Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1.CC1(C)C2C=CC=CC=2I([C:37]([F:40])([F:39])[F:38])O1>C(Cl)(Cl)Cl.[Zn](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>[CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH2:6][CH2:7][N:8]2[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]4[CH:24]=[C:23]([CH2:25][O:26][C:37]([F:40])([F:39])[F:38])[N:22]=[CH:21]4)[CH:14]=[C:9]23)[CH2:3][CH2:2]1
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: O=C1CN=C(n2cnc(CO)c2)C=C2c3cccc(C4CC4)c3CCN12
Agent: O=S(=O)(N([Zn]N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1CN=C(n2cnc(COC(F)(F)F)c2)C=C2c3cccc(C4CC4)c3CCN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.9 %

Procedure:
A solution of 9-cyclopropyl-2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (135 mg, 0.38 mmol) in CHCl3 (50 mL) under Ar, was treated with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). The mixture was stirred at RT for 16 h, and then treated again with 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (245 mg, 0.78 mmol) and Zn(NTf2)2 (242 mg, 0.39 mmol). After 24 h, the mixture was poured onto H2O and extracted with DCM. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 100:0 to 95:5) and by SFC (column: PPU 5 m, 250×30 mm, 60A, Princeton; eluent: isocratic 20% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (3 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 1.15 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.56-0.71 (m, 2H); 0.93-1.05 (m, 2H); 1.91-2.04 (m, 1H); 3.14-3.20 (m, 2H); 3.89-4.01 (m, 2H); 4.34 (br s, 2H); 5.00 (s, 2H); 7.03 (s, 1H); 7.18-7.26 (m, 1H); 7.26-7.34 (m, 1H); 7.69-7.85 (m, 2H); 8.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].C(CN)O.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Solvent: NCCO
Product: Cc1ccc(C(=O)NCCO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 63 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using ethanolamine (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (551.7 mg, 63%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.68 (t, 2H), 3.48 (t, 2H), 2.19 (s, 3H) ; ES-HRMS m/z 494.0518 (M+H C21H19BrF2N3O4 requires 494.0522).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH:24][CH:25]([C:27]1[S:31][C:30]([CH:32]=[O:33])=[N:29][CH:28]=1)[CH3:26].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:32]([C:30]2[S:31][C:27]([CH:25]([OH:24])[CH3:26])=[CH:28][N:29]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Yield: 81.8 %

Procedure:
A mixture of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.56 g), 5-(1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.30 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.66 g, yield 81%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate. MS: 514 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[CH2:23]([O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:10]2[C:18](=[O:19])[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]2=[O:20])[CH:4]=1)[CH:22]=[CH2:21]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Yield: 73.9 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.61 mmol), allylbromide (0.15 mL, 1.77 mmol) and potassium carbonate (0.22 g, 1.61 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-(5-allyloxy-2,4-dichlorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.42 g, yield:73.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 2-nitrophenol (1.5 g, 0.0101 mole) in DMF (15 mL) was added cesium carbonate (16.4 g, 0.0505 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 0.0101 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (20% ethyl acetate in hexane) to afford 1.5 g (47%) of 4-(2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 323.15 (M+1)+, 98%,
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][O:16][C:12]=2[C:11]([OH:23])=[C:10]([C:24](OCC)=[O:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].[O-]CC.[Na+].Cl>CN(C=O)C.C(=O)(O)[O-].[Na+].CCOC(C)=O.O>[CH2:1]([C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][O:16][C:12]=2[C:11]([OH:23])=[C:10]([C:24]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:25])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Ethyl 4-benzyl-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (36 mg, 0.096 mmol), glycine (145 mg, 1.93 mmol), sodium ethoxide (98 mg, 1.44 mmol) in 3 mL of DMF were refluxed for 2 h. After cooling to room temperature, water (15 mL) and EtOAc (20 mL) were added. The mixture was acidified to pH 2 by addition of 4M hydrochloric acid. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4. After evaporation of solvent, the residue was redissolved in EtOAc and washed several times with water to remove residual DMF. Drying over MgSO4 followed by evaporation afforded 28 mg of crude solid. The solid was dissolved in 50 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 2 with 4M hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 26 mg of the title compound. MS: (+) m/z 404.33 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([F:25])=[O:18])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 3.00 g, 11.7 mmol) and pyridine (1.13 mL, 14.0 mmol) in dichloromethane (100 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (1.18 mL, 14.0 mmol). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (300 mL), washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane (200 mL), and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol, 96% yield) as a yellow, viscous oil. The product was found to react readily with methanol and on analysis was characterized as the methyl ester, which had an HPLC ret. time=2.56 min. —(Condition A); LC/MS M+1=272.3 (methyl ester).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
When a toluene solution of benzyl alcohol and 0.1% complex 2′ was refluxed for 24 hrs in an open system, benzyl benzoate was formed in 70% yield, accompanied by a small amount of benzaldehyde (4%) (Table 24, entry 1). Refluxing 1-hexanol with 0.1% 2 in toluene (115° C.) or neat (157° C.) for 24 hrs resulted in formation of 60-70% of hexyl hexanoate, accompanied by 2.5-10% hexanal (Table 24, entries 2 and 3). Complex 6′ was slightly less catalytically active than 2 (Table 24, entry 7). The PNN complex 4′ exhibited significantly higher catalytic activity than that of the PNP complexes 2′ and 6′; benzyl alcohol, 1-hexanol and 1-butanol were dehydrogenated to the corresponding esters in over 90% yield after heating with 0.1% 4′ in toluene (Table 24, entry 4-6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccccc2)c1
Yield: 136.1 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (1.03 g, 3 mmol), phenylboronic acid (920 mg, 7.5 mmol), Pd(0) (100 mg) and Na2CO3 (4 mL of a 2M solution) were mixed in 20 mL of toluene, and the mixture was stirred at reflux for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with chloroform:methanol 100:2, to afford 1.39 g of the title compound. MS (CI/NH3) m/z 341 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.38 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.21 (m, 1H), 4.41 (m, 1H), 4.54 (m, 1H), 7.40 (m, 3H), 7.50 (m, 2H), 8.10 (m, 1H), 8.54 (m, 1H), 8.20 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9][NH2:10].[C:11]([C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:32]4[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34](F)[CH:33]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.O>[C:11]([C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:32]4[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:43]([NH:10][CH2:9][CH2:8][F:7])[CH:44]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)#[N:12]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCF
Temperature: 90 °C
Yield: 19.6 %

Procedure:
4.83 g of potassium carbonate and 3 g (40 mmol) of 2-fluoroethylamine are successively added to a solution of 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 5 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 50 minutes in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with dichloromethane, so as to give 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]([C:24]1[CH:25]=[C:26]([SH:35])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([S:35][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC(C)(C)c1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc(C(C)(C)C)c1O

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,5-di-tert.butyl-4-hydroxy-thiophenol.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:29])=[C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[C:78]([NH2:81])(=[O:80])[CH3:79]>O1CCOCC1.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]>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[NH:19][C:17]1[CH:18]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:81][C:78](=[O:80])[CH3:79])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:29]
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
Sprage a mixture of 1-(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,3-dimethylbutyl)urea (0.200 g, 0.482 mmol), XantPhos (0.028 g, 0.048 mmol), Cs2CO3 (0.314 g, 0.964 mmol) and acetamide (0.142 g, 2.410 mmol) in dioxane (5 mL) with Ar, add Pd2(dba)3 (0.022 g, 0.024 mmol), heat at 100° C. for 7 h, then cool to RT overnight. Remove the solids via filtration through diatomaceous earth, rinse well with THF, wash the filtrate with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (MeOH/DCM). Triturate with MTBE, collect the solid via filtration and dry to afford the title compound (105 mg, 49%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 9.15 (d, J=0.8 Hz, 1H), 8.49 (s, 1H), 8.41 (d, J=2.6 Hz, 1H), 8.26 (dd, J=7.9, 2.3 Hz, 1H), 8.20 (s, 1H), 7.30 (dd, J=11.4, 8.4 Hz, 1H), 7.03 (ddd, J=8.4, 4.7, 2.3 Hz, 1H), 6.57 (t, J=5.6 Hz, 1 H), 3.11-3.05 (m, 2H), 2.57 (s, 3H), 2.15 (s, 3H), 1.36-1.31 (m, 2H), 0.88 (s, 9H); MS (ESI) m/z: 438.3 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]2=[O:26])C1C=CC=CC=1.CO>[Pd].O1CCCC1>[O:19]([C@H:13]1[C@@H:12]([OH:26])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15][CH2:14]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)[C@H](O)[C@H](Oc1ccccc1)CO2
Reaction time: 24 h
Yield: 65.5 %

Procedure:
A mixture of 10.04 g of the title product of Example 9, 200 ml of methanol, 100 ml of tetrahydrofuran and 1 g 10% Pd/C catalyst was hydrogenated at 44 psig for 24 hours. The catalyst was recovered by filtration and the filtrate was evaporated in vacuo to obtain the crude product, which was triturated with dichloromethane and filtered to give 4.9 g of title product having properties identical to those of the cis-title product of the preceding Example.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), 3-chlorophenyl isocyanate (28 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 10 (16 mg, 25% yield) as an off-white solid. LC-MS (M+H=418, obsd.=418).
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.P(Cl)(Cl)(Cl)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:31])[N:22]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][CH:17]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1.CC(=O)OCC>[Cl:8][C:6]1[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:23]2[C:19]([C:20]=1[CH:21]=[O:31])=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:24]=2
Reactant: COc1ccc2c(c1)N(c1ccccc1)C(=O)C2
Reactant: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Temperature: 0 °C

Procedure:
A solution of DMF (2.1 ml) and DCM (2.1 ml) was cooled to 0° C. and stirred under argon. Within 15 min phosphorus oxychloride (2.1 ml, 22.6 mmol) was added and the reaction mixture was stirred for 30 min at 0° C. The compound of step 1 (550 mg, 2.30 mmol), dissolved in chloroform (5.27 ml) and pyridine (1.05 ml), was then added to the cooled solution. The reaction mixture was stirred at room temperature overnight. The mixture was slowly poured into 300 ml of ice, and after a few minutes EA was added. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography on silica gel (EA/HEP 1:4) yielded 369 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(Cl)cc1C
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-N-methoxy-N-methylpropanamide and 4-bromo-2-methylpyridine was prepared the title compound as a light brown solid, MS (ESI+): m/z=430.04 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[ClH:17].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]>C(O)C>[O:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][C@H:7]1[CH2:6][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]([C:29]2[S:39][C:38]3[N:40]4[C:31](=[CH:32][N:33]=[C:34]4[CH:35]=[CH:36][CH:37]=3)[CH:30]=2)=[O:28])[CH2:21][CH2:20]1.[ClH:17].[CH2:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH3:42]
Reactant: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(C[C@@H]2COc3ccccc3O2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
A solution of the above crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane, 1.05 g (2.71 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride, and 1.20 ml (8.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 3 days. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=4/1 to 3/1) to provide the title compound and triethylamine hydrochloride as a mixture. This mixture was diluted with ethyl acetate and washed serially with aqueous solution of sodium hydrogen carbonate, water, and saturated aqueous solution of NaCl. The organic layer was dried over MgSO4 and the solvent was distilled off to provide the title compound.