Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][O:5][CH3:6])[CH3:3].[C:7]([C:11]1[O:12][C:13]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[C:18]([Cl:24])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CCOC(C)=O>[CH2:2]([N:4]([O:5][CH3:6])[S:20]([C:19]1[C:13]2[O:12][C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])=[N:15][C:14]=2[CH:16]=[CH:17][C:18]=1[Cl:24])(=[O:21])=[O:22])[CH3:3]
Reactant: CCNOC
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(OC)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N-Ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) (3.39 g, 30.4 mmol) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring. TEA (4.24 ml, 30.4 mmol) was added followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (4.68 g, 15.19 mmol) in THF (10 ml) over 2.5 hours. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 0-10% EtOAc in iso-hexane, to yield a white solid [M+H]+ 347.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([C@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][C@@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)[CH:21]=1)[CH3:27])[CH:6]=[N:5]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: C[C@@H](N)c1cccc(N2CCN(C)CC2)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-bromo-2-chloroquinoxaline (0.365 g 1.5 mmol) was dissolved in DMSO (10 mL) at room temperature and (R)-1-[3-(4-Methyl-piperazin-1-yl)-phenyl]-ethylamine (0.33 g, 1.5 mmol) and triethylamine (0.626 mL, 4.50 mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (100 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The organic layer was washed with water (10 mL) followed by brine solution (10 mL) and dried over Na2SO4. The organic layer was concentrated in vacuo to afford the crude product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[NH:9][C:8]3[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc(C(C)(C)C)cc3)nc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(OCc2nc3cc(C(=O)O)ccc3[nH]2)cc1
Temperature: 10 °C
Yield: 91.1 %

Procedure:
A mixture of 2-(4-tert-butyl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (150 mg, 0.44 mmol), acetic acid (30 mL) and concd HCl (39 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10° C., neutralize with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(4-tert-butyl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid as a colorless powder (0.13 g, 90% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-]#N.[K+].[I-].[K+].[Cl-].C([C:36]([NH3+:55])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>O.C1(C)C=CC=CC=1>[C:36]([CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:9][C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:55]
Reactant: O=c1cc(-c2cccc(F)c2)oc2c(CBr)cccc12
Reactant: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [C-]#N
Agent: [Cl-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1cccc2c(=O)cc(-c3cccc(F)c3)oc12

Procedure:
A suspension of 11.2 g of the above prepared 8-bromomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one, 3.2 g of potassium cyanide, 5.7 g of potassium iodide and 1.3 g of aliquot 336 (tricaprylylmethylammonium chloride) in 45 ml of water and 485 ml of toluene was stirred for 25.5 hours at 73° C., cooled, diluted with water and extracted with methylene chloride. The solvents in the organic layer were concentrated in vacuo and the resulting residue chromatographed over silica gel with 3-5% acetone in a 1:1 mixture of methylene chloride and hexane to give 4.6 g of 8-cyanomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one. IR 1643 cm-1 ; NMR (CDCl3): δ 4.06 (2, 1H), 6.8 (s, 1H), 7.0-7.85 (m, 6H), 8.2 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=S)=[O:5])[CH3:2].[NH2:9][C:10]1[C:11]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])=[N:12][C:13]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:14][C:15]=1[NH2:16].C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(#N)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:13]1[N:14]=[C:15]2[C:10]([N:9]=[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])[NH:16]2)=[C:11]([NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[N:12]=1
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N
Reactant: CCOC(=O)N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)Nc1nc2c(N[C@H](C)CO)nc(SCc3ccccc3F)nc2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethoxycarbonylisothiocyanate (0.48 ml) in dry acetonitrile (20 ml) at 0° C. under an atmosphere of nitrogen was added a suspension of the product from example 4, step (e) (1.15 g) in dry acetonitrile (20 ml) containing 2.5 eq triethylamine. After stirring at 0° C. for 5 min, diisopropylcarbodiimide (0.8 ml) was added and the reaction warmed to 70° C. for 1 hr. The reaction mixture was concentrated in vacuo and the residue purified twice by silica gel chromatography, eluting both times with 3:1 ethyl acetate:DCM, to afford the subtitled product as a white solid (0.045 g).
Reaction SMILES: [NH2:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Br[CH2:48][CH2:49]Cl.P(=O)(O)(O)O.[K]>C(#N)C>[N:1]1([C@:2]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:40])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])[CH2:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:49][CH2:48]1
Reactant: ClCCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
To a sealable vial was added (S)-benzyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.042 g, 0.067 mmol), 1-bromo-2-chloroethane (0.056 ml, 0.673 mmol) and phosphoric acid, potassium salt (0.071 g, 0.337 mmol). The mixture was diluted with acetonitrile (1 mL), was flushed with nitrogen, then was sealed and heated to 120° C. After 23 h of heating, the mixture was cooled to rt and the reaction mixture was filtered to remove solids. The solids were washed with dichloromethane and the filtrate was concentrated under reduced pressure to give (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate as an off-white solid. The crude product was used in the next step with no additional purification. LCMS: m/e 650.8 (M+H)+, 2.26 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1.O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:30][CH2:29][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (6 g, 25 mmol) in DMF (100 mL) was cooled to 0° C. Triethylamine (10.0 mL, 74.4 mmol) was added, and then tetrahydro-2H-pyran-4-ylmethylamine (see U.S. Patent Application Publication No. 2004/0147543 (Hays et al.) Examples 477-480) (3.4 g, 0.030 mol) was added slowly. Additional DMF was added, and the reaction was stirred at room temperature for one hour and cooled to 0° C. Water (300 mL) was added, and the mixture was maintained at 0° C. for 30 minutes. A precipitate was present and was isolated by filtration and washed sequentially with water and diethyl ether to provide 7 g of 2-chloro-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H](C3C=CC(OC)=CC=3)C)[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:31])[C:28]([CH3:30])=[N:29][C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].OP([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:26])[CH2:12]3)[CH3:10])[C:5]3[N:27]([CH3:31])[C:28]([CH3:30])=[N:29][C:4]=3[CH:3]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4nc(C)n(C)c34)CC2=O)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Product: COc1ccc(-c2cc3nc(C)n(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 100 °C

Procedure:
In a microwave vial, (R)-4-((R)-1-(6-chloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.48 (0.1 g, 0.22 mmol), 3,4-dimethoxyphenylboronic acid (43 mg, 0.23 mmol), K2HPO4 (154 mg, 0.67 mmol), X-phos (54 mg, 0.11 mmol) and Pd2(dba)3 (21 mg, 0.023 mmol) were added. Vial was sealed and reagents were taken up in isopropanol (5 mL). After evacuating and backfilling with argon, mixture was heated at 100° C. for one to three hours. After cooling to room temperature, mixture is poured into water and extracted with ethyl acetate. Combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure and resulting residues were used for next step without further purification. Residues were dissolved in trifluoroacetic acid (3 mL), and were heated at 55-60° C. for 6 hr. After cooling to room temperature, mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed with saturated NaHCO3 (aq), and layers separated. Combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield residues. Residues were purified via reverse phase chromatography to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.05.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[C:15]=3[CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)OCC>C(COC)OC>[CH:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH2:17][OH:18])[CH:13]=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc2ncc(C3CCCCC3)cc12
Agent: CCOC(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: OCc1cccc2ncc(C3CCCCC3)cc12
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
33.6 g (131.7 mmol) of the compound from Example VI are dissolved in 320 ml of dimethoxyethane and the solution is stirred with 197.6 mmol (27.6 ml) of triethylamine. After 30 minutes, 19.75 ml (197.5 mmol) of ethyl chlorocarbonate are added dropwise at 20°-30° C. The mixture is subsequently stirred for 30 minutes and the salt is filtered off with suction and washed with dimethoxyethane. The filtrate is concentrated end the residue is dissolved in a mixture of 320 ml of ethanol and 160 ml of water, and a solution of 9.25 g of sodium borohydride in 54 ml of water is added dropwise at 15°-18° C. The mixture is stirred at room temperature for 1 hour and the salt is filtered off with suction and washed with ethanol and water. The filtrate is concentrated to one third, methylene chloride and water are added and the phases are separated. The organic phase is washed 3 times with water, dried and concentrated. 26 g of a pale brown oil are obtained, which is employed without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11]C(=O)OC(C)(C)C)[CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylcarbamate (1.0 g, 2.90 mmol) in dichloromethane (28 mL) was added TFA (4 mL). After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure to provide the crude product that was used without further purification.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]5([CH3:45])[O:38][C:37]6=[N:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][N:36]6[CH2:35]5)[CH2:28][CH2:27]4)=[N:24][CH:25]=3)=[C:16]([F:46])[CH:15]=2)[CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:46][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:25]=[N:24][C:23]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]3([CH3:45])[O:38][C:37]4=[N:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][N:36]4[CH2:35]3)[CH2:28][CH2:27]2)=[N:22][CH:21]=1
Reactant: CC1(CN2CCCN(c3ncc(-c4ccc(N5CC(C(C)(C)O[SiH2]C(C)(C)C)OC5=O)cc4F)cn3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(CN2CCCN(c3ncc(-c4ccc(N5CC(CO)OC5=O)cc4F)cn3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of 5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-(3-fluoro-4-{2-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-[1,4]diazepan-1-yl]-pyrimidin-5-yl}-phenyl)-oxazolidin-2-one (580 mg, 0.84 mmol) in THF (8.0 mL) was added TBAF (3.3 mL, 3.3 mmol, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, dried with Na2SO4, purified by flash chromatography to give the title product (100 mg, 21%) as a yellow solid. ESI MS m/z 569 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.60 (dd, J=30, 3.0 Hz, 1H), 7.36 (t, J=20 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.25 (s, 2H), 4.70 (m, 1H), 4.10 (d, J=25.0 Hz, 1H), 3.95-4.06 (m, 2H), 3.82-3.88 (m, 2H), 3.76 (d, J=23.0 Hz, 1H), 3.64 (dd, J=33, 10.0 Hz, 1H), 3.41-3.58 (m, 2H), 3.31 (bs, 3H), 3.02 (d, J=38.0, 1H), 2.94 (q, J=16.0 Hz, 1H), 2.82-2.84 (m, 1H), 2.70-2.78 (m, 1H), 2.60 (d, J=38.0, 1H), 1.64-1.72 (m, 1H), 1.50-1.58 (m, 1H), 1.48 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[N:10]=2)=[CH:5][C:4]=1[N+:24]([O-:26])=[O:25])#[N:2]>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][N:11]1[CH:12]=[CH:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N+:24]([O-:26])=[O:25])[CH:5]=2)=[N:10]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 105.7 %

Procedure:
To a solution of tert-butyl 2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)-ethylcarbamate (0.92 g) in DCM (3 ml) 17% HCl-ethanol solution (10 ml) was added and the mixture was stirred at RT until disappearance of the starting material. The precipitate was filtrated, washed with diethylether and dried to give 0.70 g of the product as HCl-salt. 1H-NMR (400 MHz; d6-DMSO): δ 3.31 (m, 2H), 4.50 (t, 7.12 (d, 1H), 7.99 (d, 1H), 8.19 (d, 1H), 8.27-8.35 (m, 3H), 8.37 (dd, 1H), 8.73 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:3][CH2:4][C:5]([N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][OH:10])=[O:6].[N+:23]([C:26]1[C:27]([CH:39]=O)=[CH:28][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][CH:31]=1)([O-:25])=[O:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:17]1([CH:2]([NH:1][CH2:39][C:27]2[C:26]([N+:23]([O-:25])=[O:24])=[CH:31][N:30]=[C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:28]=2)[CH2:3][CH2:4][C:5]([N:7]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:8][CH2:9][OH:10])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: NC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(CCC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(CCO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-butyramide (2.0 g, 6.5 mmol) and 5-nitro-2-phenoxypyridine-4-carbaldehyde (1.6 g, 6.5 mmol) in 1,2 dichloroethane (50 mL), NaBH(OAc)3 (2.0 g, 9.4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After the addition of 1N NaOH solution, the reaction mixture was then extracted with EtOAc (200 mL×2). The organic layer was dried with Mg2SO4 and then evaporated to a residue which was purified by column chromatography to yield 4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyramide as an oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CC(N(C)C)=O.[Cu]I>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1coc2cc(Br)ccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Cu]I
Agent: [K]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1coc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 6-bromo-1-benzofuran-3-carboxylate (14.90 g, 55.4 mmol) in 200 mL of DMA was added potassium phthalimide (10.3 g, 55.4 mmol) and CuI (10.6 g, 55.4 mmol) and the mixture was stirred at 150° C. under nitrogen atmosphere overnight. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM, filtered through Celite®. The filtration was concentrated and purified with silica gel column chromatograph to give ethyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-benzofuran-3-carboxylate.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Product: O=C(c1c(F)cccc1Cl)c1c[nH]c2cnc(NC(=O)C3CC3)cc12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 19).
Reaction SMILES: O1CCCC1.CO.C([O:10][C:11]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[N:18]=[C:17]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:12])C.[OH-].[Li+]>C1(C)C=CC=CC=1.C(O)CCC.O>[C:11]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[N:18]=[C:17]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)([OH:12])=[O:10]
Reactant: CCOC(=O)CCCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a mixture of tetrahydrofuran (72 ml), methanol (24 ml), and water (24 ml), were added 1-[3-(ethoxycarbonyl)propyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (2.0 g, 5.2 mmol) and lithium hydroxide (642 mg, 3 eq.). The resulting mixture was stirred overnight at room temperature and was then concentrated in vacuo to yield a white solid. This residue was taken into 250 ml of a 3:1 butanol:toluene solution. The organic fraction was washed once with 200 ml of water and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 1.56 grams of tan solid, which was further purified by flash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 1.31 grams (70%) of the desired title product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[F:48]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:44]3[CH:45]=[CH:46][C:47]([F:48])=[C:42]([Cl:41])[CH:43]=3)=[CH:2][CH:32]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(F)c(Cl)c2)cc1
Yield: 81.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (0.123 mg, 0.69 mmol) by following general procedure D to afford title compound (89 mg) as a white solid.