Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)(O)[O-:33].[Na+]>CN(C)C=O>[C:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])(=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(NC(=O)OC(=O)c2ccccc2)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1

Procedure:
To a solution of 838 mg 2-benzyloxycarbonylamino-5-oxo-2tetrahydrofurancarboxylic acid in 5 ml of dimethylformamide 120 mg sodium hydride (60% dispersion in mineral oil) was added, while stirring and ice-cooling the solution. 648 mg 4-nitrobenzyl bromide was then added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture a saturated aqueous solution of sodium bicarbonate was added, then the resulting mixture was extracted with ethyl acetate. The organic layer, after washing with brine, was dried (MgSO4), and the solvent was distilled off. The resulting residue was eluted with hexane-ethyl acetate (1:1) via column chromatography using silica gel. The eluted fraction containing the desired product was collected and concentrated under reduced pressure to yield 687 mg 4-nitrobenzyl 2-benzoyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate in the form of a colorless crystal.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[CH:12][C:11]=1[O:18][CH2:19][C:20]1[C:21]([C:26]#N)=[N:22][CH:23]=[CH:24][CH:25]=1.C1C[O:31]CC1>>[O:7]1[CH2:8][CH2:9][O:5][CH:6]1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[CH:12][C:11]=1[O:18][CH2:19][C:20]1[C:21]([C:26](=[O:31])[CH2:1][CH3:2])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2C#N)cn1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(=O)c1ncccc1COc1cnc(OC)cc1C1OCCO1
Temperature: 25 °C
Yield: 58 %

Procedure:
Ethylmagnesium bromide (3M/ether, 1.53 mL, 4.60 mmol, 1.5 eq.) was added to a stirred solution of 3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (960 mg, 3.07 mmol, 1 eq.) in THF (15.0 mL) at −78° C. After addition, the reaction mixture was allowed to warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (611 mg, 58%) as a colorless oil. LRMS (M+H+) m/z 345.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[NH:18][C@@H:17]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N([CH2:43][CH3:44])CC)C.[N-:45]=[C:46]=[O:47]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:9]1[CH:14]=[C:13]([CH2:15][C@H:16]2[C:19](=[O:20])[N:18]([C:46](=[O:47])[NH:45][C:44]3[CH:43]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:17]2[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: [N-]=C=O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N[C@@H]2C(=O)OCc2ccccc2)ccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N(C(=O)Nc3ccccc3)[C@@H]2C(=O)OCc2ccccc2)ccn1
Reaction time: 8 h
Yield: 169.9 %

Procedure:
Deprotected lactam 19 (72 mg, 0.14 mmol) was dissolved in 4 mL dry THF at room temperature. Triethylamine (71 mg, 5 equiv.) was added, then 42 mg (2.5 equiv.) of the isocyanate. The reaction was stirred overnight under argon and concentrated in vacuo. The residue was purified by column chromatography eluting with methylene chloride to yield 20 (75 mg, 85%). MS: 631.3. [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23](O)=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2].S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([Cl:29])=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC

Procedure:
The compound (3) (1.1 g) was dissolved in 20 ml of benzene, and 2 ml of thionyl chloride was added dropwise at room temperature with stirring. Then, the mixture was refluxed with stirring. The reaction mixture was concentrated, and n-hexane was added to the concentrate to crystallize it. The resulting crystals wer collected by filtration, washed with n-hexane and dried to afford 980 mg of the desired product.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1>C(Cl)Cl.CO>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][N:46]([C:11]([NH:9][CH:1]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:12])[CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: NC1CCCCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCCCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, cyclooctylamine (234.1 mg, 1.82 mmol), 4-nitrophenyl chloroformate (366 mg, 1.82 mmol), diisopropyl(ethyl)amine (554 mg, 4.3 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (300 mg, 1.21 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccnc(Cl)c1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
A mixture of pyridine-4-carboxylic acid-N-oxide (28 g) and phosphorous oxychloride (120 g) was heated at reflux for 7 hours. The reaction mixture was cooled and poured into ice-water (500 mL). The precipitate was collected and crystallized from a large volume of ethyl acetate and gave 23.1 grams of 2-chloropyridine-4-carboxylic acid as a white granular solid having a melting point of 225°-227° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1.[C:23](OC=C)(=[O:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:23]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1)(=[O:25])[CH3:24]
Reactant: C=COC(C)=O
Reactant: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
4-Hydroxy-2-(3-Benzyloxybenzyl)cyclopent-2-enone (2.1 kg, 7.14 mol) was dissolved in isobutyl methyl ketone (21 L), and vinyl acetate (4.2 kg, 51.16 mol) and Lipase derived from Pseudomonas cepacia (210 g) was added to the solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (20 L), and triphenylphosphine (625 g, 2.38 mol) and AcOH (145 g, 2.41 mol) was added to the solution. Then diisopropylazodicarboxylate (413 g, 2.04 mol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was dissolved in EtOAc (5 L) and hexane (5 L) was added. The mixture was stirred at room t temperature overnight. The mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 1.8 kg (yield: 75%, 97% ee by HPLC using a chiral column)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([NH:26][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:22]2)=[CH:27][CH:28]=1
Reactant: N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.78 g) and (3R)-1-(4-chlorobenzyl)-3-pyrrolidinamine (2.65 g) in DMF (25 mL) was added K2CO3 (5.79 g). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.58 g).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=O.[CH:8]([NH:11][CH3:12])([CH3:10])[CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:34]3[C:33]4[CH2:32][CH2:31][NH:30][CH2:29][C:28]=4[S:27][C:26]=3[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[Cl:20].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:34]3[C:33]4[CH2:32][CH2:31][N:30]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:11]([CH:8]([CH3:10])[CH3:9])[CH3:12])[CH2:29][C:28]=4[S:27][C:26]=3[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: CNC(C)C
Reactant: O=C(O)C=CCBr
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reaction time: 2 h
Yield: 39.7 %

Procedure:
To 4-Bromo-but-2-enoic acid (638 mg, 3.87 mmol) in CH2Cl2 was added isopropylmethyamine (1.1 ml, 10.3 mmol), the mixture was stirred for 2 hours followed by addition of (3,4-dichloro-phenyl)-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)-amine (1.0 g, 2.57 mmol), EDCI (493 mg, 2.58 mmol), DIPEA (1.8 ml, 10.3 mmol). The resulting mixture was stirred at RT overnight. Solvents were removed and residue was purified by HPLC to gave the desired compound (500 mg, 13%). 1H-NMR (DMSO-d6) δ 8.46 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.42 (t, 1H), 6.67 (m, 1H), 3.94 (m, 2H), 3.87 (m, 4H), 2.75 (m, 2H), 2.11 (s, 3H), 0.96 (d, 6H); LCMS RT=2.72 min, [M+1]+=490.3.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 292°-293° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])[N:6]=1.C1(N)C(F)=C(F)C(F)=C([NH2:21])C=1F.Cl.Cl.CO[C:28]1[C:32](OC)=[N:31][S:30](=[O:35])[N:29]=1>CO>[NH2:21][C:28]1[C:32]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[N:31][S:30](=[O:35])[N:29]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: NCCSCc1csc(N)n1
Agent: Cl
Solvent: CO
Product: NC1=NS(=O)N=C1NCCSCc1csc(N)n1
Reaction time: 1.5 h

Procedure:
A solution of 2-[(2-aminothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 2.62 g; 10.0 mmoles) [prepared in Example 122, Step A] in 20 ml of methanol was added dropwise over 30 minutes to a cold (5°) solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10.0 mmoles) in 50 ml of methanol. After stirring for 1.5 hours, anhydrous ammonia was bubbled into the solution for 30 minutes and the solution kept at 5° for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on a Preparative HPLC system using μ-porasil silica gel. The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as an amorphous solid; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.4 moles of ethanol.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH2:29]([O:31][C:32]1[N:37]=[N:36][C:35]([NH2:38])=[C:34]([CH3:39])[C:33]=1[CH3:40])[CH3:30].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH2:29]([O:31][C:32]1[C:33]([CH3:40])=[C:34]([CH3:39])[C:35]2[N:36]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][CH2:13][CH2:14]4)=[CH:7][CH:6]=3)[N:38]=2)[N:37]=1)[CH3:30]
Reactant: CCOc1nnc(N)c(C)c1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 70 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (300 mg, ˜80% purity, 0.540 mmol, 1.0 eq), 6-ethoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-36, Step 1, 124 mg, ˜80% purity, 0.590 mmol, 1.1 eq) and N,N-diisopropylethylamine (100 μL, 0.590 mmol, 1.1 eq) in butyronitrile (3.3 mL) was heated for 3.5 hours at 125° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via preparative MPLC (Biotage Isolera; 50 g SNAP-cartridge: hexane/EtOAc 9/1→hexane/EtOAc 1/1) to give 220 mg (70% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=O)OC(C)(C)C)[CH2:12]3)=[N:7][C:6]=12.IC.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12]3)=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
(5)-tert-butyl (1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (3.6 g, 9.4 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (1.026 mL, 16.5 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (754 mg, 18.8 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 2.72 g crude product carried on as is to part C. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[NH:8]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(OCC)C>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[N:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(=O)c2c(Cl)ccc(Cl)c21
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a mixture of sodium hydride (0.17 g, 6.94 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (5.00 mL) was added a solution of 4,7-dichloro-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. The brown reaction mixture was stirred for 0.5 h followed by the addition of a solution of 1-bromopentane (0.84 g, 5.55 mmol) in anhydrous N,N-dimethylformamide (5.00 mL). The reaction mixture was stirred at ambient temperature for 16 h and poured into wet ethyl ether (30.0 mL). After the organic layer was separated, it was washed with water (2×20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy residue was dried under vacuum and the solid was triturated with ether to give the title compound (0.98 g, 98%): MS (ES+) m/z 286.2 (M+1).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].FC(F)(F)C(O)=O.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:20]1[CH2:19][CH2:18][N:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Methanesulfonic anhydride (9.3 mg, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.44 (22.38 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dichloromethane (1.8 mL). After two hours, reaction mixture was loaded directly onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.46 (19.2 mg).
Reaction SMILES: CN(C)CCO.[Li]CCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CCCCCC.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[N:15]=1
Reactant: COc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-dimethylaminoethanol (3.50 mL, 16.36 mmol) in hexane (20.0 mL, HPLC grade) cooled at −5° C. was added drop wise n-BuLi (3.60 M, 9.0 mL, 32.40 mmol) under nitrogen atmosphere. After 30 min at 0° C., 2-methoxy-pyridine (0.60 g, 5.45 mmol) in hexane (20.0 mL) was added drop wise. After stirring the reaction mixture for 1 h at 0-5° C., the reaction medium was cooled to −78° C. followed by drop wise addition of tributyl tin chloride (3.70 mL, 13.62 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then allowed to stir at 0-5° C. for 30 min. The reaction mixture was then allowed to come to room temperature. After the completion of reaction (TLC monitoring), the reaction mass was cooled to 0° C. and water was added slowly. The aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue (1.80 g, 72%) was carried forward to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:21]([O:23]CC)=[O:22].Cl>O1CCCC1.O>[C:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:21]([OH:23])=[O:22])([OH:11])=[O:10]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(=O)O)c1ccc(O)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
About 0.5 mole of 4-hydroxybenzeneacetic acid is dissolved in about 50 ml of anhydrous tetrahydrofuran at -40° C. To this solution is added 3 equivalents of lithium diisopropylamide. The temperature is maintained at about -40° C. for about 15 minutes. Then 1 equivalent of ethyl chloroformate is added and the temperature is raised from about -40° C. to about 20° C. and the reaction mixture stirred for about 60 minutes. The reaction mixture is poured into water and the monoester of α-carboxy-4-hydroxybenzeneacetic acid is recovered from the aqueous solution. Hydrolysis of the half-ester with sodium hydroxide followed by acidification with hydrochloric acid gives α-carboxy-4-hydroxybenzeneacetic acid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1>>[OH:8][C:9]1[CH:10]=[C:11]([S:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(S)c1
Product: CCOC(=O)CSc1cccc(O)c1
Yield: 41 %

Procedure:
Ethyl [(3-hydroxyphenyl) sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromoacetate (7.95 g, 47.6 mmol) and 3-hydroxythiophenol (7.95 g, 47.6 mmol); 4.21 g yellow oil. Yield 41%; MS: 211.2 (M−H)−