Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:38][CH2:37][N:36]1[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([CH:35]2[CH2:38][CH2:37][N:36]2[C:39]([O:41][CH2:42][C:43]([Cl:45])([Cl:46])[Cl:44])=[O:40])=[C:28]([CH2:27][NH:26][C:20](=[O:21])[C@@H:19]2[CH2:23][CH2:24][CH2:25][NH:18]2)[CH:33]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl)[C@@H]1CCCN1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-Fmoc-L-proline (0.249 g, 0.739 mmol) was added to a stirred mixture of 2,2,2-trichloroethyl 2-[2-(aminomethyl)-4-chlorophenyl]azetidine-1-carboxylate (0.275 g, 0.739 mmol), EDC (0.213 g, 1.11 mmol) and HOAT (50 mg, 0.37 mmol) in DMF (2 mL). After 16 h the reaction mixture was partitioned between ethyl acetate and dilute HCl solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to a foam. This material was dissolved in DMF (2 mL) and piperidine (0.5 mL) and stirred for 30 min. The solution was poured into water (50 mL) and the precipitated solids were removed by filtration, washing with water (5×10 mL, which was collected and set aside) and methanol. The methanol was evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with ethyl acetate followed by chloroform/methanol/ammonium hydroxide, 90:9:1) to give 2,2,2-trichloroethyl 2-{4-chloro-2-[(L-prolylamino)methyl]phenyl}azetidine-1-carboxylate (66 mg) as a gum. The milky aqueous washings were extracted into ethyl acetate (adding brine to dispel the emulsion) and the organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give more of the desired compound (0.206 g) as a gum: MS 468.5 (M+1) with an isotope distribution consistent with four chlorines.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH2:8][O:7][C:6]2[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]1=2
Reactant: OC1c2ccccc2COc2cc(F)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2c(c1)OCc1ccccc1C2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 1.5 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ol in 20 ml of methylene chloride is added dropwise a solution of 1.6 g of thionyl chloride in 10 ml of methylene chloride under ice cooling over 30 minutes and then the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated at room temperature under reduced pressure to give 1.5 g of 11-chloro-3-fluoro-6,11-dihydrodibenz[b,e]oxepin (oil). Mass spectrum m/z: 248(M+)
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][CH2:19][CH2:18][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][CH:26]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: BrCCCSc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCSc2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (10 mL) at 0° C. The mixture was stirred for 30 min at 50° C., cooled to room temperature and 1-bromo-3-(4-benzyloxy-phenylsulfanyl)-propane (CAB02037, 1.686 g, 5.0 mmol) was added. The reaction mixture was stirred for 15 h and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography (eluent: ethyl acetate, Rf: 0.41). Yield: 1.724 g (78%) colourless oil. The oil was crystallised from a small amount of methanol. Yield: 1.517 g (68%). 1H-NMR (400 MHz, CDCl3) δ=1.84 (tt, J=6.4, 6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 5.06 (s, 2H, —OCH2Ph), 6.52 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.33-7.44 (m, 5H), 7.52 (d, J=9.0 Hz, 2H), 8.26 (s, 2H). LRMS (FAB+): 442.2 (100, [M+H]+)
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH2:17][CH2:18][NH:19][C:20](=[S:22])[CH3:21]>C(Cl)Cl>[CH3:2][S:22][C:20](=[N:19][CH2:18][CH2:17][S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)[CH3:21]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC(=S)NCCSc1ccccn1
Solvent: ClCCl
Product: CSC(C)=NCCSc1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Add methyl trifluoromethanesulfonate (65.5 mg, 0.4 mmol) to a solution of N-(2-(pyridin-2-ylsulfanyl)ethyl)thioacetamide (85.0 mg, 0.4 mmol) in methylene chloride (10 mL) under nitrogen. Stir the reaction mixture at room temperature for 5 minutes and remove the solvent under reduced pressure to give N-[2-(pyridin-2-ylsulfanyl)ethyl)thioacetimidic acid methyl ester (0.4 mmol) as a colorless oil. MS (ES): m/z 227 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:7][CH2:6]1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(c2ccc(N)cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester (279 mg, 1 mmol) from above in a mixture of tetrahydrofuran (10 mL) and methanol (50 mL) was added 10% palladium on carbon (50 mg). The mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated to give (5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester that was used in the next step without further purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].CO[SiH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][C:23]=3[F:32])=[C:18]([F:33])[CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[CH2:1]([Si@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][C:23]=3[F:32])=[C:18]([F:33])[CH:17]=2)[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: CCCOc1ccc(-c2ccc(C3CC[SiH](OC)CC3)cc2F)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCCC)cc3F)c(F)c2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.5 g (20 mmol) of 4'-(4-methoxy-4-silacyclohexyl)-2,2'-difluoro-4-propoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2, 2'-difluoro-4-propoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 7.1 g of the trans isomer (yield 86%).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:14][CH3:15])[CH:1]=[O:13]
Reactant: CCI
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(C=O)cc1OC
Yield: 102.1 %

Procedure:
A mixture of syringaldehyde (50 g, 0.275 mol), ethyl iodide (85.8 g, 0.55 mol) and potassium carbonate (151.7 g, 1.09 mol) in DMF (60 ml) was stirred and heated at 60°-70° for 6 h. The mixture was cooled and evaporated in vacuo then treated with water and extracted with diethyl ether. The extracts were dried (Na2SO4) and evaporated to give the title compound (59 g) as a white solid, pure by tlc, and used without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:27][O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1.O>[OH:24][CH:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)[CH:29]([O:28][CH3:27])[C:30]([O:32][CH3:33])=[O:31]
Reactant: COCC(=O)OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
Sodium bis-(trimethylsilyl)amide (440 mL 0.44 mol 1.0 M in THF) was cooled to −70° C. under a nitrogen atmosphere. A solution of 4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl methoxyacetate (52 g, 0.5 mol) in THF (0.5 L) was added dropwise at −70° C. over 2 hours, and the mixture was stirred for an hour. A solution of concentrated HCl (85 mL) and water (85 mL) was added at −70° C. The resulting solution was allowed to warm to ambient temperature and was extracted with MTBE (2×0.5 L). The combined extracts were washed with brine (0.5 L), dried (MgSO4), filtered, and concentrated under to give 133 g of a red oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH3:8])=[O:6].[CH3:9][NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17]O)=[CH:14][CH:13]=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[CH3:9][NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][S:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: CNCc1ccc(CO)o1
Reactant: CNC(=O)NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNCc1ccc(CSCCNC(=O)NC)o1
Reaction time: 24 h
Yield: 11.5 %

Procedure:
To a stirred solution of N-[2-mercaptoethyl]-N'-methylurea (2.0 g) in concentrated hydrochloric acid at 0° was added dropwise a solution of 5-(methylamino)methyl-2-furanmethanol (2.0 g) in water (3 ml). After 24 hr, ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added. The suspension was filtered, the filtrate evaporated to dryness and the oily residue column chromatographed (silica/methanol:0.88 ammonia 79:1). The relevant eluate was evaporated to dryness to give an oil identical to product of Example 4 (0.42 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(COS(C)(=O)=O)n2)CC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-{[6-(hydroxymethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.34 g, 1.10 mmol) and methanesulfonyl chloride (0.13 mL, 1.64 mmol) were dissolved in DCM (15 mL) and stirred at 0° C. (ice bath). DIPEA (0.57 mL, 3.29 mmol) was added to the reaction mixture and stirred for 2 hours. The resulting mixture washed with water (2×15 mL), dried over a phase separator, concentrated in vacuo and was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(C)CCN(C)C.[Li]CCCC.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCCC.CCCCCC>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([C:10]2[C:4]3[O:3][C:2]([CH3:11])([CH3:1])[CH2:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)([OH:38])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1(C)Cc2ccccc2O1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CC1(C)Cc2cccc(C3(O)CCN(Cc4ccccc4)CC3)c2O1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 2,3-dihydro-2,2-dimethylbenzofuran (25 g) and tetramethylethylenediamine (46 g) in heptane (250 ml) was treated dropwise at room temperature with 1.6M BuLi in hexane (250 ml). After stirring for 1.5 h at 30°-40° C. the mixture was cooled to -40° C. and 1-benzyl-4-piperidinone (32 g) was added dropwise at -40° C. The reaction mixture was allowed to warm to room temperature during 3 h followed by quench with water. After concentrating the reaction mixture in vacuo dichloromethane (500 ml) was added followed by wash with water (3×500 ml). Removal of solvent in vacuo gave an oil which was purified by flash chromatography (silica gel, heptane/ethyl acetate/triethylamine 50:48:2) giving an oil. Addition of heptane gave the product, 7-(1-benzyl-4-hydroxy-4-piperidinyl)-2,3-dihydro-2,2-dimethylbenzofuran as a solid (11 g).
Reaction SMILES: [OH:1][C:2]1[C:21]([CH2:22][CH:23]=[CH2:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([O:25][CH2:26][O:27][CH3:28])[CH:19]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:3]=1[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: C=CCc1c(OCOC)cc(OCOC)c(C(=O)C=Cc2ccc(OCOC)cc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(OCOC)cc(OCOC)c(C(=O)CCc2ccc(OCOC)cc2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Then, an ethyl acetate solution of 21.1 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(2-propenyl)chalcone was added to a suspension of 8.0 g of 5% palladium/carbon in 50 ml of ethyl acetate, in which a hydrogen gas had been sufficiently absorbed, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation to obtain quantitatively 21.2 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-n-propylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:21])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[K+].C(O)(=O)C>CO>[O:21]1[CH2:2][CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OC(CCl)COc1cccc(-c2nc(C(F)(F)F)c[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1c[nH]c(-c2cccc(OCC3CO3)c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[3-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (3.8 g.) in methanol (150 ml.) is added powdered potassium hydroxide (3. g.) and the mixture is allowed to stir 4 hours at room temperature. Glacial acetic acid (2.75 ml.) is added and the mixture concentrated under reduced pressure (20 mm. Hg.) over steam. The resulting residue is stirred with water, filtered and recrystallized from xylene to yield 2.5 g. of 2-[3-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 145°-146.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 L of carbon tetrachloride; to this solution was added N-bromosuccinimide (61.65 g, 0.346 mole) at room temperature. A portion of dibenzoyl peroxide (0.6 g, 0.008 equivalents) was added and the solution heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo to yield a solid. The solid was dissolved in 200 mL of warm hexane, filtered and cooled to room temperature. Crystallizations ensued; the crystals were filtered off and washed with cold hexane and air dried to give 45.15 g (44%) of 3,5-dibromobenzyl bromide. 1H-NMR(CDCl3); δ 7.6 (1H), 7.47 (2H), 4.36 (2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COc1cccc(C(=O)Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09 mmol, Example 1, Step H), 3-methoxybenzoyl chloride (389 mg, 2.28 mmol), and triethylamine (757 μL, 5.43 mmol) were placed in DCM (5 mL) and stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was added. The reaction was stirred for 10 minutes and then poured onto water. The mixture was then filtered and washed with DCM and water to provide solid N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide (219 mg, 55% yield).
Reaction SMILES: [OH-].[Co+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].CCCCCC>O>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Co+2:2].[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Co+2]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 3 h

Procedure:
The recovered cobalt hydroxide was then placed into a beaker provided with a reflux condenser and Dean Stark water trap. 29.2 grams (0.2 Mole) of lysine was added and thereafter 100 ml hexane was subsequently added and stirred and boiled at atmospheric pressure for 3 hours. In the course of reaction about 3.6-3.8 ml of water was removed from the reaction media and acquired in the Dean Stark apparatus. The reaction mixture was then cooled and filtered yielding 35 grams of cobalt lysinate in the form of a fine pink powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 36 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (95 mg, yield 36%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.59-8.58 (t, J=1.5 Hz, 1H), 8.28-8.26 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.17-8.14 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.09-8.05 (m, 2H), 7.90 (m, 1H), 7.67-7.63 (t, J=7.8 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.14-7.10 (m, 2H), 3.99-3.93 (ddd, J=13.2 Hz, 6.4 Hz, 4.3 Hz, 1H), 3.53-3.46 (ddd, J=13.2 Hz, 8.8 Hz, 4.3 Hz, 1H), 3.19-3.12 (m, 1H), 1.41-1.39 (d, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C22H16F4N4O3: 460.12. found: 461.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>N1CCCCC1.[Cu]I>[C:18]([O:17][C:16]([NH:15][CH2:12][C:13]#[C:14][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Methyl-4-iodobenzoate (1.5 g, 5.7 mmol) and t-butyl prop-2-ynylcarbamate (0.89 g, 5.7 mmol, reference example 82) are dissolved in piperidine (12 mL) and this solution purged with nitrogen. Copper(I) iodide (22 mg, 0.11 mmol) and dichlorobis(triphenylphosphine) palladium (40 mg, 0.057 mmol) is added and the mixture is stirred at R.T. After 2 hours, the solvent is removed in vacuo and the residue added to CH2Cl2 and washed with 1N HCl, water and brine, then dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography, eluting with 20% ethyl acetate/hexane to provide the title compound as a white solid (1.1 g, 67% yield): 1H NMR (300 MHz, CDCl3) d 7.98 (d, 2H), 7.48 (d, 2H), 4.79 (bs, 1H), 4.17 (d, 2H), 3.91 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH3:13])=[O:5])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH2:13][Br:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1onc(CC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(CC)c1CBr
Temperature: 25 °C
Yield: 20.6 %

Procedure:
3-Ethyl-4-methyl-isoxazole-5-carboxylic acid ethyl ester (3.5 g, 19.1 mmol), NBS (3.4 g, 19.1 mmol), and benzoyl peroxide (0.46 g mg, 1.91 mmol) were added to 110 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% EtOAc/hexanes) to give 1.03 g of the title compound. MS: (+) m/z 262.17, 264.14 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][Br:29]
Reactant: COc1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cl)c1CBr

Procedure:
To 13.0 g (84.92 mmol) 3-chloro-2-methylanisole in 80 ml CCl4 at reflux were added 0.4 g dibenzoyl peroxide and then, subsequently and portion-wise, a mixture of 15.2 g N-bromosuccinimide and 0.4 g dibenzoyl peroxide. After completion of reaction the mixture was evaporation-concentrated, the residue was dissolved in dichloromethane, was sequentially washed with water and saturated NaCl solution, was dried over MgSO4, was filtered and again evaporation-concentrated. 20.8 yellow oil.