Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([O:28]C)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1>[NH:1]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Same procedure as above with N-Boc-Tyr(Bn)-Leu-OMe (1.034 g, 2.073 mmol), aqueous LiOH (1 M, 2.2 mL, 2.2 mmol) in THF (15 mL). A white solid was obtained (1.035 g, 100%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 0.90 (d, J=5 Hz, 1H, Me2 Leu), 1.40 (s, 9H, (CH3)3), 1.60 (m, 3H, CH2—CH Leu), 3.00 (m, 2H, CH2), 4.29 (m, 1H, CHα), 4.44 (m, 1H, CHα), 4.88 (s, 2H, CH2 (Bn)), 5.29 (broad s, 1H, NHBoc), 6.70 (m, 1H, NH amide), 6.91 (d, J=5 Hz, 2 aromatic H), 7.12 (d, J=5 Hz, 2 aromatic H), 7.33-7.44 (m, 5 aromatic H). 3C NMR (75 MHz, CDCl3) δ 21.8, 22.9, 24.7 (CH-Me2 Leu), 28.2 ((CH3)3), 37.0 CH2 Leu), 41.1 (CH2 Tyr), 51.6 (CHα Leu), 55.7 (CHα Tyr), 70 (CH2 (Bn)), 80.4 (C(CH3)3), 114.9, 127.5, 127.9, 128.5, 128.9, 130.5, 137.0 (11 aromatic C), 155.8, 157.8 (Car-O, CO carbamate), 172.0, 176.8 (CO acid, CO amide).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:38][CH:37]2[CH2:39][CH:33]([CH2:34][CH2:35][CH2:36]2)[CH2:32]1>>[CH:37]12[CH2:39][CH:33]([CH2:34][CH2:35][CH2:36]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:38]2
Reactant: ClCCN1CC2CCCC(C2)C1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CC2CCCC(C2)C1)C3
Reaction time: 96 h
Yield: 63.9 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.011 moles), triethylamine (6.4 ml, 0.046 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (3.0 g, 0.013 moles). The reflux time is 96 hours. Recrystallization from ethanol gave the product (2.9 g), mp 122°-125° C.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C@H:11]([CH3:19])/[CH:12]=[CH:13]/[C@H:14]([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8][C@H:7]1[C@@H:6]([OH:20])[CH2:5][CH2:4][CH2:3]2>C(O)(=O)C.[Pt]>[CH3:1][C@@:2]12[C@@H:10]([C@H:11]([CH3:19])[CH2:12][CH2:13][C@H:14]([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH2:9][CH2:8][C@H:7]1[C@@H:6]([OH:20])[CH2:5][CH2:4][CH2:3]2
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)[C@@H](C)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C

Procedure:
The compound of Example 7A (400 mg, 1.4 mmol) was dissolved in 20 mL of acetic acid and hydrogenated using a 10% platinum on carbon catalyst. After purging with nitrogen and filtering to remove catalyst, the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine and dried over sodium sulfate. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient from 5% to 30% ethyl acetate in hexanes to furnish the titled compound, 390 mg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:20]=[C:21]([SH:27])[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]>>[Br:18][C:19]1[CH:20]=[C:21]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Nc1c(Br)cc(S)cc1Br
Product: Nc1c(Br)cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3,5-dibromo-4-amino-thiophenol.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])C.[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH2:3][CH3:5])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CI
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (0.678 g, 3.34 mmol) in THF (11.1 mL) at 0° C. was added MeI (2.09 mL, 33.4 mmol, 10.0 equiv). NaH (60%, 1.33 g, 33.4 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1a (0.73 g) which was used for the next step without further purification. MS m/z (M+Na) 240.2. 1H NMR (400 MHz, CDCl3) 4.56 and 4.37 (br-s, 1H), 2.83 (br-s, 3H), 2.08-1.92 (m, 1H), 1.85-1.68 (m, 1H), 1.48 (br-s, 9H), 0.96 (t, J=7.38 Hz, 3H).
Reaction SMILES: [CH3:1][C@:2]12[C@H:54]3[CH2:55][C@H:52]([C:53]3([CH3:57])[CH3:56])[CH2:51][C@H:3]1[O:4][B:5]([C@@H:7]([NH:10][C:11]([C@H:13]1[N:17]3[C:18](=[O:40])[C:19]([N:22](CC4C=CC=CC=4)C(=O)OCC4C=CC=CC=4)=[CH:20][N:21]=[C:16]3[C@:15]([CH3:50])([CH2:41]/[CH:42]=[CH:43]/[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:14]1)=[O:12])[CH2:8][CH3:9])[O:6]2>CO.Cl.[Pd]>[CH3:1][C@:2]12[C@H:54]3[CH2:55][C@H:52]([C:53]3([CH3:56])[CH3:57])[CH2:51][C@H:3]1[O:4][B:5]([C@@H:7]([NH:10][C:11]([C@H:13]1[N:17]3[C:18](=[O:40])[C:19]([NH2:22])=[CH:20][N:21]=[C:16]3[C@:15]([CH3:50])([CH2:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:14]1)=[O:12])[CH2:8][CH3:9])[O:6]2
Reactant: CC[C@H](NC(=O)[C@@H]1C[C@@](C)(C/C=C/c2ccccc2)c2ncc(N(Cc3ccccc3)C(=O)OCc3ccccc3)c(=O)n21)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC[C@H](NC(=O)[C@@H]1C[C@@](C)(CCCc2ccccc2)c2ncc(N)c(=O)n21)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of 116d in MeOH (2 mL), were added conc. HCl (3 drops) and 10% Pd-C (10 mg). The mixture was evacuated and flushed with H2 (3×), then stirred under an atmosphere of H2 for 45 min. The mixture was filtered and concentrated to afford 17.3 mg (96%) of 116e as the HCl salt. MS (ESI) 547.3 (M+H+), 569.3 (M+Na+), 545.2 (M−H+).
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.[CH3:18][N:19]([CH3:24])[CH2:20][C:21](O)=[O:22].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.O>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:13]3[CH2:17][CH2:16][N:15]([C:21](=[O:22])[CH2:20][N:19]([CH3:24])[CH3:18])[CH2:14]3)[N:4]=[C:3]([I:2])[C:11]=12
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.367 g, 1.00 mmol) in dichloromethane (10 mL) was added 2-(dimethylamino)acetic acid (0.134 g, 1.30 mmol), 1-hydroxy-7-azabenzotriazole (0.150 g, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.249 g, 1.30 mmol), and diisopropylethyl amine (0.65 g, 0.87 mL, 5.0 mmol). The reaction mixture stirred at room temperature for 18 h and was then poured into water (10 mL). The organic phase was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-1-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone as a yellow-orange solid (0.278 g, 67%) which was used in subsequent reactions without further purification. RP-HPLC Rt 4.881 min, 80% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 mn; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 416 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CCOC(=O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
A solution of non-polydispersed ethyl 6-hydroxyhexanoate (50.76 ml, 50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in a ice bath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml, 24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride (19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was added dropwise from an addition funnel. The mixture was stirred for three and one half hours, slowly being allowed to come to room temperature as the ice bath melted. The mixture was filtered through silica gel, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to a pale yellow oil. Final purification of the crude product was achieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) to give the non-polydispersed product (46.13 g, 85%) as a clear, colorless oil. FAB MS: m/e 239 (M+H), 193 (M-C2H5O).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.[N:16]1[C:25]2[C:20](=[CH:21][C:22](C3(C#N)CC3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:11]3([CH:15]=[O:14])[CH2:13][CH2:12]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: N#CC1(c2ccc3ncccc3c2)CC1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=CC1(c2ccc3ncccc3c2)CC1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Diisobutylaluminum hydride in THF (1.0 M, 96 mL, 0.096 mol) was added to a solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 0.0639 mol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to −5 to 0° C., and stirred at that temperature for 3 h. The mixture was re-cooled to −60° C. Isopropyl alcohol (10 mL) was carefully added dropwise. After stirring for 30 min, the mixture was warmed to −5 to 0° C. The mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered through a pad of silica gel and washed with ethyl acetate in hexanes (40%). The filtrate was concentrated to yield the desired 1-quinolin-6-ylcyclopropanecarbaldehyde (12 g, 95.1%).
Reaction SMILES: [Na].C[Si](N[Si](C)(C)C)(C)C.C1COCC1.[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=3F)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17].OC1C=C2C(=CC=1)[NH:48][C:47]([CH3:52])=[CH:46]2>CS(C)=O>[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[C:36]4[C:35](=[CH:34][CH:33]=3)[NH:48][C:47]([CH3:52])=[CH:46]4)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)O
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a suspension of 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (105 mg, 0.28 mmol) and 5-hydroxy-2methylindole (82 mg, 0.56 mmol), (prepared as described for the starting material in Example 48), in DMSO (1.5 ml). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and 70/30) to give 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[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]>C1COCC1>[N:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([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])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cc(-n2cccc2)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccc2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, 2-bromo-4-(1H-pyrrol-1-yl)pyridine (0.20 g, 0.90 mmol) was dissolved in THF (6 mL). The light yellow solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 0.78 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min and at room temperature for 2 h. The reaction mixture was cooled to 0° C. and tributyltin chloride (0.28 mL, 1.03 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with ˜5 mL water and ˜5 mL brine then dried over sodium sulfate, filtered and concentrated to provide 4-pyrrol-1-yl-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: CB1OB(C)OB(C)O1.[C:10]([NH:14][C:15]([C:17]1[C:22]([CH2:23][C:24](=[O:26])[CH3:25])=[C:21](Cl)[CH:20]=[CH:19][N:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:28](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([NH:14][C:15]([C:17]1[C:22]([CH2:23][C:24](=[O:26])[CH3:25])=[C:21]([CH3:28])[CH:20]=[CH:19][N:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cc1c(C)ccnc1C(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 77.9 %

Procedure:
Trimethylboroxine (5.7 mL, 41 mmol) is added to 4-chloro-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (3.63 g, 13.5 mmol), potassium carbonate (9.33 g, 67.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (1.10 g, 1.35 mmol) in DMF (60 mL) and the reaction mixture is heated at 100° C. overnight. Volatiles are evaporated under reduced pressure and the residue dissolved with EtOAc/water. The organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-30% EtOAc/cyclohexane) to furnish 4-methyl-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (2.61 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@@H:28]([C:30]([O:32]C)=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@@H:28]([C:30]([OH:32])=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@H](C)C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-D-alaninate (D75) (262 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl aquous solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-D-alanine (E49) (130 mg) as a hydrochloride salt. δH (MeOD-d4, 400 MHz): 1.43 (6H, d), 1.64 (3H, d), 4.15 (1H, q), 4.54 (2H, q), 4.84-4.90 (1H, m), 7.31-7.37 (2H, m), 7.70 (1H, s), 8.03 (1H, d), 8.11 (1H, d), 8.18 (1H, dd), 8.30 (1H, d). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—NHC2H4COOH+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Into a 3 L 4-necked round-bottom flask under nitrogen was placed a solution of 3-nitro-1H-pyrazole (100 g, 884.37 mmol, 1.00 equiv.) in THF (1.5 L), followed by the addition of NaH (53 g, 1.32 mol, 1.50 equiv, 60% suspension) batchwise at 0° C. The resulting solution was stirred at 0° C. for 1 h. A solution of [2-(chloromethoxy)ethyl]trimethylsilane (117.4 g, 704.17 mmol, 1.20 equiv) in THF (500 mL) was then added dropwise with stirring at 0° C. The resulting solution was stirred at 25° C. for 1 h, quenched by the addition of EtOH (200 mL), concentrated under vacuum and diluted with 2 L of EtOAc. The resulting mixture was washed with 2×1 L of brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with 200 mL of petroleum ether. The solids were collected by filtration and washed with petroleum ether (2×500 mL) to afford 125 g (52%) of 3-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](CO)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 46.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide (45 mg) was prepared by following General Procedure F starting 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), (R)-4-amino-2-methyl-butan-1-ol (25 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 493.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5]2.[O:23]1[C:27]2[CH:28]=[C:29]([C:32]3([C:35](O)=[O:36])[CH2:34][CH2:33]3)[CH:30]=[CH:31][C:26]=2[O:25][CH2:24]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[O:25]1[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([C:35]([NH:1][C:2]4[CH:3]=[C:4]5[C:8](=[CH:9][CH:10]=4)[NH:7][C:6]([C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:5]5)=[O:36])[CH2:33][CH2:34]3)=[CH:28][C:27]=2[O:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
tert-Butyl 2-(5-amino-1H-indol-2-yl)-2-methylpropylcarbamate (58 mg, 0.19 mmol), 1-(benzo[d][1,3]dioxol-6-yl)cyclopropanecarboxylic acid (47 mg, 0.23 mmol), EDC (45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (80 μL, 0.57 mmol) were dissolved in DMF (4 mL) and stirred overnight at room temperature. The mixture was diluted with water and extracted with ethylacetate. The combined organic phases were dried over magnesium sulfate and to dryness. The residue was purified by silica gel chromatography (10-30% ethylacetate in hexane) to give tert-butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2-methylpropylcarbamate (88 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.18-7.16 (m, 2H), 7.02-6.94 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.19 (d, J=1.5 Hz, 1H), 6.02 (s, 2H), 4.54 (m, 1H), 3.33 (d, J=6.2 Hz, 2H), 1.68 (dd, J=3.7, 6.8 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H), 1.09 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>O.[OH-].[Na+].C1COCC1.C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)=[O:9]
Reactant: CNOC
Reactant: Cc1nc(C(=O)O)cs1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
Analogous to the general method described in J. Med. Chem., (2005), 48(6), 2134-2153. To a flask containing 2-methylthiazole-4-carboxylic acid (1.10 g, 7.68 mmol) was added DCM (30 mL) and the homogeneous solution was stirred at room temperature as carbonyldiimidazole (1.30 g, 8.02 mmol) was added. A white opaque suspension resulted. After the mixture was stirred at room temperature for 2.25 hours a colorless homogeneous solution resulted and then N,O-dimethylhydroxylamine hydrochloride (820 mg, 8.41 mmol) was added which caused an opaque solution to result once again. The mixture was stirred at room temperature for 18 hours, then diluted with water and 1 N NaOH (to pH ˜9) and extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a colorless oil, which was passed through a plug of silica gel eluting with (20% THF-DCM) to provide the title compound as a colorless oil.