Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]2([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[S:17][C:16](=[O:18])[N:15]([CH3:33])[C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)N(C)C2=O)cc1

Procedure:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione (Example 100) is reated with sodium hydride in DMF, followed by methyl iodide to give the title compound as colorless crystals, mp 113-115° C.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=1)[N:18]([S:37]([C:40]1[C:41]([CH3:46])=[N:42][O:43][C:44]=1[CH3:45])(=[O:39])=[O:38])[CH2:17][CH2:16]2)C1C=CC=CC=1.CO>C(Cl)Cl>[CH3:46][C:41]1[C:40]([S:37]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([OH:12])[CH:14]=3)[CH:19]2[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:28]=2)(=[O:39])=[O:38])=[C:44]([CH3:45])[O:43][N:42]=1
Reactant: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.095 ml, 0.095 mmol) was added slowly to a solution of 6-benzyloxy-2-(3,5-dimethylisoxazole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.037 g, 0.063 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 1 hr, then warmed to rt and stirred at rt for 4 hr. MeOH (5 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to an orange residue. Purification by preparative TLC, eluting with EtOAc:MeOH (1:1), and then purification again by preparative TLC, eluting with EtOAc:MeOH (8:2), gave 0.011 g (35% yield) of white solid.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH:21]=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>[Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH2:21][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-1H-isochromene-4-carbaldehyde (Intermediate B59.2, 0.5 g, 1.5 mmol) and morpholine (0.12 ml, 1.35 mmol) in DCM (20 ml), dry Na2SO4 was added and the mixture stirred RT for 10 min. Sodium triacetoxyborohydride (0.286 g, 2.25 mmol) and acetic acid (0.09 ml, 1.5 mmol) were added and the reaction mixture was stirred for 24 h at RT. The reaction was quenched by the addition of 2M HCl (3 ml), the heterogeneous mixture was filtered and the filtrate was purified by flash chromatography on silica NH cartridge (cyclohexane:EtOAc=90:10 to 80:20) affording 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (Intermediate B59.3, 0.183 g, 0.45 mmol, 30%).
Reaction SMILES: [CH:1]([NH:3][CH:4]([P:18]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42](=[O:46])[CH2:43][O:44][CH3:45]>CC(C)=O>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:5]([CH:4]([P:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])[N:3]=[CH:1][S:2][CH2:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])=[O:6])=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(NC=S)P(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC(=O)CSC=NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of p-nitrobenzyl α-thioformamidodiphenylphosphonoacetate (2.43 g), powdered potassium carbonate (0.73 ), 1-chloro-3-methoxy-2-propanone (0.63 g), and acetone (25 ml) is stirred in a capped flask at room temperature for 16 hours. The mixture is filtered and the filtrate is evaporated in vacuo to afford 3-methoxy-2-oxopropyl N-(p-nitrobenzyloxycarbonyl-diphenylphosphonomethyl)thioformimidate.
Reaction SMILES: OC([CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)=O.[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].C(OO)(=O)C>C(Cl)Cl.C(O)(=O)C.[C].[Ru]>[C:9]([O:12][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(=[O:11])[CH3:10]
Reactant: O=C1CC(C(=O)O)N1
Reactant: CC(=O)[O-]
Agent: [Ru]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC1CC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.9 %

Procedure:
0.3 g of 4-hydroxycarbonylazetidine-2-one, 0.43 g of anhydrous sodium acetate and 100 mg of 5% ruthenium-carbon were suspended in a mixture of 12 ml of methylene chloride and 4 ml of acetic acid and cooled to -3° C., to which 1.1 ml of acetic acid solution containing 40% peracetic acid was carefully dropped, subjected to stirring at 0° C. for 1 hour. The catalyst was separated by suction filtration, then solvent was distilled off under reduced pressure. 20 ml of n-hexane was added thereto. Undissolved matter was filtered off, the filtrate was concentrated under reduced pressure to obtain 0.37 g of the title compound (yield: 82%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.CN(C)C=O.F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)([O-:28])=[O:27]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isoindoline (679 μl, 5.98 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (508 mg, 2.43 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=15/1). Thus, 2-[2-nitro-4-(trifluoromethyl)phenyl]isoindoline (749 mg, quant.) was yielded as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20])([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate (1.8 g, 5.28 mmol, 1.00 equiv) in methanol (15 mL), and a solution of NH4Cl (850 mg, 15.89 mmol, 3.00 equiv) in water (7.9 mL). This was followed by the addition of iron (2.9 g, 51.79 mmol, 9.99 equiv) in several batches at 70° C. The resulting solution was stirred for 4 h at 70° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×20 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 1.4 g (85%) of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate as a black semi-solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2>O>[CH2:3]([O:10][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2ncnc3nc[nH]c23)cc1
Temperature: 100 °C

Procedure:
Sodiumhydride (60% Dispersion in mineral oil; 3.23 g; 80 mmol) was slowly added to benzyl alcohol (30 ml; 34.7 mmol). After the addition of more benzyl alcohol (10 ml) and 6-chloropurine (5.36 g;). The reaction mixture was heated to 100° C. for 4 hours. When the reaction mixture has reached room temperature, water (1 ml) was slowly added. 6-Benzyloxypurine was precipitated by the addition of acetic acid (4.6 ml) and diethylether (550 ml). The precipitate was separated by filtration (11.72 g). Re-crystallization from ether gave (4.78 g; 65.4%). Melting point was 175-177° C. (litt. 170-172° C.) [Ramazaeva N., 1989 #473] 1H-NMR (DMSO-d6): 8.53 (1H, s); 8.39 (1H, s); 7.54-7.35 (5H, m); 5.62 (2H, s).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)[C:11](=[O:13])[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.9 %

Procedure:
To a solution of Boc-D-Phe(4-Cl)—OH (3.65 g, 12.2 mmol), piperazine (10 g, 116 mmol) in DCM (200 mL) were added HOBT (3.3 g, 24 mmol) and EDCI (4.7 g, 25 mmol). The mixture was stirred at room temperature for 12 hours. The solution was washed with water, brine and dried over magnesium sulfate. After filtration, the organic solvent was evaporated and the residue was subject to silica gel chromatography to afford the product [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (0.58 g, 13%). 1H NMR (CDCl3, 400 Hz) δ 7.25 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.52 (d, J=8.4 Hz, 1H), 4.83-4.77 (m, 1H), 3.63-3.45 (m, 2H), 3.37-3.32 (m, 1H), 3.08-3.04 (m, 1H), 2.99-2.90 (m, 2H), 2.81-2.70 (m, 3H), 2.42-2.38 (m, 1H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 369.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>C(O)C>[CH2:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[O:5])[CH3:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](NCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of L-alanyl-L-prolyl-L-proline (12.83 g, 9.99 m mole), benzaldehyde (5.50 g, 51.8 m mole), zeolite "3A" (20 g), and ethanol (60 ml), was stirred overnight at room temperature. Sodium borohydride (1.609 g, 42.3 m mole) - ethanol (70 ml) suspending solution was added dropwise thereto, and after that, the mixture was stirred for 10 hours. The zeolite was removed by filtration and the filtrate was concentrated under reduced pressure. To the solution, ether was added to effect crystallization. The thus produced crystals were obtained by filtration, washed with three 50 ml portions of ether, then purified with the ion exchange resin "Dowex 50 W-X4", and then recrystallized with ethanol-ether to give N-benzyl-L-alanyl-L-prolyl-L-proline (2.10 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(C(F)(F)F)ccc(F)c2o1
Product: Fc1ccc(C(F)(F)F)c2nc(CCC#Cc3ccccn3)oc12
Yield: 14.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (49 mg, 0.31 mmol) and 2-(but-3-ynyl)-7-fluoro-4-(trifluoromethyl)-benzo[d]oxazole (80 mg, 0.31 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 15 mg (44 μmol, 14%) of 7-fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:28][N:29]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:40]([CH3:41])[CH2:39][CH2:38][CH2:37][N:29]([CH3:28])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:6]
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (150 mg, 0.810 mmol) was dissolved in methylene chloride (8 mL), triethylamine (0.135 mL, 0.972 mmol) and pivaloyl chloride (0.100 mL, 0.810 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of tert-butyl methyl[3-(methylamino)propyl]carbamate (described in J. Med. Chem. 1990, 33, 97-101) (164 mg, 0.810 mmol) in methylene chloride (4 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (300 mg; yield, 100%) as a yellow oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(CCOc2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 10.2 %

Procedure:
To a solution of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.020 g, 0.053 mmol) in DMSO (1 ml) were added N-methylpiperazine (11 μl, 0.106 mmol) and triethylamine (12 μl, 0.106 mmol). The reaction was heated to 150° C. via microwave irradiation and held at that temperature for 25 minutes. Purification was performed by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide (0.0024 g, 0.0054 mmol, 10%) as an off white powder. 1H NMR (CD3OD) δ 2.57 (3H, s), 2.76-2.96 (10H, m), 4.24 (2H, t), 7.06 (2H, m), 7.22 (2H, m), 7.64 (1H, m), 8.26 (2H, m). LCMS (2) 2.25 min; m/z (ES+) 443.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5](I)[CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1>[F-].[K+].C(#N)C.O>[Br:11][C:12]1[CH:13]=[C:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=2[NH2:9])[C:15]([F:18])=[N:16][CH:17]=1
Reactant: COc1cc(I)c(N)cn1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Temperature: 95 °C
Yield: 70.6 %

Procedure:
A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38 mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.5 g, 2 mmol) in 1N aqueous potassium fluoride (95 mL) and acetonitrile (200 mL) was heated at 95° C. for 16 h. The cooled reaction mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by flash chromotagraphy (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a yellow/orange solid (8.0 g, 71%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(Cl)ccc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2,5-di-chloro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): 6 ppm 7.50 (d, J=8.6 Hz, 1 H), 7.39 (dd, J=8.3, 2.526 Hz, 1 H), 7.22 (d, J=2.5 Hz, 1 H), 5.41 (s, 1 H), 5.01-4.93 (ABq, J=41.9, 16.2 Hz, 2H), 3.25 (m, 2 H), 3.10 (s, 3H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.67 (m, 1 H), 1.91 (m, 1 H), 1.75 (m, 1 H), 1.45 (m, 2 H). MS (ES) [m+H] calc'd for C17H21Cl2N4O2, 383.1. found 383.1.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8](=O)([O-])[NH2:9].Cl[CH2:13][CH2:14]Cl>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:9]1[CH2:8][CH2:14][CH2:13][CH2:1]1
Reactant: NC(=O)[O-]
Reactant: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (3 mL, 38.9 mmol) was added to a stirred solution of carbamate J1c (238 mg, 0.367 mmol) in DCE (7 mL) and the reaction was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum to yield a TFA salt of pyrrolidine J1d (260 mg) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([C:26]#[N:27])[C:23]4[N:28]=[CH:29][N:30]([CH3:31])[C:22]=4[CH:21]=3)=[CH:16][C:15]=2[C:32]([F:35])([F:34])[F:33])[CH2:7][CH2:6]1)=[O:4].[CH:36]([N:39]([CH:42]([CH3:44])C)CC)([CH3:38])C.N1CCCC1>CO>[CH3:31][N:30]1[C:22]2[CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH:8]4[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:39]5[CH2:36][CH2:38][CH2:44][CH2:42]5)[CH2:10][CH2:9]4)=[C:15]([C:32]([F:34])([F:33])[F:35])[CH:16]=3)[N:25]=[C:24]([C:26]#[N:27])[C:23]=2[N:28]=[CH:29]1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)CCl)CC4)c(C(F)(F)F)c3)cc21
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCNC1
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)CN5CCCC5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 6-(4-(2-(1-(2-chloroacetyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (25 mg), diisopropylethylamine (82 μL), and pyrrolidine (21 μL) in MeOH (1 ml) was stirred for 36 hours at room temperature. The mixture was purified by prep HPLC (acidic) to give the expected product (14 mg). 1H NMR (CD3OD) δ: 8.42 (s, 1H), 8.24-8.35 (m, 3H), 7.27 (d, 1H), 4.50 (d, 1H), 4.23 (t, 2H), 3.91-4.07 (m, 4H), 3.22-3.61 (m, 6H), 3.05 (t, 1H), 2.64 (t, 1H), 1.76-2.02 (m, 9H), 1.10-1.30 (m, 2H). MS m/z 541 (M+H).