Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Cl-].[NH4+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0 g, 5.20 mmol) in methanol (58 mL) and add potassium hydroxide (9.36 g, 167 mmol). Heat at 50° C. for 2 h. Cool to ambient temperature, add aqueous saturated ammonium chloride and water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.62 g, 5.20 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.40 g, 4.46 mmol) in dry DMF (49.8 mL) and add DBU (0.80 mL, 5.35 mmol) and 3-bromopropyl phthalimide (1.55 g, 5.80 mmol). Stir at ambient temperature for 3 h. Add aqueous saturated ammonium chloride and water. Extract twice with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give the free base of title compound (1.64 g, 74%).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][N:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O)[C:12](=O)[C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>[OH-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12]3[N:13]([CH:14]=2)[CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][S:29]3)=[CH:6][CH:5]=1
Reactant: CC(C)(CO)CN1CC(c2ccc(Cl)cc2)=C(c2ccccc2)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CSc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1

Procedure:
At a 170-180° C. bath temperature, in a protective atmosphere of N2, 4-(4-chlorophenyl)-1-(2,2-dimethyl-3-hydroxypropyl)-3-phenyl-1,5-dihydro-pyrrol-2-on (5, 10.7 g, 0.03 mol) is melted with phosphorus pentasulfide (3.33 g, 2.5 equiv., 0.015 mol), which is added in small portions until the gas development comes to a halt (1 h). Then the cooled reaction mixture is akalyzed with caustic soda (100 mL, 10%) and extracted with chloroform; the organic phase is washed with water and dried. The residue remaining after the evaporation of chloroform is crystallized from diisopropyl ether having a melting point of 147-148° C. (5.5 g, 52%).
Reaction SMILES: C(CC(O[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[OH:18])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[C:11]([OH:18])[CH:12]=1)#[N:17]
Reactant: CC(C)(C)CC(=O)ONc1ccc(C#N)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
To a solution of N-t-butylacetoxy-4-cyano-2-hydroxyl aniline (3.1 g, 13 mmol) in methylene chloride (100 mL) at 0° C. was added trifluoroacetic acid and the reaction mixture was allowed to warm to rt. After 2.5 h, the reaction was quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (50% ethyl acetate/hexanes) to give 1.7 g (96%) of 4-cyano-2-hydroxyl aniline as a tan solid. 1H NMR (400 MHz, DMSO) δ 7.0 (d, 1H), 6.85 (s, 1H), 6.65 (d, 1H); MS(EI) m/e 134 (M+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:14][CH3:15])=[CH:6][C:7]([N:10]([O:12][CH3:13])[CH3:11])=[N:8][CH:9]=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>N1C=CC=CC=1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:3][C:4]2[C:5]([NH:14][CH3:15])=[CH:6][C:7]([N:10]([O:12][CH3:13])[CH3:11])=[N:8][CH:9]=2)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CNc1cc(N(C)OC)ncc1CCl
Agent: Cl
Solvent: c1ccncc1
Product: CNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of the above 5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine HCl (3.5 g, 16.3 mmol) and 4-fluoro-3-nitroaniline (41.5 mL, 0.3 mol) in pyridine (150 mL) was stirred at 50° C. for 8 h. The reaction mixture was concentrated in vacuo to afford a crude product which was washed with H2O and dried to give 5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.3 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (m, 1 H), 7.62 (s, 1 H), 7.30 (t, J=9.2 Hz, 1 H), 7.20 (m, 1 H), 6.98 (m, 1 H), 6.81 (s, 1 H), 5.98 (s, 1 H), 4.14 (s, 2 H), 3.69 (s, 3 H), 3.30 (s, 3H), 2.89 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 336.2 (M+H+)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([C:12]2[CH2:16][C:15](=O)[N:14]([CH3:18])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>>[Cl:3][C:15]1[N:14]([CH3:18])[N:13]=[C:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:16]=1
Reactant: CN1N=C(C2CCCCC2)CC1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(C2CCCCC2)cc1Cl
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (15.3 g, 0.1 mole) is added to 3-cyclohexyl-1-methyl-2-pyrazolin-5-one and the mixture stirred and heated at 120° C. to 135° C. for 8 hours. The cooled reaction mixture is then poured into ice-water, made alkaline with 1% aqueous sodium hydroxide and extracted with methylene chloride. Removal of solvent under reduced pressure, then in vacuo at 70° C. affords an oil, 8 g, (93.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)[CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]2[S:26][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ncc(-c3ccc(OC)cc3)s2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a suspension of 1.4 g (4.3 mmol) N-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester from Preparation 2 in 30 mL of dry dioxane was added 1.1 g (5.2 mmol) of P2S5 in one portion. The resulting mixture was warmed to 50° C. for 1 hour before cooling to room temperature and adding about 60 ml water. Stirred 2 hours and then filtered off solid product. Triturated in hot MeOH and filtered. Dissolved in THF and filtered through a plug of flash silica gel with THF eluent. Concentration gave 1.4 g (100%) of desired product. Used directly in the procedure of Preparation 11 without characterization.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[C:4]2[C@H:14]3[CH2:15][C@H:13]3[C:12]([F:17])([F:16])[C:5]=2[N:6]([CH2:8][C:9](O)=[O:10])[N:7]=1.[NH2:19][C@H:20]([C:30]1[N:35]=[C:34]([N:36]2[CH2:39][C:38]([CH3:41])([OH:40])[CH2:37]2)[CH:33]=[CH:32][C:31]=1[Br:42])[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:42][C:31]1[C:30]([C@@H:20]([NH:19][C:9](=[O:10])[CH2:8][N:6]2[C:5]3[C:12]([F:17])([F:16])[C@@H:13]4[CH2:15][C@@H:14]4[C:4]=3[C:3]([CH:2]([F:18])[F:1])=[N:7]2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[N:35][C:34]([N:36]2[CH2:39][C:38]([OH:40])([CH3:41])[CH2:37]2)=[CH:33][CH:32]=1
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: CC1(O)CN(c2ccc(Br)c([C@@H](N)Cc3cc(F)cc(F)c3)n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)n2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (33 mg, 0.13 mmol), (S)-1-(6-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-bromopyridin-2-yl)-3-methylazetidin-3-ol (50 mg, 0.13 mmol) and HATU (57 mg, 0.15 mmol) were dissolved in 1 mL of DMF and cooled to 0° C. To it was dropwise added N,N-diisopropylethylamine (0.07 mL, 0.38 mmol). The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (saturated aqueous) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 644.33[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:33])[CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+].Cl.O>C(O)C>[OH:33][CH:15]([C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]
Reactant: CCOC(=O)COc1ccc(C(=O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc(C(O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
To a suspension of ethyl [2-methyl-4-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}acetyl)phenoxy]acetate (intermediated 15, 0.165 g) in absolute ethanol (5 ml) at 0° C. under nitrogen was added sodium borohydride (0.013 g) after stirring for an hour the reaction was allowed to come to room temperature and stirred for a further two hours. 2M aqueous hydrochloric acid was then added drop-wise and once the effervescence had subsided water was added, the product was extracted twice with ethyl acetate and the combined organic extracts were dried (magnesium sulfate) filtered and evaporated. The product was purified by flash column chromatography using cyclohexane then ethyl acetate:cyclohexane(1:4) as eluents to give title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1)([O:16][CH3:17])=[O:15]>>[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23]/[N:24]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:20][CH:19]=1)([O:16][CH3:17])=[O:15]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: COC(=O)c1ccc(CON)cc1
Agent: Cl
Product: COC(=O)c1ccc(CO/N=C(\C)c2ccc(OC)c(O)c2)cc1
Yield: 71.6 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(4-carbomethoxybenzyl)hydroxylamine hydrochloride (27) (72 mg, 0.331 mmol) according to the general procedure II-B defined above. After being heated at reflux for 15 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL) and the resulting solution washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (1:9 v/v ethyl acetate/hexane elution) to afford the title compound CP30263 (71 mg, 82%) as a white solid, m.p. 97.7-98.7° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([OH:27])[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][C:22]=2[CH2:35][CH3:36])[C:3]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42]C)=[O:40]>[Pd].S(=O)(=O)(O)O.CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]([OH:27])[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][C:22]=2[CH2:35][CH3:36])[C:3]=1[CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]
Reactant: CCOC(=O)CCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc(CCCCC(=O)OC)c1O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccc(CCCCC(=O)OC)c(O)c1CCC(=O)OC
Yield: 80 %

Procedure:
A mixture 250 mg of ethyl 3-(2-hydroxy-3-(4-methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)phenyl)propionate, 0.1 gm of 10% palladium on carbon, and several drops of concentrated sulfuric acid in 125 mL of methanol was hydrogenated on a Parr™ apparatus at 45 psi for 18 hours. The mixture was filtered and the filtrate was evaporated in vacuo giving the title intermediate in 80% yield, NMR
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:24]=1)C1C=CC=CC=1.Cl>[Pd].CCO>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]([F:34])([F:32])[F:33])[CH:24]=1
Reactant: FC(F)(F)COc1cccc(CNCCc2c[nH]c3ccc(OCc4ccccc4)cc23)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Oc1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)F)c3)c2c1

Procedure:
Combine N-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine hydrochloride (295 mg, 0.6 mmol) and 25 mL EtOH and treat with 0.3 mL 5 N HCl and 300 mg 5% Pd/C and hydrogenate at atmospheric pressure overnight. Filter the reaction through a pad of celite and concentrate to dryness then chromatograph on silica gel to give the title compound: ISMS 365 (M+1); 1H NMR (DMSO-d6) 10.6 (bs, 1H), 9.4 (bs, 2H), 8.75 (s, 1H), 7.45–6.6 (m, 7H), 4.9–4.7 (m, 2H), 4.2 (bs, 2H), 3.2–2.9 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)=[C:4]([I:9])[CH:3]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1ccc(Cl)cc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C=C(Nc2ccc(Cl)cc2I)CCC1
Yield: 80.7 %

Procedure:
A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methylbenzenesulfonyl chloride according to METHOD A, giving 0.36 g (66%) of a pink solid; mp 173° C.; MS (Ionspray, [M+H]+) m/z 341.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccccn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 9): tR=1.46 min; Mass spectrum (ESI+): m/z=389 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:36][CH2:37][S:38][CH3:39])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:22])[CH2:36][CH2:37][S:38][CH3:39]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CSCC[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSCC[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), (S)-2-amino-4-(methylthio)butan-1-ol (32 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (4 mL) followed by N,N-diisopropylethylamine (0.19 mL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-50% EtOAc) to afford 105 mg (83%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methylsulfanyl-propyl)-amide as an off-white foam. MS: [M+H]+=559.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)(=[O:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC.O>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:26])=[O:25]
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.100 g, 0.269 mmol), (2-methylsulfonylphenyl)boronic acid (0.081 g, 0.404 mmol), sodium carbonate (0.228 g, 2.16 mmol), tetrabutylammonium bromide (0.087 g, 0.269 mmol) and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.035 g, 0.0538 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.19 (dd, 1H, J=7.6 Hz, J=1.2 Hz), 7.76-7.71 (m, 2H), 7.66-7.62 (m, 4H), 7.48 (dd, 1H, J=7.6 Hz, J=1.2 Hz), 7.34 (dd, 1H, J=8.4 Hz, J=1.2 Hz), 7.26 (d, 2H, 8.8 Hz), 5.45 (s, 2H), 2.64 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H21F3N3O3S: 488.5 (M+MeCN+H), Found 488.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Then, 21.60 g of 4-(4-propylphenyl)anisole was dissolved in 45 mL of dichloromethane, and the resultant solution was cooled with ice. Then, 35.79 g of boron tribromide was added to the solution at such a rate that the inside temperature did not exceed 10° C., followed by stirring at room temperature for 1 hour. Water was added to separate the mixture into layers, and an organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to yield 15.91 g of 4-(4-propylphenyl)phenol.
Reaction SMILES: [CH3:1][P:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[OH:11]O>C(Cl)Cl>[CH3:1][P:2]([CH3:10])([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)=[O:11]
Reactant: Cc1ccc(P(C)C)cc1
Reactant: OO
Solvent: ClCCl
Product: Cc1ccc(P(C)(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl-p-tolyl phosphane (25 g, 0.165 mol) (1a) in diclholoromethane (DCM) (50 mL) was added an aqueous solution of hydrogen peroxide (10%, 60 mL, 0.176 mol) in drops. This is an exothermic reaction so the flask was cooled in ice water during the addition. After the addition the reaction was allowed to stir at rt overnight until the HPLC showed no starting material (18 h). From the resulting reaction mixture the organic phase was separated and the aqueous phase was extracted with additional dichloromethane (3—60 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were washed with a solution of sodium bisulfite (10 mL) followed by water (10 mL) and dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by Crystallization from ethyl acetate/hexane (18.8 g). m.p. 90–92° C., 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.469 (d, J=13 Hz, 6H), 2.16 g (s, 3H), 7.04 (d, J=5.5 Hz, 2H), 7.38 (m, 2H). 3P NMR (121 MHz, CDCl3) δ 34.327.
Reaction SMILES: [CH3:1][N:2](CC1C=CC=CC=1)[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=[O:21])[CH:4]=1.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1

Procedure:
4-[methyl(phenylmethyl)amino]-6-[3-(trifluoromethyl) phenoxy] picolinic acid (0.42 g, 0.0010 mol) and a small amount of 10% palladium/carbon were added to about 30 ml of methanol. The obtained mixture was stirred at room temperature for about 10 hours in a hydrogen atmosphere. The obtained reaction solution was filtered using High-Flow Super Cell, and then concentrated, thereby obtaining an aimed product.