Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=34)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:46]([C:49]1[CH:54]=[CH:53]C(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCC3COC4)N=2)=CC=1)=[C:47]=[O:48]>ClCCl.C(N(CC)CC)C>[CH:49]1([NH:46][C:47]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]4=[C:9]([N:8]4[CH:5]5[CH2:6][CH2:7][CH:1]4[CH2:2][O:3][CH2:4]5)[N:14]=3)=[CH:16][CH:17]=2)=[O:48])[CH2:54][CH2:53]1
Reactant: O=C=Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: NC1CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3C4CCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1)NC1CC1
Reaction time: 8 h
Yield: 41 %

Procedure:
A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (30 mg, 0.074 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.05 mL), followed by a solution of triphosgene (11 mg, 0.037 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (17 mg, 0.30 mmol)—was added to the 8-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Gemini 21 mm×100 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 60% or 75% acetonitrile over 30 minutes to provide 1-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (15 mg, 41%). MS (ES+): 488.2 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:13][CH2:14][C:15](Cl)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25]>O1CCCC1.O>[CH:8]1([CH2:13][CH2:14][C:15]([NH:18][C:19]2[NH:20][CH:21]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)[C:23]=2[C:24]([NH2:26])=[O:25])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC(=O)CCC1CCCC1
Reaction time: 16 h
Yield: 96.5 %

Procedure:
0.171 cm3 (1.22 mmol) of triethylamine and 0.098 mg (0.61 mmol) of 3-cyclopentylpropionyl chloride are added, at a temperature close to 25° C., to a solution of 0.15 g (0.61 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 25 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 40 cm3 of water and then extracted with three times 40 cm3 of ethyl acetate. The organic phase is washed with 80 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.218 g of 2-(3-cyclopentyl-propionylamino)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.11 (m, 2H); from 1.42 to 1.65 (m, 6H); from 1.69 to 1.86 (m, 3H); 2.39 (t, J=8.0 Hz, 2H); from 6.17 to 8.50 (very broad m, 2H); 6.79 (d, J=2.5 Hz, 1H); 7.63 (d, J=9.0 Hz, 2H); 8.18 (d, J=9.0 Hz, 2H); 10.35 (broad s, 1H); 11.6 (broad s, 1H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[CH:35][CH:34]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.50) (0.15 g, 0.36 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.103 g, 0.47 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.144 g, 84%). MS (ISP) 476.0 [(M+H)+]; mp 223° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:8].[Al+3].[Cl-].[Cl-].[CH2:12]([SiH:15]([Cl:17])[Cl:16])[CH:13]=[CH2:14].[Cl-].[Na+]>>[CH3:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:13]([CH3:14])[CH2:12][Si:15]([Cl:8])([Cl:17])[Cl:16]
Reactant: C=CC[SiH](Cl)Cl
Reactant: [Cl-]
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Na+]
Product: Cc1ccccc1C(C)C[Si](Cl)(Cl)Cl
Temperature: 50 °C
Yield: 73 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 14.6 g (159 mmol) of toluene and 0.18 g (1.6 mmol) of aluminum chloride were placed and reacted with 5.0 g (32 mmol) of allyldichlorosilane under the dry nitrogen atmosphere for 20 min. After stirring the solution for another an hour, 2.0 g (30 mmol) of sodium chloride was added to reaction mixture, warmed up to 50° C. and stirred for two hours to deactivate the catalyst. Vacuum distillation of the reaction products gave 6.3 g (bp 73°-76° C./0.5 mmHg) of of 3-(methylphenyl)-1,1,1-trichloro-1-silabutane in 73% yield.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOc1ccc(OCC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOc1ccc(OCC(=O)n2n[n+]([O-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.53 g) and 2-(4-octyloxyphenoxy)acetic acid (1 g) in dichlormethane (30 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.886 g), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[2-(4-octyloxyphenoxy)actyl]benzotriazole 3-oxide (892 mg). To a solution of The Starting Compound (1.79 g) and 1-[2-(4-octyloxyphenoxy)acetyl]benzotriazole 3-oxide (892 mg) in N,N-dimethylformamide (18 ml) was added 4-(N,N-dimethylamino)pyridine (0.297 g), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The powder was added to water, and subjected to ion-exchange column chromatography on DOWEX-50WX4, and eluted with water. The fractions containing the object compound were combined, and subjected to column chromatograph on ODS (YMS-gel.ODS-AM.S-50), and eluted with 50% methanol aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove methanol. The residue was lyophilized to give The Object Compound (24) (1.75 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C.CCOCC.O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]1[C:3]([CH2:2][C:19]#[N:20])=[CH:4][C:5]([C:15]([F:18])([F:17])[F:16])=[N:6]1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Into a 250 mL flask was weighed 11.3 g of 5-(bromomethyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole (33 mmol) which was then dissolved in 40 mL of dry DMF. The resulting solution was treated with 2.5 g of sodium cyanide (52 mmol). The resulting suspension was heated to 50° C. After 4 hours at 50° C., heating was discontinued and the reaction was allowed to cool to room temperature. After standing at room temperature for 2 days the reaction was diluted with ether and H2O. The layers were separated and the aqueous layer was extracted with ether (4×). The combined organic layers were washed with H2O (3×), then brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to afford crude 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetonitrile as a red oil, yield 8.2 g (86%), 1H NMR (400 MHz, CDCl3): δ 7.62-7.46 (m, 4H), 6.82 (s, 1H), 3.9-3.4 (broad hump, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=1>O1CCOCC1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:19]1[CH:20]=[N:21][CH:22]=[C:17]([O:16][CH3:15])[N:18]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Solvent: C1COCCO1
Product: COc1cncc(-c2nc3c(Cl)cccc3cc2C=O)n1
Temperature: 110 °C
Yield: 63.4 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (0.5 g, 2.21 mmol), 2-methoxy-6-(tributylstannanyl)pyrazine (1.0 g, 2.51 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.2 g, 0.173 mmol) in 1,4-dioxane (10 mL) was degassed and heated at 110° C. overnight. The mixture was allowed to cool to room temperature and diluted with EtOAc. The resulting solid was collected by filtration, washed with EtOAc, then ether, and dried to give the title compound (0.42 g, 63%) as a yellow solid. δH(DMSO-d6) 10.58 (s, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.27 (dd, J 8.3, 1.2 Hz, 1H), 8.17 (dd, J 7.5, 1.2 Hz, 1H), 7.75 (m, 1H), 3.96 (s, 3H). LCMS (ES+) 300 (M+H)+, RT 1.51 minutes.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:13][C:3]1[C:2]([S:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)c1cccc(Br)c1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(SCc2ccc(OC)cc2)c1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound 2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound 3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: S(NN=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C@H:22]([CH2:23][C@H:24]([OH:36])[C@@H:25]([O:32][CH:33]([CH3:35])[CH3:34])[CH2:26]1)[CH2:21][CH2:20]3)(C1C=CC(C)=CC=1)(=O)=O.[BH3-]C#N.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O>O.CN(C=O)C>[CH:33]([O:32][C@H:25]1[CH2:26][C@@:27]2([CH3:28])[C@@H:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:29]2[CH2:30][CH2:31][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH2:18][CH2:13]2)[CH2:23][C@@H:24]1[OH:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OC(C)C)C[C@]5(C)[C@H]4CC[C@]23C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]32)C[C@@H]1O
Temperature: 110 °C
Yield: 19.1 %

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone (300 mg), NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added DMF and sulfolane (1:1, 3 mL) and the mixture obtained was heated to 110° C. for 3 h. Then additional amount of NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added and it was heated for another hour. Water was then added and the mixture was extracted with EtOAc (2×45 mL). The combined extracts were dried over Na2SO4 and the crude product obtained by removal of the solvent was purified by flash chromatography over silica gel to yield the pure 2β-isopropoxy-3α-hydroxy-5α-androstane (37 mg); TLC Rf (EtOAc:hexane 1:9)=0.17.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:12][CH:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: COC(=O)C(S)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Sc1c(Cl)cccc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2,3-dichloronitrobenzene (3.84 g), methyl 2-mercapto-3-methybutyrate (2.96 g), potassium carbonate (2.37 g), and N,N-dimethylformamide (40 ml) was stirred at room temperature for 5 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was evaporated off, to give quantitatively methyl 2-(2-chloro-6-nitrophenylthio)-3-methylbutyrate as an oil.
Reaction SMILES: [S:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[NH2:45])[CH:22]=1>ClCCl.N>[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:36])[F:37])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[N:45]=[S:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=1
Reactant: O=S1CCCC1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nn(-c2ncccn2)c(N=S2CCCC2)c1-c1cc(Cl)c2c(c1)OCO2
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 equivalents of tetrahydro-thiophene 1-oxide (0.23 g, 2.2 mmo) in dichloromethane at −60° C. under argon was added dropwise trifluoroacetic anhydride (0.46 g, 2.2 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.383 g, 1.00 mmol) was added and the solution stirred at −60° C. for 1 h. The reaction was diluted with aqueous ammonia; the organic layer separated and further washed with water and then dried and concentrated.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCOCC>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C@H:27]2[CH2:28][CH2:29][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)c1ccc(I)cc1
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 4-iodobenzoyl chloride (10 g, 37 mmol) in ether (400 mL) at 0° C. was added triethylamine (4.7 g, 45 mmol). (3-S)-1-Benzyl-3-aminopyrrolidine (7.3 g, 41 mmol) in ether (100 mL) was then added slowly via dropping funnel at 0° C. After the addition was complete, the mixture was further stirred for 18 hrs. Water (200 mL) was added and the mixture extracted with methylene chloride (3×200 mL) dried and concentrated to give the title compound (9.7 g, 64%) as beige powder. 1H NMR (CDCl3) δ: 7.79 (m, 2H), 7.47 (m, 2H), 7.26-7.35 (m, 5H), 6.51 (d, 1H, J=8.8 Hz), 4.62-4.68 (m, 1H), 3.63 (s, 2H), 2.91-2.96 (m, 1H), 2.70-2.74 (m, 1H), 2.58-2.63 (m, 1H), 2.25-2.44 (m, 2H), 1.68-1.77 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([N:28]([CH:29]2[CH2:30][CH2:31]2)[S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)(=[O:11])=[O:10])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC2CC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 37 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
3-Trifluoromethylphenylsulfonyl chloride (4) (12 g, 49 mmol, Aldrich) was added to a mixture of the crude compound 3, triethylamine (TEA, 10 mL) and dichloromethane (DCM, 10 mL) at room temperature. The resulting mixture was heated and stirred at 37° C. for 2 days. The reaction mixture was cooled to room temperature, washed with water (10 mL) and then with brine, and concentrated and purified by column (silica gel) eluting with EtOAc/hexanes (3/7) to afford 3-[N-cyclopropyl-N-(3-trifluoromethylbenzenesulfonyl)amino]piperidine-1-carboxylic acid tert-butyl ester (5) as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the desired title compound 6 as an oil (6.5 g, 81%). 1H NMR (400 MHz, CD3OD): δ 8.22 (d, j=7.9 Hz, 1H), 8.17 (s, 1H), 8.06 (d, j=7.8 Hz, 1H), 7.90 (d, 1H, j=7.8 Hz, 1H), 4.17-4.24 (m, 1H), 3.34-3.38 (m, 2H), 3.22-3.29 (m, 1H), 2.87-2.95 (m, 1H), 1.98-2.18 (m, 3H), 1.68-1.82 (m, 2H), 1.04-1.09 (m, 1H), 0.79-0.92 (m, 3H); LC: 100%; MS: m/z=349 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FCBr
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)=NOCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
Potassium carbonate (110.6 g, 0.8 ml) was added to ethyl 2-hydroxyimino-cyanoacetate (56.8 g, 0.4 mol) in dimethylsulfoxide (200 ml) under ice-cooling, and the mixture was stirred for 10 mins, and then Fluoromethyl bromide (48.8 g, 0.4 mol) in N,N-dimethylformamide (40 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred at an internal temperature of 20° to 30° C. for 2.5 hrs. The reaction solution was dispersed in ice water (1 L), and it was extracted with ethyl acetate (800 ml, 500 ml, and 500 ml). The combined extracts were washed twice with saturated brine (300 ml) and dried over sodium sulfate, and then concentrated to give a concentrate (66.4 g) which was purified by column chromatography using silica gel (60 g) to give ethyl 2-fluoromethoxyimino-cyanoacetate (46.6 g, yield: 66.9%) as an oily substance.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[NH:20][C:19](=[O:26])[CH2:18][CH2:17]3)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36]>CN(C)C=O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[CH2:28][N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:4]([F:3])[CH:5]=3)=[C:23]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:26]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Yield: 52 %

Procedure:
To a suspension of 95% sodium hydride in anhydrous N,N-dimethylformamide (2 mL) at room temperature in a dry flask equipped with an inlet of dry nitrogen was added a solution of 6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one, prepared a shown above (53 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) with stirring. The reaction mixture was stirred for 30 minutes, followed by addition of 1-(bromomethyl)-2,4-difluorobenzene (207 mg, 1.0 mmol), and the reaction mixture stirred overnight. The reaction was followed by LCMS and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase was successively washed with 2N sodium carbonate (20 mL), 30% aqueous ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (25 mg, 0.05 mmol, 52%). LCMS mz 466.0 (M+H), 487.9 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; CDCl3) δ7.58 (t, J=7.8 Hz, 1H); 7.34 (m, 2H); 7.21 (m, 1H); 7.10 (s, 1H); 6.80-6.89 (m, 2H); 6.57 (s, 1H); 5.24 (s, 2H); 3.70 (s, 3H); 2.94 (m, 2H); 2.81 (m, 2H).