Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH:9]1[CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: COC(=O)CC1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methoxycarbonylmethyl-piperazine (0.13 g, 0.5 mmol) in acetonitrile/water (8:2) (10 mL) was added K2CO3 (0.2 g, 0.42 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.16 g, 0.42 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated, partitioned between EtOAc/H2O, and extracted with EtOAc (3×). The organics were combined, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1S
Reactant: ClCc1c(Cl)cccc1Cl
Agent: [Na]
Solvent: CCO
Product: [O-][n+]1ccccc1SCc1c(Cl)cccc1Cl
Yield: 92 %

Procedure:
A mixture of 37 gms (0.1 mole) 2-mercaptopyridine N-oxide, sodium salt (40% aqueous solution) and 19.5 gms (0.1 mole) 2,6-dichlorobenzylchloride in 200 ml of ethanol is warmed to 65° - 70° for thirty minutes, cooled and filtered. The filter cake is washed thoroughly with water and finally with 40 ml of acetone. The dry cake (25.3 gms) represents a 92% yield of 2-(2,6-dichlorophenylmethylthio)pyridine N-oxide. Melting point 240° - 241° C. Structure confirmed by IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([CH3:31])[NH:27]1.N12CCCN=C1CCCCC2.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:27]4[C@@H:28]([CH3:31])[CH2:29][CH2:30][C@@H:26]4[CH3:25])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C[C@H]1CC[C@H](C)N1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cc2ccc(N3[C@@H](C)CC[C@@H]3C)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456, 100 mg, 0.289 mmol), (2S,5S)-2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60 mmol). The mixture was heated to 160° C. for 3 hours and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% acetone/dichloromethane as the eluent to produce 10 mg of P-577 as a pale viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 425.1 (M+1) LC-MS: 92%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C@H:24]1[N:37]2[C:28]([CH2:29][O:30][C:31]3[C:36]2=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=3)=[N:27][NH:26][C:25]1=[O:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:28]2[N:37]3[C@H:24]([CH3:23])[C:25](=[O:47])[NH:26][N:27]=2)[CH:10]([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC1CN(C(=O)OC(C)(C)C)CC=C1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC=C1c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a mixture of 3-methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Preparation #13, 5.07 g, 14.69 mmol), (R)-4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #11, Step E, 2.8 g, 8.16 mmol) and K3PO4 (3.46 g, 16.32 mmol) in DMF (60 mL) and water (10 mL) was added Pd(Ph3P)4 (3.77 g, 3.26 mmol). The reaction mixture was stirred at 80° C. overnight then cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-50% EtOAc in petroleum ether) to give 3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g) as a yellow liquid. Further purification by prep-HPLC (Table 3, Method 33) ave 3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 44%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.03 (brs, 1H), 7.02-6.93 (m, 2H), 6.87 (s, 1H), 5.81 (brs, 1H), 4.77 (q, J=6.8 Hz, 1H), 4.66-4.53 (d, J=13.2 Hz, 2H), 4.47-4.18 (m, 1H), 3.95-3.77 (m, 2H), 3.32 (d, J=13.2 Hz, 1H), 2.79 (brs, 1H), 1.53 (m, 3H), 1.51 (s, 9H), 1.02 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 44) Rt=3.339 min.; MS m/z: 414 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[O:8][CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:7]2[O:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2nc(CN=[N+]=[N-])co2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2nc(CN)co2)OCCO1
Temperature: 60 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[NH:18][CH3:19]>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[N:18]([CH3:19])[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNc1ccccc1OC
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with 2-methoxy-N-methylaniline (933 mg, 6.8 mmol) using method A to give 4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as an off white solid. Yield: 515 mg (71%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.33 (ddd, J=8.5, 7.5, 1.5 Hz, 1H), 7.17 (dd, J=7.5, 1.5 Hz, 1H), 7.00-6.92 (m, 2H), 3.33 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>C1(C)C=CC=CC=1>[F:13][C:6]1[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[C:10]2[C:5]=1[N:4]([C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:3]=[C:2]2[CH:33]=[CH2:34]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(F)c2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c(F)cc(C#N)cc12
Temperature: 100 °C
Reaction time: 1.58 h

Procedure:
Under nitrogen atmosphere, 3.32 g of 3-bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile was dissolved in 100 mL of toluene, added with 398 mg of tetrakis(triphenylphosphilne)palladium(0) and 2.50 mL of vinyltributyltin, and stirred at 100° C. for 95 minutes. After cooling to room temperature, 10 g of silica gel was added, the solvent was evaporated, followed by purification by silica gel column chromatography, to afford 2.59 g of the title compound as white crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN([CH:22]=[O:23])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][CH:11]=[C:10]2[CH:22]=[O:23]
Reactant: Cc1cc2[nH]ccc2cc1Br
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2[nH]cc(C=O)c2cc1Br
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
Phosphorus oxychloride (0.73 g, 4.79 mmol) and DMF (5.0 mL) were mixed together and stirred for 5 min. A solution of 5-bromo-6-methyl-1H-indole (500 mg, 2.39 mmol) in DMF (3.0 mL) was added to the solution slowly and complete solid was formed which stopped stirring. The solution was adjusted to pH=10 with 1N NaOH, then heated to 100° C. for 1 min. The reaction was cooled to room temperature. The precipitated solids were filtered and dried to give the title compound (480 mg, 85%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 9.88 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.49 (s, 1H), 2.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N+:5]([O-:30])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1
Solvent: ClCCl
Product: [O-][n+]1ccc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Reaction time: 3 h

Procedure:
A solution of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (900 mg, 2.165 mmol, 1 equip) and meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) in dichloromethane (30 mL) was stirred at room temperature for 1 h, at which point additional meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) was added and the solution stirred for an additional 3 h. The reaction mixture was washed with 10% Na2CO3 and the aqueous layer extracted with dichloromethane (2×). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide as a pale yellow semi-solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>>[CH3:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CC(C)(C)CN
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNCC(C)(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with 2,2-dimethyl-propylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 26.3, 26.4, 27.8, 32.1, 35.9, 43.1, 53.2, 59.3, 61.2, 63.0, 102.6, 102.8, 103.1, 105.2, 112.3, 112.6, 131.7, 137.6, 138.8, 162.0, 164.4, 164.5, 169.2, 169.3; MS m/z 478.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:27][OH:28])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH:27]=[O:28])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)n(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1

Procedure:
5-(Benzyloxy)-1-(biphenyl-3-yl)-2-(hydroxymethyl)pyridin-4(1H)-one (112 g, 292 mmol) was dissolved in 2.2 L of anhydrous THF and active manganese dioxide (407 g, 4.68 mol) was added. The reaction mixture was heated under reflux for 3 hours. The insoluble part was filtered off and the filtrate was concentrated to give crude 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carbaldehyde, which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: NC(=O)c1c(N)ncn1CCc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1CCc1ccccc1

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22 using 2.00 g (8.69 mmol) of 4-amino-1-(2-phenylethyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 56 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain crude 4-(2-fluorobenzoylamino)-1-(2-phenylethyl)-5-imidazolecarboxamide.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1.CCOC(C)=O>[CH2:5]([O:12][C:13](=[O:14])[NH:4][CH2:1][C:2]#[CH:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CCNC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over 0.5 h. The reaction benzylchloroformate (13.37 g, 78.2 mmol) in 100 mL CH2Cl2over0.5 h. The reaction dissolved in EtOAc and the organic solution was washed with water (2×). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (4.43 g).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28]([O-])(=[O:30])[CH3:29].[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>>[C:28]([O:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:30])[CH3:29]
Reactant: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 180.3 %

Procedure:
A mixture of 1 g of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.1 g of sodium acetate (anhydrous) and 12 ml of acetic anhydride is stirred vigorously at room temperature for 4 h, then poured onto ice water, neutralized with 2 molar aqueous sodium hydroxide solution and extracted three times with 50 ml of ethyl acetate each time, the collected organic extracts are dried over potassium carbonate, the solvent is stripped off in vacuo and the residue is well dried in a high vacuum. 0.9 g of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13](Br)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21]1([CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([C:30]2([OH:33])[CH2:29][CH2:28][CH:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:32][CH2:31]2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a solution of tert-butyl(3-bromopyridin-2-yl)carbamate (4 g) in THF (dry) (20 mL) was added dropwise n-butyllithium (1.6 M in hexane) (20.1 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 1 hr to give a yellow suspension. A solution of 4-phenylcyclohexanone (3.06 g) in THF (dry) (30 mL) was added dropwise at −78° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (560 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:16][CH:17]([CH2:20][CH3:21])[C:18]#[CH:19]>C(Cl)Cl>[OH:16][CH:17]([CH2:20][CH3:21])[C:18]#[C:19][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C#CC(O)CC
Solvent: ClCCl
Product: CCC(O)C#Cc1cnc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
546 mg of dimethyl 5-bromodicarboxylate (from Example 3) and 202 mg of 3-hydroxy-1-pentine are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 28 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 18 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation, 404 mg of a yellow oil which crystallizes at 0° C. remain.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH3:18])[N:14]=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:18][N:13]1[C:12]([C:10]([NH:9][C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:8]=[CH:7][CH:6]=2)=[O:11])=[CH:16][C:15]([CH3:17])=[N:14]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)c2)n(C)n1
Yield: 63.8 %

Procedure:
In a manner similar to that described in Example 449, 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide (0.0354 g, 0.222 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) were reacted to give the title compound as a white solid (47 mg, 64%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([Li])[N:3]=[CH:2]1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[O:1]1[C:5]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:4][N:3]=[CH:2]1
Reactant: C(=Nc1ccncc1)c1ccccn1
Reactant: [Li]c1cocn1
Product: c1ccc(C(Nc2ccncc2)c2cnco2)nc1

Procedure:
The title compound is prepared by reacting 4-oxazolyl lithium (obtained from 5-bromooxazole and butyl lithium) with 4-(2-pyridylmethyleneamino)pyridine in a manner similar to Examples 5, 6 and 7.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10](B(O)O)[C:4]=2[O:3]1.[OH:16]O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10]([OH:16])[C:4]=2[O:3]1
Reactant: Cc1ccc(B(O)O)c2c1OC(F)(F)O2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(O)c2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)boronic acid (Intermediate 36, 150 mg, 1.28 mmol) was dissolved in THF (1.5 mL) and a 30% w/w aqueous solution of H2O2 (2.56 mmol) and NaOH (51 mg, 1.28 mmol) were added and the reaction mixture stirred for 2 days at room temperature. The reaction was quenched with a 2N aqueous solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness, affording the title compound (140 mg) as yellow oil.