Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1.[I-].[Na+].[OH-].[NH4+]>O.[Cu].CCOCC.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: [Cu]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 2.02 g (7 mmol) of 4,6-dichloro-2-(4-methylphenyl)quinoline, 1.6 g (12 mmol) of isonipecotamide, 5 g of phenol, and small amounts of sodium iodide and copper powder were stirred and heated at 160° for 4 hr. The reaction mixture was then diluted to 50 ml with water and made alkaline by the addition of concentrated ammonium hydroxide. The addition of ethyl acetate and ether induced the crystallization of 2.7 g of crude damp product. mp 260°-265°. The above-named compound was obtained as white needles, mp 265°-267° dec on recrystallization from ethanol.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I.O>CN(C)C=O>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCI
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCn1c(-c2ccccc2)nc2ccccc21
Yield: 95.4 %

Procedure:
2.5 g (12.88 mmol) of 2-phenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) of K2CO3 and 2.0 ml (16.7 mmol) of 1-chloro-4-iodobutane were added to the resulting solution, followed by mixing the mixture at a room temperature for 10 hours. The reactant was combined with 100 ml of water and extracted with ethylacetate (70 ml×5) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=2/1) to obtain 3.5 g (yield 96%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:17][NH2:18]>C(O)C>[C:7]1([C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[NH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
To a stirred mixture of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.0 g, 23.13 mmol) in dry ethanol (100 mL) was added hydrazine hydrate (1.737 g, 34.7 mmol) dropwise. The resulting solution was refluxed for 16 h. The reaction was cooled to room temperature and concentrated. The oil was diluted with saturated NaHCO3 solution and extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear liquid which was crystallized in hexanes/ethyl acetate (3.25 g). LCMS m/z=213.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 6.77 (s, 1H), 7.36-7.51 (m, 3H), 7.53-7.64 (m, 2H), 11.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+]([O-])=O)=C[CH:29]=1)=[O:26].C1(C(C)O)CC1>N1C=CC=CC=1.Cl>[CH:33]1([CH:28]([O:27][C:25](=[O:26])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:20]4[CH2:21][CH2:22][CH2:23]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=4)=[CH:4][CH:3]=2)[CH3:29])[CH2:32][CH2:31]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(O)ccc12
Agent: CC(O)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (909 mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6 mmol) at room temperature and then stirred for 2 h at room temperature. To the reaction is added cyclopropyl methyl carbinol and then stirred for 8 h at 80° C. The reaction mixture is diluted with 1N HCl and then extracted with ethyl acetate. The organic layer is concentrated and the residue is dissolved in EtOAc and triturated with hexane. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (996 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:17]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C(=O)O)c1ccc(NC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.50 g (7.6 mmol) of compound (7) in a solvent mixture of 10 mL of methanol and 0.2 mL of acetic acid, 1.4 mL (15.2 mmol) of cyclopentanone and 0.96 g (15.2 mmol) of sodium cyanoborohydride (NaBH3CN) were added. The obtained solution was stirred at room temperature for 12 hours. Next, the reaction mixture was dried under a vacuum and extracted with dichloromethane, followed by drying over anhydrous sodium sulfate and subsequent filtration. The filtrate was dried under a vacuum, and the residue was purified by silica gel chromatograph (n-hexane/ethyl acetate 3:2) to give a methyl ester of compound (11a). This compound was hydrolyzed with sodium hydroxide to give 1.09 g (yield 54%) of compound (11a) of interest as brown powder.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:18])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[C:6]([F:19])[CH:5]=[CH:4][C:3]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:18])=[C:6]([F:19])[CH:5]=[CH:4][C:3]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3nccnc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To propane-1-sulfonic acid 2,4-difluoro-3-[hydroxy-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-methyl]-phenyl-amide (9, 0.243 g, 0.635 mmol), 15 mL of tetrahydrofuran was added, followed by Dess-Martin periodinane (0.270 g, 0.635 mmol). The reaction was allowed to stir at room temperature for 15 minutes, then extracted with ethyl acetate and 5:1 saturated sodium bicarbonate:saturated sodium thiosulfate. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 1 to 5% methanol in dichloromethane. The resulting material was re-purified by silica gel column chromatography eluting with a gradient of 10 to 80% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to give the desired compound (P-0001, 188 mg). MS (ESI)[M+H+]+=381.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccc(F)cc2)Oc2ccc(Br)cc21
Yield: 22.2 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (30 g, 0.14 mol), 4-fluorobenzaldehyde (19.3 g, 0.14 mol) and borax (53.34 g, 0.14 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(4-fluoro-phenyl)-chroman-4-one (10 g, 20%). 1H-NMR (CDCl3): 2.81 (dd, 1H), 2.99 (t, 1H), 5.49 (dd, 1H), 6.87 (d, 1H), 7.04 (t, 2H), 7.38 (t, 2H), 7.51 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Cl>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCOCC1>[F:22][C:20]1[CH:21]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:18]=2[CH:19]=1)=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3
Reactant: Fc1ccc(Nc2ccc(F)cc2Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc2[nH]c3ccc(F)cc3c2c1
Temperature: 110 °C
Yield: 36.1 %

Procedure:
A reaction tube was charged with sodium tert-butoxide (7.218 g, 75.1 mmol), 2-chloro-4-fluoro-N-(4-fluorophenyl)aniline (3.600 g, 15.0 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.305 g, 1.1 mmol), palladium diacetate (0.169 g, 0.8 mmol), and anhydrous 1,4-dioxane (80 mL). The tube was sealed under nitrogen and heated in an oil bath at 110° C. for 20 hrs. After cooling to room temperature, the mixture was treated with 2M aqueous hydrochloric acid (90 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (20-50% methylene chloride/hexanes). The solids were rinsed with hexanes and dried to afford pure compound as a white powder (1.1 g, 36%). 1H NMR (300 MHz, CDCl3) δ 7.99 (br s, 1H), 7.67 (dd, 2H, J=8.7, 2.4 Hz), 7.36 (dd, 2H, J=8.7, 4.2 Hz), 7.19 (td, 2H, J=9.0, 2.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21].CO[C:32](OC)([CH3:34])[CH3:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]1[CH2:22][O:23][C:32]([CH3:34])([CH3:33])[O:21][CH2:20]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC(CO)CO)cc1OC
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2COC(C)(C)OC2)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide (117 mg) in dichloromethane (5.0 mL) were added 2,2-dimethoxypropane (0.36 mL) and 4-toluenesulfonic acid (10 mg), and the mixture was stirred for 30 minutes under reflux. The resulting mixture was diluted with ethyl acetate and washed successively with diluted sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give N-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5-ylamino)-5-nitrobenzamide (105 mg) as a solid substance.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]([N:34]1[CH:38]([CH3:39])[CH2:37][CH2:36][C@@H:35]1[C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])=[N:29][N:28]=[CH:27]2.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([N:34]3[CH:38]([CH3:39])[CH2:37][CH2:36][C@@H:35]3[C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])=[N:29][N:28]=[CH:27]4)[CH:7]=2)=[O:22])[CH2:2][CH2:3]1
Reactant: CC(C)NC(=O)[C@H]1CCC(C)N1c1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3C(C)CC[C@@H]3C(=O)NC(C)C)nncc2c1
Reaction time: 0.17 h

Procedure:
N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (64 mg, 212 μmol), tetrakis(triphenylphosphine)palladium (18 mg, 16 μmol), and (R)-1-(6-bromophthalazin-1-yl)-N-isopropyl-5-methylpyrrolidine-2-carboxamide (40 mg, 106 μmol) were dissolved/suspended in ethanol (2120 μl, 106 μmol) before potassium carbonate −1 M in water (424 μl, 424 μmol) was added to the vial which was then placed in the microwave for 10 min at 160° C. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give crude. After purification by chromatography, the title compound was obtained. MS (ES+): 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([NH:34][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:23])[CH:36]=1
Reactant: Nc1cccnc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)Nc2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 3-aminopyridine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 538.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][N:10]=1>[Ni].CO.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1Cl
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)cnc1-c1ccc(F)cc1Cl
Reaction time: 2.5 h

Procedure:
A 250 mL round bottom flask was charged with 2-(2-chloro-4-fluorophenyl)-3-methyl-5-nitropyridine (4 g) and methanol (50 mL). To the flask was added Raney nickel/methanol slurry (approx 4 g). The flask was evacuated and charged with hydrogen several times. The mixture was stirred under a balloon of hydrogen for 2.5 h. The flask was purged with nitrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure giving 6-(2-chloro-4-fluorophenyl)-5-methylpyridin-3-amine as an off white solid. Mass spectrum (EST) 237 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=3)[N:8]=2)[CH2:23]1
Reactant: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](N)C3)ccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-6-(4-(diethylamino)phenylamino) pyridin-2-yl)piperidin-3-ylcarbamate (1.41 g, 2.92 mmol) in CH2Cl2 (2 mL) was treated with TFA (4 ml) and stirred at rt for 4 h. The reaction mixture was concentrated and the residue dissolved in CH2Cl2 and washed with 1N NaOH and concentrated to give 1.07 g of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(diethylamino)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=383.25.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:40]=[CH:39][C:19]4[N:20]=[C:21]([C:23]([NH:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[O:24])[O:22][C:18]=4[CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[ClH:43]>O1CCOCC1>[ClH:43].[ClH:43].[NH:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:23]([C:21]2[O:22][C:18]3[CH:17]=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:42])([F:1])[F:41])=[CH:8][CH:7]=5)[CH2:14][CH2:13]4)[CH:40]=[CH:39][C:19]=3[N:20]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3o2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1nc2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (compound 1) (0.16 g, 0.27 mmol) and 4N hydrochloric acid in dioxane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with diethyl ether (2×3 mL) and then dried under reduced pressure to afford N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide dihydrochloride salt as a off-white solid (0.15 g, 99%). 1H NMR (CD3OD, 300 MHz) 7.83 (m, 5H), 7.48 (s, 1H), 7.23 (m, 1H), 4.93 (m, 1H), 4.22 (m, 1H), 3.90 (m, 3H), 3.35 (m, 2H), 3.17 (m, 2H), 2.23 (m, 8H), 1.98 (m, 2H) ppm; MS (ES) 489.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11]C3CCCCO3)[C:5]=2[O:4][C:3]1=[O:18].Cl>CO>[OH:11][C:10]1[C:5]2[O:4][C:3](=[O:18])[N:2]([CH3:1])[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)oc2c(OC3CCCCO3)cccc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)oc2c(O)cccc21
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a suspension of 3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (280 mg) in methanol (2.3 ml) was added 1N hydrochloric acid (0.5 ml) at ambient temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to 1/3 volume, and water was added thereto. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 7-hydroxy-3-methyl-2(3H)-benzoxazolone (164 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[O:23][S:24]([CH:27]=[CH:28][CH2:29][CH2:30][CH3:31])(=[O:26])=[O:25].[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:28]([CH2:29][CH2:30][CH3:31])[CH2:27][S:24]([OH:26])(=[O:25])=[O:23])[C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC=CS(=O)(=O)OC
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CS(=O)(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in THF (1.0 mL) arc added Pent-1-ene-1-sulfonic acid methyl ester (56 mg, 0.34 mmol) and solid NaOH (14 mg, 0.34 mmol) in order. The resulting suspension is stirred at room temperature for 1 hr and it turned into a clear solution. Then 5 mL of sat.NH4Cl is added along with 5 mL of water. The mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried (MgSO4) and concentrated to give crude product. Purification by flash column chromatography affords 11 mg (15%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentane-1-sulfonic acid. LCMS (ESMS): m/z 445.13 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH:18]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])=[CH2:19].[NH2:25][C@H:26]([C:32](O)=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[OH:30].N[C@H](C(O)=O)CC(=O)N>>[NH2:25][C@H:26]([C:32]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:33])[CH2:27][CH2:28][C:29](=[O:30])[OH:31].[CH:18]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])=[CH2:19]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C=CS(=O)(=O)C=C
Agent: NC(=O)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)O

Procedure:
This compound is synthesized as described above for compound (i), except that Glu-asparagine is used in step (g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.