Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:7]=1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:18])=[CH:4][C:3]=1[F:21]
Reactant: C[C@H](Nc1cc(Br)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(Br)c(F)cc1N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (S)-5-bromo-4-fluoro-N-(1-(4-fluorophenyl)ethyl)-2-nitrobenzenamine (Method 46; 0.63 g, 1.76 mmol) and zinc dust (0.554 g, 8.47 mmol) in MeOH:THF (1:1, 24 ml) was slowly added the saturated ammonium chloride solution (4 ml). The reaction mixture was stirred at 25° C. for 2 hours followed by addition of saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (20 ml). The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, and concentrated under reduced pressure to give the crude product which was directly used for the next step without further purification. MS: Calcd.: 326. Found: [M+H]+ 327.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
A mixture of 3-phenoxybenzoic acid (0.200 g, 0.934 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.215 g; 0.934 mmol), HATU (0.389 g; 1.03 mmol) and N,N-diisopropylethyldiamine (0.402 mL; 2.33 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified twice by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.068 g (19%) of the title compound as a colourless solid.
Reaction SMILES: [O:1]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[C@H:2]1[CH2:3][OH:4].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[O:1]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[C@H:2]1[CH:3]=[O:4]
Reactant: Cc1cccc([C@H]2O[C@@H]2CO)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cccc([C@H]2O[C@@H]2C=O)c1

Procedure:
The title compound is prepared analogously to Example 5a) from (2R,3R)-2,3-epoxy-3-(3-methylphenyl)-propanol; light-yellow oil. IR (methylene chloride): 2920, 2820, 1730, 1610, 1140, 1070 cm-1 ; Rf =0.49 (hexane/ethyl acetate 3:2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:25][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2cccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3cccs3)no2)CC1
Yield: 78.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(2-methoxyphenyl)piperazine (9.2 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 10 hr and followed the same processes as in Example 1 to obtain 15 mg (81.5%) of the target compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([C:11](O)=O)=[N:2]1.C(Cl)(=O)C(Cl)=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH:24]=[C:25]([N+:28]([O-])=O)[C:26]=1[NH2:27].[H-].[Na+]>C1COCC1.[Fe].CN(C=O)C.C(Cl)Cl>[Cl:20][C:21]1[C:26]2[NH:27][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:28][C:25]=2[CH:24]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:38])([F:39])[F:40])[CH:22]=1
Reactant: Nc1c(Cl)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Agent: [Fe]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-c1cc(Cl)c2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (4.02 g, 21.9 mmol, as prepared in Example 1, step B) was placed in a round-bottom flask equipped with a magnetic stir bar. DCM (40 mL) and DMF (50 μL) were added. Oxalyl chloride (2.5 mL, 28.5 mmol) was added dropwise via syringe, and the mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure. 3-Chloro-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (6.96 g. 21.9 mmol) was placed in a round-bottom flask equipped with a magnetic stir bar. The flask was evacuated and backflushed with argon, and dry THF (50 mL) was added. The mixture was cooled to 0° C. in an ice bath, then NaH (2.64 g, 65.8 mmol, 60% dispersion in oil) was added in small portions. The above-prepared acid chloride was taken up in dry THF (20 mL) and added dropwise to the 3-chloro-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine solution at 0° C. over 10 min. After the addition was complete, the mixture was allowed to stir an additional 30 min at 0° C. then warm to RT and stir at that temperature for 16 h. The mixture was quenched with water, diluted with brine, and extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in AcOH and placed in a round-bottom flask equipped with a magnetic stir bar. Fe powder (6.14 g, 110 mmol) was added. The flask was tightly capped, and the mixture was heated to 80° C. for 1 h. The mixture was cooled to RT and poured into ice. The resulting precipitate was filtered and washed with water. The filtrate was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was chromatographed on an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min. The resulting material was recrystallized from MeOH and isolated by filtration, yielding 5.12 g (54%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 13.52 (br. s., 1H), 7.86 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 1.63-1.82 (m, 6H), 1.34-1.60 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH:6]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)(=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:7]2[N:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)[N:34]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
The material of step 3 of Example 17 (15 g, 0.044 mol) was dissolved in 100 mL of glacial acetic acid and then 4-fluorophenyl hydrazine hydrochloride (7.15 g, 0.044 mol) was added. The reaction was then stirred at room temperature for 18 hours, under argon, and then concentrated to remove most of the acetic acid. The remaining viscous oil was triturated with 250 mL acetonitrile. The resulting solid was isolated by vacuum filtration and dried to yield the product as an orange/pink solid. 11 g (MW=424.38, 59% yield). LC/MS m/z=425.2 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:8]2[S:7][C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Clc1ccc2ccsc2c1
Product: Clc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1

Procedure:
A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at 210° C. for 40 minutes. The mixture was cooled to room temperature and diluted with diethyl ether, and insoluble materials were filtered off. The filtrate was washed successively with 10% aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 6-chlorobenzo[b]thiophene (1.79 g) as colorless crystals. (3) The above 6-chlorobenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give 5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene as colorless crystals.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:17]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Prepared as in example 5-27 from dibenzylamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 380.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 4.52 (s, 4H), 7.10 (m, 4H), 7.25 (m, 6H), 8.00 (d, 2H, J=8.4 Hz), 8.15 (d, 2H-J=8.4 Hz), 13.5 (s, broad, 1H).
Reaction SMILES: C1CO[C:3]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:19][CH2:18][C:11]3([NH:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[CH2:10][CH2:9]2)[O:2]1.Cl>CO>[ClH:26].[Cl:26][C:24]1[CH:23]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:19][CH2:18][C:11]3([NH:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[CH2:10][CH2:9]2)[CH:25]=1
Reactant: COc1ccc(Cl)cc1C1(CCCCN2CCC3(CC2)NC(=O)NC3=O)OCCO1
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)CCCCN1CCC2(CC1)NC(=O)NC2=O
Reaction time: 4 h

Procedure:
A mixture of 8-[5,5-ethylenedioxy-5-(5-chloro-2-methoxyphenyl)pentyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione (1-1.1 g, 2.3-2.6 mmol), prepared as in Example 23, 10% hydrochloric acid (approximately 1 mL) and methanol (approximately 30 mL) was heated to a boil and then allowed to cool and stand approximately 4 hour at 25° C. The solids were collected and dried under vacuum at 70° C. to give 8-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (0.37 g, 0.57 mmol), m.p. 260°-262° C.
Reaction SMILES: ClC1C=CC(NC2N=C(C3C(F)=CC=CC=3F)N=C(NN=CC3C=CC(OC(F)(F)F)=CC=3)N=2)=CC=1.C(NC(C)C)(C)C.[Li].Cl.C(N(CC)CC)C.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[CH:55]=1.[N:61]1[C:68]([Cl:69])=[N:67][C:65](Cl)=[N:64][C:62]=1[Cl:63]>O1CCCC1.C(Cl)Cl>[Cl:63][C:62]1[N:61]=[C:68]([Cl:69])[N:67]=[C:65]([C:55]2[C:54]([F:53])=[CH:59][CH:58]=[CH:57][C:56]=2[F:60])[N:64]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: Fc1cccc(F)c1-c1nc(NN=Cc2ccc(OC(F)(F)F)cc2)nc(Nc2ccc(Cl)cc2)n1
Agent: [Li]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cccc(F)c1-c1nc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 8.9 %

Procedure:
Also Example 1 For this general method we also provide a specific detailed example, i.e. Example 1, which is the compound named N-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)-1,3,5-triazin-2-amine (1). See also Example Scheme 1, above. A solution of lithium diisopropylamine in tetrahydrofuran (THF) (15 mL, 2M, 30 mmol) was added dropwise to a room temperature stirred suspension of triethylamine hydrochloride (0.25 g, 1.8 mmol) in dry tetrahydrofuran (THF; 10 mL). When the mixture became homogeneous, the solution was cooled to −78° C. in a dry-ice/acetone bath. Neat 1,3-difluorobenzene (3 mL, 30.4 mmol) was added dropwise and the solution stirred for 15 minutes. The −78° C. solution was poured rapidly into a −78° C. solution of cyanuric chloride (5.5 g, 30 mmol) in dry THF (25 mL). The dry-ice/acetone cold bath was removed and the mixture allowed to come to room temperature. Once at room temperature the orange-red mixture was poured into 100 mL of saturated aqueous bicarbonate solution. The mixture was allowed to stand for 15 minutes. Hexanes (100 mL) were added and after thorough mixing the organic layer was separated from the aqueous layer. The organic layer was dried over magnesium sulfate and then filtered to remove the magnesium sulfate. The solution was concentrated on a rotary evaporator to yield an oil. The oil was dissolved in a minimal amount of methylene chloride and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate in hexanes. The organic eluent was concentrated on a rotary evaporator and the product precipitated from methylene chloride and hexane to yield 0.7 g of 2,4-dichloro-6-(2,6-difluorophenyl)-1,3,5-triazine (XXV). ESI/MS 261.9, 263.9, 265.8 (M+H).
Reaction SMILES: IC1C=CC(C)=CC=1S(O)(=O)=O.OOS([O-])=O.[K+].[CH3:19][CH2:20][CH2:21][CH2:22][CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][CH3:27]>C(#N)C>[CH3:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)CCCC
Agent: Cc1ccc(I)c(S(=O)(=O)O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 3 h

Procedure:
8.9 mg (0.03 mmol) of 2-iodo-5-methylbenzenesulfonic acid prepared by Preparation Example 2, 1.48 g (2.4 mmol) of Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added in 3.75 ml of acetonitrile, and the mixture was heated at 70° C. while being stirred for three hours. The later treatment was carried out in the same way as in Example 1, and then 5-nonanone was obtained. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([SH:16])[CH:13]([SH:15])[CH3:14].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22][C:23](=[CH:25][CH:26]=O)[CH3:24])[CH3:19]>C1CCCCC1>[CH3:24][C:23]([CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])=[CH:25][CH:26]1[S:15][CH:13]([CH3:14])[CH2:12][S:16]1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(S)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)=CCCC(C)=CC1SCC(C)S1

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 0.5 grams para-toluenesulfonic acid, 5.0 ml cyclohexane and 5.4 grams (0.05 moles) of 1,2-propanedithiol. 7.6 grams (0.05 moles) of citral is then added to the reaction mass over a period of 30 minutes. After the addition of the citral, the reaction mass is heated to reflux and refluxed for a period of 10 hours while removing water of reaction. After the 10 hour reflux period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride solution followed by drying over anhydrous sodium sulfate and filtration. The resulting filtrate is distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: C(CC(Cl)=S)(=O)C.C(CCC(Cl)=S)(=O)C.SCC(SC)C([N:21]1[CH2:28][C:27](=[O:29])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=O>>[O:29]=[C:27]1[CH2:28][NH:21][C@H:22]([C:23]([OH:25])=[O:24])[CH2:26]1
Reactant: CSC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: CC(=O)CC(=S)Cl
Agent: CC(=O)CCC(=S)Cl
Product: O=C1CN[C@H](C(=O)O)C1

Procedure:
Following the procedure of Example 1 but substituting acetylthioacetyl chloride for the 3-acetylthiopropionyl chloride in part (d), one obtains 1-[2-acetylthio)-1-oxoethyl]-4-oxo-L-proline.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Li])CCC.[I:21]I.O>O1CCCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([I:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: II
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 15.0 grams (0.051 mole) of 3,5-di(trifluoromethyl)phenyl bromide in 45 mL of dry tetrahydrofuran was cooled to below -80° C., and 20.5 mL (0.051 mole) of n-butyllithium (2.5M in hexanes) was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, an additional 50 mL of tetrahydrofuran was added to promote stirring. The reaction mixture was then stirred at -80° C. for an additional one hour. After this time a solution of 13.0 grams (0.051 mole) of iodine in 30 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then poured into 400 mL of water, and the mixture was extracted with one 200 mL portion of diethyl ether. The ether extract was washed with an aqueous solution of 10 % meta-sodium bisulfate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 13.1 grams of 3,5-di(trifluoromethyl)phenyl iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([C:34]2([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.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]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([C:34]3([C:40]#[N:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: N#CC1(c2ncc(Br)s2)CCCCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCCCC3)s2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 134 mg, 0.35 mmol), the compound from Step 2 (96 mg, 0.35 mmol), cesium carbonate (346 mg, 1.06 mmol), X-Phos (16.9 mg, 0.035 mmol) and Pd2(dba)3 (16.2 mg, 0.018 mmol) were placed in a flask and evacuated/purged with N2 for three times. Dioxane (1.5 mL) and water (0.15 mL) were degassed by undersurface N2 bubbling and added to the reaction vessel. The resulting reaction mixture was stirred at 100° C. for 5 hrs and then diluted with EtOAc (5 mL), washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes) to give the title compound (128 mg, 0.289 mmol, 82% yield) as an off white foam. MS ESI: [M+H]+ m/z 444.1. 1H NMR (500 MHz, CD3-OD) δ 8.72 (d, J=5.0, 1H), 8.06 (bs, 1H), 8.00 (s, 1H), 7.48 (bs, 1H), 7.16 (bs, 1H), 7.14 (d, J=4.9, 1H), 2.41-2.37 (m, 5H), 2.06-2.00 (m, 2H), 1.94-1.89 (m, 2H), 1.85-1.73 (m, 3H), 1.40 (m, 1H). rhSYK activity=++.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)nc3)cc2)CC1
Yield: 76.1 %

Procedure:
The title compound (0.34 g, 75%) was prepared as a white solid from 4-[6-(methylsulfonyl)-3-pyridinyl]phenol (0.25 g, 1.00 mmol), N-Boc-4-piperidinemethanol (0.23 g, 1.00 mmol) and Ph3P (0.27 g, 1.00 mmol) in THF (6 mL) followed by diisopropyl azodicarboxylate (0.22 g, 94%, 1.0 mmol) in THF (2 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.96 (d, 1H, J=2.2 Hz), 8.28 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.70 (d, 2H, 8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 2H), 3.92 (d, 2H, J=6.1 Hz), 3.24 (s, 3H), 2.90-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (2H); LRMS (APCI), m/z 469 (M+Na).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH3:12])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOCC>[OH:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)[CH3:12]
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tert-butyl (2S,3S)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (2000 mg, 4.5 mmol) in 25 mL ether at 0° C. was added 1.0 M tetrabutylammonium fluoride in THF (8.9 mL, 8.9 mmol). After the addition, the ice-bath was taken away. The reaction progress was monitored by TLC. After 60 minutes, the solvent was evaporated and 100 mL diethyl ether was added. The organic layer was washed with water and brine solution, and then dried over sodium sulfate. The crude product was then chromatographed eluting with 30% EtOAc in hexane. After removing the solvent, the desired product was obtained as a white solid (1.25 g, 84%). 1H NMR (400 MHz, CD3OD) δ ppm 1.26-1.31 (m, 9H) 1.34 (d, J=7.04 Hz, 3H) 3.02-3.13 (m, 1H) 3.61-3.67 (m, 2H) 3.75 (dd, J=8.71, 4.60 Hz, 1H) 7.44 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.22 Hz, 2H).