Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), 1-(bromomethyl)-2,3-dichlorobenzene), prepared as described in Example 3, step f, (259 mg, 1.08 mmol and Na2CO3 (229 mg, 2.16 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). It was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (243 mg, 78%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.40 (t, J=4.2 Hz, 4H), 3.67 (t, J=4.2 Hz, 4H), 3.92 (s, 3H), 5.50 (s, 2H), 6.60 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)C.CCN=C=NCCCN(C)C.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.NC1C=CC=CC=1>CN(C=O)C.CCOCC>[C:32]1([NH:34][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH:33]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCOCC
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a stirred solution of 4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid (500 mg, 2.16 mmol) in dry DMF (2 mL) at 0° C. were added EDCI (456 mg, 2.38 mmol), HOBT (331 mg, 2.16 mmol) and aniline (0.22 mL, 2.38 mmol). The solution was stirred at room temperature overnight. The solvent was evaporated and the resulting residue was poured onto water and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with brine and dried (MgSO4), filtered and evaporated. To this crude material dissolved in CH2Cl2/CH3OH (3 mL/0.3 mL) was added TFA (1.5 mL), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and dried in vacuo to afford a light brown oil. Et2O and hexanes were added and a precipitate crashed out. The mixture was sonicated and filtered to afford the title compound (604 mg). LC-MS (ES) m/z=207 [M+H]+.
Reaction SMILES: [ClH:1].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC(C1C=CC=CC=1)[CH2:11][NH2:12].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.Cl.N[C:49]1[CH:82]=[CH:81][C:52]([C:53]([NH:55][CH2:56][CH:57]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:58][O:59][CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:73])[F:72])[CH:62]=2)=[O:54])=[CH:51][CH:50]=1.Cl.O1CCOCC1>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:12][CH2:11][C:49]1[CH:50]=[CH:51][C:52]([C:53]([NH:55][CH2:56][CH:57]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:58][O:59][CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:72])[F:73])[CH:62]=2)=[O:54])=[CH:81][CH:82]=1
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: Nc1ccc(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCc1ccc(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Yield: 59 %

Procedure:
Compound 69 (1.05 g, 86%) was produced as an oily product from 4-tert-butoxycarbonylaminomethylbenzoic acid (0.60 g, 2.4 mmol), the compound produced in Example 17 (0.83 g, 2.0 mmol), triethylamine (0.28 mL, 2.0 mmol), WSC.HCl (0.46 g, 2.4 mmol) and CH2Cl2 (10 mL) according to the same manner as in Example 30. In the same manner as in the case of synthesis of Compound 61, Compound 63 (0.55 g, 59%) was produced from Compound 69 (1.04 g, 1.7 mmol), 4 mol/L hydrogen chloride/dioxane (2.6 mL) and dioxane (2.6 mL).
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39]>C1COCC1.CCO>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: CC[O-]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of NaH (1.87 g, 77.9 mmol) in THF (26 mL) under nitrogen was slowly added EtOH (80 mL, Aldrich>99.5%, 200 proof) and the resulting homogeneous solution was stirred for 10 minutes. The sodium ethoxide solution was then added to a mixture of 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide (37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resulting mixture was stirred at room temperature for 1 h before being concentrated in vacuo. The residue was suspended in water (500 mL) and the mixture was sonicated and stirred for about 1 h at room temperature until the remaining solid became a filterable powder. The resulting powder was collected, triturated with ethyl ether (50 mL) and dried under high vacuum for 48 h to afford 3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (30.8 g, 95%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[S:20][CH:21]=[CH:22][C:15]=12>CN(C)C=O>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[S:20][CH:21]=[CH:22][C:15]=23)[CH2:5][CH2:4]1
Reactant: CN(C)C1CCC(O)CC1
Reactant: Clc1ccnc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Oc2ccnc3sccc23)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(dimethylamino)cyclohexan-1-ol (127 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL). This was followed by the addition of sodium hydride (71 mg, 1.77 mmol, 3.00 equiv, 60%). The resulting solution was stirred for 30 minutes at 80° C. in an oil bath. 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of ethanol. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (10:1). The resulting product (50 mg) was further purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% NH4HCO3 (3.0% water with 0.05% NH4HCO3 up to 3.0% in 1 min, up to 4.7.0% in 13 min, up to 100.0% in 2 min); Detector, uv 254/220 nm. This resulted in 9.6 mg (6%) of N,N-dimethyl-4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexan-1-amine as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([NH2:11])[N:8]=[CH:7]1)[CH3:2]
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Yield: 100.5 %

Procedure:
A mixture of 5.9 g of 4-nitro-a-hexyl-1H-imidazole-1-acetic acid ethyl ester, 3 g of palladium-on-carbon and 150 ml of absolute alcohol were subjected to catalytic hydrogenation. Both theoretical and actual hydrogen uptake was 73 pounds. The catalyst was removed by filtration and the filtrate concentrated in vacuo to provide 5.3 g of the desired title intermediate which was used directly.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:16])[O:13][C@@H:14]([CH3:15])[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C@H:14]1[C@@H:7]2[CH2:6][CH2:5][C:4]3[C:9]([N:8]2[C:12](=[O:16])[O:13]1)=[CH:10][CH:11]=[C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=3
Reactant: C[C@@H]1OC(=O)N2c3ccc(O)cc3CC[C@@H]12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1OC(=O)N2c3ccc(OCCCC(F)(F)F)cc3CC[C@@H]12
Temperature: 90 °C
Yield: 75.9 %

Procedure:
To a solution of 0.70 g (3.2 mmol) of cis-(±)-7-hydroxy-3-methyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.90 g (4.8 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.90 g (6.4 mmol) of potassium carbonate. The mixture is heated at 90° C. for 4 hours and then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.80 g of product is obtained.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2=[CH:9][CH2:10][S:11][C:6]2=[CH:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.B.CSC.CO>O1CCCC1>[S:11]1[C:6]2[CH2:5][N:4]3[CH:12]=[CH:13][CH:14]=[C:3]3[CH2:2][NH:8][C:7]=2[CH:9]=[CH:10]1
Reactant: O=C1NC2=CCSC2=Cn2cccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2n(c1)Cc1sccc1NC2
Temperature: 25 °C

Procedure:
To a suspension of 7.0 g of 5-oxo-4,5-di-hydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed to give a solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH2:6](Cl)[CH2:7]Cl.C[CH:11]([OH:13])C>C(#N)C.[OH-].[Na+]>[C:1]([O:5][C:11](=[O:13])[CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3]
Reactant: ClCCCl
Reactant: CC(C)O
Reactant: CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(=O)OC(=O)CC
Reaction time: 8 h

Procedure:
A representative procedure was as follows: A solution of propionic anhydride was prepared in situ by reacting propionic acid (0.48 g, 6.5 mmol) with EDC (614 mg, 3.2 mmol) in acetonitrile for 15 min at room temperature. This solution was then added over the course of 5 min to a magnetically stirred solution of N-ε-benzyloxycarbonyl lysine (Lys(Cbz)) (1 g, 3.6 mmol) in 36 mL 0.1 M NaOH and 20 mL 2-propanol. A fine white precipitate formed, another 36 mL 0.1 M NaOH was added, and stirring was continued overnight. The reaction mixture was then concentrated in vacuo to remove the organic solvents and acidified to a pH of 2.5 with 1M HCl. During acidification, the white precipitate dissolved. The aqueous solution was extracted with chloroform and then ethyl acetate. These organic solvents were combined and concentrated on the rotary evaporator to yield a colorless oil which was used without purification in the next step.
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>C(OCC)C>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccccc2)CC(=O)O1

Procedure:
10 mmol of 3-phenylglutaric acid and 30 mmol of acetic anhydride are heated under reflux until they have dissolved completely. After cooling, 3 ml of diethyl ether are added and the precipitate is filtered off and washed with diethyl ether. This gives 3-phenylglutaric anhydride.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[CH3:20]I.O>CN(C=O)C>[CH3:20][NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 80 °C

Procedure:
0.084 g of 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of DMF, and 0.5 mL of methyl iodide were added. The reaction mixture was heated to 80° C., allowed to react at that temperature for 6 h, cooled, and 100 mL of water were added. The reaction solution was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with 30 mL of and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.033 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[C:5]([F:16])=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, white solid (72 mg, 86%), MS (ISP) m/z=335.3 [(M+H)+], mp 317.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:9]2[C@@H:11]([CH:12]([CH3:14])[CH3:13])[C@H:10]2[C:15]([O:17][CH3:18])=[O:16])=[O:8])=[CH:3][CH:2]=1.C(OCC)(=[O:22])C.CCCCC>>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:9]2[C@@H:11]([CH:12]([CH3:14])[CH3:13])[C@H:10]2[C:15]([O:17][CH3:18])=[O:16])(=[O:22])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1[C@H](C(C)C)N1S(=O)c1ccc(C)cc1
Reactant: CCOC(C)=O
Solvent: CCCCC
Product: COC(=O)[C@@H]1[C@H](C(C)C)N1S(=O)(=O)c1ccc(C)cc1
Yield: 95 %

Procedure:
Following the procedure of Example 11A, but replacing the (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine with (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-isopropylaziridine (prepared according to Example 4), and performing the flash chromatography with ethyl acetate:n-pentane (2:8) as the eluent afforded the titled compound (0.565 g, 95%): mp 52°-4° C.; [α]D20 -34.3° (c 1.2, CHCl3); IR (KBr): 2963.9, 1755.8, 1597.5, 1209.6 1102.1, 1091.4 cm-1 ; 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz 3H), 0.89 (d, J=6.8 Hz, 3H), 1.57-1.68 (m 1H), 2.45 (s, 3H), 2.68 (dd, J=7.6 Hz, 9.9 Hz, 1H), 3.45 (d, J=7.44 Hz, 1H),3.74 (s, 3H), 7.35 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H); 13C NMR (CDCl3) δ145.0, 134.0, 129.7, 128.3, 52.6, 50.8, 41.1, 26.7, 21.6, 20.5, 18.9. Anal. Calcd for C14H19 NO4S: C, 56.55; H, 6.44. Found: C, 56.36; H, 6.63.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].[N+:7](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].C([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=O)=O.Cl>CO>[O:27]1[C:25]([C:24]2[CH:29]=[C:30]([CH:31]=[CH:22][CH:23]=2)[C:1]([OH:4])=[O:2])=[CH:8][N:7]=[CH:28]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(-c2cnco2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
MeOH (54 mL) was added to a round bottom flask containing K2CO3 (6.74 gm, 48.70 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (5.00 gm, 25.60 mmol), and methyl 3-formylbenzoate (4.00 gm, 24.37 mmol). The reaction mixture was heated at 80° C. for 3 h and then stirred at rt overnight. The mixture was concentrated under reduced pressure. The remaining residue was partitioned between EtOAc and water. The aqueous solution was isolated and acidified using 1N HCl. The acidified aqueous phase was extracted with EtOAc (2×). The organic extracts were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the product, 3-(oxazol-5-yl)benzoic acid, (4.00 gm, 21.15 mmol, 86% yield) as a white solid. Anal. Calcd. for C10H7NO3 m/z 189.0, found: 190.1 (M+H)+. Crude product was used without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].[C:15](O)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH:6][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(=O)O
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=N)N)NC(=O)CC(C)C

Procedure:
A 2.0 g (8.9 mMol) portion of arginine methyl ester hydrochloride was contacted with isovaleric acid (755 mg), HOBT (1 g), triethylamine (747 mg) and DCC (1.52 g) in DMF (150 ml) under the conditions described in Example 30 to give N-isovaleryl-arginine methyl ester as a crystalline solid (1.71 g).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:10]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[S:16]/[C:15]/1=[N:23]\[C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1F)[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:10]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[S:16]/[C:15]/1=[N:23]\[C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(O)CCO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)sc2ccncc21
Temperature: 2.5 °C
Yield: 90.3 %

Procedure:
3-Methylbutane-1,3-diol (42 mg, 0.4 mmol) in THF (1 mL) was treated with NaH (60%) (16 mg, 0.4 mmol) at room temperature for 20 min. To the above mixture, which was cooled to 0-5° C., was added the product from Example 20B (80 mg, 0.2 mmol) in THF (1 mL). After 20 min. the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 87 mg (90%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.32 Hz, 3H) 1.36 (s, 6H) 1.47-1.55 (m, 2H) 1.88-1.96 (m, 2H) 2.13 (t, J=5.80 Hz, 2H) 4.35 (t, J=5.80 Hz, 2H) 4.54 (t, J=7.63 Hz, 2H) 5.12 (brs, 1H) 7.11 (d, J=8.54 Hz, 1H) 7.61 (d, J=5.19 Hz, 1H) 7.74 (dd, J=8.54, 2.14 Hz, 1H) 8.49 (d, J=5.19 Hz, 1H) 8.68 (s, 1H) 8.72 (s, 1H); MS (ESI+) m/z 482 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[OH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: NCc1ccccc1O
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccccc1O
Yield: 2 %

Procedure:
The title compound was prepared in 2% yield from 2-(aminomethyl)phenol and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.30 (br s, 1H), 9.67 (s, 1H), 8.20 (s, 1H), 7.79 (d, 1H, J=4.9 Hz), 7.54 (d, 1H, J=4.9 Hz), 7.20 (d, 1H, J=7.0 Hz), 7.09 (t, 1H, J=7.6 Hz), 6.84 (d, 1H, J=8.1), 6.84 (dd, 1H, J=7.4 Hz), 4.44 (s, 2H). [M+H] calc'd for C13H12N2O3, 245; found 245.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([Br:18])C(=O)C1>CC(O)=O>[Br:18][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cnccc2c1
Solvent: CC(=O)O
Product: Brc1cc2ccccc2cn1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 mL) was added NBS (36.2 g, 204.6 mmol) at RT and the reaction mixture was heated to 100° C. overnight. Then it was cooled to RT and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5% EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:48]([C:45]3[CH:44]=[CH:43][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)=[CH:47][CH:46]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 19 %

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.028 g, 0.076 mmol), EtOH (1.3 mL) and DMF (0.18 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.025 g, 0.083 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8) to give the title compound as a solid (0.009 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.62-2.70 (m, 7H), 3.29-3.35 (m, 4H), 3.55 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.67-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.44 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.66 min—623/625 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 623.2680, calculated for C31H40ClN8O2S (M+H)+: 623.2683.