Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[S:33][C:32]([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]2)=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[S:33][C:32]([N:34]3[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C1CN(c2ncc(Br)s2)CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
N-[3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (Intermediate IV, 35.4 g, 93 mmol) and 4-(5-bromo-1,3-thiazol-2-yl)-1,4-diazepan-2-one (21.5, 78 mmol) were combined in a 2 L RB flask follwed by DMF (473 mL) and aqueous Na2CO3 solution (1 M, 311 mL). The solution was sparged with N2 for 15 minutes and then [Pd(Ph3P)4](3.6 g, 3.11 mmol) was added. The mixture was heated at 85° C. for 12-15 hours. The reaction was cooled to 0° C. and saturated NH4Cl (500 mL) was added followed by EtOAc (2 L) and DCM (2 L). The aqueous layer was extracted with DCM (1 L) and the combined organic layer was washed with 10% aqueous LiCl solution (1 L) and then dried over Na2SO4. The organic layer was concentrated and slurried in MTBE (500 mL) and filtered. The solid was then dissolved in THF (870 mL), degassed and then treated with 300 wt % Silicycle Si-triamine resin at 40° C. for 1 hour. The suspension was then filtered, the residue washed with 40° C. THF (400 mL) and concentrated. A final slurrying in MTBE (200 mL) for 1.5 hours, filtration and drying gave 13.1 g of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (37%). MS APCI: [M+H]+ m/z 449.2. 1H NMR (600 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.79 (d, J=6.0 Hz, 1H); 7.77 (s, 1H), 7.57 (t, J=4.7 Hz, 1H); 7.44 (s, 1H); 7.34 (s, 1H); 7.23 (d, J=4.9 Hz, 1H); 6.9 (s, 1H), 4.19 (s, 2H); 3.76 (m, 2H); 3.19 (m, 2H); 2.26 (s, 3H), 1.76 (m, 2H). rhSyk=+++
Reaction SMILES: [CH3:1][C:2]1([C:10]([NH:12][C@H:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH3:14])=[O:11])[NH:9][CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][C:2]1([C:10]([NH:12][C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH3:14])=[O:11])[N:9]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[CH2:8][CH2:7][C:4]2([CH2:5][CH2:6]2)[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2Cc2ccc(C(F)(F)F)cc2)CC3)cc1

Procedure:
The title compound (D130) (19 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-(5-methyl-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D92) (16 mg) and 4-(Trifluoromethyl)benzylbromide (0.011 ml). (Na2CO3: 3 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1.C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:26]([NH2:25])=[S:27])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1
Reactant: COc1cc(N)ccc1-c1sc(C)nc1C
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-c1sc(C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenylamine (100 mg, 0.43 mmol) in tetrahydrofurane (4 mL) was added drop wise under stirring and under an atmosphere benzoyl isothiocyanate (63.6 ul, 0.45 mmol). The reaction was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (177 mg, 1.28 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (90 mg, 72%). MS ISP (m/e): 294.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.81 (s, 1H, NH), 7.35 (s, 1H), 7.21 (d, 1H), 7.01 (s, 1H), 3.76 (s, 3H), 2.59 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N+:17]([O-])=O)[CH:8]=1)(=[O:4])=[O:3].Cl.[H][H]>CO.[Pd]>[NH2:17][C:9]1[CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Yield: 87.5 %

Procedure:
13.25 g (46 mmol) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate are dissolved in 200 ml of methanol. After addition of 1.4 ml (46 mmol) of concentrated hydrochloric acid and 1 g of Pd catalyst (10% on active charcoal), the mixture is hydrogenated with hydrogen under atmospheric pressure until the hydrogen uptake is complete. The mixture is removed from the catalyst by filtration and the filtrate is concentrated completely. Crystallization of the residue from water yields 10.4 g (88%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 121-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:18])([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[N:9]2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a stirred solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (4.2 g, 12.4 mmol) in N,N-dimethylformamide (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.5 g, 37.2 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min and then iodomethane (2.4 mL, 37.2 mmol) was added to above mixture dropwise at 0° C. The solution was stirred at 0° C. for 2 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 10% ethyl acetate/hexane) to afford 2-(3-bromo-phenyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (1.1 g, 70%) as a yellow oil: MS obsd. (ESI+) [(M+H)+] 355.0 & 357.0.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]2[CH2:22][CH2:21]2)=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]2[CH2:21][CH2:22]2)=[CH:8][CH:9]=1
Reactant: O=C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Reaction time: 16 h
Yield: 39.2 %

Procedure:
Sodium borohydride (94 mg) was added to a stirred solution of Intermediate 29 (238 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (20 ml) and water (15 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (2×10 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a dichloromethane:methanol 0-25% gradient. The fractions were combined and concentrated under vacuum. The residue was purified by MDAP (Method B, UV detection only). The solvent was evaporated in vacuo to give the required product (94 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:13]([C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccco1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2

Procedure:
To a well stirred mixture of 6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acid (3.3 g.), furan-2-carbonyl-chloride (3.6 g.) and 200 ml methylene chloride, protected from the atmosphere with a calcium chloride tube is added anhydrous aluminum chloride (3.7 g.) over an one-half hour period. The reaction solution is stirred 18 hours at 25° C. and then refluxed for 1 hour. The solvent is removed and the residue added to ice water (200 ml.) and hydrochloric acid (20 ml.). The product is extracted into ether, washed with water, then extracted into aqueous sodium bicarbonate (200 ml.) from which the sodium salt of the product precipitates. The sodium salt of the product is placed in a separatory funnel with dilute hydrochloric acid (100 ml.) and ether (100 ml.) and shaken until the solid dissolves. The ether solution is washed with water, brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The 6,7-dichloro-2,3-dihydro-5-(2-furoyl)benzofuran-2-carboxylic acid melts at 166° C. after crystallization from acetonitrile/n-butyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[NH2:18].[C:19](Cl)(Cl)=[S:20]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[N:18]=[C:19]=[S:20]
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of 4.8 g of 5-(4-chloro-3-aminophenyl)-3-(2-furyl)-1,2,4-oxadiazole in 400 ml of tetrahydrofuran, 5 ml of triethylamine and 2.1 g of thiophosgene are added. After stirring at room temperature for 4 hours, the reaction mixture is filtered and evaporated to dryness in vacuo. The residue is crystallized from petroleum ether to yield 1.5 g (27%) of the title product, m.p. 131°-132°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(C=O)cccc1Oc1ccccc1C
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Yield: 53.3 %

Procedure:
2-Methoxy-3-(o-tolyloxy)benzaldehyde (28 g), malonic acid (24 g), pyridine (200 ml) and piperidine (2 ml) were treated in a similar manner to that of Example 4-(4), and the resultant crude product was crystallized with a mixture of benzene and n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17.5 g). mp 143°-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc2[nH]ccc2c1Br
Reaction time: 0.5 h
Yield: 3 %

Procedure:
To a −40° C. solution of 2-bromo-4-nitro-anisole (1.16 g, 5 mmol) in THF (10 ml) was added vinylmagnesium bromide (1M in THF, 15 ml). The reaction mixture was stirred for 30 min while allowing the temperature to rise to −20° C. The reaction was quenched by addition of a saturated solution of NH4Cl, diluted with Et2O, and the aqueous layer was extracted twice with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 4-bromo-5-methoxyindole XLVI (38 mg, 3% yield) as an oil.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:30]C(=O)CC)[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.CO.Cl>>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCC(=O)Nc1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: Nc1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
A mixture of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-propionamido-1H-indole-1-carboxylate (150 mg, 0.26 mmol) and 3 N MeOH—HCl (3 mL) was stirred at 60° C. overnight. The reaction mixture was quenched with water and neutralized with K2CO3. The resulting precipitate was filtered, washed with water and dried to obtain the crude product. The crude product was purified by prep HPLC (column: Zorbax Eclipse XDBC Prep C18 5 μm 21.2*150 mm; flow rate: 15.0 mL/min; mobile phase: A: 0.1% TFA in water. B: ACN+MeOH (1:1); gradient: % B, 10% to 50%) to obtain the title compound (25 mg, 28%). MS (ESI, pos. ion) m/z: 309.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][C:16]3([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10]=2[C:9]2[NH:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCC1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1CC1(O)CCCC1)NCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A mixture of 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol (511 mg), platinum oxide (511 mg), and trifluoroacetic acid was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight on a Parr apparatus. The mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was combined with concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 2 hours. The mixture was diluted with water (10 mL) and then cooled to 0° C. The pH was adjusted to 12 with 6N sodium hydroxide and then the mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with acetonitrile, purified by HPFC eluting with a gradient of 0-35% CMA in chloroform, and then triturated with acetonitrile to provide 167 mg of 1-[(4-amino-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol as a white powder, mp 207.0-208.0° C. Anal. Calcd for C18H27N5O .0.25H2OC, 64.74; H, 8.30; N, 20.97; Found: C, 64.71; H, 8.29; N, 20.98.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[OH:22].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:16]([OH:22])=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2O)cc1
Yield: 35.8 %

Procedure:
4′-(Methylsulfonyl)-2,4-biphenyldiol (500 mg, 36%) was prepared as a clear oil from [4-(methylsulfonyl)phenyl]boronic acid (1.06 g, 5.29 mmol), 4-bromo-1,3-benzenediol (1 g, 5.29 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.52 (s, 1H), 7.88-7.80 (m, 2H), 7.75-7.69 (m, 2H), 7.13 (d, 1H, J=8.4 Hz), 6.41 (d, 1H, J=2.2 Hz), 6.32 (dd, 1H, Ja=8.4 Hz, Jb=2.4 Hz), 3.31 (s, 3H); LRMS (ESI), m/z 263 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:19])[CH:12]([CH2:15]N(C)C)[CH2:13][CH2:14][C:3]=12.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.Cl.C(O)(C)C>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:19])[CH:12]([CH2:15][N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(CN(C)C)CC2
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 53.8 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-(dimethylaminomethyl)pyrido[1,2-a]indol-6(7H)-one (0.65 g), 2-methylimidazole (0.76 g), 2N hydrochloric acid (1.27 ml), and isopropyl alcohol (4 ml) was heated at 100° C. for 3 hours and 15 minutes. After evaporation of the solvent, the residue obtained was dissolved in methylene chloride. The methylene chloride solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification with neutral alumina column chromatography (0.5% methanol-methylene chloride), followed by recrystallization with ethyl acetate-hexane, gave 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)-methyl]pyrido[1,2-a]indol-6(7H)-one (0.40 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(O)ccn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
To a solution of tert-butyl 4-hydroxypyridin-2-ylcarbamate (4.12 g, 19.6 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (3.34 g, 21.6 mmol) in DMF (40 mL) was added K2CO3 (4.06 g, 29.04 mmol). After heating to 65° C. for 64 hours, the mixture was cooled to room temperature and poured into ice water (200 mL). The reaction mixture was extracted several times with ethyl acetate. The combined organics were concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (2.03 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([C@@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[CH2:33][C:34]#[CH:35].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][C@@H:36]4[CH2:40][O:39][C:38](=[O:41])[NH:37]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCC[C@@H]1COC(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCC[C@@H]3COC(=O)N3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (4R)-4-(3-butynyl)-1,3-oxazolidin-2-one (83.4 mg). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 95.6 mg (31%) of the desired product as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:26][CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCO)O2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of tert-butyl [2,3-dihydro-2-(2-hydroxyethyl)-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (7.7 g) and carbon tetrabromide (8.0 g) in tetrahydrofuran (80 mL) was added 6.3 g of triphenylphosphine under ice-cooling and the mixture was stirred for 30 minutes. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97:3 to 4:1) to provide 7.5 g of the title compound. Yield 82%.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:9]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)C(=O)Nc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
Diethyl 2-ethylmalonate (8.76 ml) and p-chloroaniline (4 g) were dissolved by heating at 130° C. for 11 hours, and the mixture was cooled and dissolved in ethyl acetate, and further, the mixture was washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and water, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with chloroform to give the oily desired product (6.66 g).