Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.Cl.[C@H:5]12[CH2:11][C@H:8]([CH2:9][CH2:10]1)[C@@H:7]([C:12]1[NH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]4[NH:37][C:36]([C@@H:38]6[CH2:44][C:41]7([CH2:43][CH2:42]7)[CH2:40][N:39]6[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:35][CH:34]=4)[CH:27]=[CH:26]5)=[CH:19][CH:18]=3)=[CH:15][N:16]=1)[NH:6]2.[F:56][CH:57]([F:70])[O:58][CH2:59][CH2:60][C@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[C:62](O)=[O:63].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C)C=O>[CH3:53][O:52][C:51](=[O:54])[NH:50][C@@H:46]([CH:47]([CH3:49])[CH3:48])[C:45]([N:39]1[C@H:38]([C:36]2[NH:37][C:33]([C:28]3[CH:27]=[CH:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([C:20]5[CH:19]=[CH:18][C:17]([C:14]6[NH:13][C:12]([C@@H:7]7[C@@H:8]8[CH2:11][C@@H:5]([CH2:10][CH2:9]8)[N:6]7[C:62](=[O:63])[C@@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[CH2:60][CH2:59][O:58][CH:57]([F:70])[F:56])=[N:16][CH:15]=6)=[CH:22][CH:21]=5)[CH:24]=4)[CH:29]=3)=[CH:34][N:35]=2)[CH2:44][C:41]2([CH2:42][CH2:43]2)[CH2:40]1)=[O:55]
Reactant: COC(=O)N[C@@H](CCOC(F)F)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@H]6N[C@@H]7CC[C@H]6C7)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](CCOC(F)F)C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CC7(CC7)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate tetrahydrochloride (66 mg, 0.096 mmol), (S)-4-(difluoromethoxy)-2-(methoxycarbonylamino) butanoic acid (20 mg, 0.088 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (24 mg, and hydroxybenzotriazole hydrate (HOBt) (17 mg, 0.125 mmol) were all weighed out in a flask and anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was cooled down in an ice bath to 0° C. and N-methylmorpholine (NMM) (58 mg, 0.576 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC. 37 mg, (43%). 1H-NMR: 400 MHz, (CD3OD) δ 8.08 (s, 1H), 8.01 (d, J=16 Hz, 1H), 7.86-7.66 (m, 10H), 7.38 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.58 (t, J=75.6 Hz, 1H), 5.32 (t, J=7.2 Hz, 1H), 4.70 (s, 1H), 6.6-6.25 (m, 1H), 4.51 (s, 1H), 4.14 (m, 1H), 3.98-3.78 (m, 4H), 3.63 (s, 6H), 3.50-3.46 (m, 1H), 2.70 (brs, 1H), 2.39-1.78 (m, 7H), 1.71-1.40 (m, 2H), 0.99-0.90 (m, 5H), 0.82-0.60 (m, 4H). MS (ESI) m/z 894.16 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13]Cl)[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[I-].[Na+]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cc(C#N)c(N)cc1OCCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: COc1cc(C#N)c(N)cc1OCCCN1CCOCC1

Procedure:
A mixture of 2-amino-4-chloropropoxy-5-methoxy-benzonitrile (1.000 g, 4.12 mmol), morpholine (1.0 mL) and catalytic amount of sodium iodide were added into a round bottom flask. The solution was stirred and heated under reflux for 2 h. After reaction, extracted the solution with dichloromethane and water, and then combined the organic phases. After evaporating most of the solvent, equivalent amount of hydrochloric acid ether was added into the solution, and filtered to yield 1.100 g of white solid product with a recovery rate of 91%.
Reaction SMILES: N.[Li].[C:3]1([C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(OC)[CH2:10][CH:11]=[CH2:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=CC(=C)C>C1COCC1.C(Cl)(Cl)Cl>[C:3]1([CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:11]=[CH2:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCC(OC)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: C=CC(=C)C
Product: C=CCC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 102.6 %

Procedure:
Ammonia, 400 mL, was cooled to -78° C. and 1.15 g of lithium wire was added. After the lithium had dissolved, a solution of 15.5 g of 4,4-diphenyl-4-methoxybut-1-ene in 100 mL of THF was added dropwise, over 1 hr. The mixture was warmed to reflux, then cooled to -78° C. Isoprene, 4 mL, was added to the reaction mixture to quench excess lithium, followed by 4 mL of methanol to quench the diphenylalkyl anion. The mixture was acidified with 9 g of ammonium chloride and the ammonia allowed to evaporate at room temperature. The residue was shaken with chloroform and water. The organic layer was dried and concentrated in vacuo to give 14.3 g of crude residue which, after chromatography on silica gel with chloroform as eluent, gave 13.9 g of 4,4-diphenylbut-1-ene which is characterized by:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH2:5]([N+:7]1[CH:11]=[CH:10][N:9]([CH2:12]C)[CH:8]=1)[CH3:6].[C:14]([O-])(=O)CCCCCCC.C([N+]1C=CN(CC)C=1)C.CCCCCCCCCCCC(O[Sn](OC(CCCCCCCCCCC)=O)(CCCC)CCCC)=O>>[C:1]([O-:4])(=[O:3])[CH3:2].[CH2:5]([N+:7]1[CH:11]=[CH:10][N:9]([CH3:12])[C:8]=1[CH3:14])[CH3:6]
Reactant: CCn1cc[n+](CC)c1
Reactant: CCCCCCCC(=O)[O-]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC
Product: CC[n+]1ccn(C)c1C

Procedure:
1,3-diethylimidazolium acetate and 1,3-diethylimidazolium octanoate are better relative to DBTL as reference, in terms of drying and the early development of pendulum hardness.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(#N)C.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Yield: 88 %

Procedure:
1.15 g of the N-hydroxysuccinimide ester of N-(tert-butoxycarbonyl)-L-alanine are dissolved in 100 ml of DMF and the solution is added dropwise over 6 hours to a mixture of 3.4 g (10 equivalents) of piperazine in 200 ml of DMF. The mixture is concentrated and the residue is taken up in water and extracted three times with 200 ml of dichloromethane each time. The organic phase is dried and the solvent is removed under reduced pressure. The target compound is obtained in a yield of 88%. [TLC: acetonitrile/water/glacial acetic acid 5:1:0.2 Rf =0.42].
Reaction SMILES: S(Cl)(C1C=[CH:9][C:7]([CH3:8])=[CH:6]C=1)(=O)=O.[Cl:12][C:13]1(C(O)=O)[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][NH:14]1.N1C=CC=CC=1.[C:29]([O-:32])(O)=[O:30].[Na+]>C(O)(C)(C)C>[Br:19][C:16]1[C:15]([C:29]([O:32][C:7]([CH3:9])([CH3:8])[CH3:6])=[O:30])=[N:14][C:13]([Cl:12])=[CH:18][CH:17]=1
Reactant: O=C(O)C1(Cl)C=CC(Br)=CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5-bromo picolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0° C. The reaction was then stirred at room temperature for 12 hours. NaHCO3 (aqueous, saturated) was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over Na2SO4. Filtration and evaporation of the organic solvent provided the title compound which was used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([NH:38][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) in dimethylformamide (2 mL) were added 1-hydroxybenzotriazole (96.4 mg), benzylamine (0.063 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137 mg). The mixture was stirred for 3 hours at 20° C. The resulting mixture was diluted with ethyl acetate and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with methanol to give N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (150 mg) as a solid substance.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1.C([O-])(=[O:20])C.[K+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)(=O)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:20])[CH:7]=1
Reactant: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Reactant: CC(=O)[O-]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: CC(=O)O
Product: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide (from Step 1) (30.0 g, 0.127 mol), anhydrous potassium acetate (25 g, 0.25 mol), acetic anydride (25 g, 0.25 mol), and 10 ml acetic acid were combined in a 250-ml round-bottomed flask with overhead stirring and heated to 130° C. for 4 hours. The mixture was concentrated under vacuum, the solids dissolved in 95 ml acetonitrile; 5 ml water, filtered through charcoal and poured into 600 ml ice with stirring. The mixture was allowed to stand overnight at room temperature, then 9.62 g (30%) product collected by filtration as a medium brown solid (adequate for the next step without purification). 1H-NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.59 (quartet, J=9.91 Hz, 1H), 7.29 (t, J=10.36 Hz, 1H), 7.21 (d, J=8.20 Hz, 1H), 7.11 (t, J=8.48 Hz, 1H), 5.83 (m, 2H), 5.02 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.57 (quintet, J=7.66 Hz, 1F)-113.88 (quartet, J=8.93 Hz, 1F). LC/MS tr=4.29 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 238 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[S:29]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[O:34]=[S:29]1(=[O:35])[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 54.1 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (274 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1>CC(C)=O>[O:20]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:15][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: BrCC1CCCO1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(SCC2CCCO2)cc1
Temperature: 45 °C
Yield: 113.5 %

Procedure:
4-Bromothiophenol (1.9 g, 10 mmol) and potassium carbonate (1.5 g, 11 mmol) were stirred in acetone (40 ml). Tetrahydrofurfurylbromide (2 g, 12 mmol) was added dropwise, and the mixture was then heated at 45° C. for 2 hours. The mixture was allowed to cool, the insolubles removed by filtration and the filter pad washed with acetone. The volatiles were removed from the filtrate by evaporation to give crude 1-(2-tetrahyrofurylmethylthio)-4-bromobenzene (3.1 g) an oil (m/z 273). This crude product was dissolved in methanol (60 ml) and water (10 ml). Oxone (8 g) added in portions and the mixture stirred for 2.5 hours. Water (20 ml) was added and the methanol was removed by evaporation. Further water (20 ml) was added to the aqueous residue, which was then extracted with DCM (2×50 ml). The extracts were combined, washed with brine (15 ml), dried and the solvent evaporated. The residue was purified by chromatography on silica eluting with DCM/isohexane/EtOAc (10:8:2) to give the title compound (1.7 g, 56%) as a solid. NMR (CDCl3): 1.56 (m, 1H), 1.88 (m, 2H), 2.13 (m, 1H), 3.20 (dd, 1H), 3.39 (dd, 1H), 3.72 (m, 2H), 4.26 (m, 1H), 7.68 (d, 2H), 7.79 (d, 2H); m/z 305.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][C@H:10]([CH3:12])[NH:9][C@H:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[C:14]1(C)[CH:19]=CC(S(OCCC)(=O)=O)=C[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][C@@H:8]([CH3:13])[N:9]([CH2:15][CH2:14][CH3:19])[C@@H:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)N1C[C@@H](C)N[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: CCCN1[C@H](C)CN(C(=O)OCC)C[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of 25.8 grams of 1-ethoxycarbonyl-cis-3,5-dimethylpiperazine, 38.6 grams of propyl 4-toluenesulfonate, 90 ml. of absolute ethanol and 9.5 grams of sodium carbonate is stirred and heated to reflux. After 30 minutes of reflux, vigorous evolution of carbon dioxide begins and continues for about 5 hours. Refluxing is continued for a total of 22 hours. The reaction mixture is then cooled and filtered and the solvent is evaporated. The resulting residue is mixed with 300 ml. of aqueous 1 N sodium hydroxide solution and the mixture is extracted with ethyl ether. The ether extract is washed successively with 100 ml. of aqueous 1 N sodium hydroxide and 100 ml. of water and then dried over anhydrous sodium sulfate. The organic solution is then treated with charcoal and the solvent is evaporated to leave a residue which is purified by chromatography to give 4-ethoxycarbonyl-cis-2,6-dimethyl-1-propylpiperazine.
Reaction SMILES: [O:1]=[C:2]([CH3:21])[CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:5].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][CH:3]([C:2](=[O:1])[CH3:21])[C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:5])=[CH:27][CH:26]=1
Reactant: CC(=O)CC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of (R)-benzyl 2-(3-oxobutanoyl)pyrrolidine-1-caboxylate (670 mg, 2.32 mmol) in anhydrous THF (20 mL) was added sodium hydride (111 mg, 60 wt. % in mineral oil, 2.78 mmol). The mixture was stirred at room temperature for 30 min and added to a solution of 4-chlorobenzyl bromide (715 mg, 3.48 mmol) in THF (10 mL). The reaction mixture was stirred at 60° C. for 18 h and then the solvents were removed in vacuo. Purification of the resulting residue by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) afforded the desired product (812 mg, 86%). MS: calculated: 413.14, found (MH+): 414.3.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:28])=[O:29])[CH2:43][CH3:44]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 53.2 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19](Cl)(=[O:21])=[O:20])=[N:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][N:17]=1)(=[O:20])=[O:21]
Reactant: COc1ccccc1N
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of 2-methoxy-phenylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:18][C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:18][C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncccn3)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(Oc2ncccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of [4-ethyl-1-hydroxy-6-(pyrimidin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.13 g, 0.38 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH (0.091 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give [4-ethyl-1-hydroxy-6-(pyrimidin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.030 g, 25%). 1H NMR (400 MHz, DMSO-d6δ9.00 (br s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 5.51 (m, 1H), 3.01 (m, 1H), 2.61 (m, 2H), 2.14 (m, 1H), 1.17 (m, 3H). MS (ES) m/z: 313 (M−1)−. HPLC purity: 99.12% (220 nm), 98.58% (Maxplot).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[K].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>CN(C=O)C.C(O)C.O>[NH2:17][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: NN
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(CN)c(F)c1
Temperature: 130 °C
Reaction time: 9 h
Yield: 4.3 %

Procedure:
4-(Bromomethyl)-3-fluorobenzonitrile (CAS 105942-09-4, 21 g) was dissolved in DMF (90 ml). Phthalimide potassium salt (19.64 g) was added and the mixture was stirred for 9 h at 130° C. After cooling to rt, the mixture was poured on ice. The solid was filtered off. Ethyl acetate and water were added and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated to give a light brown solid (14.1 g, 42% pure as judged by NMR). This solid was suspended in ethanol (50 ml). A solution of hydrazine in water (24%, 15 ml) was added and the mixture was refluxed for a total of 14 h. The mixture was filtered and the solvent was evaporated. The product was purified by chromatography (silica gel, CH2Cl2=>CH2Cl2/MeOH 4:1) to give 4-aminomethyl-3-fluoro-benzonitrile (0.63 g) as a brown oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18](=O)[CH3:19])[CH:12]=[CH:11]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]([CH3:19])=[CH2:1])[CH:12]=[CH:11]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2n1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred suspension of (methyl)triphenylphosphonium bromide (2000 mg, 5.60 mmol) in dry THF (15 ml) was added a solution of potassium tert-butoxide (628 mg, 5.60 mmol) in dry THF (10 ml) with ice cooling. The mixture was then allowed to warm to room temperature. After 2 hours at room temperature, to this was added a solution of 1-(6-bromoquinolin-2-yl)ethanone (Step CA1B) (700 mg, 2.80 mmol) in dry THF (15 ml) with ice-cooling then the mixture was allowed to warm to room temperature. After 3 hours at ambient temperature, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel (250 g) with hexane-ethyl acetate (10:1) to furnish the title compound (661 mg, 95%) as a tan solid. 1H NMR (270 MHz, CDCl3) δ 2.34 (3H, s), 5.50 (1H, s), 5.93 (1H, s), 7.65-7.78 (2H, m), 7.88-8.03 (3H, m). MS (ESI): m/z 248.11, 250.14 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C([Sn](CCCC)(CCCC)CCCC)=NN2C)=CC=1.CN(C=[O:54])C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:54][CH2:17][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[CH:2][N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:15])[CH3:16]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Product: CC(C)(CO)NC(=O)c1c[nH]c2nccnc12
Temperature: 90 °C
Yield: 37 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 0.203 mmol) and 6-chloro-1-methyl-3-(tributylstannyl)-1H-indazole (0.148 g, 0.228 mmol) were dissolved in DMF (3 mL). The reaction mixture was evacuated and filled with nitrogen then copper(I) iodide (9 mg, 0.081 mmol) and tetrakis(triphenylphosphine)palladium (0) (46 mg, 0.046 mmol) were added. The reaction mixture was heated at 90° C. for 2 h then partitioned between ethyl acetate and water. The organic phase was washed with brine then dried over magnesium sulfate. The crude material was purified by chromatography using 25% ethyl acetate/hexane to obtain 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-trimethyl-silanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (40 mg, 37%).