Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH:25]([CH3:27])[CH3:26])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14]([NH:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[O:15])=[O:4].[CH2:28]([O:35][C:36]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:14]([C@H:6]1[N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:40](=[O:41])[C@@H:39]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:36](=[O:37])[O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:43])[CH:25]([CH3:27])[CH3:26])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:15]
Reactant: CC(C)[C@H](N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Reactant: C[C@@H](C(=O)O)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (Intermediate 6) (29 mg, 77.5 μmol, Eq: 1.00), (S)-2-((benzyloxycarbonyl)(2-(methylsulfonyl)ethyl)amino)propanoic acid (Intermediate 9) (30.6 mg, 93.0 μmol, Eq: 1.2), HATU (35.3 mg, 93.0 μmol, Eq: 1.2) and diisopropylethylamine (16 μL, 93.0 μmol, Eq: 1.2) were combined with DMF (2 mL) to give a colorless solution. The reaction mixture was stirred at rt overnight and then partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 50% EtOAc in hexanes) to give benzyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(2-(methylsulfonyl)ethyl)carbamate (33 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>CC#N.C(O)(C(F)(F)F)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cccc(Oc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Oc1ccc(Cl)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.7 %

Procedure:
3-Phenoxyphenol (1.00 g, 5.4 mmol) was dissolved in MeCN (40 mL) and TFA (0.5 mL). N-Chlorosuccinimide (717 mg, 5.4 mmol) was added and the reaction stirred at ambient temperature for 48 h. Solvents were removed in vacuo to afford the crude product as an oil (2.15 g). 300 mg of this crude material was purified by HPLC to afford in order of elution 4-chloro-3-phenoxyphenol (68 mg, 0.31 mmol, 41%) M.S. (ESI) (m/z): 219,221 [M−H]−; and 6-chloro-3-phenoxyphenol (73 mg, 0.33 mmol, 44%) M.S. (ESI) (m/z): 219,221 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:25].[Na+]>O1CCOCC1>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:25])=[CH:23][CH:24]=3)=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: N#Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
4-[(6-Oxo-5,6-dihydrobenzo[c]-1,8-naphthyridin-9-yl)amino]benzonitrile (40 mg, 0.13 mmol) and NaOH (1.3 mL, 1.00 M; 1.28 mmol) were suspended in dioxane (2 mL), and stirred for 120 min at 120° C. in the microwave. The crude material was purified directly via prep-LC-MS to provide 249 (2 mg, 6% yield) as a brown solid. LC-MS (M+H=331 obsd.=331).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1ccc2ncccc2c1)C(=O)OC
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Hydroxyquinoline (25.1 g), methyl 2-bromobutyrate (32.3 g) and anhydrous potassium carbonate (23.0 g) in dry N,N-dimethylformamide (100 ml) were stirred at 100° C. for 3 hours then stored at ambient temperature for 18 hours. The mixture was added to water, extracted with ethyl acetate (three times) and the extracts combined, washed with water (four times) then dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the required product (39.0 g) as a red oil.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.4 mL, 7 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g, 7 mmol) (60% in oil) and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (3.01 g, 7 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate (3.11 g, 88.9%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-n1ccc2ccc([N+](=O)[O-])cc2c1=O
Yield: 23.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 400 mg, 2.0833 mmol) was reacted with 3-iodo-4-methyl-pyridine (456.2 mg, 2.08331 mmol), 1,4-dioxane (4.1 mL), copper iodide (39.6 mg, 0.2083 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (88.7 mg, 0.6249 mmol) and potassium phosphate (1.1 g, 5.2082 mmol) to afford the crude product. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 140 mg of the product (23.9% yield).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27]C)=[O:25])[C:19]([O:21][CH2:22]C)=[O:20])(=[O:16])[CH3:15].C[O-].[Na+]>CCO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:15][C:14]([NH:17][CH:18]([C:24]([O:26][CH3:27])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[O:16]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(NC(=O)CCc1ccc2ccccc2n1)C(=O)OC
Yield: 107.4 %

Procedure:
To a solution of 2(chloromethyl)quinoline monohydrochloride (5.0 g, 23.4 mmol) and diethyl acetamidomalonate (10.1 g, 46.7 mmol) in EtOH (60 mL) was added sodium methoxide (3.78 g, 70 mmol). The reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled, filtered, and concentrated. The residue was dissolved in EtOAc (400 mL) and extracted with cold 4NHCl (3×150 mL). The aqueous layer was neutralized with 10N NaOH and extracted with EtOAc (3×200 mL). The combined organic extract was washed with water, dried (anhydrous MgSO4), filtered, and concentrated to give the title compound (8.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24]>>[CH3:25][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH:34][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=2)=[CH:28][CH:27]=1)([CH3:22])=[O:24]
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Reactant: COc1nc(P(C)(C)=O)ccc1N
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(C)c(Nc2ccccc2S(=O)(=O)C(C)C)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26]CCC)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CCCCC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(C)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:38][CH2:39]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: OCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(CCO)CC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), 4-piperidineethanol (30 mg, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on column chromatography (eluent: dichloromethane/MeOH, 95/5) to give a white solid. This solid was triturated in MeOH, filtered, washed with MeOH and diethyl ether and dried to give the title compound (35 mg, 55%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]>CC(O)=O.[Fe]>[NH2:11][C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(C#N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cccc(C#N)c1N
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
3-Methoxy-2-nitrobenzonitrile (Step 1, 43.3 g, 243 mmol) was suspended in AcOH (1000 mL) and degassed thoroughly. To this was added iron powder (40.7 g, 729 mmol) slowly. After 30 min an exotherm was observed and moderated by the use of an ice bath. After 2 h Celite was added and the entire mixture filtered through a pad of Celite. The Celite was washed well with AcOH, and the combined filtrates concentrated under reduced pressure to approximate volume of 100 mL AcOH. The residue was diluted with EtOAc (1000 mL), solid K2CO3 added and the mixture stirred overnight. The mixture was then filtered through Celite again and washed well with EtOAc. The solvent was removed under reduced pressure until a volume of approximately 500 mL EtOAc. This solution was washed with a saturated NaHCO3 solution (500 mL) and brine (300 mL) then the solvent removed under reduced pressure. The resulting solid was purified via silica gel chromatography (0-30% EtOAc/Hexanes). Fractions containing product were combined, the solvent removed under reduced pressure to give the title compound (26.6 g, 74%): HPLC MS RT=2.19 min, MH+=149.0; 1H NMR (DMSO-d6) δ: 3.77 (3H, s), 5.61 (2H, bs), 6.57 (1H, t), 6.96 (1H, dd), 7.00 (1H, dd).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:3]=1.C(N(CC)CC)C.[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][NH:36][CH3:37]>O1CCCC1>[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][N:36]([CH3:37])[S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=1)(=[O:20])=[O:19]
Reactant: CNCC(O)C1COC(C)(C)O1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC(O)C1COC(C)(C)O1)S(=O)(=O)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
8.36 g (20 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzenesulfonic acid chloride is dissolved in 40 ml of tetrahydrofuran, 2.52 g (25 mmol) of triethylamine and 4.03 (25 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-methylethylamine are added and stirred for 3 hours at 45° C. The reaction mixture is then concentrated by evaporation under reduced pressure, the residue is extracted with ethyl acetate and the extract is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 9.35 g (16.8 mmol)=84% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[CH:34]=[CH:33][C:32]6[O:28][CH2:29][O:30][C:31]=6[CH:36]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
The title compound, white solid (110 mg, 92%), MS (ISP) m/z=479.4 [(M+H)+], mp 213.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and benzo[d][1,3]dioxole-5-carboxylic acid.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][S-:42].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([CH2:16][NH:17][C:18]([C:20]2[N:21]=[C:22]3[N:27]([C:28](=[O:38])[C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25][O:24][C:23]3([CH3:39])[CH3:40])=[O:19])=[C:9]([C:8]#[C:7][CH2:6][S:42][CH3:41])[CH:14]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml) was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) and the resulting mixture stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.28 (3H, s, SCH3), 3.45 (2H, s, SCH2), 4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.31 (2H, s, OCH2), 6.98 (1H, m, aromatic), 7.15 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32-7.38 (4H, m, aromatics), 7.50-7.53 (2H, m, aromatics), 7.80 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN3O4S [M+H+]: 522.1863; found: 522.1844.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, brown oil (0.47 g, 72%), MS (ISP) m/z=303.4 [(M+H)+], was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-methoxy-phenylboronic acid (0.36 g, 2.38 mmol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:20][CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=1)[O:21][C:22]1[CH:23]=[N:24][C:25]([C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(C)C)Oc2ccc(Cl)nc2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)CCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 527.2 [M−H]−.
Reaction SMILES: [C:1]12([C:11]3[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][C:12]=3[O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[I-:21].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][I:21])=[CH:13][C:12]=3[O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1cc(CCl)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CI)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To all of the above benzyl chloride in acetone (30 mL) is added sodium iodide (1.70 g., 10.0 mmol, 2.90 equiv.) and potassium carbonate (0.450 g., 10.5 mmol, 3.04 equiv.). The mixture is allowed to stir for 18 hours at room temperature. The solvents are evaporated, and the residue extracted twice with EtOAc. The extracts are washed with water and then brine. The organic phase is dried (MgSO4), and concentrated to afford 4-[1-adamantyl]-3-methoxybenzyl iodide (18b) (1.10 g., 2.88 mmol, 84%): mp=143°-144° C.; 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J=7 Hz, 1H, ArH), 6.95 (d, J=7 Hz, 1H, ArH), 6.85 (s, 1H, ArH), 4.46 (s, 2H, ArCH2I), 3.85 (s, 3H, OCH3), 2.07 (s, 9H, adamantyl), 1.77 (s, 6H, adamantyl) .
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:20]I>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:20])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C(=O)Nc1cccnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-(2-chloro-3-pyridinyl)-2-methylnicotinamide (1.48 g) in DMSO (20 mL) was added NaH (60% in oil, 0.26 g). After 20 minutes, methyl iodide (0.45 mL) was added, and stirring was continued for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.51 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:13][CH:14]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2cccnc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.4 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500 mg) and Pd—C (100 mg) in MeOH (30 mL) was stirred at room temperature for 5.5 h. The mixture was filtered by Celite, and the filtrate was concentrated. The resulting solid was rinsed with 1Pr2O to give 3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg) as a pale brown solid.