Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:24][CH2:23][C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]=2[CH3:25])=[CH:29][CH:28]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(Cl)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-methanol (Example 21) (300 mg, 0.83 mmol), 4-chlorophenol (107 mg, 0.83 mmol), and triphenylphosphine (219 mg, 0.83 mmol) in THF (20 ml), diethyl azodicarboxylate (132 μl, 0.83 mmol) was added. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the crude (830 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 3-[(4-chlorophenoxy)methyl]-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (29 mg, 7%): mp (DSC) 145° C. Anal Calc'd. for C25H21NSClFO3 ·0.25 H2O: C, 63.29; H, 4.57; N, 2.95. Found: C, 63.46; H, 4.57; N, 2.81.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C=C/C=O
Agent: [Br-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCC=CC=CCCCCC(=O)O
Yield: 42.6 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in 10%HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yielded the product (1.91 g, 43%) as a pale yellow oil (bp 122-125° C./0.01 torr). IR: 3500-2500, 1730 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.40 (m, 10 H), 2.30 (m, 6 H), 6.00 (m, 4 H), 11.30 (bs, 1 H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.
Reaction SMILES: N1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.O=[C:8]([CH3:21])[CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OCC)=[O:11].[CH3:22]N(C=O)C>C(N(CCCC)CCCC)CCC.O.ClCCl>[CH3:21][C:8]1[N:6]2[CH:22]=[CH:5][N:4]=[C:3]2[N:2]=[C:10]([OH:11])[C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: Nc1nc[nH]n1
Solvent: O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Cc1c(-c2ccccc2)c(O)nc2nccn12
Temperature: 180 °C

Procedure:
A solution of 3.8 g 1,2,4-triazol-3-amine and 6 g ethyl 3-oxo-2-phenylbutanoate is suspended in a mixture of 32 ml DMF and 32 ml N,N-dibutylbutan-1-amine and heated by microwave irradiation to 180° C. for 10 h. The reaction mixture is diluted with water and dichloromethane, the phases separated, the aqueous layer extracted twice with dichloromethane, the combined organic layers are dried over Na2SO4 and concentrated to give the crude product. The crude product is purified by column chromatography (silica gel, dichloromethane/methanol).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15]([O:17][CH3:18])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.O.[NH2:30][NH2:31].C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)C>[CH2:22]([O:21][C:19](=[O:20])[NH:1][CH:2]([C:15]1[O:17][CH:18]=[N:30][N:31]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: NN
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nnco2)ccc1O
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (4.0 g, 10.39 mmol) in ethanol (100 ml), hydrazine monohydrate (6.4 ml, 103.9 mmol) was added at room temperature. The mixture was stirred overnight and evaporated under reduced pressure to remove the solvent. The thus obtained residue was mixed with ethyl orthoformate (100 ml) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol) at room temperature. The mixture was stirred for 1.5 hours and mixed with 1N HCl (100 ml). The mixture was stirred for 20 min., and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.34 g, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:18]([NH2:21])[CH2:19][CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([NH:21][CH2:18][CH2:19][CH3:20])=[O:15])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCCN
Reactant: CCOc1ccc2nc(SCC(=O)O)sc2c1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCNC(=O)CSc1nc2ccc(OCC)cc2s1
Reaction time: 20 h
Yield: 45.5 %

Procedure:
To a stirred solution of 24 (110.3 mg, 0.41 mmol) and n-propylamine (50.5 mg, 0.50 mmol) in CHCl3 (2.0 ml), HOBt (190 mg, 1.41 mmol) and EDC (120 mg, 0.63 mmol) were added at room temperature. After stirring for 20 hours, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by HPLC (gradient from 20%, acetonitrile 80% in DDW to 100% acetonitrile, in 15 minutes) to give 33 (57.9 mg, 36% yield) as a brown amorphous solid, range of m.p. temperature was too large for a clear determination. 1H NMR (DMSO-d6): δ 0.97 (t, 3H, J=6.8), δ 1.27 (t, 3H, J=7.1), δ 1.53 (m, 2H, J=6.8, 3.5), δ 3.54 (d, 2H, J=3.7), δ 4.01 (s, 2H), δ 4.19 (q, 2H, J=7.3), δ 6.23 (amide broad peak), δ 6.97 (dd, 1H, J=10.8, J=3.7), 7.33 (d, 2H, J=8.8). 13C NMR (DMSO-d6): δ 12.8, 13.76, 20.6, 39.56, 40.78, 65.1, 101.79, 114.78, 123.6, 135.79, 145.8, 154.67, 168.4, 169.95. MS: MW=310.07 g/mol, MNa+=333.18 g/mol.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:16])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1.C[Si](C)(C)[Si](C)(C)C.[Li]>C1(C)C=CC=CC=1.C1(B(O)O)C2=C3C(=CC=C2)CCCN3C=1>[C:24]1([C:2]2[C:3](=[O:23])[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:16])[C:6]=2[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: OB(O)c1cn2c3c(cccc13)CCC2
Agent: [Li]
Solvent: Cc1ccccc1
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)-4-(tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:10]([O:9][C:8]([NH:7][C:2]1[C:3]([B:20]([OH:25])[OH:21])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Temperature: -6 °C

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(2-pyridyl)carbamate (15.71 g, 80.9 mmol) and N,N,N′N′-tetramethylethylenediamine (TMEDA, 25.3 g, 218 mmol) in THF (400 mL) was cooled to −78° C. n-Butyllithium (81 mL of a 2.5 M solution in hexanes) was added dropwise over a period of 20 minutes. The solution was stirred for ten minutes, and then the addition funnel was rinsed with additional THF (20 mL). The solution was warmed to −6° C., stirred for two hours, and cooled again to −78° C. Triisopropyl borate (57.7 g, 307 mmol) was added over a period of ten minutes. The resulting solution was warmed to 0° C. and then poured into saturated aqueous ammonium chloride (500 mL). A yellow solid formed and was stirred with diethyl ether (300 mL), isolated by filtration, washed with diethyl ether and water, and air-dried overnight to provide 2-tert-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[OH:24])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[C:30](Cl)(=O)[C:31](Cl)=O>C1COCC1>[C:1]([O:5]/[N:6]=[C:7](\[O:24][CH2:30][CH3:31])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)O/N=C(\O)c1cccnc1C(=O)c1cc(Br)ccc1O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCO/C(=N\OC(C)(C)C)c1cccnc1C(=O)c1cc(Br)ccc1O
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinic acid O-t-butyloxime (540 mg) and DMF (0.02 ml) in THF (6 ml) was added, at room temperature, oxalyl chloride (0.33 ml). The mixture was stirred for 2 hours at the same temperature and then concentrated, which was dissolved in THF (2 ml). To the solution was added ethanol (8 ml) at room temperature. The mixture was stirred for 1.5 hour at the same temperature and concentrated. To the concentrate was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give ethyl(Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinate O-t-butyloxime (403 mg) (Compound 139).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=O)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].[NH2:14][C:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(#[N:29])CCC>>[CH3:2][C:1]1[N:29]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[C:11]([CH3:12])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Reactant: CCCC#N
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C)n(-c2ccccn2)c1C
Yield: 14 %

Procedure:
To a solution of ethyl 2-acetamido-3-oxobutanoate (compound 10, 2.0 g, 10.6 mmol), aniline (compound 11b, 2.0 g, 21.3 mmol) in butyronitrile (15 mL) was added acetic acid (1.2 mL, 21.3 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 160° C. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (purification system, Gilson) to provide the title compound (340 mg, 14%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[C:11]([OH:17])(=[O:16])[CH2:12]C(O)=O.C([O-])(=O)C.[NH4+:22]>C(O)C>[NH2:22][CH:5]([C:4]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([Br:1])[CH:3]=1)[CH2:12][C:11]([OH:17])=[O:16]
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
4.72 g (23.25 mmol) 3-bromo-5-fluorobenzaldehyde were suspended in 10 ml ethanol. 2.42 g (23.25 mmol) propanedioic acid and 3.76 g (48.82 mmol) ammonium acetate were added. The mixture was refluxed for 5 hours and after cooling to room temperature filtrated. The residue was washed with cold ethanol and dried in vacuum at 30° C. to give 880 mg (13%) 3-amino-3-(3-bromo-5-fluorophenyl)propionic acid. The filtrate was concentrated and crystallized from ethanol to give further 706 mg (12%) 3-amino-3-(3-bromo-5-fluorophenyl) propionic acid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].O>O1CCCC1>[OH2:3].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6]
Reactant: O=C(COc1ccc(C2=NNC(=O)NC2)cc1)NCCN1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(CCNC(=O)COc2ccc(C3=NNC(=O)NC3)cc2)CC1
Reaction time: 0.5 h

Procedure:
0.15 ml of ethyl chloroformate were added, whilst ice-cooling, to a mixture of 0.360 g of N-[2-(1-piperazinyl)ethyl]-α-[4-(2,3,4,5-tetrahydro-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetamide [prepared as described in step (a) above], 0.13 g of sodium bicarbonate, 10 ml of water and 50 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluent: a 1:1 by volume mixture of ethanol and methylene chloride), followed by recrystallization from ethanol, to give 0.264 g of the title compound as colorless fine crystals melting at 200°-240° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(OCC)(=O)C>[N+:1]([C:4]1[O:8][C:7]([C:9]([Cl:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.2 g of 5-nitrofuran-2-carboxylic acid in 15 ml of ethyl acetate, was added 2.5 g of phosphorous pentachloride. The resulting mixture was stirred for 45 minutes at room temperature. Distilling off the solvent gave the oily substance, 5-nitrofuran-2-carboxylic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)C.[Pd]>[C:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2ccc(N)cc21
Yield: 89 %

Procedure:
6-Nitroindoline (15.63 g, 0.095 mol) was refluxed for 0.25 h in acetic anhydride (100 ml), cooled, and the precipitate filtered and washed with water, before drying in vacuo. This material (16.6 g, 0.08 mol) was hydrogenated in ethanol (500 ml) over 10% palladium on charcoal (3.4 g of 50% paste in water). The catalyst was removed by filtration and the filtrate was evaporated to leave the title compound as an off-white/cream powder (12.59 g; 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51]C)=[O:50])=[CH:47][CH:46]=2)[CH:5]=[CH:6][CH:7]=1.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCOc2c(-c3cccc(Cl)c3)cc(C(=O)NCCCCCCCCn3ccc4ccccc43)cc2-c2cccc(Cl)c2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(OCCOc2c(-c3cccc(Cl)c3)cc(C(=O)NCCCCCCCCn3ccc4ccccc43)cc2-c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared as a light green solid (0.073 g, 62%) from 4-{2-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}benzoic acid, methyl ester using a procedure similar to step 4 of example 165; dec. >65° C.; 1H NMR (400 MHz, DMSO-d6) δ1.16-1.30 (m, 8H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.20-3.26 (m, 2H), 3.56-3.60 (m, 2H), 3.72-3.76 (m, 2H), 4.12 (t, J=7.0 Hz, 2H), 6.37 (dd, J=0.66, 3.1 Hz, 1H), 6.66-6.70 (m, 2H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.32 (d, J=3.1 Hz, 1H), 7.38-7.52 (m, 6H), 7.57-7.60 (m, 2H), 7.67 (t, J=1.8 Hz, 2H), 7.76-7.80 (m, 2H), 7.88 (s, 2H), 8.55 (t, J=5.7 Hz, 1H), 12.54 (broad s, 1H); IR (KBr) 3420, 2920, 1680, 1600, 1260, 1160 cm−1; mass spectrum [(−)APCI], m/z 747 (M−H)−; Anal. Calcd. for C44H42Cl2N2O5: C, 70.49; H, 5.65; N, 3.74, Found: C, 70.12; H, 6.01; N, 3.44.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2NC=CN=2)=[N:4][CH:5]=[CH:6][CH:7]=1.FC1N=C(C2NC=CN=2)C=CC=1.[Li]CCCC.FC1C=NC=CC=1.C([O:39]CC)C>O.CN(C=O)C>[F:1][C:2]1[C:3]([CH:8]=[O:39])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Fc1cccnc1-c1ncc[nH]1
Agent: Fc1cccc(-c2ncc[nH]2)n1
Agent: Fc1cccnc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ncccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Fluoro-2-(1H-imidazol-2-yl)-pyridine, which is used as a starting material (e.g., in place 6-fluoro-2-(1H-imidazol-2-yl)-pyridine in the procedure given above) in the synthesis of certain compounds is prepared as follows: n-BuLi (2.5 M in hexane, 86 mL, 1.05 eq.) is added dropwise over a 90 minute interval to a solution of 3-fluoropyridine (20 g,.0.206 mol) and N,N,N′N′-tetramethylethylenediamine (31.3 mL, 0.206 mol) in ethyl ether (350 mL) at −78° C. under nitrogen. The mixture is stirred at this temperature for an additional 3 hours. Anhydrous DMF (45 mL) is then added at the same temperature. The mixture is allowed to warm to room temperature overnight. Water (170 mL) is added and organic layer separated. The aqueous layer is extracted with ether (3×200 mL), and then with ethyl acetate (2×200 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo. The crude is purified by column chromatography (hexane:ether 2:1) to give 3-fluoro-pyridine-2-carbaldehyde as a yellowish oil.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: Ic1ccc[se]1
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(c2ccc(-c3ccc[se]3)cc2)CC1

Procedure:
A mixture 0111.0 g (41.1 mmol) of 2-iodoselenophene, 7.98 g (32.4 mmol) of 4-(4-propylcyclohexyl)phenylboronic acid, 3.70 g (3.20 mmol) of tetrakis(triphenylphosphine)palladium(0) and 60 ml of 2 N sodium carbonate soln. in 160 ml of toluene/ethanol (1:1) is heated under reflux for 22 h. After cooling, water is added, and the batch is extracted a number of times with MTBE. The combined organic phases are washed with water, sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1). The further purification is carried out by recrystallisation from n-heptane; 2-[4-(4-propylcyclohexyl)phenyl]selenophene is obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].CC(O)C.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].N1CCCCC1>C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:20]([C:19](=[O:24])[CH3:18])[C:21](=[O:23])[CH3:22])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1cc(C=O)ccc1Cl
Solvent: C1CCNCC1
Solvent: O=CO
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(Cl)c(S(C)(=O)=O)c1)C(C)=O
Temperature: 23.5 °C
Reaction time: 20 h

Procedure:
4-Chloro-3-(methylsulfonyl)benzaldehyde (760 mg), 2-propanol (10 mL), 2,4-pentanedione (0.8 mL), formic acid (22 mL) and piperidine (57 mL) were mixed and stirred at 22-25° C. for 20 h. The product was filtered, washed with 2-propanol and dried. The compound was purified by crystallization from toluene (15 mL, yield 790 mg, melting point 170-172° C.). 1H-NMR (400 MHz, DMSO-d6) d=2.27 (s, 3H), 2.47 (s, 3H), 3.40 (s, 3H), 7.72 (dd, J=8.3 Hz, 2.2 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.84 (s, 1H), 8.19 (d, J=2.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:46](=[O:47])[CH2:45][C:43]#[N:44])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)-phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (60 mg, 0.37 mmol, 1.50 equiv), and 2-cyanoacetic acid (110 mg, 1.29 mmol, 5.23 equiv). The resulting solution was stirred for 60 min at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.06 g (51%) of 3-[(3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a light yellow solid.