Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:19](=[O:21])[CH3:20])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(OC(C)C)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1cc(OC(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-isopropyloxy-2-methylpyridine (687 mg) in tetrahydrofuran (7 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 3.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.549 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(4-isopropyloxypyridin-2-yl)-propan-2-one (652 mg).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-tert-butylbenzaldehyde (3.24 g, 20.0 mmol) and 4-chlorobenzylamine (2.43 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the reaction mixture was stirred at room temperature overnight. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (50 mL) and aqueous 1 M KOH (50 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 4.31 g (75%) of white solids.
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:28])([F:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21](OC)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH:31]1[CH:36]=[C:35]2[CH:37]([CH2:44][O:45][C:46](ON3N=NC4C3=CC=CC=4)=[O:47])[C:38]3[C:43]([C:34]2=[CH:33][CH:32]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:61]>O1CCOCC1>[C:9]([O:8][P:6]([C:13]([F:28])([F:27])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:21]([OH:61])=[O:22])[NH:20][C:46]([O:45][CH2:44][CH:37]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:34]3[C:35]2=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:47])=[CH:25][CH:26]=1)([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of amino ester 12 (15 mg, 0.036 mmol) in dioxane (0.5 mL) is added 1 N NaOH (0.18 mL) and the reaction is stirred at ambient temperature. After 20 minutes CO2 gas is bubbled into the reaction for 5 minutes, then solid Fmoc-OBt (15 mg, 0.043 mmol) is added and stirring continued for 1 hour. Cold 5% citric acid (10 mL) is added and the mixture is extracted with CHCl' (3×10 mL); the combined extracts are dried (MgSO4) and the solvent evaporated in vacuo to yield crude 14 (13.7 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[N:32]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][CH2:38][N:32]([CH2:39][CH2:40][OH:41])[CH2:33][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: OCCN1CCCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-[1,4]diazepan-1-yl-ethanol following General Procedure C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and methyl thioglycolate
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.F[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=C[C:40]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O.C[N:58](C=O)C>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>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:22]([C:44]4[CH:39]=[CH:40][N:58]=[C:42]([O:45][CH3:46])[CH:43]=4)=[N:21][CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OS(=O)(=O)C(F)(F)F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CN(C)C=O
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: [Na+]
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3ccnc(OC)c3)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((5-neopentyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)oxy)methyl)phenyl)propanoate (200 mg) in DMF (5.0 mL) were added 2-fluoro-5-methoxyphenylboronic acid (80 mg), 2.0M aqueous sodium carbonate solution (0.52 mL) and tetrakistriphenylphosphinepalladium (40 mg), and the mixture was stirred at 90° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (27 mg) as a colorless oil.
Reaction SMILES: ClCC1C=CC(CCl)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C1(=O)[O:19][CH2:18]CC1.C1C2[C:32](C3C=CC(O)=CC=3)([C:34]3C=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[C:31]3C(=CC=CC=3)C=2C=CC=1>>[CH3:38][C:37]([CH2:36][CH2:35][CH2:34][CH2:32][CH3:31])=[O:40].[CH3:18][OH:19]
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C1CCCO1
Agent: ClCc1ccc(CCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(C)=O
Product: CO
Reaction time: 0.17 h

Procedure:
8.75 g (0.05 mol) of α,α′-dichloro-p-xylene, 26.66 g of aluminum chloride, and 200 g of γ-butyrolactone were introduced into 1 l 4-neck flask having a mechanical agitator, a condenser, 300 ml add in a dropwise funnel, and a nitrogen gas inlet and well stirred while flowing nitrogen gas in. After 10 minutes, 35.03 g (0.10 mol) of 4,4′-(9-fluorenylidene)diphenol was dissolved into 200 g of γ-butyrolactone to provide a solution. The solution was slowly dripped for 30 minutes and reacted for 12 hours. After completing the reaction, the acid was removed by using water and condensed by an evaporator. Then it was diluted by using methylamylketone (MAK) and methanol to provide a solution of MAK/methanol=4/1 (weight ratio) having a concentration of 15 wt %. The solution was introduced into 3 l separating funnel and added with n-heptane to removed a low molecular weight-containing monomer to provide a polymer (Mw=12,000, polydispersity=2.0) represented by the following Chemical Formula 11.
Reaction SMILES: [CH2:1]1[CH2:33][O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1.CO.[Na].Cl>O.O1CCCC1>[CH2:1]1[CH2:33][O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(NCc3ccc4c(c3)OCCO4)cc2)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCNc2ccc(NCc3ccc4c(c3)OCCO4)cc2)cc1
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To methyl 4-[3-[N-[4-(3,4-ethylenedioxybenzylamino) phenyl]amino]propoxy]benzoate (2.1 g) were added methanol (100 ml), tetrahydrofuran (20 ml) and 2N sodium hydroxyide (12 ml), and the mixture was stirred at 45°-50° C. overnight. To the reaction mixture was added water (150 ml), then, after the mixture was neutralized with 2N hydrochloric acid, the resulting precipitate was collected by filtration, washed with water and ethanol to give 4-[3-[N-[4-(3,4-ethylenedioxybenzylamino)phenyl]amino]propoxy]benzoic acid (0.4 g). mp. 246°-247° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:31][CH3:32])=[C:11]([C:13]2([F:30])[C:21]3[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[N:15]([CH2:26]SC)[C:14]2=[O:29])[CH:12]=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:31][CH3:32])=[C:11]([C:13]2([F:30])[C:21]3[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[N:15]([CH2:26][Cl:4])[C:14]2=[O:29])[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)N(CSC)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
Alternate Method: Sulfuryl chloride (135 mg, 80.2 μL, 1 mmol) was added at room temperature to a dichloromethane (10 mL) solution of 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-methylsulfanylmethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one (420 mg, 1 mmol) in a round-bottomed flask equipped with nitrogen inlet and magnetic stirrer. After stirring the reaction mixture at room temperature for 20 minutes, the crude solution was concentrated in vacuo to afford 3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (425 mg, 100% crude yield) as a light yellow solution. Step C: Phosphoric acid mono-[3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl] ester, bis-[tris(hydroxymethyl)ammoniummethane] salt
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH:15][NH2:16])[CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[NH2:9][C:8]1[N:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:16]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: CCCCCNN
Solvent: CCO
Product: CCCCCn1ncc(C#N)c1N
Yield: 88 %

Procedure:
A warm solution of 6.02 g (49.3 mM) ethoxymethylenemalononitrile in 20 ml of ethanol was added via a cannula to a stirred solution of 6.04 g (59.1 mM)n- pentylhydrazine in 20 ml of ethanol at 50° C. The reaction mixture was then heated to reflux for 30 minutes, then cooled in a refrigerator for 18 hours. The off-white crystalline precipitate was filtered to yield 7.73 g (88%) of the title compound, mp=143°-144° C.; tlc, Rf =0.5, silica gel, methanol:chloroform (1:19).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[C:3]1=[S:17].[CH3:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH3:34])=[N:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25].C(O)C>CO>[C:14]([C:10]1[CH:9]=[C:8]([N:4]2[C:5](=[O:7])[CH2:6][N:2]([N:1]=[CH:32][C:29]3[C:28]([CH3:34])=[N:27][N:26]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([CH3:18])[CH:20]=4)[C:30]=3[OH:31])[C:3]2=[S:17])[CH:13]=[CH:12][CH:11]=1)([OH:16])=[O:15]
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Reactant: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-n2nc(C)c(C=NN3CC(=O)N(c4cccc(C(=O)O)c4)C3=S)c2O)cc1C
Yield: 78.7 %

Procedure:
50 mg (0.2 mmol) of the 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one synthesized above in 1) and 55 mg (0.22 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) of Reference Synthetic Example 1 were stirred in a liquid mixture of 10 ml of ethanol and 5 ml of methanol at room temperature for 96 hours. The resulting insoluble was collected by filtration to obtain 73 mg of the desired product as a yellow solid (yield 72%).
Reaction SMILES: [C-]#N.[K+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:21])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Yield: 41.5 %

Procedure:
To a solution of KCN (5 g) in water (35 mL) is added 4-methoxybenzaldehyde (27.2 g, 0.2 mole), benzaldehyde (21.2 g, 0.2 mole) and 95% ethanol (70 mL). The mixture is refluxed under nitrogen for 4.5 hours and the ethanol removed in vacuo. Water (200 mL) is added to the residue and then distilled off at reduced pressure (to remove remaining unreacted bezaldehyde). The procedure is repeated twice and the residual water azeotroped with ethanol. The crude product (56.3 g, orange semi-solid) is purified by flash-chromatography (on silica Merck-60, preabsorbed in dichloromethane-ethyl acetate and eluted with hexane-ethyl acetate 8:2) to yield a light yellow solid (20.1 g, 41.5%), m.p. 99°-101° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:16].[N:17]([O-])=[O:18].[Na+]>O>[ClH:16].[CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N:17]=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCN(CCCC)c1ccc(N=O)cc1

Procedure:
A solution of N,N-dibutylaniline (10.25 g; 0.05 moles; Aldrich No.: 30,446-8, 97%) in a mixture of concentrated HCl (15 ml; Aldrich No.: 25,814-8, 37%) and distilled water (20 ml) was cooled to −5° C. to −15° C. in a freezing mixture (ice+salt) (Solution A). Sodium nitrite (3.62 g; 0.052 moles; Aldrich No: 43,089-9, granular, 99.5%, DuPont product) was dissolved at room temperature in distilled water (10 ml) and cooled to and kept at 0° C. (Solution B). Cold (0° C.) Solution B was gradually added over 1-2 hours to a magnetically stirred Solution A (at −5 to −15° C.) and the reaction temperature was carefully monitored and not allowed to rise above 0° C. During addition, the reaction mixture changes from pale red to almost black. The mixture was then allowed to attain room temperature over two to three hours. During this time, a dark crystalline mass was deposited. The crystals were collected on Buchner funnel and washed with acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6][NH:5]2.[N+:15]([O-])([OH:17])=[O:16].C1OC2C(=CC=C([N+]([O-])=O)C=2)[O:20]1.C1OC2C=C3C(NC(=O)C(=O)N3)=CC=2O1.C(C1C(CC)=CC=CC=1N)C>C(C(O)=O)(F)(F)F>[Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[C:6](=[O:20])[NH:5]2
Reactant: CCc1cc2c(cc1Cl)NCC(=O)N2
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Agent: CCc1cccc(N)c1CC
Agent: O=c1[nH]c2cc3c(cc2[nH]c1=O)OCO3
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 137 mg (0.65 mmol) of 36 in 4 mL of CF3CO2H kept in an ice bath was added dropwise 0.4 mL of fuming HNO3. The solution was stirred in the ice bath for 1 h and at room temperature overnight. It was evaporated and the residue was treated with 6 mL of water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid, 140 mg (80%); mp>330° C.; 1H NMR (DMSO-d6), 1.161 (t, 3, J=7.4), 2.712 (q, 2, J=7.6), 7.192 (s, 1), 12.209 (mb, 2). MS, 269 (M+, 100), 254 (12), 226 (15), 160 (20). HRMS, Cacld for C10H8ClN3O4 269.0198; Found 269.0196.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].O>ClCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
To a solution of Example 1 (0.5 g, 1.65 mmol) in dichloromethane (4.8 mL) was added triethylamine (0.46 mL, 3.30 mmol) and methyl 4-bromobutyrate (0.24 mL, 1.90 mmol). The resulting solution was stirred at ambient temperature for 16 hours. Water (25 mL) and dichloromethane (25 mL) were added to the reaction mixture and the crude residue was extracted into dichloromethane. The organic portion was washed with water (25 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.15 g, 24%); 1H NMR (400 MHz, CDCl3); δ 1.66-1.86 (m, 5H), 1.96 (m, 1H), 2.20-2.45 (m, 4H), 2.86 (m, 2H), 3.14 (m, 1H), 3.63 (s, 3H), 3.74 (m, 1H), 3.89 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 368.4 (M+1); LC (90.6%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH:19]4[CH:17]([CH:18]4[NH2:21])[CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.O>ClCCl>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH:17]4[CH:19]([CH:18]4[NH:21][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[C:23]([F:22])([F:33])[F:34])[CH2:20]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCC1CC1)c1ccc(N2CC3C(C2)C3NC(=O)c2ccccc2C(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.258 g, 0.90 mmol) in dichloromethane (10 mL) was added 2-trifluoromethylbenzoyl chloride (0.2 mL, 1.00 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, followed by the addition of triethylamine (0.1 mL, 1.000 mmol). The reaction mixture was stirred at ambient temperature for another 10 minutes. Water (5.0 mL) was added to the mixture and the organic phase was separated, washed with brine, dried over MgSO4 and then concentrated in vacuo. The obtained crude product was purified by column chromatography to yield the title compound as a white powder in 15% yield (0.055 g). 1H NMR (300 MHz, CDCl3) δ 7.97 (t, J=5.5 Hz, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.63-7.42 (m, 4H), 6.67 (d, J=9.4 Hz, 1H), 6.51 (s, 1H), 4.00-3.97 (m, 2H), 3.66 (d, J=10.7 Hz, 2H), 3.51-3.44 (m, 2H), 2.63 (m, 1H), 2.03 (s, 2H), 1.49-1.42 (m, 2H), 0.72-0.66 (m, 1H), 0.45-0.39 (m, 2H), 0.07-0.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.4, 168.9, 163.4, 158.1, 144.4, 135.4, 135.3, 132.0, 129.9, 128.5, 126.7, 112.5, 127.3, 48.9, 39.6, 34.5, 33.8, 24.5, 8.6, 4.2. MS (ES+) m/z 460 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.C(N(CC)[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])C>C1COCC1>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCN(CC)C(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 1.25 h
Yield: 65 %

Procedure:
To a stirred solution of the (4-bromobenzyloxy)-(tert.-butyl)-dimethylsilane (24.94 g, 82.8 mmol) in THF (420 mL) at −78° C. was added dropwise a 1.6 M solution of nBuLi in hexane (62 mL, 99.2 mmol) over a 1 h period. After stirring the mixture at the same temperature for 75 min, a solution of N,N-diethyltrifluoroacetamide (19.19 g, 113 nmol) in THF (60 mL) was added dropwise over 1 h. Following the addition the mixture at −78° C. for a further 75 min before the reaction was quenched with an aqueous solution of NH4Cl. Ether was added and the organic layer was extracted 3 times with ether (3×300 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuum. The resulting pale yellow liquid was distillated in vacuo to give the 1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone (65%) as a colorless liquid; b.p. 170-180° C. (10 torr), 1H NMR (CDCl3): δ 0.12 (s, (CH3)2Si), 0.96 (s, CH3)3C), 4.83 (s, CH2), 7.50 (d, J=8.2 Hz, C6H4), 8.05 (d, J=8.2 Hz, C6H4); 13C NMR (CDCl3): δ −5.4 (CH3Si), 18.3 (C(CH3)3), 25.8 (C(CH3)3), 64.2 (CH2O), 116.7 (q, J=289.7 Hz, CF3), 126.2 (C6H2), 128.6 (C6H2), 130.2 (C6H2), 150.1, (C6H2), 180.2 (q, J=34.5 Hz, CO).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:19]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[ClH:17].[Cl:28][C:26]1[N:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:11][CH:12]=3)[C:19]=2[CH:27]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Cl
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1

Procedure:
Prepared according to Procedure A from 4-phenylsulphonylaniline (Helv. Chim. Acta., 1983, 66 (4), 1046) and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.09 (1H,s), 8.80-8.88 (2H,m), 8.19 (2H,d), 7.94-8.09 (4H,m), 7.53-7.20 (3H,m); m/z (M+1)+397.