Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O.CCOC(C)=O>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:23](=[O:26])(=[O:25])[N:24]=1
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpiperidin-2-yl)methoxy)benzonitrile (Example 16a, 1.0 g, 3.32 mmol) in DMA (15.0 mL) was added sulfamoyl chloride (2.68 g, 23.21 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 2 hrs and the solution was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%). The intermediate was dissolved in EtOH (25.0 mL) and aq.NaOH (2.0N, 5.0 mL) was added at room temperature. The reaction mixture was then refluxed overnight then cooled to 0° C. and neutralized carefully with 1 N HCl. The precipitate was collected by filtration and was recrystallized with 20% water/EtOH to provide the title compound as a white solid (730 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6, room temperature) δ0.86 (t, J=7.6 Hz, 3H), 1.35-1.76 (m, 8H), 2.28-2.32 (m, 2H), 3.14 (t, J=13.6 Hz, 1H), 3.74 (d, J=14 Hz, 1H), 4.07-4.11 (m, 1H), 4.25-4.38 (m, isomer), 4.50 (t, J=10 Hz, 1H), 5.16 (t, J=4.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.68 (s, isomer), 7.77 (s, 1H), 8.23 (s, 1H), 8.36 (s, isomer), 10.89 (s, 1H). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ0.88 (t, J=7.6 Hz, 3H), 1.35-1.40 (m, 1H), 1.49-1.67 (m, 7H), 1.77 (d, J=11.6 Hz, 1H), 2.27-2.32 (m, 2H), 3.85-3.90 (m, 1H), 4.18-4.20 (m, 1H), 4.07-4.11 (m, 1H), 4.46 (t, J=10 Hz, 1H), 5.00-5.03 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.81 (s, 2H), 10.64 (s, 1H). MS 381 (MH+).
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O>[CH2:37]([NH:47][S:25]([C:2]([F:29])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:11])([F:12])[F:10])(=[O:27])=[O:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 15.73 g (100.0 mmol) of decylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][CH:33]([CH3:36])[CH2:34][OH:35].[H-].[Na+].Cl>CN(C=O)C.O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:35][CH2:34][CH:33]([CH3:36])[CH3:32])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: CC(C)CO
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCC(C)C)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
A mixture of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.11 mmol), 2-methyl-1-propanol (20 μl, 0.22 mmol) and 60% NaH (13 mg, 0.33 mmol) in DMF was stirred at ambient temperature for 4 hrs. The reaction mixture was diluted with water and then acidified with 2N HCl solution. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/2) to give the title compound (12 mg, 40%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCCC2C(=O)O)cc1

Procedure:
Proline is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 1-[(4-methoxyphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>C(#N)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[N:15]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Yield: 88.1 %

Procedure:
1-N-Boc-1,2-cis-cyclohexyldiamine 5 (CAS 184954-75-4) (1.65 g, 7.7 mmol) was dissolved in 100 mL acetonitrile. Potassium carbonate (5.3 g, 39 mmol) and 1,4-dibromobutane (2.8 g, 13 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-(2-pyrrolidin-1-yl-cyclohexyl)-carbamic acid tert-butyl ester as a yellow liquid (1.82 g, 88%), MS: m/e=269.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6]2.[I:15]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(C(F)(F)F)=O>[I:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]#[N:14])=[CH:9]2
Reactant: COc1ccc2cc(C#N)ccc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2cc(C#N)ccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-methoxynaphthalene-2-carbonitrile (1.0 g, 5.5 mmol), N-iodosuccinimide (1.4 g, 6.0 mmol) in ACN (10 ml) and TFA (125 μl) is stirred at RT for 4 h. A saturated aqueous solution of sodium hydrogencarbonate is added and the mixture extracted with DCM. The combined organic layers are extracted with an aqueous solution of sodium thiosulfate, dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 1.68 g (99%). HPLC-MS: tR=1.32 min (METHOD—1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[N:10][C:11]=1Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[K].O.Cl>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:11]2[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:7]([Cl:14])[N:8]=[C:9]([Cl:13])[N:10]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
5-(2-Methoxyphenoxy)-2,4,6-trichloropyrimidine (4) (4.8 g; 15.6 mmol) was dissolved in dimethyl sulfoxide (45 ml). Potassium 4-t-butylbenzenesulfonamide (8.0 g; 32 mmol) was added to the mixture while being cooled on ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from ether, to thereby obtain 4.9 g (yield: 65%) of the title compound as colorless needles.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26]>C[O-].[Na+]>[CH3:24][C:25]([NH:28][CH2:29][CH2:30][NH:31][C:19](=[O:20])[CH2:18][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)([CH3:27])[CH3:26]
Reactant: CC(C)(C)NCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)NCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Yield: 66.8 %

Procedure:
A solution of 10.7 g (0.035 mol) of ethyl 4,5-diphenylpyrazole-1-acetate of example 1 in 10.9 g (0.094 mol) of 2-[(1,1-dimethylethyl)amino]ethanamine was heated with about 50 mg of sodium methoxide at about 150° C. for two hours. The excess amine was stripped off under vacuum and the residue was triturated in acetonitrile. The solid product was filtered off and recrystallized from isopropyl acetate to yield 8.8 g of white crystals, mp 115°-116° C.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N+:23]([O-])=CC=[CH:20]2.Cl>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:20]2
Reactant: COC(=O)CC(C)=O
Reactant: [O-][n+]1cccc2cc(Cl)ccc21
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1ccc2cc(Cl)ccc2n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-oxobutyrate was added to an acetic anhydride solution of 6-chloroquinoline 1-oxide, followed by 30 minutes of stirring at an oil bath temperature of 40° C. Thus obtained compound was added to 10% hydrochloric acid and the mixture was reacted at room temperature to obtain methyl (6-chloroquinolin-2-yl)acetate. The compound was further treated in a similar manner to Reference Example 11, Example 22 and Example 4, successively, to obtain an objective compound.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([O:17]CC)=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+].[CH2:26]1COC[CH2:27]1>>[CH2:26]([C:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH3:27]
Reactant: CCOC(=O)C12CC=CCC1COc1ccccc12
Reactant: C1CCOC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Product: CCc1cccc2c1C1(C(=O)O)CC=CCC1CO2

Procedure:
A solution of the compound from Example 16 (4.4 g, 17 mmol) and potassium trimethylsilanolate (4.36 g, 34 mmol) in 50 ml THF was refluxed for 2 hours. The precipitate was collected by filtration, dissolved in water and acidified with 1N HCl. After further workup, the title compound was obtained as a white solid (3.9 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[C:9]([NH:12]C(=O)C)[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].C(Cl)(=O)C>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methylpyridine-2-carboxylic acid methyl ester (369 mg, 1.0 mmol) was dissolved in methanol (10 mL) and acetyl chloride (1.07 mL, 15 mmol) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate; and the organic phase was dried and concentrated. Purification by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient) followed by a second purification by flash chromatography (hexane/ethyl acetate gradient) yielded the title compound (292 mg, 88% yield) as a white solid, mp 122-125° C. 1H NMR (CDCl3) δ 7.65 (m, 1H), 7.26 (s, 1H), 7.1 (m, 1H), 4.35 (br s, 2H), 3.99 (s, 3H), 3.98 (d, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])/[CH2:7][CH2:6]2
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)/C=C1\CCc2cc(OC)ccc21
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 5-methoxy-1-indanone (2.50 g, 15.4 mmol) and methyl bromoacetate (1.84 mL, 20.0 mmol) in THF (15 mL) was added dropwise to a mixture of activated zinc dust (1.51 g, 23.1 mmol) in THF (10 mL). During the addition the reaction mixture reached reflux temperature, which was maintained for an additional hour after the addition was completed. After cooling to ambient temperature, the reaction mixture was poured into ice-cold 2.0 N HCl and extracted into EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 afforded 2.45 g of the title compound: 1H NMR (CDCl3) δ 3.04-3.07 (m, 2H), 3.30-3.33 (m, 2H), 3.77 (s, 3H), 3.85 (s, 3H), 6.19 (t, 1H, J=2.5 Hz), 6.83 (dd, 1H, J=2.3, 8.7 Hz), 6.85 (s, 1H), 7.52 (d 1H J=8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[F:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:25]=[CH:26][C:27]=1[CH2:28]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:42])(=[O:43])[NH:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[CH:23][C:22]=2[F:21])[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 93 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 75, Step A) with [3-fluoro-2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step B) was carried out according to the procedure of Example 13, Step A, to give a 93% yield of the title compound as a brownish, stiff foam, mp 137°-139° C., homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 666, 668 (M+Li)+.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][NH:21][N:20]=1.O>CS(C)=O>[I:8][C:7]1[C:2]([N:21]2[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([C:18]([F:17])([F:29])[F:30])=[N:20]2)=[N:3][C:4]([S:13][CH:14]([CH3:16])[CH3:15])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)Sc1nc(Cl)c(I)c(C(F)(F)F)n1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2nc(SC(C)C)nc(C(F)(F)F)c2I)nc1C(F)(F)F
Temperature: 80 °C
Yield: 70.4 %

Procedure:
4-Chloro-5-iodo-2-isopropylthio-6-trifluoromethylpyrimidine (0.30 g) was dissolved in dimethylsulfoxide (3.0 ml) and ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.16 g) and 1,8-diazabicyclo-[5,4,0]-under-7-ene (0.12 g) was added at room temperature with stirring. The mixture was heated to 80° C. and stirred for 2 hr. After cooling to room temperature, the mixture was added water and extracted with benzene. The benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1-(5-iodo-2-isopropylthio-6-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.30 g) as colorless crystalline solid, mp 107-108° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14]Br>CC(C)=O.O>[CH3:11][O:12][CH2:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
3-Nitrophenol (25 g, 0.18 mol), 2-bromoethyl methyl ether (17 ml, 25 g, 0.18 mol) potassium carbonate (25.0 g, 0.18 mol) in acetone (150 ml) were heated under reflux for 72 h. The suspension was dissolved in water and extracted with ether. The extracts were washed with 2N sodium carbonate, water and saturated brine, dried (K2CO3), and concentrated, to give the title compound (Intermediate 50) as a brown oil (35.12 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](Cl)=[O:21].C(OCC)C>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:20](=[O:21])[CH:19]=[CH:18][C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[C:15]([F:27])([F:28])[F:14])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Reactant: O=C(Cl)C=Cc1ccccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(N)c2cc(NC(=O)C=Cc3ccccc3C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
4,6-Diamino-2-methyl-quinoline (0.5 g, 2.9 mmol) was placed in an oven-dried 100-mL three-necked flask under nitrogen followed by 3 mL of glacial acetic acid. A solution of 2-(trifluoro-methyl)cinnamoyl chloride (0.68 g, 2.89 mmol) in 1 mL of glacial acetic acid was added dropwise over a 2 min period to this mixture. A heavy precipitate resulted. The mixture was stirred at room temperature for 1 hr, diethyl ether (25 mL) added, and the hydrochloride salt filtered, washed with ether, and dried at room temperature in vacuo. The hydrochloride salt was dissolved in a warm mixture of 50% aqueous methanol and the solution filtered. The solution was made basic with sodium bicarbonate solution and the resulting solid filtered, washed with water, and dried at 50° C. under high vacuum. Recrystallization from hot methanol gave 0.68 g (63%) of the desired product; m.p. 272-273°.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:26][O:27]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCCC1>[CH3:1][O:2][CH:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][CH:11]=1)[CH2:26][OH:27]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OC)cc1
Yield: 53.2 %

Procedure:
A mixture of about 527 mg of 1-[2-methoxy-3-(triphenylmethoxy)propoxy]-4-tetradecylbenzene, about 10 mg of p-toluenesulfonic acid and about 5 ml of methanol:tetrahydrofuran (about 1:1) was stirred under argon for about 16 hours and the solvents removed under reduced pressure. The residue was dissolved in ether:hexane (about 1:1), washed with aqueous sodium bicarbonate, brine, dried and evaporated, giving about 171 mg of the desired title compound, mp 43°-45° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:12][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[CH3:13])[C:5]2[N:6]([C:2]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2c(-c3cnccc3C)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
A microwave vial was charged with a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (210 mg, 0.674 mmol), 4-methylpyridin-3-ylboronic acid (184 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol), dioxane (6 mL), and K3PO4 (1 mL, 2.023 mmol) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep. HPLC to give 56 mg (24%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.06 (1H, s), 8.93 (1H, s), 8.81 (2H, dd, J=15.23, 5.92 Hz), 8.17 (1H, s), 7.96-8.13 (2H, m), 7.68 (1H, s), 2.65 (3H, s), 2.58 (3H, s); LC/MS: Rt=0.88 min. LC/MS (Condition A): 336.14/338.15.