Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=C)[C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[O:17])[C:4]=2[CH:3]=1
Reactant: C=CCn1c(=O)cnc2ncc(Br)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)cnc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (278 mg, 1.045 mmol) was dissolved in 1,4-dioxane (10 ml) and water (10 ml). Sodium periodate (559 mg, 2.613 mmol) was added, followed by osmium tetroxide (0.22 ml of 4% aqueous solution). The mixture stirred at rt for 1 h, water 40 ml was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 50 ml and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give (7-bromo-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl)acetaldehyde (existing mostly as the hydrate) as an impure brown oil (423 mg, 107%).
Reaction SMILES: [Na].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[C:13](#[N:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:22][C:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: N#CC=Cc1ccccc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(N2N=C(N)CC2c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A 4.42 g. amount of sodium metal is dissolved in 300 ml. of absolute ethanol, then 27.8 g. of p-methoxyphenylhydrazine hydrochloride is added followed in 5 minutes by 20.64 g. of cinnamonitrile. The reaction mixture is refluxed for 7 hours, then is evaporated to dryness in vacuo. Water is added to the residue to give a sludge. The mixture is filtered and the residue is evaporated to dryness. The solid is dissolved in dichloromethane and crystallized as described in Example 16 to give 4.75 g. of the desired product as colorless needles, m.p. 163.5°-166° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]=1[CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]=1[CH:18]([NH2:20])[CH3:19]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(F)c2cccnc2n1-c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1c(F)c2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of tert-butyl {1-[3-fluoro-1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (16 mg, 0.043 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (0.033 mL, 0.43 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired amine (11 mg, 94%). LCMS calculated for C15H14F2N3(M+H)+: m/z=274.1. Found: 274.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([NH2:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:17](N1C=CC=N1)(=[NH:19])[NH2:18]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([NH:15][C:17]([NH2:19])=[NH:18])[CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N=C(N)n1cccn1
Reactant: NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 891.5 %

Procedure:
2.07 g (0.01 mol) of [1-(4-nitrophenyl)pyrrolidin-3-yl]amine (2) was heated to 90° C. in 10 ml of DMF. 1.32 g (0.0009 mol) of 1-amidinopyrazole monohydrochloride was added slowly to the reaction medium. The mixture was heated for 8 hours. A yellow solid was thus precipitated. The solid thus obtained was filtered off, washed with ethanol and dried under vacuum to give 2 g of a yellow powder (3) (70%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
Powdered aluminum chloride (270 g., 2 moles) is added slowly at 0° C. to a stirred mixture of 2,3-dichloroanisole (177 g., 1.0 mole) and succinic anhydride (100 g., 1.0 mole) in methylene chloride (800 ml.). The mixture then is stirred at 0° C. for two hours, then at 20°-25° C. for 16 hours and then refluxed for one hour and poured into ice cold 1 N HCl (2.4 l.). The aqueous mixture is heated to 65° C. and allowed to cool to 20° C. The sticky solid that separates is triturated with warm butyl chloride to obtain 136 g. product, melting point 140°-145° C. After crystallization from ethanol-water (5:7) there is obtained 3-(2,3-dichloro-4-methoxybenzoyl)propionic acid (125 g.), melting point 142°-144° C..
Reaction SMILES: [Br:1][C:2](=C)[CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=C)=[O:6]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[Br:1][C:2]1[CH2:3][N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:5](=[O:6])[C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]=1
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc(CN2CC(Br)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (1.78 g, 2.05 mmol) was added to a solution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (5.29 g, 10.2 mmol) in dichloromethane (1000 mL) and heated to 40° C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (0.79 g). MS 489 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.36-7.35 (m, 4H), 7.33-7.30 (m, 1H), 7.17-7.15 (m, 1H), 6.46-6.43 (m, 2H), 6.13 (d, J=6.1 Hz, 1H), 6.04-6.03 (m, 1H), 5.13-5.07 (m, 2H), 4.93-4.88 (m, 1H), 4.75 (d, J=14.4 Hz, 1H), 4.64-4.60 (m, 1H), 4.47 (d, J=14.4 Hz, 1H), 3.86 (d, J=18.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.68-2.63 (m, 1H), 2.24-2.05 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][N:18]([C:19]1[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])[S:12][CH:13]=1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cccc(Br)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cccc(Br)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.4 %

Procedure:
2-[(4-{2-[(3-Bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) obtained in Example 411-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (280 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:39][C:38](=[O:40])[NH:37][CH:36]=2)=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[O:39][C:38](=[O:40])[NH:37][CH:36]=4)=[CH:33][CH:34]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)o2)cc1
Reactant: COc1cn(C(CC2CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(-c3c[nH]c(=O)o3)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
103 mg (purity 94%, 0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate) and 55 mg (0.28 mmol, 1.1 eq.) of 5-(4-aminophenyl)-1,3-oxazol-2(3H)-one were reacted according to General Method 1. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 36 mg (27% of theory)
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](Cl)=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:8](=[N:9][OH:10])[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Cl)c1
Reactant: ON=C(Cl)c1ncccc1F
Solvent: C1COCCO1
Product: ON=C(Nc1cccc(Cl)c1)c1ncccc1F
Reaction time: 12 h

Procedure:
A solution of 3-fluoro-N-hydroxypicolinimidoyl chloride 2 (1.35 g, 7.73 mmol) in 1,4-dioxane (15 mL) was added via cannula to a solution of 3-chloroaniline (4.5 mL, 43 mmol) in 1,4-dioxane (10 mL). After 12 h at rt, the r×n was added to EtOAc: H2CO (1:1). The organic layer was separated and washed with brine (30 mL), dried (MgSO4), filtered and concentrated to afford N-(3-chlorophenyl)-3-fluoro-N′-hydroxypicolinimidamide was taken through to the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(C(=O)O)c1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.2 %

Procedure:
A mixture of 2-fluoro-5-methoxy-benzoic acid (4.3 g, 25 mmol) and thionyl chloride (68 mL, 937 mmol) and DMF (1 drop) was stirred at RT for 14 hours. The mixture was then evaporated to afford the title compound (4.77 g, 100%) after repeated azeotroping with toluene.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([CH2:22][O:23][CH:24]([F:26])[F:25])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=[O:11])C1C=CC=CC=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(O)C.ClCCl.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]([CH2:22][O:23][CH:24]([F:25])[F:26])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=[O:11]
Reactant: O=C(NCc1ccc(F)c(F)c1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(COC(F)F)C(=O)NCc1ccc(F)c(F)c1
Yield: 69.2 %

Procedure:
2-dibenzylamino-N-(3,4-difluoro-benzyl)-3-difluoromethoxy-propionamide (298 mg, 0.645 mmol) was stirred with 10% Pd(OH)2 (200 mg) in ethanol under H2 overnight. The reaction mixture was filtered and concentrated. The residue was mixed with triethylamine (254 mg, 2.5 mmol) in dichloromethane (2 mL) and treated with acetic anhydride (85 μL) at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was concentrated with silica gel and purified by column chromatography, eluting with 30-100% ethyl acetate in hexanes. The product was triturated with diethyl ether to give 2-amino-N-(3,4-difluorobenzyl)-3-(difluoromethoxy)propanamide (125 mg, 60%) as a white solid, MP: 146° C. 1H NMR (300 MHz, CDCl3): δ(ppm) 6.92-7.16 (m, 4H), 6.47 (d, 1H), 6.25 (wt, 1H), 4.75 (m, 1H), 4.41 (m, 2H), 4.22 (dd, 1H), 4.02 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[NH:15][C:14](=[O:21])[CH:13]=[C:12]2[O:22][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]1>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:20][O:19][C:18]1[CH:17]=[C:16]2[C:11]([C:12]([O:22][C@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]3)=[CH:13][C:14](=[O:21])[NH:15]2)=[CH:10][C:9]=1[CH:1]=[CH2:2]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(=O)[nH]c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(=O)[nH]c2cc1OC
Yield: 99.1 %

Procedure:
Potassium vinyltrifluoroborate (0.913 g, 6.82 mmol), TEA (0.950 mL, 6.82 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.186 g, 0.227 mmol) were added to a solution of the product from step 2 (2.26 g, 4.54 mmol) in EtOH (45.4 mL). The mixture was then heated to reflux for 1 h. The EtOH was removed in vacuo, and the residue was taken up in EtOAc and extracted with water. The organic layer was dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica gradient elution, 0-5% MeOH/DCM) to yield 2.0 g (99%) of the title compound. LRMS ESI+ ((M-Boc)+H)+345.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[CH3:21])=O.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reaction time: 3.5 h
Yield: 89.6 %

Procedure:
A solution of 3-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (1.993 g, 6.773 mmol) in CH2Cl2 (34 mL) at 0° C. is treated with 1.0 M diisobutylaluminum hydride in toluene (DIBAL, 14.3 mL) dropwise over 3 min. time and stirred for 3.5 h. The reaction mixture is quenched with MeOH (5.0 mL), treated with 1M tartaric acid (50 mL), and stirred overnight. The organic layer is separated. The aqueous layer is extracted with CH2Cl2 (1×50 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide (3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (1.616 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C(=O)=O.C(O)CO.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5]3[C:4]=1[C:13](=[O:17])[C:14](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: OCCO
Product: COc1ccc2cccc3c2c1C(=O)C3=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of 2-methoxynaphthalene (5 g, 31.6 mmol) and oxalyl chloride (11 mL, 126 mmol) in 150 mL of dichloromethane was cooled to −15° C. (CO2/ethylene glycol) under nitrogen. Aluminum trichloride (10.5 g, 79 mmol) was added slowly over 30 minutes. After 3 hours, the mixture was poured onto 100 g of ice. The layers were separated, and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solution was concentrated to afford 4.5 g of a solid. The solid was triturated with dichloromethane to give 1.24 g of the title compound as a solid, mp 218-220° C.;
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)=[CH:27][CH:26]=1)[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[CH3:41][NH:42][CH3:43].O>C(#N)C>[CH3:41][N:42]([CH3:43])[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)=[CH:27][CH:26]=1)[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4]
Reactant: O=C(CN(C(=O)CCl)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: CNC
Solvent: O
Solvent: CC#N
Product: CN(C)CC(=O)N(CC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide (0.300 g, 0.528 mmol) in acetonitrile (3 mL) was added at room temperature dimethylamine (0.150 mL, 1.63 mmol), and the resulting solution was stirred for 2 hours at 50° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 0.270 g of the title compound.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([O-:2])=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.1 Mol of p-Nitrobenzoylchloride and stirred overnight. The benzene was evaporated and the residue was stirred in sat. sodiumbicarbonate solution for 1 hour. The solid was filtered and recrystallized from hexane. An off white crystalline product, mp 63°-66° C., was obtained.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][N:7]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]1[C:13]([O:15]C)=O.C(O[CH:20](OCC)[CH2:21][C:22]#[N:23])C.ClC(Cl)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)C.C(O)(C)C>[Br:12][C:10]1[CH:9]=[C:8]2[C:13]([OH:15])=[C:21]([C:22]#[N:23])[CH:20]=[N:6][N:7]2[CH:11]=1
Reactant: CCOC(CC#N)OCC
Reactant: COC(=O)c1cc(Br)cn1N
Agent: CS(=O)(=O)O
Solvent: CC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cnn2cc(Br)cc2c1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a round bottom flask was added the methane sulfonic acid salt of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3-diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85° C. over 1 hour and then stirred at 85° C. for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2Cl2 and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was transferred into a 2 L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt and diluted with CH2Cl2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z=236.0 −ve. H1 NMR (400 MHz, DMSO-d6) δ ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0 Hz), 6.43 (1H, d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]2=1.S(=O)(=O)(O)O>O>[Br:1][CH:14]1[CH:9]2[CH2:15][CH:12]([C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=32)[CH2:13]1
Reactant: c1ccc2c(c1)C1CCC2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: BrC1CC2CC1c1ccccc12
Yield: 90.5 %

Procedure:
10 g of N-bromosuccinimide are added in small portions over approximately two hours to a mixture of 5 g of benzonorbornene, stirred into 10 cm3 of water and 10 cm3 of sulphuric acid and heated to a temperature between 50° C. and 55° C. The progress of the reaction is followed by gas phase chromatography. When the benzonorbornene has been completely converted, the reaction mixture, at room temperature, is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate until the pH of the washings is neutral and is then dried over magnesium sulphate and concentrated. 7 g of crude 2-bromobenzonorbornene are obtained and purified by distillation under reduced pressure. After distillation, 4 g of pure product are obtained. This product is a light-yellow liquid whose boiling point is 70°-75° C. at a pressure of approximately 2.65 10-5 bar. Its proton nuclear magnetic resonance spectrum corresponds to the 2-bromobenzonorbornene structure.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:10])[N:7]([CH3:9])[N:8]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([O:22][C:23](=[O:24])[NH:10][C:6]2[N:7]([CH3:9])[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1nc(C2CC2)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C2CC2)cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamine (3.0 g, 22 mmol) (65 ml) and sodium bicarbonate (2 g, 24 mmol) in THF is cooled to 0° C. Phenylchloroformate (3.4 g, 22 mmol) is added dropwise over 15 minutes. The reaction mixture is allowed to warm to ambient temperature and stirred for 5 hours, then filtered and the filtrate partitioned between ethylacetate and water. The organic phase is washed with water, 5% aqueous citric acid solution and brine, dried over MgSO4 and evaporated to afford (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester. [M+H] 258.17.