Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[F:24])[NH:7][CH:6]=1)=O.[NH2:25][C:26]([NH2:28])=[S:27].C1COCC1.[Cl-].[NH4+]>C(O)(=O)C.CCOC(C)=O.[Zn].CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:7][CH:6]=[C:5]([C:3]4[N:25]=[C:26]([NH2:28])[S:27][CH:2]=4)[C:13]=23)=[C:16]([F:24])[CH:17]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3[nH]cc(-c4csc(N)n4)c23)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (392 mg, 1.0 mmol) in acetic acid (10 mL) was added thiourea (228 mg, 3.0 mmol, Aldrich). The reaction mixture was stirred at room temperature for 3 h, and then diluted with 50 mL of EtOAc. The reaction mixture was washed with saturated aq. NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to give a light yellow solid. The solid was dissolved in a mixed solvent (20 mL of THF and 40 mL of MeOH). Ammonium chloride (267 mg, 5.0 mmol, EMD) and Zn dust (327 mg, 5.0 mmol, Aldrich) were added then added to the resulting solution. The reaction mixture was stirred at room temperature overnight, diluted with 100 mL of EtOAc and filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC. The desired fractions were combined, neutralized with saturated aq. NaHCO3 solution, and concentrated under reduced pressure. The solid that formed was collected by filtration (194 mg, 57% over two steps). MS(ESI+) m/z 342.2 (M+H)+.
Reaction SMILES: [I-].[K+].[CH2:3]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([CH3:7])([CH3:6])[CH3:5].[Br:18]Br>O>[Br:18][C:14]1[CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:9]=1[O:8][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: BrBr
Reactant: CC(C)(C)COc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1Br
Reaction time: 5 h
Yield: 84.2 %

Procedure:
Subsequently, a catalytic amount of potassium iodide was added to 4-neopentyloxynitrobenzene (69 g), and bromine (66 g) was added dropwise at 60° C. The mixture was stirred for 5 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with aqueous sodium sulfite solution, dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give 3-bromo-4-neopentyloxynitrobenzene (80 g), melting point: 86–88° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([N:7]([C:30]2[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=2)[C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(Nc3ccccc3-c3ccccc3)cc2)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccccc2-c2ccccc2)cc1
Yield: 87 %

Procedure:
Toluene (500 mL) was bubbled with nitrogen for 15 min, followed by addition of triphenylphosphine (0.4 g, 1.7 mmol) and Pd(OAc)2 (0.10 g, 0.42 mmol). The mixture was bubbled with nitrogen for 15 min, then N-([1,1′-biphenyl]-4-yl)-[1,1′-biphenyl]-2-amine (6.7 g, 21.0 mmol), 1,4-dibromobenzene (14.9 g, 63.0 mmol), sodium tert-butoxide (4.0 g, 42.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 12 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene (containing 0.5% triethylamine). The solvent was removed in vacuo and the residue was purified by flash chromatography using 10-20% toluene/hexane (containing 0.5% triethylamine) to afford N-([1,1′-biphenyl]-4-yl)-N-(4-bromophenyl)-[1,1′-biphenyl]-2-amine (8.7 g, 87% yield) as a white solid.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[C:43]([CH3:53])=[N:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:54])[S:31][C:32]=1[C:33](O)=[O:34].[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[C:43]([CH3:53])=[N:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:54])[S:31][C:32]=1[C:33]([NH:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)=[O:34]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 50 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(3-((3-methyl-5-phenylisoxazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 50% yield: mp 109-111° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53-8.51 (m, 1H), 7.74-7.70 (m, 1H), 7.58-7.54 (m, 2H), 7.47-7.42 (m, 3H), 7.32-7.28 (m, 1H), 6.13 (br s, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.45 (s, 2H), 3.91-3.85 (m, 2H), 3.19-3.14 (m, 2H), 2.58 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 489.3 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:31])[C:10]([CH3:30])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])=[CH:15][CH:14]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CO>Cl>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH2:22])=[O:20])=[CH:15][CH:14]=3)[C:10]([CH3:30])=[C:9]([F:31])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1

Procedure:
A solution of tert-butyl 2-({5′-[(cyclopropylamino)carbonyl]-3′-fluoro-2′-methyl-1,1′-biphenyl-4-yl}carbonyl)hydrazinecarboxylate (Intermediate 30) (400 mg) in hydrogen chloride (4.0M solution in dioxane, 5 ml) was stirred at room temperature under nitrogen for 16 hours. Methanol was added to form a solution and the solvents evaporated under vacuum. The residue was partially dissolved in water, basified with sodium hydroxide solution (2N, 10 ml) and extracted with ethyl acetate (120 ml). The organic phase was dried and the solvent removed under vacuum to give the N-cyclopropyl-5-fluoro-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:33][C:31]=2[NH2:32])[CH2:26][CH2:25]1.Cl.O1CCOCC1>CO>[N:27]1([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:33][C:31]=2[NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:3]=2[CH3:23])[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)quinoline (129 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, s), 8.04 (1H, d, J=8.6 Hz), 7.58-7.72 (2H, m), 7.46-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.30-7.40 (2H, m), 7.17-7.24 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.6, 2.7 Hz), 6.04 (1H, d, J=0.8 Hz), 3.92 (4H, t, J=4.7 Hz), 3.69-3.80 (4H, m), 3.06 (4H, br. s.), 2.82-3.00 (4H, m), 2.24 (3H, s). Mass Spectrum (ESI) m/e=567.3 (M+1).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1[CH:28]=O.C(Cl)Cl.CO>C1COCC1>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1/[CH:28]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1/C=C/c1ccc(-c2cn3cc(C)ccc3n2)cc1
Yield: 74 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 33 mg, 0.838 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (250 mg, 0.698 mmol) and 2-methoxy-4-nitrobenzaldehyde (126 mg, 0.698 mmol) in dry THF (15 ml) to give the title compound (199 mg, 74%) as an orange solid after work-up and flash chromatography (25:1 DCM/MeOH).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]=[O:18])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:37]([CH2:39]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:38]>CO>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][C:17]4[O:18][CH:39]=[N:37][CH:38]=4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CC=O)c1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2Cc2cnco2)c1F
Yield: 50.9 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3-(2-oxo-ethyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (0.020 g, 0.046 mmol) is dissolved in methanol (2 mL). Potassium carbonate (0.013 g, 0.093 mmol) and 1-isocyanomethanesulfonyl-4-methyl-benzene (0.010 g, 0.051 mmol) are added. The reaction mixture is stirred at reflux for 16 hours under N2, then concentrated under reduced pressure. The residue is dissolved in ethyl acetate and poured into a reparatory funnel and washed with water and brine. The combined aqueous layers are reextracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (eluting with 15:1 methylene chloride:methanol) to yield 0.011 g (50%) of the desired product. MS APCI (+) m/z 470, 472 (M+, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 6.92 (dd, 1H), 6.31 (d, 1H), 6.11 (br s, 1H), 5.45 (s, 2H), 3.62 (d, 2H), 2.40 (s, 3H), 0.87 (m, 1H), 0.49 (m, 2H), 0.20 (m, 2H). 19F NMR (376 MHz, CDCl3) −134.54 (s).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-]>O1CCOCC1.O>[C:3]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[O:9][C:10]1[N:11]=[C:12]([NH:2][CH3:1])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
Methylamine (280 μL, 0.56 mmol) was added into a solution of 136b (157 mg, 0.51 mmol) in 1,4-dioxane at 0° C. (1 mL) over 1 h and the resulting reaction mixture was stirred at rt. After 72 h, 40% of the starting chloride remained by HPLC. Another 1.1 eq of methylamine was added at −10° C. over 30 min. The reaction was allowed to warm to rt, stir for 30 min and was then diluted with water (1 mL) and extracted with ethyl acetate (3×1 mL). The combined organic layer was washed with brine (1 mL), dried over sodium sulfate, and concentrated to give a yellow oil. The oil was purified by SiO2 chromatography (12 g) using a gradient of ethyl acetate in hexanes to afford 136c (94 mg, 61% yield) as a yellow oil; HPLC purity 100%, 3.76 min (Method A); [M+H]+=302.24.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:3]=1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Cl)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1c(Cl)nn2CCN1CCCC1
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-4-nitro-1H-indazole (0.550 g, 2.79 mmol) was treated with potassium carbonate (1.20 g 8.70 mmol) in DMF (10 mL) for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (0.710 g, 4.20 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.46 (m, 4H), 2.90 (t, 2H, J=6.44), 4.61 (t, 2H, J=6.44), 7.66 (m, 1H), 7.98 (m, 1H), 8.25 (m, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH2:7][S:8]C(=O)C)=[O:6])[CH2:3][CH2:2]1.CO.C[O-].[Na+].Cl[C:18]1[N:25]=[C:24]([S:26][CH3:27])[C:23]([Cl:28])=[C:22]([CH3:29])[C:19]=1[C:20]#[N:21]>CCOC(C)=O.CCCCCC>[CH:1]1([NH:4][C:5]([C:7]2[S:8][C:18]3=[N:25][C:24]([S:26][CH3:27])=[C:23]([Cl:28])[C:22]([CH3:29])=[C:19]3[C:20]=2[NH2:21])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)NC1CC1
Reactant: CSc1nc(Cl)c(C#N)c(C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
To a mixture of thioacetic acid S-cyclopropylcarbamoylmethyl ester (8.58 g, 49.5 mmol) and MeOH (100 ml) is added sodium methoxide solution (25% wt. in MeOH)(15.4 ml, 67.5 mmol). The resulting solution is stirred at room temperature for 20 minutes, then treated with 2,5-dichloro-4-methyl-6-methylsulfanyl-nicotinonitrile (10.5 g, 45.0 mmol). The mixture is refluxed at 100° C. for 2 hours, cooled to room temperature, and quenched by adding water (100 ml). The mixture is partitioned between water and EtOAc (300 ml each), and the layers are shaken and separated. The aqueous layer is extracted with EtOAc (2×150 ml). The combined organic layers are washed with brine (200 ml), dried (anhydrous magnesium sulfate), filtered, and concentrated to give an orange solid. Flash chromatography (1:1 hexane:EtOAc) affords the title compound as a yellow solid (8.4 g, 57%). Mass (m/z): 328.1 (M++1).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:25][C:24]([C:26]([F:28])([F:27])[F:29])=[CH:23][N:22]=3)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
In trifluoroacetic acid (2.9 mL) and water (0.3 mL) was dissolved methyl 2,2-dimethyl-3-(4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (144 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. To the residue obtained by concentrating the reaction mixture under reduced pressure were added chloroform and a saturated aqueous sodium bicarbonate solution. The formed insoluble material was dissolved in methanol and combined with the organic layer. The organic layer was washed with water, and concentrated under reduced pressure. The obtained residue was pulverized by cooled ether, collected by filtration and dried to obtain methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-propanoate (85.9 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.[Na+].O.CCOC(C)=O>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:5]1[C:4]([O:14][CH3:15])=[CH:3][C:2]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)c1cc(I)cc(OC)c1OC
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 5-iodo-2,3-dimethoxy-benzoate (2.25 g, 7.0 mmol) in 20 mL DMF, sodium p-toluenesulfinate hydrate (2.21 g, 11.26 mmol, 1.6 eq.) and CuI (2.22 g, 11.6 mmol, 1.66 eq.) were added and light green solution was stirred at 110° C. for 14 h. H2O and EtOAc were then added to the mixture and the phases were separated. The organic layer was washed with saturated NaCl solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 8:2→3:2) to yield the desired product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:37]1[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH:37]4[CH2:42][CH2:41][S:40][CH2:39][CH2:38]4)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: IC1CCSCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CCSCC5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.073 mmol) in acetonitrile (1 mL) was added Cs2CO3 (47 mg, 0.15 mmol) and 4-iodotetrahydro-2H-thiopyran (48 mg, 0.22 mmol). This mixture was then stirred at 80° C. for 16 hr. After cooling down to room temperature, the mixture was treated with saturated aqueous NH4Cl solution (3 mL) and extracted with EtOAc (3×3 mL). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography (Gradient 0˜8% MeOH/CH2Cl2 with NH3) to provide 5-chloro-N2-(2,5-dimethyl-4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 512.2 (M+H+).
Reaction SMILES: C(S[S:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:26](O)=[O:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[O:27]=[C:26]1[CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH2:23][CH2:22][S:21]1
Reactant: O=C(O)CCC(CCCSSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CCCSC1=O
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-[3-(tritylthio)mercaptopropyl]pentanedioic acid (150 g, 0.33 mol) in dichloromthane (500 mL) was added dropwise trifluoroacetic acid (110 mL) over 30 minutes. After being stirred for an additional 30 minutes, a solution of triethylsilane (45 mL, 0.33 mol) in dichloromethane (50 mL) was added and the mixture was stirred at 45° C. for 1 hour. The volatiles were removed in vacuo and the residue was triturated with hexanes (500 mL×2). The oily residue was dissolved in toluene (500 mL) containing 10-camphorsulfonic acid (14 g) and refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1/4). Subsequent recrystallization from EtOAc/hexanes afforded 23.3 g of 3-(2-oxotetrahydro-2H-thiopyran-3-yl)propanoic acid as a white solid (37% yield): 1H NMR (CD3OD) δ 1.65-1.78 (m, 2 H), 2.05-2.18 (m, 4 H), 2.35-2.48 (m, 2 H), 2.65-2.74 (m, 1 H), 3.13-3.29 (m. 2 H); 13C NMR (CD3OD) δ 23.3, 27.4, 29.3, 31.2, 32.3, 50.0, 177.0, 206.4. Analysis calculated for C8H12O3S: C, 51.04; H, 6.43; S, 17.03. Found: C, 51.08; H, 6.38; S, 17.16.