Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH2:17]2.[N-:24]=[N+:25]=[N-:26].C[Si](Cl)(C)C>CCCCCC.O1CCCC1>[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH:17]2[N:24]=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCCC2CC(=O)N21
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21

Procedure:
In a nitrogen stream under stirring, 50 ml of dry tetrahydrofuran is cooled to -78° C. and, then, 20 ml of a solution of 15% n-butyllithium in n-hexane is added thereto. After dropwise addition of 3.66 ml of diisopropylamine, the mixture is stirred at -78° C. for 15 minutes. A solution of 3.1 g of 2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -78° C. for one hour. Then, a solution of 4.34 g of p-toluenesolfonyl azide in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -50° C. to -60° C. for 1.5 hours. To this mixture 5.1 ml of trimethylsilyl chloride is added dropwise and the reaction mixture is heated under reflux for 5 hours. Ater cooling, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is shaken with water and ethyl acetate and the ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solvent is then distilled off and the residue is purified by silica gel column chromatography to give 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]-octan-8-one as a 1:4 mixture of cis- and trans-isomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:7]=1
Reactant: OC(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)CCO2
Reaction time: 16 h
Yield: 100 %

Procedure:
(5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanol 5c (10.5 g, 30.9 mmol) was dissolved in 100 mL dichloromethane, followed by addition of triethylsilane (14.8 mL, 92.7 mmol) and dropwise addition of boron trifluoride etherate (7.8 mL, 61.8 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound 5-[(5-bromo-2-chloro-phenyl)methyl]-2,3-dihydrobenzo-furan 5d (10.0 g, pale yellow grease), yield: 100%. 1H NMR (400 MHz, CDCl3): δ 7.29-7.21 (m, 3H), 7.00 (s, 1H), 6.93 (d, 1H), 6.73 (d, 1H), 4.56 (t, 2H), 3.98 (s, 2H), 3.18 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>C1COCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([C:21]([OH:22])([CH3:23])[CH3:20])[CH:7]=[CH:6][CH:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cccc(Br)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A solution of 1-(3-bromophenyl)-2,5-dimethyl-1H-pyrrole (1.50 g, 6.00 mmol) in THF (25 mL) was cooled to −78° C. under an atmosphere of argon. To this solution was added n-BuLi (2.50 M in hexane, 2.76 mL, 6.90 mmol) dropwise via syringe. After 30 min, acetone (0.572 mL, 7.8 mmol) was added to the cold solution dropwise via syringe. After 10 min, the cold bath was removed and the reaction mixture was allowed to warm to rt. After 5.5 h, the reaction was quenched by the addition of water. The mixture was extracted with EtOAc and the organic solutions dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the desired product (0.84 g, 61%). LCMS: (FA) ES+ 230.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[O:17]1[CH2:20][C:19](=[O:21])[CH2:18]1.CC(=O)OCC>C1COCC1>[Br:1][C:2]1[C:7]([C:19]2([OH:21])[CH2:20][O:17][CH2:18]2)=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1COC1
Reactant: Clc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2c(Cl)ccnc2Br)COC1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (14 g, 70 mmol) in dry THF (200 mL) was added LDA (42.0 mL, 84.0 mmol, 2.0 M) dropwise at −70° C. After stirring for 0.5 h at this temperature, a solution of oxetan-3-one (6.6 g, 90 mmol) in dry THF (40 mL) was added slowly and the reaction mixture was stirred at 0° C. for an additional 1 h. Saturated aqueous NH4CI (50 mL) and EA (200 mL) were added. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by SGC eluting with DCM) to afford 148a as a yellow solid (8.8 g, 45%). MS: [M+H] 266.0.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1>CCCCO>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 35.2 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (100 mg, 0.3 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (199 mg, 1.0 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (51 mg, 32% yield) as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]2[CH2:32][NH:31][CH2:30][CH2:29][NH:28]2)[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:31]3[CH2:30][CH2:29][NH:28][CH:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)[CH2:32]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCN(CC2CNCCN2)CC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CN4CCN(C)CC4)C3)cc21

Procedure:
A 425 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.25 g of 1-methyl-4-(2-piperazinylmethyl)piperazine were suspended in 5 ml of pyridine and heated at reflux, under argon, for 18 hours. The solvents were removed and the residue evaporated twice from toluene. The residue was dissolved in dichloromethane, hexane was added, the resulting gum was separated, dissolved in dichloromethane and filtered. Ether was added to the filtrate, the resulting solid collected and recyrstallized, giving 360 mg of the desired product as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:23]1([C:29]2[N:30]=[C:31]([NH:40][CH2:41][CH2:42][CH3:43])[S:32][C:33]=2[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].O>CN(C)C=O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][N:40]([C:31]2[S:32][C:33]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=2)[CH2:41][CH2:42][CH3:43])=[CH:4][CH:5]=1
Reactant: CCCNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)OC)s1
Yield: 77.8 %

Procedure:
To a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (433 mg) and methyl 3-[4-phenyl-2-[N-(1-propyl)amino]-5-thiazolyl]propionate (400 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 55.2 mg) at 0° C. and the mixture was stirred at said temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionate (595 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][I:17])=[CH:13][C:12]([F:18])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[I-:17].[CH2:1]([O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([F:18])=[CH:13][C:14]=1[CH2:15][CH2:16][P+:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(CCI)c1
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [I-]
Temperature: 100 °C
Yield: 56 %

Procedure:
To a solution of 2-(benzyloxy)-1,5-difluoro-3-(2-iodoethyl)benzene (630 mg, 1.684 mmol) in toluene (8 ml) was added Ph3P (442 mg, 1.684 mmol) and the mixture was heated at 100° C. for 16 h. The mixture was then cooled to rt and toluene was decanted via pipet and remaining residue was washed with ether and ethyl acetate, dried under high vac to afford (2-(benzyloxy)-3,5-difluorophenethyl)triphenylphosphonium, iodide salt (600 mg, 0.943 mmol, 56.0% yield) as white solid. Used as-is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.81-7.71 (m, 9H), 7.62 (td, J=7.8, 3.5 Hz, 5H), 7.39-7.33 (m, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.25 (d, J=7.3 Hz, 2H), 7.22-7.14 (m, 2H), 6.75 (ddd, J=11.2, 8.2, 2.8 Hz, 1H), 5.01 (s, 2H), 3.92 (dt, J=12.4, 7.9 Hz, 2H), 3.02-2.94 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.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(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 40.8 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 126, 0.226 g, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.340 g, 3.50 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.340 g, 0.77 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.108 g, 0.84 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.115 g, 41%) as a white solid: HR-ES-MS m/z calculated for C20H23FN4O4 [M+Na]+ 425.1595, observed 425.1597, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.45 (m, 1H), 1.53-1.63 (m, 1H), 1.67-1.79 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.5 Hz, 1H), 4.57 (d, J=18.5 Hz, 1H), 4.84-4.92 (m, 2H), 6.40 (d, J=1.7 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H), 6.91 (t, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), H), 7.54 (d, J=1.7 Hz, 1H), 10.35 (br. s., 1H), 10.72 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNC(=O)N2CCOCC2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL flask, 3-aminomethyl-7-chloro-1-phenyl-1H-quinolin-4-one hydrochloride salt (intermediate I) (50 mg, 0.132 mmol) and morpholine-4-carbonyl chloride (21.7 mg, 0.145 mmol) were combined with CH2Cl2 (5 mL) and stirred at 0° C. for 10 min. Then N,N-diisopropylethylamine was added at 0° C. over 1 hr. The reaction mixture was stirred at and stirred at 0° C. for 4 hr. The reaction mixture was concentrated. The crude product was purified using preparative reverse phase HPLC to yield the product 7-chloro-3-{[(morpholine-4-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester. MS calcd. for C23H23ClN3O5 [(M+H)+] 456.1, obsd. 455.9.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[CH2:16]=O.Cl.[CH3:19][NH:20][CH3:21].Cl>C(O)C.O>[CH3:19][N:20]([CH:1]([CH3:16])[C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3])[CH3:21]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)C(C)N(C)C)cc(OC)c1OC
Yield: 90.5 %

Procedure:
3,4,5-Trimethoxyacetophenone (50 g, 237.8 mmol), paraformaldehyde (9.75 g, 304.7 mmol), dimethylamine hydrochloride (26.42 g, 324.0 mmol) and 5 mL conc. HCl were dissolved in 200 mL absolute ethanol and refluxed for 10 hours. Additional dimethylamine hydrochloride (13.21 g, 162.0 mmol) and paraformaldehyde (9.75 g, 304.7 mmol) were added and the solution returned to reflux. After 54 hours (total reaction time), 80 mL of 10% HCl and 500 mL of water were added and the solution was extracted with ethyl ether. The acidic aqueous layer was adjusted to pH 10 with 10% NaOH. The basic solution was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated in vacuo to provide 57.5 g of a yellow oil (92%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.30 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 1 h. THF was evaporated and the residue was purified by silica gel column chromatography using 25% acetone-chloroform as eluent to obtain 6 mg of N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=[O:5].[Si:13](C#N)([CH3:16])([CH3:15])[CH3:14].[CH3:19][N+:20]1([O-])CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]([O:5][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:19]#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[Si](C)(C)OC(C#N)c1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of 2-chloro-6-nitrobenzaldehyde (1.0 g, 5.4 mmol) in DCM (15 mL) were added TMSCN (1.0 mL, 8.1 mmol) and NMO (0.19 g, 1.6 mmol) at room temperature and stirred for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get compound A84-1 (1.0 g, 67%) as a brown color oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:37](I)([CH3:39])[CH3:38].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:37]([CH3:39])[CH3:38])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To ethyl 3-{3-chloro-5-[5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}propanoate (D108) (180 mg, 0.40 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry DMF (5 ml) was added isopropyl iodide (85 mg, 0.50 mmol) and the mixture stirred at 80° C. for 30 minutes. Cooled mixture and added EtOAc (50 ml). Washed with water (2×50 ml) and dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 120 mg of white solid. δH (400 MHz, d6-DMSO) 1.12 (3H, t), 1.37 (6H, d), 2.91 (2H, t), 4.02 (2H, q), 4.50 (2H, t), 4.89-4.98 (1H, m), 7.72-7.85 (5H, m), 7.95-8.00 (1H, m), 8.24 (1H, d). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([F:15])[CH:7]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C(#N)CC>[Cl:16][CH2:17][C:18]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][C:8]=2[F:15])[O:11][CH:20]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1F
Reactant: O=C(CCl)CCl
Solvent: CCC#N
Product: Fc1cc(OCCCCl)ccc1-c1nc(CCl)co1
Temperature: 100 °C
Reaction time: 60 h
Yield: 44 %

Procedure:
A mixture of 4-(3-chloropropoxy)-2-fluorobenzamide i82 (0.41 g, 1.75 mmol, 1 eq) and 1,3-dichloroacetone (0.49 g, 3.85 mmol, 2.2 eq) in propionitrile (9 ml) is stirred at 100° C. for 60 h. The mixture is then concentrated under vacuum, taken up in dichloromethane, and washed with water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silicagel (eluent: dichloromethane) to afford 0.23 g of 4-(chloromethyl)-2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazole i84.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=2)[CH:5]=1.C1COCC1.[OH-].[Na+].Cl>O.CO>[NH2:18][C:16]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=[C:13]([NH:12][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:25])=[O:2])[N:17]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2nc(N)n(-c3ccccn3)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1Nc1nc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A suspension of 3-(5-Amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-4-methoxy-benzoic acid methyl ester (1.31 g, 3.85 mmol) in a mixed solvent of THF (40 mL), MeOH (5 mL) and water (10 mL) was treated with 2N NaOH (8 mL) at 50° C. for 1 h. The reaction mixture was cooled to room temperature, neutralized with 6N HCl. Precipitate came out and collected by filtration to give the title compound (1.20 g) in 95% yield. Small amount was further purified by HPLC. FIA-MS: m/e=327.1 (M+H), 325.0 (M−H). Rt=3.09 min (Method A). 1H-NMR (500 MHz, DMSO(d6)): 12.53 (s, 1H), 8.81 (d, 1H), 8.43 (dd, 1H), 8.01 (td, 1H), 7.78 (s, 2H), 7.65 (d, 1H), 7.56 (s, 1H), 7.353 (dd, 1H), 7.23 (dd, 1H), 7.07 (dd, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)=[CH:2]\[CH3:3].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[O:14])=[CH:2]\[CH3:3]
Reactant: C/C=C/c1ccccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C/C=C/c1ccccc1C=CC(=O)OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, 2-((E)-1-propenyl)bromobenzene (2.1 g, 11.0 mmol), methyl acrylate (4.5 mL, 50 mmol) and triethylamine (1 mL) were added to a solution (15 mL) of palladium (II) diacetate (11 mg, 0.05 mmol) and tris(2-methylphenyl)phosphine (60 mg, 0.2 mmol) in N,N-dimethylformamide, followed by stirring at 80° C. for 1 hour. Next, the reaction solution was filtered through Florisil, and the solvent contained in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane=1/10) to give methyl 2-((E)-1-propenyl)cinnamate (740 mg, yield 34%).