Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1.O>CN(C=O)C>[CH:31]1([CH2:30][N:16]2[CH2:15][CH2:14][CH:13]([N:12]3[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=[C:8]3[N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:18][CH2:17]2)[CH2:34][CH2:33][CH2:32]1
Reactant: CN1CCN(c2nc3ccccc3n2C2CCNCC2)CC1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nc3ccccc3n2C2CCN(CC3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.4 %

Procedure:
A mixture of 2-(4-methylpiperazinyl)-1-(4-piperidinyl)-1H-benzimidazole (300 mg, 1 mmol), K2CO3 (165.9 mg, 1.2 mmol), and (bromomethyl)cyclobutane (178.8 mg, 1.2 mmol) in DMF (4 ml) was stirred at room temperature for 17 h. Then K2CO3 (110 mg, 0.8 mmol), and (bromomethyl)cyclobutane (119 mg, 0.8 mmol) were added to the reaction mixture. After 16 h stirring, the reaction mixture was poured into water and extracted with CH2Cl2. The extracts combined were dried (MgSO4), filtered, and concentrated in vacuo to give 369 mg of oil which was purified by preparative TLC (1 mm thick plate, CH2Cl2/MeOH:10/12 developped) to afford 147.6 mg (40%) of title compound as light brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Yield: 80.7 %

Procedure:
A solution of triphenylphosphine (248 mg, 0.94 mmol) in methylene chloride (9 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (190 mg, 1.07 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (208 mg, 0.63 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminothiazole (95 mg, 0.94 mmol) and pyridine (0.092 mL, 1.13 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (210 mg, 81%) as a white foam: [α]23589 =−54.3° (c=0.081, chloroform); EI-HRMS m/e calcd for C18H21ClN2O3S2 (M+) 412.0682, found 412.0679.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet, mechanical stirring apparatus, and septum was added D-allo-threonine (24.98 g, 210 mmol) followed by anhydrous DMSO (250 mL) and potassium carbonate (63.7 g, 460 mmol). This mixture was stirred under nitrogen at room temperature for a period of 30 min. To this mixture was then added 2-chloro-4-fluoro-3-methylbenzonitrile (35.51 g, 210 mmol) followed by heating of the reaction mixture to 70° C. in an oil bath for a period of 48 hs. The reaction was then allowed to cool to room temperature followed by subsequent cooling to 0° C. and a 5% citric acid/water solution (1.5 Liters) was slowly added followed by careful addition of solid citric acid until evolution of gas was no longer observed. This solution was then extracted with EtOAc (5×1 L). The combined organic extracts were then dried over Na2SO4 and decanted away from the drying agent. The solvent was then removed under reduced pressure using rotary evaporation to reveal a red oil that was purified by silica gel chromatography by first eluting with hexanes/EtOAc, 1/1 (2 L) followed by methanol/EtOAc 1/7 (5 L) to afford of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid as a light red oil/solid (27.05 g, 48%). 1H NMR (500 MHz, CD3OD, δ in ppm) 7.42 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.32 (s, 3H), 1.35 (d, J=6.6 Hz, 3H); 13C NMR (125.6 MHz, CD3OD) δ 174.2, 151.9, 137.16, 134.0, 122.6, 119.1, 110.1, 101.2, 69.1, 63.2, 20.0, 14.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.[NH4+]=S>CCO.O>[N+:10]([C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5-dinitrobenzotrifluoride (10 g, 42 mmols, 1 eq.) in 150 mL of EtOH was added 17.6 mL (258.3 mmols, 6.15 eq.) of ammonium sulfide in water (50% by weight, Aldrich). The reaction was heated to reflux for 16 h during which time it became orange and a yellow precipitate formed. After cooling the volume was reduced to approximately 50 mL. The solid was removed by filtration and the filtrate evaporated to dryness in vacuo. The resulting orange solid was purified by column chromatography eluting with a step gradient of 20-30% EtOAc:hexane to provide the compound as a yellow/orange solid.
Reaction SMILES: C(OC([N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]3[N:28]=[CH:29][CH:30]=[C:31]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:26]3=[N:25][C:24]=2[C:38]#[C:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)=[CH:19][N:18]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].C(Cl)Cl>CCOCC>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[O:35]1[CH2:36][CH2:37][N:32]([C:31]2[C:26]3[N:27]([C:23]([C:20]4[CH:21]=[CH:22][C:17]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[N:18][CH:19]=4)=[C:24]([C:38]#[C:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:41]=4)[N:25]=3)[N:28]=[CH:29][CH:30]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CNc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 0 °C

Procedure:
Compound 38b (0.40 g, 0.57 mmol) was treated with TFA:DCM (1:4 v/v, 15 mL) dropwise with stirring at 0° C. The resulting mixture was stirred for 30 min at rt and concentrated under reduced pressure. The residue obtained was treated with 10 mL of Et2O. The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain the title compound 24 as an orange solid. 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.64 (s, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.35 (d, J=9.3 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.01-7.99 (m, 2H), 7.82 (t, J=15.3 Hz, 1H), 7.70-7.63 (m, 2H), 7.10 (d, J=9.3 Hz, 1H), 6.43 (d, J=5.7 Hz, 1H), 4.16 (s, 2H), 4.02-3.94 (m, 4H), 3.82-3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N2O3: 506.2 (M+H). Found: 506.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[I-].[Na+]>C(#N)C>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Under nitrogen, 11.0 g (66.2 mmol) of 4-(methylthio)acetophenone (prepared in Step 1 of Example 1) and 13.8 mL (99 mmol) of triethylamine in 50 mL of acetonitrile was treated with 12.6 mL (99.3 mmol) of chlorotrimethylsilane at ambient temperature and allowed to stir for 20 minutes prior to the slow addition of a suspension of 14.9 g (99.4 mmol) of sodium iodide in 60 mL of acetonitrile. The reaction was stirred for 3 hours, poured into ice/water, and extracted with hexane. The extracts were combined, dried (K2CO3), and concentrated in vacuo to give 16 g of crude 1-methylthio-4-[1[(trimethylsilyl)oxy]ethenyl]benzene as an oil: NMR (CDCl3) δ0.26 (s, 9H), 2.48 (s, 3H), 4.39 (d, J=2 Hz, 1H), 4.87 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
To a solution of 4-bromo-6-(methyloxy)-1H-indazole (200 mg, 0.88 mmol) in dichloromethane (10 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (433 mg, 1.76 mmol), pyridine (0.14 mL, 1.73 mmol), copper acetate (239 mg, 1.32 mmol) and powdered 4A molecular sieves (500 mg). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-80% dichloromethane in hexane to yield the title compound (D3) (176 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([O:16]C)=[O:15])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:18])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:18])[CH:4]=[N:3]1
Reactant: CCc1sc(C(=O)OC)cc1-c1c(C)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Yield: 100 %

Procedure:
A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (143 mg, 0.54 mmol) in 6N sodium hydroxide (0.90 ml, 5.41 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (136 mg, 0.54 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 251 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1I.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: N#Cc1nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-iodopyrazole (5.489 g) in dimethylformamide (4 ml) at room temperature was added trimethylsilylacetylene (3.35 ml), cuprous iodide (0.116 g), bis(triphenylphosphine)palladium(II) chloride (0.228 g) and triethylamine (1 ml). The mixture was heated at 60° C. for 2.5 hours. Trimethylsilylacetylene (1.675 ml), cuprous iodide (0.058 g) and bis(triphenylphosphine)palladium(II) chloride (0.114 g) were then added and stirring and heating was continued for a further period of one hour. The cooled reaction mixture was diluted with water and extracted with ether. The ether extract was dried (MgSO4) and evaporated to give the crude product which was purified by column chromatography on silica gel eluted with dichloromethane/hexane. Combination and evaporation of suitable fractions followed by recrystallisation of their residue from dichloromethane/hexane provided the title compound as a pale yellow solid, m.p. 151.5-152.1° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A mixture of N-(2-methyl-3-nitro-phenyl)-methanesulfonamide (1.5 g) and tin(II) chloride dihydrate (7.4 g) in ethanol (15 mL) and ethyl acetate (15 mL, from Burdick and Jackson, Muskegon, Mich.) was stirred at room temperature overnight. The reaction mixture was treated with saturated sodium bicarbonate solution to pH>9. The mixture was filtered and the filtrate was washed with water and brine. After drying over anhydrous sodium sulfate and evaporation of solvent, N-(3-amino-2-methyl-phenyl)-methanesulfonamide (1 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:34]([C:36]1[CH:37]=[C:38]([CH:47]=[CH:48][CH:49]=1)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[O:35].N1C=CC=CC=1>O1CCCC1.O>[N:27]1([C:24]2[CH:25]=[CH:26][C:2]([NH:1][C:34]([C:36]3[CH:37]=[C:38]([CH:47]=[CH:48][CH:49]=3)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[O:35])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:8]=[N:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=4)=[N:11][CH:12]=3)[CH:23]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (234 mg, 0.53 mmol, 1.00 equiv), tetrahydrofuran (5 mL), a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (145 mg, 0.53 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and pyridine (80 mg, 1.01 mmol, 2.00 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was diluted with 10 mL of water and then extracted with 2×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 0.28 g (78%) of product as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].C>C(O)C>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:5][CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: CCCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)pyrimidine-5-carboxylate (3.16 g., 0.01 mole), 1.0N sodium hydroxide (25 ml.), and 95% ethanol (10 ml.) was heated under reflux for 10 minutes. The hot solution was treated with charcoal and filtered. The filtrate was acidified with 1.0N hydrochloric acid (26 ml.) to precipitate the title compound (2.8 g., 97%), m.p. 163°-165°. Recrystallization from ethanol gave analytical product, m.p. 165°-166°.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1([F:32])[O:25][C:24]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:23]=2[O:22]1>>[F:32][C:21]1([F:20])[O:25][C:24]2[CH:26]=[CH:27][C:28]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][C:23]=2[O:22]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Product: FC1(F)Oc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2O1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Phenomenex Luna C18 100A, 10 m silica, 21 mm diameter, 150 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1OS(C(F)(F)F)(=O)=O.[I-:25].[Na+]>O>[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1[I:25]
Reactant: [I-]
Reactant: O=[N+]([O-])c1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dimethylformamide (4 L) and trifluoromethane sulfonic acid 2,6-dibromo-4-nitrophenyl ester (1135 g, 2.65 moles) were charged into a 22 L jacketed vessel equipped with a mechanical stirrer, a condenser, and a nitrogen purge. Sodium iodide (1595 g, 10.64 moles) was added to the reaction mixture in portions while maintaining the reaction temperature below 25° C. The reaction mixture was then heated to 100° C. and monitored for completion by HPLC. Upon completion, the reaction mixture was cooled to 0° C. Water (4 L) was added while maintaining the temperature below 14° C. The reaction mixture was stirred for 30 min, then filtered and washed with water (1.5 L). The resultant solid product was dried overnight by evaporation under air flow at room temperature to yield 1,3-dibromo-2-iodo-5-nitrobenzene (892.7 g, 82.9%). The product may optionally be purified further by recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22]O)=[CH:7]2.O=S(Cl)[Cl:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][Cl:26])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2cc1CCl

Procedure:
Prepared according to Procedure C using (8-chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)methanol (1.10 g, 3.26 mmol) and SOCl2 (1.19 mL, 16.3 mmol, 5 eq) in dichloromethane (5 mL). 8-chloro-3-(chloromethyl)-2-(2-trifluoromethylphenyl)quinoline was obtained as a yellow syrup. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1 H, s), 8.10 (1 H, d, J=8.2 Hz), 8.02 (1 H, d, J=6.3 Hz), 7.95 (1H, d, J=7.4 Hz), 7.72-7.87 (2 H, m), 7.58-7.71 (2 H, m), 4.71 (2 H, dd, J=82.2, 12.1 Hz) Mass Spectrum (ESI) m/e=356.0 and 358.0 (M+1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=1.Cl>>[OH:25][C:22]([C:17]1[C:16]([CH2:15][O:14][C:7]2[C:6]([CH:2]=[O:1])=[CH:11][C:10]([O:12][CH3:13])=[N:9][CH:8]=2)=[CH:21][CH:20]=[CH:19][N:18]=1)([CH3:23])[CH3:24]
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2C(C)(C)O)cn1
Agent: Cl
Product: COc1cc(C=O)c(OCc2cccnc2C(C)(C)O)cn1
Temperature: 40 °C
Yield: 38.8 %

Procedure:
To 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (30 mg, 0.087 mmol, 1 eq.) in a RB flask was added HCl (6 N, 3.0 mL). The mixture was warmed to 40° C., O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(2-hydroxypropan-2-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (10.2 mg, 99%) as a pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.46 (dd, J=4.7, 1.6 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H), 7.24 (dd, J=7.8, 4.7 Hz, 1H), 7.05 (s, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 1.57 (s, 6H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7](Br)[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.Cl>O.CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl>[Cl:23][C:24]1[CH:29]=[C:28]([C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C2CCCC2)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
6-Bromo-5-cyclopentyl-pyridine-2-carboxylic acid methyl ester (0.6 g, 2.1 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 90 mg, 0.11 mmol) and potassium carbonate (0.37 g, 2.68 mmol) were added to a solution of 3-chlorophenylboronic acid (CAN 63503-60-6, 0.42 g, 2.69 mmol) in water (20 mL) and DMF (2 mL). The mixture was stirred for 48 h at 100° C. Its pH was adjusted to pH=3 with diluted hydrochloric acid. The mixture was extracted with methylene chloride (3×20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (130 mg, 20%) which was used in the next step without further purification; MS (EI): m/e=302.0 [M+H]+.