Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[O:6])[CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:10]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:31]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN)cc1
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (1.27 g, 2.6 mmol) obtained in Example 1201 and hydrazine hydrate (261 mg, 5.2 mmol) in ethanol (20 ml) was boiled under reflux for 3 hr, and the precipitated insoluble material was filtered off. The filtrate was concentrated to dryness to give the title compound as a white powder (0.9 g, 97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[S:39][CH:38]=[N:37][CH:36]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=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>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[S:39][CH:38]=[N:37][CH:36]=2)=[C:3]([F:29])[CH:4]=1)[CH3:28]
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cncs2)c(F)c1
Yield: 48.5 %

Procedure:
A mixture of 5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide from step 4 of Example 19 (450 mg, 0.912 mmol), 5-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred at reflux for 5 h. After cooling, the mixture was diluted with ethyl acetate, washed with water. The organic layer was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:3/1:2) to afford 220 mg (48.5%) of the titled compound as a slight yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16](O)=[O:17]>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][OH:17]
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1.17 h

Procedure:
Lithium aluminum hydride (65 g) was suspended in dry THF (1.5 L) under a nitrogen atmosphere and this mixture was then treated with a solution of 2,4-difluorophenylacetic acid (169 g) in dry THF (1 L) over a period of 90 min at 0° C. The reaction mixture was stirred for 70 min at 0° C. and then quenched dropwise with the slow addition of 20% w/v KOH(aq) (340 mL) at 0° C. The inorganic salts were then filtered over Hi flo (200 g) and MgSO4 (200 g), washed with ethyl acetate (200 g), and the filtrate concentrated in vacuo to provide the 2,4-difluorophenethyl alcohol. This alcohol was brominated and converted to its Grignard salt in the same manner described for COMPOUNDS I and II respectively. This 0.5M solution of 2,4difluorophenethyl magnesium bromide was used in the following transformation to generate EXAMPLE 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1

Procedure:
77 mg of solid yellow 3-{4-[3-(3-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=[N:24][OH:25]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.25 g) in ethanol (3 ml) was added hydroxylamine hydrochloride (0.075 g), sodium acetate (0.1 g) and water (0.1 ml). After stirring at room temperature overnight the mixture was evaporated. The residue was taken up in ether and washed with water, then brine, then dried and evaporated. The residue was crystallised from propan-2-ol/water and further purified by column chromatography on silica gel eluted with dichloromethane then dichloromethane:methanol (99:1). After combination and evaporation of suitable fractions the residue was further purified by column chromatography on silica gel eluted with ether. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 175-178° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([O:20][CH:21](OCC)[CH2:22][C:23](Cl)=[O:24])[CH3:19]>ClCCl>[CH2:18]([O:20]/[CH:21]=[CH:22]/[C:23]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:24])[CH3:19]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(CC(=O)Cl)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
To a solution of 4-(trifluoromethyl)aniline (2.56 g, 15.9 mmol) in dichloromethane (40 ml) was added pyridine (3.77 g, 47.7 mmol). The solution was cooled to 0° C. before a solution of 3,3-diethoxypropanoyl chloride (4 g, crude) in dichloromethane (10 ml) was added dropwise with stirring. The resulting solution was stirred for 4 hours at 20° C. and then washed with water (200 ml). The resulting mixture was extracted with dichloromethane (3×80 ml) and the organic layers were combined and concentrated under vacuum. The crude residue was purified by Pre-TLC with 1-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide as a yellow solid (4.0 g). (ES, m/z): [M+H]+ 260; 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.50-7.56 (m, 1H), 5.52 (d, J=12.4 Hz, 1H), 3.90-4.01 (m, 2H), 1.15-1.30 (m, 3H).
Reaction SMILES: CN(C)C(=O)C.[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29](O)(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8].P(Cl)(Cl)([Cl:37])=O>C(#N)C>[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29]([Cl:37])(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)O)c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)Cl)c2)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
10 ml of N,N-dimethylacetoamide was added dropwise to a mixture of 13 g of N,N-diethyl-4-[4-(2-methoxyethoxy)-3-sulfophenylazo]-aniline prepared in Step (1) described above, 100 ml of acetonitrile and 13 ml of phosphorus oxychloride while the reaction mixture was maintained at a temperature of 30° C. or lower. After completion of the addition, the mixture was allowed to stand with stirring over a period of 3 hours and then, it was poured little by little into 500 ml of ice water. The crystals thus precipitated were recovered by filtration, washed with 200 ml of water and air-dried. Yield 11.0 g, Melting Point 103°-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: Cc1cccc(C)c1B(O)O
Product: Cc1cccc(C)c1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 62 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2,6-dimethylbenzeneboronic acid according to the procedure described in example 8 gave 4-(2,6-dimethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (17) (I, Ar=2,6-dimethylphenyl) in a 62% yield; mp 230–238° C. (dec). 1H NMR δ [(CD3)2SO] 11.72 (s, 1H), 10.95 (s, 1H), 9.25 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.35 (s, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H), 7.06 ((dd, J=8.7, 2.3 Hz, 1H), 1.93 (s, 6H). EIMS found M+: 356,1159, C22H16N2O3 requires 356,1161.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 813.7 %

Procedure:
Ethyl 4-hydroxybenzoate (16.6 g), geranyl bromide (23.9 g), and potassium carbonate (27.6 g) were refluxed in acetone (200 ml) with stirring for 1 hour . The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the residue dissolved in ethanol (150 ml) were added sodium hydroxide (3.90 g) and water(50 ml) and the mixture was refluxed with stirring for 1 hour. After being concentrated under a vacuum, the reaction mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethyl acetate mixed solution, thereby yielding 223 g of the aimed compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([Cl:18])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitrophenyl)propanoic acid prepared in Example DD (12.5 g, 64 mmol) was suspended in CH2Cl2 (300 mL) and treated with oxalyl chloride (7.4 mL, 85 mmol) and DMF (5 drops). The solution was stirred overnight at room temperature. The solution was concentrated, and the residue was dissolved in CH2Cl2 and re-concentrated. The crude product was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:34][CH3:35].[OH-].[Na+].CN(C)C=O>O>[CH2:34]([N:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[CH:20][CH:19]=1)[C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:26]=1)[CH3:35]
Reactant: COc1ccc(N2CCN(c3ccc(Nc4nc(-c5ccccc5)cs4)cc3)CC2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of 4.6 parts of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine, 2 parts of bromoethane, 1 part of sodium hydroxide and 94 parts of N,N-dimethylformamide was stirred for 16 hours at room temperature. Another portion of 2 parts of bromoethane and 1 part of sodium hydroxide was added and stirring was continued for 4 hours at 50° C. The reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 4.0 parts (81.7%) of N-ethyl-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-phenyl-2-thiazolamine; mp. 223.6° C. (int. 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(F)c1CBr
Temperature: 25 °C

Procedure:
To a stirred solution of 1-fluoro-2-methyl-3-nitrobenzene (1.0 g, 0.00645 mol) in carbon tetrachloride (50 mL) were added N-bromosuccinimide (1.25 g, 0.00709 mol) and benzoylperoxide (0.3 g, 0.00129 mol) at room temperature with constant stirring. Reaction mass was refluxed for 5 h. The reaction mixture was cooled to room temperature and filtered through CELITE bed and the bed was washed thoroughly with carbon tetrachloride. The filtrate was concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO) δ 7.93-7.91 (d, J=8 Hz, 1H), 7.723-7.653 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
(See FIG. 10.) To a solution of 29 (249 mg, 1.05 mmol) in CH2Cl2 (3 mL) at 0° C. was added TFA (2 mL, excess), the ice bath was removed and the resultant solution was stirred at ambient temperature for 1 h. The solvent and excess TFA were removed with a stream of nitrogen and the residue was partitioned between HCl(aq) (1.0 M, 2 mL) and EtOAc (10 mL). The aqueous fraction was collected and subsequently washed with EtOAc (2×10 mL). To the remaining aqueous fraction was added CH2Cl2 (20 mL) and water (20 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the remaining aqueous fraction was extracted with CH2Cl2 (2×15 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford the title compound 30 (97 mg, 68% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.35 (m, 2H), 7.42 (m, 1H), 7.12 (m, 1H), 2.67-2.54 (m, 4H), 1.73-1.63 (m, 4H); LRMS (ESI) m/z calcd for C8H13N2 [M+H]+ 137. found 137.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccccc2)c(OCCCCl)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 3-hydroxy-4-phenylbenzonitrile (3.0 g) in N,N-dimethylformamide (30.7 mL) was added potassium carbonate (6.37 g). Then 1-bromo-3-chloropropane (3.6 mL) was added, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was partitioned between diethyl ether (45 mL) and water (10 mL). The organic layer was washed with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1) to give the title compound (4.08 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>[Pd].O1CCCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:4]2[C:5]([NH:10][CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1NCC(O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8 g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml of tetrahydrofuran was hydrogenated in a large glass Parr bottle at room temperature. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. p-Chlorobenzoyl chloride (15.1 ml, 0.12 mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneously dropwise to the stirred filtrate at 12°-15° C. (ice-water bath) and the mixture was allowed to stir at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated and extracted with water (1×), 5% potassium hydroxide (2×), and water (2×). The methylene chloride layer was separated, dried, and evaporated to dryness. The residue was purified on a silica gel column (400 g) by eluting with 50% ethyl acetete/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-g sample was recrystallized from ethyl acetate/hexanes to give 2.71 g of solid, mp. 157°-159° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[CH2:17]([O:24][CH:25]([CH3:28])[CH2:26][O:27][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CC(CO)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(COc1cccc(C=O)c1Br)OCc1ccccc1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N2. The reaction mixture was cooled to rt and diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[F:13][C:14]([F:29])([S:25](F)(=[O:27])=[O:26])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].[OH-].[K+]>>[F:29][C:14]([F:13])([S:25]([O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])(=[O:27])=[O:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
2,2,3,3,4,4,4-heptafluorobutan-1-ol (200 g, 1.0 mol, obtained from 3M Company) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (300 g, 1.0 mol, obtained from 3M Company) were combined in a 1-liter, 3-necked round bottom flask. The flask was equipped with an overhead mechanical stirrer, cold water condenser, thermocouple and an addition funnel. Aqueous potassium hydroxide (45 percent by weight in water, 154 g, 1.05 mol) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase and washed once with water to give 350 g crude product. The product was distilled at atmospheric pressure and the distillation cut boiling from 140-150° C. used without further purification (96.3 percent purity by GC).
Reaction SMILES: [NH2:1][CH:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])=[CH:3]1.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>>[N:1]1[CH:23]=[CH:24][N:7]2[C:2]=1[CH:3]=[C:4]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:13][CH3:14])=[O:12])[CH:5]=[N:6]2
Reactant: CNC(=O)c1cccc(C2=CC(N)NN=C2)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC(=O)c1cccc(-c2cnn3ccnc3c2)c1

Procedure:
3-(6-Amino-1,6-dihydro-pyridazin-4-yl)-N-methyl-benzamide (1 eq, 1.07 mmol, 245 mg) is added to a solution of chloroacetic aldehyde (5 eq, 5.4 mmol, 0.69 ml) in EtOH (15 ml). NaHCO3 (2 eq, 2.15 mmol, 180 mg) is then added and the reaction mixture is heated at reflux for 17 h. The solvent is then removed in vacuo and the product is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford 3-imidazo-[1,2-b]-pyridazin-7-yl-N-methyl-benzamide as an orange solid; [M+H]+=253