Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 6.05 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 5.72 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 4.22 g of 4-bromo-1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH2:2][CH3:3].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:39][O:38][C:36](=[O:37])[CH:35]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1cc(C(F)(F)F)ccc1C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of the aldehyde obtained above in toluene was added methyl (triphenylphosphoranylidene)acetate (285 mg, 0.85 mmol), and the resulting mixture was heated at 80° C. for 3 hrs. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=4/1) to give the title compound (220 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH3:19]O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH3:19])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: CO
Reactant: COC(=O)C1CCCC(O)N1C(=O)OC(C)(C)C
Product: COC(=O)C1CCCC(OC)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude 6-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 36, obtained in the previous step is dissolved in methanol (500 mL) and treated with Dowex-50 (1.0 g). After stirring at rt for 3 hr, the solution is filtered and concentrated in vacuo, and the residue is purified over silica (hexanes/ethyl acetate, 5:1) to afford 2.1 g of the desired product. 1H NMR (CDCl3) δ 5.43 (br s, 0.5H), 5.28 (br s, 0.5H), 4.88 (br s, 0.5H), 4.66 (br s, 0.5H), 3.73 (s, 3H), 3.33 (s, 3H), 2.32 (m, 1H), 1.87 (m, 2H), 1.70–1.40 (m, 3H), 1.51 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](COCC[Si](C)(C)C)[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:23][C:16]=23)=[C:10]([F:38])[CH:9]=1)(C)(C)C.Cl>CO>[F:38][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:23][C:16]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3c2cc(-c2ccccc2)n3COCC[Si](C)(C)C)c(F)c1
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]c(-c4ccccc4)cc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of 3-fluoro-4-[2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy]-phenyl-carbamic acid t-butyl ester in methanol, a 1:1 solution (10 mL) of hydrochloric acid and methanol was added. The mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated under reduced pressure and ether was added to the resulting residue. After stirring for 2 hours, the produced solid was collected by filtering. Thus obtained hydrochloride was dissolved in water and neutralized to about pH 8 by adding 1 M sodium hydroxide aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was separated and washed with sodium chloride aqueous solution. The organic layer was dried with Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a white solid (81 mg, 0.25 mmol, 40% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:17])([CH2:15][OH:16])[C:3]=1[C:4]=23>CN(C=O)C.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:17])([CH2:15][OH:16])[C:3]=1[C:4]=23
Reactant: O=C1CNc2ccc(F)c3c2N1CC3(O)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=c1cnc2ccc(F)c3c2n1CC3(O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
A mixture of 7-fluoro-6-hydroxy-6-(hydroxymethyl)-1,2,5,6-tetrahydro-3H-pyrrolo[1,2,3-de]quinoxalin-3-one (0.331 g, 0.001 mol), and manganese (IV) oxide (1.84 g, 0.021 mol) in DMF (50 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite®, washed with methanol and the solvent was removed. The residue was placed directly onto the top of a 20 g silica gel column and chromatographed, eluting with a 0-100% ethyl acetate in hexane gradient, then with a 0-50% methanol in ethyl acetate gradient to afford the product (0.267 g, 81%).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].FC(S(O[CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])(=O)=O)(F)F.C(=O)([O-])[O-].[K+].[K+]>C=C.CCOCC>[N:30]([CH2:29][CH2:28][O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[N+:31]=[N-:32]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NCCOS(=O)(=O)C(F)(F)F
Agent: C=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: [N-]=[N+]=NCCOC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg) and 2-azidoethyl trifluoromethyl sulfonate (26 mg) in anhydrous acetene (0.5 ml) containing powdered potassium carbonate (28 mg) is stirred at 25° C. in a capped flask for 2 hrs. The mixture is diluted with anhydrous ether (5 ml) and filtered. The filtrate is washed with water (2 ml) and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residue is purified by plc on a silica gel GF plate to afford benzyl 3-(2-azidoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:30])C.[Li+].[OH-]>>[CH2:32]([O:31][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[S:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:30])[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:12]3[N:13]=[C:14](S(C)=O)[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][NH2:26].C1COCC1.O>C(Cl)Cl.CCCCCC>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:12]3[N:13]=[C:14]([NH:26][CH3:25])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(S(C)=O)nc21
Reactant: CN
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2ccc(F)c(N)c2)cc2cnc(NC)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
Using general method E, 6-(3-amino-4-fluorophenyl)-8-ethyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one from Example 2 (0.94 g, 2.73 mmol) and 2.0M methylamine/THF (2.73 mL, 5.5 mmol) were stirred overnight at RT. Water (50 mL) was added and the product was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product. This crude product was stirred with 60% CH2Cl2/hexane solution (10 mL) for 10 min. The resultant solid was filtered and washed with 60% CH2Cl2/hexane solution and dried to afford 6-(3-amino-4-fluorophenyl)-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.32 g, 37% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 7.82-7.77 (m, 2H), 7.11 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.00 (dd, J=11.2 Hz, 8.0 Hz, 1H), 6.78-6.74 (m, 1H), 5.14 (s, 2H), 4.39-4.35 (m, 2H), 2.89 (d, J=4.4 Hz, 3H), 1.26-1.22 (m, 3H); MS (ESI) m/z: 314.3 (M+H+).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15][CH:16]([CH3:40])[CH:17]([N:22]([CH3:39])[C:23]([C:25]1[S:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[CH3:15][CH:16]([CH3:40])[CH:17]([N:22]([CH3:39])[C:23]([C:25]1[S:26][C:27]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:10](=[O:11])[C:9]3[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=3)=[CH:34][CH:35]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3cnc(C(=O)N(C)C(C(=O)OC)C(C)C)s3)cc2)cc1
Yield: 59 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-pentylbenzoyl chloride and intermediate 4. Yield: 59%; 1H NMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.86 (d, 1H), 7.95 (m, 4H), 7.78 (d, 2H), 7.37 (d, 2H), 6.27-4.76 (d, 1H), 3.68 (s, 3H), 3.47-2.95 (s, 3H), 2.68 (t, 2H), 2.38 (m, 1H), 1.63 (m, 2H), 1.30 (m, 4H), 1.03 (m, 3H), 0.90 (dd, 6H); MS (ESI) m/z 522.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH2:3][CH2:4][C:5]#[N:6].[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[N:8]=[CH:9][C:10]([NH:13][C:27]([C:25]2[N:26]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:23][C:24]=2[C:30]([F:32])([F:33])[F:31])=[O:28])=[CH:11][CH:12]=1)#[N:6]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(CCC#N)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCC#N)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 34.7 %

Procedure:
3-[Methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile (103 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (108 mg, 0.423 mmol), Et3N (297 uL, 2.11 mmol) and BOP (196 mg. 0.444 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a solid (61 mg). ES-MS calcd for C20H16F3N5O2 (m/e) 415.38, obsd 416.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:14](=[O:18])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(N2CCN(c3ncccn3)C(=O)C2)C1
Temperature: 110 °C
Yield: 36.8 %

Procedure:
A mixture of intermediate 4b (52 mg, 0.204 mmol), 2-bromopyrimidine 1i (65 mg, 0.41 mmol), CuI (8 mg, 0.04 mmol), 1,10-phenanthroline (18 mg, 0.10 mmol), and K3PO4 (95 mg, 0.45 mmol) in toluene (1 mL) was heated at 110° C. under N2 for 9 h. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave intermediate 3c as light yellow solid (25 mg).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])=[CH:6][CH:5]=1>C(OCC)C>[Br:1][CH:10]([C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:16][CH:15]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
Bromine (2.6 ml) was added dropwise to a solution of 3-(4-chlorobenzoyl)propionic acid (10.6 g) in ethyl ether (200 ml) under stirring. The ethyl ether was distilled off to give 3-bromo-3-(4-chlorobenzoyl)propionic acid. Acetamide (30 g) was added thereto, and the mixture was heated with stirring on an oil bath at 140° C. for an hour. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the resulting crystalline precipitate was collected by filtration and washed with ethyl ether to give crystals of 4-(4-chlorophenyl)-2-methyloxazole-5-acetic acid, yield 3.9 g (31.1%). Recrystallization from ethanol gave needles, yield 3.5 g (27.9%), m.p. 215°-216° C.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[C:5](O)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
48 ml of allylmercaptan and 129.6 g of trityl alcohol were suspended in 500 ml of acetic acid and 2.0 ml of concentrated sulfuric acid was dropwise added thereto at room temperature with stirring. Then, the mixture was further stirred for one hour under the same conditions as above, and the precipitates were recovered therefrom by filtration, washed with 200 ml of methanol and then thoroughly washed with water. The resulting colorless powder was dissolved in benzene, washed with an aqueous 5% sodium hydrogen carbonate solution and then with water, and dried over anhydrous magnesium sulfate, and the solvent was removed therefrom by distillation under reduced pressure. The residue was treated with a small amount of methanol to obtain 130 g of allyl tritylsulfide (melting point: 99°-101° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](#[N:32])[CH2:30][CH3:31].[CH:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>>[OH:40][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:30]([CH3:31])[C:29]#[N:32]
Reactant: CCC#N
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C#N)C(O)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Under an argon atmosphere, CuO(tert-Bu) (0.03 mmol, 60 μL in THF) and 1,2-bis(diphenylphosphino)ethane (hereinafter, referred to as dppe) (18 mg, 0.045 mmol) were mix dried under vacuum for 1 hour. To the residue, dimethylsufoxide (hereinafter, referred to as DMSO) (0.3 mL), propionitrile (0.3 mL), and benzaldehyde (30 μL, 0.3 mmol) were added to start the reaction. After 2 hours, saturated ammonium chloride was added, and the product was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over sodium sulfate. Filtration, evaporation, and purification by silica gel column chromatography (ethyl acetate/hexane=1/3) gave the product in 90% yield (44 mg). A diastereomeric rate of the obtained compound was determined to be 1.5:1 (syn:anti).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[O:13]([CH2:20][CH2:21]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(Br)ccc1OCCOc1ccccc1
Reaction time: 48 h
Yield: 71.3 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (308 mg, 1.33 mmol) and 2-phenoxyethanol (183 mg, 1.33 mmol) were stirred in dry DCM (10 mL). PPh3-polystyrene bound (665 mg, 2.0 mmol) was added, followed by the drop-wise addition of DIAD (0.387 mL, 2.0 mmol). The mixture was stirred for 48 hours, then filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE/EtOAc 9:1-7:3 to provide 334 mg (72%) of the desired compound methyl 6-bromo-3-(2-phenoxyethoxy)picolinate (27A): 1H NMR (300 MHz, CDCl3) δ7.58-6.90 (7H, m), 4.43 (2H, m), 4.34 (2H, m), 3.91 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]2)[CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCN1CCC[C@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((S)-3-aminopiperidin-1-yl)ethyl ester (1.565 g, 6.85 mmol) in DMF (30 mL) was added 2,4-difluoronitrobenzene (1.517 g, 8.92 mmol) and potassium carbonate (1.9 g, 13.8 mmol). The reaction mixture was stirred at RT for 16 h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a yellow oil (2.307 g, 92%). LCMS (Method J): RT 2.34 min [M+H]+ 368.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]#[CH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C@H:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2.[OH-].[Na+:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]#[CH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C@H:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O-:18])=[O:17])=[CH:7]2.[Na+:22]
Reactant: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)O)[C@@H](C(F)(F)F)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)[O-])[C@@H](C(F)(F)F)O2

Procedure:
A solution of 50.0 mg (0.165 mmole) of (2S)-(-)-8-chloro-6-ethynyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 1.5 mL of ethanol was treated with 1.64 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 39.0 mg (quant.) of an yellow solid: MS (ES+) 303 (M+1, 100); 1H NMR (CD3OD/400 MHz) 5.95 (q, 1H, J=7.1 Hz), 7.29 (d, 1H, J=1.8 Hz), 7.37 (s, 1H), 7.39 (d, 1H, J=1.8 Hz); 19F NMR (CD3OD/400 MHz) 80.3 (d, 3F, J=6.8 Hz).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32](Cl)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([N:44]1[CH2:49][CH2:48][N:47]([C:32]2[C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[C:15]([C:19]5[CH:24]=[CH:23][C:22]([N:25]6[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]6)=[CH:21][CH:20]=5)[CH:14]=4)[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:11]=3[N:35]=[CH:34][CH:33]=2)[CH2:46][CH2:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(Cl)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(N5CCN(Cc6ccccc6)CC5)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
9-Benzenesulfonyl-4-chloro-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-9H-pyrido[2,3-b]indole (building block A, 50 mg, 0.0967 mmol) and benzylpiperazine (0.21 mL, 12.5 eq) were heated at 150° C. for 7 h. After cooling to r.t., the reaction mixture was diluted with DCM (20 mL), washed 3 times with water (3×10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica gel flash chromatography (DCM/MeOH 100:0 to 98:2) to afford the desired product in 57% yield (36.1 mg) as an uncoloured amorphous solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=8.7 Hz, 1H), 8.40 (d, J=5.6 Hz, 1H), 8.16 (d, J=8.8 Hz, 2H), 8.07 (d, J=1.9 Hz, 1H), 7.71 (dd, J=8.8, 1.9 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.49 (t, J=7.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.38-7.27 (m, 5H), 7.07 (d, J=8.8 Hz, 2H), 6.82 (d, J=5.6 Hz, 1H), 3.64 (s, 2H), 3.36-3.31 (m, 4H), 3.30-3.18 (m, 4H), 2.88-2.68 (m, 4H), 2.68-2.60 (m, 4H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.3 (C), 152.9 (C), 150.6 (C), 147.9 (CH), 138.9 (C), 137.8 (C), 136.8 (C), 135.6 (C), 133.8 (CH), 132.2 (C), 129.2 (CH), 128.9 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 127.4 (CH), 125.8 (CH), 123.1 (C), 120.7 (CH), 116.3 (CH), 114.7 (CH), 110.4 (C), 108.5 (CH), 63.1 (CH2), 55.2 (2CH2), 53.0 (2CH2), 50.6 (2CH2), 49.0 (2CH2), 46.3 (NCH3); MS (ESI) m/z: 657.3 [M+H]+; 1314.7 [2M+H]+; 516.5 [M-SO2Ph+H]′.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:2])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), glycine (2.73 g, 36 mmol) and NaOMe solution (55 mL, 27 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The solid obtained was further purified by silica gel chromatography (0-70% EtOAc/hexanes+2% AcOH) to give 36 mg of the title compound. MS: (+) m/z 506.13 (M+1).