ +NH4), 315 (75, M+ +H), 289 (80), 272 (100). Analysis calculated for C17 H15FN2O3 : C, 64.95, H, 4.81, N, 8.91; found: C, 64.67, H, 4.76, N, 8.81.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[O:14][N:13]=1)=[O:11])[CH3:8].[CH:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](Cl)=[S:28])=[CH:22][CH:21]=1>ClCCl>[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][O:19][C:27]([O:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[S:28])[O:14][N:13]=1)=[O:11])[CH3:8]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1cc(CCO)on1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CCOC(=S)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Pyridine (2.4 g, 31 mmol) was added to a stirred solution of 5-hydroxyethylisoxazole-3-carboxylic acid ethyl ester (4.75 g, 26 mmol) (prepared analogously to Example 64 part a) in dichloromethane (150 ml) under nitrogen at room temperature. The mixture was cooled to 0° C. and phenyl chlorothionoformate (5.3 g, 31 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hand at room temperature for 2 h, then diluted with dichloromethane (200 ml) and washed with water (×2). The organic layer was dried MgSO4) and evaporated in, vacuo. Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane, gave the title-compound (6.7 g, 81%), 1H NMR (250 MHz, CDCl3) δ 1.43 (3H, t, J=7.1 Hz, CH3), 3.37 (2H, t, J=6.3 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, CH2), 4.83 (2H, t, J=6.3 Hz, CH2), 6.60 (1H, s, Ar—H), 7.08-7.11 (2H, m, 2 of Ar—H), 7.29 (1H, m, Ar—H), 7.38-7.46 (2H, m, 2 of Ar—H); MS (ES+) m/e 322 [MH]+, m/e 168 [MH—154]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:7]2[N:12]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cncc(N2CCCCC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCCC2)n1

Procedure:
To a suspension fo 1.28 g of 6-(1-piperidinyl) pyrazine-2-carboxylic acid in 18 ml of tetrahydrofuran, 0.95 ml of triethylamine and 0.84 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 0.58 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 30 minutes at room temperature, and then refluxed for 12 hours. The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.55 g of the desired compound as yellow columns. The obtained crystal was consistent with that of (a).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([N:18]3[C:17](=[O:19])[C:16]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]4[C:14]3=[O:24])[CH2:8]2)[CH:2]=1
Reactant: O[C@H]1CCC[C@H](c2cccnc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
A solution of trans-3-(3-pyridyl)cyclohexanol (3.99 g, 22.5 mmol) in THF (90 mL) was cooled to 4° C. and treated with phthalimide (3.65 g, 24.8 mmol), Diisopropylazodicarboxylate (4.88 mL, 24.8 mmol) and triphenylphosphine (6.50 g, 24.8 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield cis-N-[3-(3-pyridyl)cyclohexyl]phthalimide (1.66 g, 24%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[K+].O>C(O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCCCCCCC1=C(C)CCCC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=C(CCCCCCCCC(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
To ethyl 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoate (13.2 g, 42.9 mmol) in ethanol (80 mL) was added 4 M KOH (43 mL). The mixture was stirred at room temperature for 1.5 h. Water (350 mL) was added and the solution was washed with tert-butyl methyl ether (2×100 mL). The SimVA, aqueous phase was cooled, acidified with 4 M HCl (˜45 mL) and extracted with pentane (3×100 mL). The combined pentane extracts were washed with water (200 mL), dried (MgSO4), filtered, concentrated and dried under high vacuum. The material was redissolved in pentane (100 mL), concentrated and dried under high vacuum one more time to give 9-(2,6,6-trimethylcyclohex-1-en-1-yl)nonanoic acid as a colorless oil (11.1 g, 92% yield). MS ESI− m/z 279 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:32]([O:39][NH2:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][NH:40][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 85.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanoic acid (1.30 g, 3.14 mmol), N,N′-carbonyldiimidazole (533 mg, 3.28 mmol) and O-benzylhydroxylamine hydrochloride (550 mg, 3.45 mmol) in tetrahydrofuran (10 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide as a yellow solid (1.4 g, 86% yield): mp, 137.0-139.0° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.8 Hz, 3H, CH3), 3.05-3.16 (m, 2H, CH2), 3.72 (s, 3H, CH3), 4.09 (q, J=6.8 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.68 (t, J=7.8 Hz, 1H, NCR), 6.87-7.02 (m, 3H, Ar), 7.23-7.41 (m, 5H, Ar), 8.11 (d, J=8.1 Hz, 1H, Ar), 8.48 (s, 1H, Ar), 8.62 (dd, J=1.8, 8.2 Hz, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.64, 34.17, 50.76, 55.45, 63.71, 76.67, 111.68, 112.37, 118.02, 119.76, 124.70, 128.16, 128.62, 129.75, 130.42, 132.52, 135.74, 135.79, 147.73, 148.69, 151.50, 165.73, 165.99, 166.17. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.34; H, 4.71; N, 8.05.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>C(#N)C>[CH2:15]([C:13]1[CH:12]=[CH:11][C:10]([O:17][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[C:9]([O:8][CH3:7])[CH:14]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CCc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of K2CO3 (2 mmol; 276 mg) in anhydrous acetonitrile (1 mL) under argon, was added 2-methoxy-4-ethylphenol (0.285 mL; 2 mmol) followed by 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (418 mg; 2 mmol). The reaction mixture was stirred at 80° C. overnight. Concentrated under argon, washed with NaOH (0.1N; 3 mL), the mixture was extracted with ethyl acetate (2*3 mL). Combined organic phases were dried over MgSO4, concentrated in vacuo, to give the title product as a light brown oil (651 mg; 95%), used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:4]([Br:23])[CH:3]=1.[Cl:24][C:25]1[S:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[Br:23][C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[C:5]=1[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cc(Br)c(NC(=O)CCC2CCCCC2)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(Cl)s1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(CCC1CCCCC1)Nc1c(Br)cc(NCc2ccc(Cl)s2)cc1C(F)(F)F
Temperature: 130 °C
Yield: 33 %

Procedure:
N-(4-Amino-2-bromo-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide (1.03 g) and 5-chloro-thiophene-2-carbaldehyde (310 uL) were dissolved in methanol (16 mL) and heated to 130° C. for 8 minutes in a sealed microwave process vial. Sodium cyanoborohydride (800 mg) was added and the reaction mixture was heated to 130° C. for 5 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate (100 mL) was added, the product was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 517 mg (33% yield) of the title compound as a yellow solid. LC-MS (m/z) 524 (MH+); tR=4.09, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.86 (q, 2H), 1.15 (m, 3H), 1.26 (m, 1H), 1.46 (q, 2H), 1.65 (m, 5H), 2.24 (t, 2H), 4.89 (d, 2H), 6.94 (d, 1H), 6.95 (d, 1H), 6.98 (d, 1H), 7.04 (t, 1H), 7.13 (d, 1H), 9.32 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20].C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:15][O:14][C:4]1[CH:5]=[C:6]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:22][CH2:21][C:19](=[O:18])[CH2:20]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 140 °C
Reaction time: 48 h

Procedure:
90.0 g of 3,4-dimethoxy-ω-nitrostyrene (compound G2), 90 ml of 2-trimethylsilyloxy-1,3-butadiene and 180 ml of abs. Toluene are put in an autoclave, where the mixture is stirred at 140° C. for 2 days and then cooled. After addition of 1000 ml of ethyl acetate, 300 ml of a 2 N solution of hydrochloric acid are dropped under stirring. The phases are separated and the aqueous layer is extracted three times with dichloromethane. The combined organic extracts are washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate and the solvents are removed under reduced pressure to give 150 g of the crude title compound. Further purification is carried out by chromatography on silica gel using petroleum ether/ethyl acetate in the ratio 1/1 as eluent to give 81.5 g (67% of theory) of the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[S:13][C:6]=12.[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH3:32]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:29][CH2:30][O:31][CH3:32])[CH:18]=3)[S:13][C:6]=12
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of 93 (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. was added NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture was allowed to warm to room temperature over 0.5 h then re-cooled to 0° C. Bromoethylmethyl ether (123 mg, 0.88 mmol) was added and mixture was allowed to warm to room temperature over 20 hours, concentrated and partitioned between EtOAc and water. The EtOAc phase was dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (eluents hexane and acetone/hexane 75:25) to afford the title compound 94 (126 mg, 36% yield) as a pale yellow solid. MS (m/z) 415.1.0 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (244 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (110 mg, 18%). MS (ISP) 590.3 [(M+H)+]; mp 252–253° C.