Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1I.[CH2:16]([O:23][CH2:24][C@@H:25]([CH3:35])[C:26]#[C:27][Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH2:16]([O:23][CH2:24][C@H:25]([C:26]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:4]=2)[NH:1][C:27]=1[Si:28]([CH2:33][CH3:34])([CH2:29][CH3:30])[CH2:31][CH3:32])[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(C)(C)c1cnc(N)c(I)c1
Reactant: CC[Si](C#C[C@H](C)COCc1ccccc1)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Temperature: 90 °C
Yield: 88.3 %

Procedure:
A vigorously stirred suspension of methyl 2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate (4.61 g, 14.4 mmol), (S)-(4-benzyloxy-3-methylbut-1-ynyl)triethylsilane (4.98 g, 17.3 mmol), Pd(dppf)Cl2.CH2Cl2 (0.59 g, 0.72 mmol) LiCl (0.61 g, 14.4 mmol), Na2CO3 (3.82 g, 36.0 mmol) and N,N-dimethylformamide (60 mL) was degassed via three vacuum/nitrogen ingress cycles and the resulting mixture was heated at approximately 90° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered through celite® washing copiously with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution; 20-25% ethyl acetate/hexanes as eluent) to give the title compound as an oil (6.11 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[NH:35]1[CH2:41][C:39](=[O:40])[NH:38][C:36]1=[O:37]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:41]4[C:39](=[O:40])[NH:38][C:36](=[O:37])[NH:35]4)=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)s1
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)s1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (30 mg, 0.075 mmol) in EtOH (1 mL) was added piperidine (20 μL, 0.150 mmol), and hydantoin (10 mg, 0.075 mmol). The reaction mixture was stirred at 85° C. for 3 hours. The solid formed was isolated by filtration to provide 5-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide. LCMS (M+1=482)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Product: CCCCCCNc1nc(SC)[nH]c2nccc1-2

Procedure:
To 200 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]-pyrimidine was added 2 ml of n-hexylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of ethyl alcohol up to 40% ethyl alcohol. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from ethyl alcohol/water to afford white crystals of product, yield 79 mg (60%), m.p. 117.5° - 118.5°.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17](Cl)[CH:18]=1)[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[Br-].[Cl:21]C1C=C(C=CC=1Cl)C[N+]1C=CN2C=CC=CC=12.[Br-].COC1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12.[Cl-].COC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[I-].C(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)#N.[Br-].BrC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Cl-].C1(C2C=C(C=CC=2)C[N+]2C=CN3C=CC=CC=23)C=CC=CC=1.[Cl-].S(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)(=O)(=O)N.[Cl-].CS(C1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12)(=O)=O.[Br-].FC(F)(F)C1C=CC(C[N+]2C=CN3C=CC=CC=23)=CC=1>>[Cl-:2].[Cl:21][C:4]1[C:3]([Cl:2])=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Clc1cc(Cl)cc(C[n+]2ccn3ccccc32)c1
Reactant: Clc1ccc(C[n+]2ccn3ccccc32)cc1Cl
Agent: Brc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1ccccc1C[n+]1ccn2ccccc21
Product: Clc1cccc(C[n+]2ccn3ccccc32)c1Cl

Procedure:
1-(3,5-dichlorobenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3,4-dichlorobenzyl)-imidazo[1,2-a]pyridinium bromide; 1-(2-methoxybenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-methoxybenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-cyanobenzyl)imidazo[1,2-a]pyridinium iodide; 1-(3-bromobenzyl)imidazo[1,2-a]-pyridinium bromide; 1-(3-phenylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-sulfamoylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(2-methylsulfonylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(4-trifluoromethylbenzyl)imidazo[1,2-a]pyridinium bromide; and 1-(3-furfuryl)imidazo[1,2-a]pyridinium bromide.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>>[Cl:41][C:17]1[CH:18]=[CH:19][C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH2:12]2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a solution of rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.86 g, 1.61 mmol) in CH2Cl2 (12 ml) was added TFA (3 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.68 g (98%) of the title compound as a white solid. ES-MS m/e: 401.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9](N)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(ON=O)CC(C)C.[CH3:25][S:26]SC>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([S:26][CH3:25])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSC
Reactant: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1c(SC)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
2 g 5-tert-butyl-2-methoxy-3-nitro-phenylamine are dissolved in 20 ml acetonitrile, combined successively with 3.6 ml isopentylnitrite as well as 2.4 ml dimethyldisulphide and refluxed for 2 h. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 90:10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19][C@H:20]([OH:23])[CH2:21][OH:22])=[CH:17][C:16]([O:24][CH3:25])=[C:15]2[C:10]=1[C@@H:11]1[CH2:26][C@H:14]2[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:22][CH2:21][C@@H:20]([OH:23])[CH2:19][C:18]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=2)[C@H:14]2[CH2:26][C@@H:11]3[CH2:12][CH2:13]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C[C@H](O)CO)c(OCc2ccccc2)c2c1[C@@H]1CC[C@H]2C1
Solvent: c1ccncc1
Product: COc1cc(C[C@H](O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c2c1[C@@H]1CC[C@H]2C1

Procedure:
Treatment of (2S*)-3-[(1R*,4S*)-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]propane-1,2-diol (13.95 g, 39.56 mmol) with p-toluenesulfonyl chloride (8.25 g, 43.92 mmol) in anhydrous pyridine (350 mL) generally according to the procedure described for Intermediate 18 gave (2S*)-3-[(1R*,4S*)-5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (10 wt. %, 1.6 g) generally according to the procedure described for Intermediate 4 provided 12.77 g (77%) of (2S*)-2-hydroxy-3-[(1R*,4S*)-5-hydroxy-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-6-yl]propyl 4-methylbenzenesulfonate. Treatment of the phenyl (12.73 g, 30.4 mmol) with triphenylphosphine (8.78 g, 33.5 mmol) followed by diethylazodicarboxylate (5.83 g, 33.5 mmol) generally according to the procedure described for Intermediate 5 afforded 7.67 g (48%) of [(2R*,6R*,9S*)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C22H24O5S: C, 65.98; H, 6.04. Found: C, 65.61; H, 5.92.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:32])[CH:18]=[N:19][O:20][CH2:21][C:22]1[CH2:27][C:26]([CH3:28])=[C:25]([CH3:29])[CH2:24][C:23]=1[CH2:30]Cl>>[CH3:15][O:16][C:17](=[O:32])[CH:18]=[N:19][O:20][CH2:21][C:22]1[CH2:27][C:26]([CH3:28])=[C:25]([CH3:29])[CH2:24][C:23]=1[CH2:30][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: COC(=O)C=NOCC1=C(CCl)CC(C)=C(C)C1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C=NOCC1=C(COc2ccccc2C)CC(C)=C(C)C1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
20 g of o-cresol and 40 g of potassium carbonate are added to a solution of 27.5 g of methyl(2-chloromethyl-4,5-dimethylcyclohexa-1,4-dienyl)methoxyiminoacetate. The mixture is now heated for 14 hours at 65°, cooled to room temperature and filtered with suction, and the filtrate is evaporated. The residue is taken up in 150 ml of ethyl acetate, the mixture is washed with potassium carbonate solution and filtered with suction, and the filtrate is evaporated. In this manner, 34 g of the title compound are obtained as a pale brown oil.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[C:11]([C:15]1[CH:16]=[C:17]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:18]([C:20](=[CH:25]N(C)C)[C:21]([NH:23][CH3:24])=[O:22])=O)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].O>CC(O)C.C(O)(C)(C)C.ClCCl.C(OCC)(=O)C>[C:11]([C:15]1[CH:16]=[C:17]([C:18]2[C:20]([C:21]([NH:23][CH3:24])=[O:22])=[CH:25][N:9]=[C:8]([O:7][CH3:6])[N:10]=2)[CH:29]=[C:30]([C:33]([CH3:35])([CH3:36])[CH3:34])[C:31]=1[OH:32])([CH3:12])([CH3:13])[CH3:14]
Reactant: CNC(=O)C(=CN(C)C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COC(=N)N
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CNC(=O)c1cnc(OC)nc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.7 %

Procedure:
O-methylisourea hydrogensulfate (3.44 g, 20 mmol) was added to a solution of 2-(3,5-ditert-butyl-4-hydroxy-benzoyl)-3-dimethylamino-N-methyl-prop-2-enamide (3.55 g, 9.87 mmol) in 2-propanol (37.5 mL). The suspension was stirred at room temperature for 10 min then a 1 M solution of potassium tert-butoxide in tert-butanol (37.5 mL) was added and the mixture was immersed into a bath maintained at 80° C. and stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then distributed between dichloromethane (150 mL) and water (75 mL). The organic layer was washed with water (2×50 mL), once with brine (10 mL), dried over magnesium sulfate and evaporated. The residue obtained was dissolved in dichloromethane and flash-chromatographed using DCM, 1:19, 1:9, and 1:3 ethyl acetate-dichloromethane, followed by ethyl acetate as mobile phases. Early fraction eluted 3-(3,5-ditert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl amide, which is the solvolysis product of the starting material; the title compound was eluted using 1:3 ethyl acetate-dichloromethane. The fractions containing the product were evaporated; the residue redissolved in hot DCM, diluted with cyclohexane then heated to remove some DCM and allowed to crystallize. The solids obtained were redissolved in ethyl acetate, the solution filtered, concentrated, diluted with cyclohexane and allowed to crystallize to give white crystals. The solids were filtered off, washed with cyclohexane and hexane, and dried to constant weight at 55° C. and 20 ton to afford 1.20 g of the title compound (32.7% yield). TLC (ethyl acetate), Rf 0.68, 1H-NMR (300 MHz, DMSO-d6) δ 1.40 (9H, s), 2.75 (3H, d, J=3.9 Hz), 3.98 (3H, s), 7.55 (1H, s), 7.69 (2H, s), 8.44 (1H br s), 8.49 (1H, s).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH3:16])=[N+]=[N-].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[NH2:1][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH3:16]
Reactant: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Br)cc(N)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To methyl 4-azido-6-bromo-3-methoxypyridine-2-carboxylate (0.500 g, 1.74 mmol) in 10 mL of methanol was added NaBH4 (0.046 g, 1.22 mmol). The reaction mixture was stirred at room temperature for 10 min. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with H2O, dried (MgSO4) and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel). Elution with 100% ethyl acetate gave 0.300 g of a white solid. 1H NMR(CDCl3): δ 3.90 (s, 1H); 3.95 (s, 1H); 4.60 (s, 2H); 6.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(CC(=O)O)c(OCc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To a solution of [4-methyl-2-(phenylmethoxy)phenyl]acetic acid (10.25 g, 40 mmol) in toluene (70 ml containing 2 drops of DMF) was added oxalyl chloride (4.0 ml, 46 mmol, 1.15 equivalents) dropwise, the mixture was stirred at room temperature for 5 hr then 44 ml of tert-butanol was added, the resulting solution was stirred at room temperature for 20 hr. The solvents were evaporated and the residue obtained was purified by chromatography on silica gel (EtOAc-hexanes, 1:40 to 1:25) to provide the desired product [4-methyl-2-(phenylmethoxy)-phenyl]acetic acid tert-butyl ester as an oil (11.70 g, 92.80% yield). 1H NMR (CDCl3) δ: 7.521˜7.364 (5H, m), 7.147 (1H, d, J=7.81 Hz), 6.810 (2H, m), 5.118 (2H, s), 3.629 (2H, S), 2.391 (3H, s), 1.461 (9H, s) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1>>[CH2:10]([O:9][C:3]([C:4]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)[NH:20][C:5]=1[CH3:7])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C)[nH]c2ncc(Br)nc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
To a flask charged with 20 mL of anhydrous N-meythlpyrrolidine at 0° C. was added 60% NaH (840 mg, 21 mmol). After stirring 15 min, ethyl acetoacetate (2.73 g, 10.8 mmol) was added slowly. After stirring an additional 20 min 3,5-Dibromo-pyrazin-2-ylamine (5.04 g, 20 mmol). The reaction vessel was then removed from the ice bath and heated to 140° C. for 3 days. The dark mixture was cooled to rt and diluted with diethyl ether and water. The mixture was filtered and then partitioned. The organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated to afford a dark red oil. This was purified by silica gel chromatography (4:1 Hexanes:EtOAc) to afford 290 mg of 2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:53])C(=O)C1>C(O)(=O)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[Cl:53])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(Cl)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.064 mmol, 1 equiv) in acetic acid (0.64 mL) was added NCS (10 mg, 0.077 mmol, 1.2 equiv). After stirring 18 h, reaction is pale yellow solution. LCMS indicated complete conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a viscous yellow oil (22 mg, 52% yield). 1H NMR (500 MHz, CDCl3) δ 7.16 (s, 1H), 7.12 (d, J=5.7 Hz, 2H), 6.97 (d, J=9.1 Hz, 1H), 6.83 (d, J=10.6 Hz, 1H), 4.97 (s, 1H), 4.62-4.50 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.19-4.11 (m, 2H), 2.84 (s, 3H), 2.75 (s, 2H), 2.27 (d, J=1.7 Hz, 3H), 2.23-2.13 (m, 2H), 1.80 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) δ −119.48 (s, 1F), −139.47 (s, 1F); LCMS (ESI, M+1): 655.5.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:9]([OH:10])[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:1]([NH:4][CH:5]1[C:9](=[O:10])[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-(acetylamino)-4-hydroxypyrrolidine-1-carboxylate obtained in Step A (680 mg) in dichloromethane (8 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.77 g) and stirred overnight at room temperature. The solution was then evaporated and purified on a Biotage Horizon® system (silica, gradient 50-90% ethyl acetate in hexane) to yield the title compound. LC-MS 243.2 (M+1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH:5]1([Mg]Br)[CH2:7][CH2:6]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH3:11]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([CH:5]2[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:11]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2CC2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Indium trichloride (2.2 g, 10 mmol) and THF (50 mL) were combined under nitrogen and cooled to −70° C. Cyclopropylmagnesium bromide solution (33 mL, 30 mmol, 0.92M) was added dropwise while maintaining the reaction temperature ≦−60° C. After the addition was complete the reaction was stirred 0.5 h with cooling then 0.5 h with the cooling bath removed. The resulting solution was added via cannula to a refluxing solution of ethyl-4-iodobenzoate (5.5 g, 20 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (421 mg, 0.60 mmol) and THF (100 mL) under nitrogen. After 24 h, the contents of the reaction flask were cooled and the solvent was removed in vactio. Water (100 mL) and 5% KHSO4 were added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and filtered. The filtrate was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:EtOAc 95:5) to give the 4-cyclopropyl-benzoic acid ethyl ester as an orange oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:14])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(C)c1ccccc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
Sodium hydride (0.1702 g, 7.09 mmol) was added slowly to a NaCl ice bath containing EtOH (2.6 mL, 2.7 M) stirring under N2. 4-Phenylpentan-2-one (55) (1.0493 g, 6.47 mmol) and diethyloxalate (0.88 mL, 6.47 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 90 min, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated to provide 56 (0.7230 g, 42.6%) which was used without further purification in the next step. 1H (CDCl3, 400 MHz): δ 7.34-7.16 (5H, m), 6.30 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.39-3.26 (1H, m), 2.82 (1H, dd, J=15.1, 6.8 Hz), 2.72 (1H, dd, J=15.1, 7.8 Hz), 1.36 (3H, t, J=7.0 Hz), 1.32 (3H, d, J=6.8 Hz) ppm. HPLC: 10.934 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C)n1

Procedure:
A mixture of 50 g of 6-amino-2-methyl-pyridine in 250 ml of acetic acid anhydride was refluxed for one hour and was then evaporated to dryness under reduced pressure. The residue was taken up in methylene chloride and the solution was washed with water and then with aqueous sodium hydroxide solution and then with water. The solution was dried and evaporated to dryness under reduced pressure. The residual oil was crystallized from isopropyl ether to obtain 41 g of 6-acetamido-2-methyl-pyridine melting at 87° C.