Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26](Br)=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:35]4[CH:36]=[C:37]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one (intermediate 2, 32 mg, 0.06 mmol), 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (Intermediate x, 18 mg, 0.06 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (4 mg, 0.006 mmol) in aqueous potassium carbonate/THF (3 mL, 3 mL) was heated at reflux for 2 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]pyridine-2-yl}methyl)-4-methyl-1,3-oxazinan-2-one as a colorless oil. LCMS=631.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atroisomers): δ 7.87 (br s, 2H), 7.82 (s, 1H), 7.58 (brs, 1H), 7.44 (br d, J=6.8 Hz, 1H), 7.32 (brs, 1H), 7.24 (brs, 1H), 7.02 (d, J=8.7 Hz, 1H), 5.62-5.41 (br m, 0.5H), 5.26-5.20 (brm, 0.5H), 5.16-5.11 (brm, 1H), 4.34 (brm, 3H), 3.80 (s, 3H), 3.62-3.44 (brm, 3H), 1.34 (brs, 3H), 1.22 (brm, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:22][CH2:21][S:20][CH2:19]3)[O:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.I([O-])(=O)(=O)=[O:30].[Na+]>CO>[CH:1]1([NH:7][C:8]2[C:9]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:22][CH2:21][S:20](=[O:30])[CH2:19]3)[O:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCSC4)C3)cnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCS(=O)C4)C3)cnc21
Reaction time: 0.08 h

Procedure:
N-cyclohexyl-1-ethyl-5-(1-oxa-7-thia-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (70 mg, 0.00018 mole) (example 13) was taken in methanol and stirring was done for about five minutes. Water (1 ml) was added. Sodium periodate (38 mg, 0.00018 mole) was added. The reaction mixture was stirred at room temperature for about 5 h. Filtration was done and the residue was washed with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. Purification was done by preparative thin layer chromatography using ethyl acetate (60%) in hexane.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br-].[CH3:13][OH:14]>>[O:10]1[CH:8]([CH:7]([O:14][CH3:13])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9]1
Reactant: OCC=Cc1ccccc1
Reactant: CO
Agent: [Br-]
Agent: [Na+]
Product: COC(c1ccccc1)C1CO1

Procedure:
Electrolyte: 300 g (2.239 moles) of 3-phenyl-2-propen-1-ol, 60 g of NaBr, and 2,640 g of methanol
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.[Mg].[Br-].[C:18](OC(=O)C)(=[O:20])[CH3:19].[OH-].[Na+]>C1COCC1.CC(OC)(C)C.O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:18](=[O:20])[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h). The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at −15° C. The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added. The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50% NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3×150 mL). The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr). The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82% yield) with a boiling point of 187-189° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OC(C)=O)c2c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl-4-hydroxy-3-methylbenzofuran-2-carboxylate (2.2 g, 10 mmol) in dry THF (30 ml) was added triethylamine (2.07 ml, 15 mmol) followed by acetyl chloride (0.85 ml, 12 mmol). The mixture was stirred at 0° C. for 1 hour, and at room temperature for 2 hours, and was then poured into ice water (200 ml). The white precipitate was collected by filtration.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][N:26]=[C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:25][N:26]=[C:27]([C:29]4[CH:33]=[C:32]([CH3:34])[O:31][N:30]=4)[N:28]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: Cc1cc(C(N)=NO)no1
Product: CCc1ccc(C2CC(c3nc(-c4cc(C)on4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 31 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-5-methylisoxazole-3-carboximidamide were reacted according to the General Method 1. Yield: 50 mg (58% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:29].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:29])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20]2)=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: CS(=O)(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: CS(=O)(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To a solution of 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde (120 mg, 0.298 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (299.5 mg, 3.29 mmol) and sodium phosphate monobasic dihydrate (697 mg, 4.47 mmol) in water (2 mL) dropwise. After the reaction mixture was stirred for 2 h at room temperature, additional sodium chlorite (399.3 mg, 4.39 mmol) and sodium phosphate monobasic dihydrate (930 mg, 5.96 mmol) in H2O (2 mL) and 2-methyl-2-butene (1 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acid (56 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[O:27][CH3:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([O:27][CH3:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(OC)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(OC)c2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 7.5 g (19.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-methoxy-benzoic acid methyl ester using 4.05 g (96.5 mmol.) LiOH in 100 mL water and 200 mL THF. The reaction mixture is stirred over night at room temperature. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and Acetonitrile. After drying 6.5 g (89%) of the desired product is obtained as solid material.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH:34]=O.O>C(OCC)C.O1CCCC1.CCCCCC.O1CCCC1>[CH3:3][C:2]([CH3:4])=[CH:34][C:33]1[CH:32]=[C:31]([C:30]([F:44])([F:43])[F:29])[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
15.88 g (36 mmol) isopropyltriphenylphosphonium iodide are dissolved in 210 mL diethyl ether/tetrahydrofuran (1:1) and cooled to −10° C. At this temperature 25 mL of a 1.6 molar solution of butyllithium in hexane are added dropwise. Then the mixture is stirred for 3 h at ambient temperature and then cooled to −50° C. 9.98 g (40 mmol) of 3,5-bis-trifluoromethyl-benzaldehyde dissolved in 15 ml of tetrahydrofuran are added dropwise and the mixture is stirred overnight while heating to ambient temperature. The reaction mixture is combined with water and hexane, stirred for 30 minutes and then filtered. The organic phase is separated off, washed repeatedly with water, dried with sodium sulphate and evaporated down. The residue is purified by chromatography on a short silica gel column (hexane/ethyl acetate=50:1). Yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Br)cc23)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2c[nH]c3ncc(Nc4ccccc4)cc23)c1
Temperature: 95 °C
Yield: 28 %

Procedure:
Compound 292 (135 mg, 0.2769 mmol) was dissolved in toluene (4.2 mL), under and atmosphere of argon. Aniline (0.154 mL, 1.69 mmol) and sodium tert-butoxide (57.7 mg, 0.60 mmol) were added to the reaction. Into the reaction was added tri-tert-butyl-phosphine (9.0 mg, 0.040 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (5.0 mg, 0.005 mmol). The reaction was heated at 95° C. for 18 hours. The solution was concentrated under reduced pressure. The remaining oil was partitioned between ethyl acetate and brine. The aqueous portion was extracted twice more with ethyl acetate. The organic portions were combined, dried with anhydrous magnesium sulfate, and concentrated to dryness. The residue was redissolved in ethyl acetate, adsorbed onto silica, and purified by silica gel flash chromatography with a step gradient of 50%-60% ethyl acetate:hexanes. The appropriate fractions were combined and concentrated to dryness to provide a light green solid. The solid was washed with hexanes and collected by filtration to provide compound 293 as a light green solid (26.6 mg, LRMS (ESI) [M+H+]+=344.1.)
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[S-2:11].[Na+].[Na+]>C(O)C>[CH2:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:11]1
Reactant: [S-2]
Reactant: Cc1ccccc1C(Br)Br
Agent: [Na+]
Solvent: CCO
Product: c1ccc2c(c1)CSC2

Procedure:
The compounds of formula 4 where n is 0, 1 or 2 are prepared by a modification of the procedure of ##STR13## Oliver, et al., in Chem. and Ind., 1024 (1965). α,α-Dibromo-o-xylene is reacted with sodium sulfide in ethanol to form 1,3-dihydrobenzo[c]thiophene. The thiophene compound is oxidized to the corresponding dioxide by means of hydrogen peroxide, m-chloroperzenxoic acid or other suitable oxidants or to the monoxide (Can. J. Chem., 51, 4082 (1973) using sodium metaperoidate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]1[N:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:39][C:36]2[CH:35]=[N:34][C:33]([C:29]3[O:28][CH:32]=[CH:31][CH:30]=3)=[CH:38][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(-c2ccco2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccco3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 125 mg, 0.38 mmol) in methylene chloride (2.5 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (217 μL, 0.43 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with toluene (2 mL) two times. The resulting oil was then dissolved in tetrahydrofuran (1 mL) at 25° C. This solution was then treated dropwise with 5-furan-2-yl-pyrazin-2-ylamine (91 mg, 0.57 mmol) and 2,6-lutidine (66 μL, 0.57 mmol) in tetrahydrofuran (1.5 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 to 60/40 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-furan-2-yl-pyrazin-2-yl)-propionamide (124 mg, 69%) as a yellow foam: (ES)+-HRMS m/e calcd for C23H24ClN3O4S (M+H)+ 474.1249, found 474.1254.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([Br:11])[C:8]([OH:10])=[O:9])[C:3](O)=[O:4].C(Cl)(=O)C>>[Br:1][CH:2]1[CH2:6][CH:7]([Br:11])[C:8](=[O:10])[O:9][C:3]1=[O:4]
Reactant: O=C(O)C(Br)CC(Br)C(=O)O
Solvent: CC(=O)Cl
Product: O=C1OC(=O)C(Br)CC1Br

Procedure:
10.0g (34.5 mmol) of 2,4-dibromoglutaric acid and 4.9 ml (69 mmol) of acetyl chloride are refluxed for a period of 2 hours. Volatiles are removed at 10 torr up to 90° C., and the residue bulb-to-bulb distilled (75°-90° C./0.25 torr), yielding 8.9g (95%) of a colourless, viscous oil. 1H NMR (CDCl3): dl isomer: δ 4.90 (t, 2H, J=6), 2.87 (t, 2H, J=6); meso isomer: 4.77 (dd, 2H, J=6, 10), 3.15 (dt, 1H, J=6 (t), 15 (d)), approx. 2.85 (1H, partially overlapping); dl/meso=5:1. IR (neat): 3007, 2942, 1817, 1775, 1439, 1242, 1109, 1038, 972, 932, 847, 691, 617 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[H-].[Na+].[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH:11][C:18]([NH:17][CH2:15][CH3:16])=[S:19])=[CH:9][N:10]=2
Reactant: Nc1cnc2ccc(Cl)nc2n1
Reactant: CCN=C=S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)Nc1cnc2ccc(Cl)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A total of 5.0 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (27.7 mmol; 1 eq) was dissolved in 150 mL of dry DMF. 1.32 g NaH (60% dispersion in mineral oil; 33.2 mmol; 1.2 eq) was added and the dark brown solution was stirred at room temperature for 1 hour. 2.4 g (27.7 mmol; 1 eq) ethyl isothiocyanate was then added and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into 500 mL of water. The solution was neutralized with 1 N HCl whereas the product crystallizes. The brown solid was filtered of and recrystallised from dichloromethane/diethyl ether to afford 3.6 g (48.5% yield) of 1-(6-Chloro-pyrido[2,3-b]pyrazin-3-yl)-3-ethyl-thiourea.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1.ClCCl>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](CCC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.5 %

Procedure:
Add triethylamine (0.04 mL, 0.32 mmol) followed by acetic anhydride (0.03 mL, 0.32 mmol) to a solution of 5-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (138 mg, 0.29 mmol) in dry tetrahydrofuran (3 mL). Stir at room temperature for 10 min. Dilute with dichloromethane, wash with 0.1 N hydrochloric acid (30 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 45:55 to 70:30 ethyl acetate:dichloromethane) to give the title compound (57 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:23])=[C:12]2[CH3:24])=[CH:8][CH:7]=1.Cl.[CH:29]1([C:32]2[CH:33]=[C:34]([C@@H:38]([NH2:40])[CH3:39])[CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[CH:29]1([C:32]2[CH:33]=[C:34]([C@@H:38]([NH:40][C:20]([C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:27])=[CH:26][CH:25]=3)[C:12]([CH3:24])=[C:13]4[CH3:23])=[O:21])[CH3:39])[CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)COc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To a solution of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.14 mmol) in DCM (1 mL) was added the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride (28 mg), DIEA (73 μL) and HATU (53 mg). The reaction mixture was allowed to stir at rt for 30 min, and then was diluted by ethyl acetate. The resulting mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated to afford a yellow oil (73 mg) which was directly used without further purification. ESI-MS (m/z): 497 [M+H]+
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]1[O:16][CH:15]2[N:12]([C:13](=[O:17])[CH2:14]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([S:8]([CH2:9][CH:10]1[O:16][CH:15]2[N:12]([C:13](=[O:17])[CH2:14]2)[CH2:11]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2OC(CSCc3ccccc3)CN12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2OC(CS(=O)Cc3ccccc3)CN12
Reaction time: 1 h

Procedure:
To the solution of (3RS, 5SR)-3-Benzylthiomethyl-4-oxa-1-azabicyclo[3,2,0] heptan-7-one (926 mg) in Dichloromethane (10 ml), the solution of m-Chloroperbenzoic acid (72%, 755 mg) in Dichloromethane (30 ml) was added dropwise under ice-cooling and stirred at same condition for 1 hr. The reaction mixture was poured into aqueous Sodium hydrogen carbonate, extracted with Chloroform, and dried over Sodium sulfate. The reaction mixture was purified by column (Ethyl acetate+Acetone 5:1). Yield: 570 mg (58%). m.p. 80.5°~94.5° C. NMR (CDCl3): 2.63-3.39 (5H, m), 4.03-4.15 (3H, m), 4.59-4.77 (1H, m), 7.26-7.40 (5H, m). IR (Nujol), cm-1 : 2940, 1706, 1494.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[N:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23].[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[N:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)nc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)nc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 20.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(2-fluoropyridin-5-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (82 mg, 0.17 mmol) obtained in step 2 and cyclopropanesulfonamide (100 mg, 0.84 mmol), the title compound (21 mg, 22%) was obtained.