Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[CH:39]=[CH2:40]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:40]=[CH:39]/[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:9][N:8]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(I)c2scc(Br)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(Br)csc12
Temperature: 80 °C
Yield: 42.8 %

Procedure:
A solution of Example 21A (2.50 g, 7.04 mmol), PPh3 (0.370 g, 1.41 mmol), and Na2CO3 (1.49 g, 14.1 mmol) in DME (35 mL) was treated with tert-butyl acrylate (2.00 mL, 14.1 mmol) and palladium(II) acetate (0.158 g, 0.704 mmol). The reaction was heated to 80° C. under an atmosphere of nitrogen for 16 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (100 mL) and brine. The organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated. The compound was purified by flash chromatography on silica gel using heptane/ethyl acetate (6:1) to (3:1) to provide the desired product (1.70 g, 3.01 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.62 (d, 1H), 7.17 (br s, 2H), 6.22 (d, 1H), 1.48 (s, 9H); MS m/e 355/357 (M+H)+.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][O:9][C:10](=[O:14])[C:11]([Cl:13])=[CH2:12].Cl>O>[CH3:8][O:9][C:10](=[O:14])[CH:11]([Cl:13])[CH2:12][S:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: C=C(Cl)C(=O)OC
Reactant: O=C(O)CS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(Cl)CSCC(=O)O
Reaction time: 24 h
Yield: 86.3 %

Procedure:
Under stirring there were added 0.063 gram (1.58 mmoles) of sodium hydroxide in 0.32 ml water to 1.00 gram (10.9 mmoles) of mercaptoacetic acid and 1.31 grams (10.9 mmoles) of 2-chloroacrylic acid methyl ester. Stirring was carried out subsequently for 24 hours at 10° C. After acidification of the reaction mixture with dilute hydrochloric acid the working up was carried out by extracting three times with diethyl ether, drying the combined ether phases with water free sodium sulfate and removal of the ether. There were obtained 2.00 grams (86% of theory) of 2-chloro-3-carboxymethylmercapto-propionic acid methyl ester as a colorless viscous oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]([C:9]2([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([NH:6][C:7]([C:9]2([CH2:22][CH2:23][CH2:24][CH2:25][N:30]3[CH2:31][CH2:32][N:27]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)[CH2:28][CH2:29]3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NC1CCCC1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NC1CCCC1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(cyclopentyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>Cl.C(Cl)(Cl)Cl>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCN
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of tert-butyl {4-[4-amino-2-propyl-7-(pyridin-3-yl)-1H-imidazol[4,5-c]quinolin-1-yl]butyl}carbamate (41.92 g, 88.32 mmol) in concentrated hydrochloric acid (210 mL) was stirred for ten minutes, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Cloroform (2.0 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (300 mL) were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The aqueous phase was treated with sodium chloride and chloroform (400 mL), and the mixture was stirred overnight. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide a yellow solid. The two solids were combined to yield 28.77 g of 1-(4-aminobutyl)-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([Cl:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1.[CH3:38][O:39][C:40](Cl)=[O:41]>N1C=CC=CC=1>[Cl:37][C:21]1[CH:22]=[C:23]([F:36])[C:24]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[CH:25][C:20]=1[C:12]1[C:13](=[O:19])[N:14]([CH2:17][CH3:18])[C:15]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([NH:6][C:40](=[O:41])[O:39][CH3:38])[CH:16]=2
Reactant: COC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of Example 21 (100 mg, 0.221 mmol) in pyridine (3 mL) was treated drop-wise with methylchloroformate (23 mg, 0.243 mmol) and stirred at RT for 4 h. Additional methylchloroformate (50 mL) was added and the mixture stirred overnight. The mixture was treated with additional methylchloroformate (100 mL) and stirred for another 2 days. The mixture was concentrated to dryness, treated with EtOAc and water and the resulting solid collected via filtration. The material was purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous mixture was neutralized with satd. NaHCO3. The resulting solid was collected via filtration, washed with water and dried to afford methyl (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (101 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (br s, 1H), 9.31-8.78 (m, 2H), 8.67 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.96 (s, 2H), 7.56 (d, J=11.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 510.1 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[C:12]([CH3:23])[CH:11]=1.CON(C)[C:27](=[O:29])[CH3:28]>C1COCC1>[Br:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[C:12]([CH2:23][C:27](=[O:29])[CH3:28])[CH:11]=1
Reactant: CON(C)C(C)=O
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(Br)cc1CC(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 2 M solution of lithium diisoproyl amine (35 ml, 70 mmol) in THF (180 mL) cooled to −78° C. was treated with slow addition of 4-bromo-N,N-diethyl-2-methylbenzamide (19 g, 70 mmol) in dry THF (180 mL). The reaction was allowed to stir at −78° C. for 1 hour before it was quenched with N-methoxy-N-methylacetamide (22 mL, 210 mmol) and allowed to slowly warm to room temperature. The reaction was stirred overnight and then partitioned between 1 N HCl (200 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was an orange/brown oil out of which the product crystallizes. The oil was decanted off and the solid was washed with hexanes and dried using a Büchner funnel to afford 4-bromo-N,N-diethyl-2-(2-oxopropyl)benzamide.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CN(C=O)C.[H-].[Na+].F[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=2[CH:24]=1>O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=2[CH:24]=1
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A mixture of 75 mg of 2,2-difluoroethanol and 0.5 ml of DMF was added to a mixture of 36 mg of sodium hydride (60%, oil-based) and 3 ml of DMF under ice-cooling. This mixture was stirred at room temperature for 15 minutes, and then ice-cooled. Subsequently, 0.20 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine was added thereto, and the mixture was stirred at room temperature for 3.5 hours. Thereto was added a mixture of 29 mg of 2,2-difluoroethanol, 0.5 ml of DMF and 14 mg of sodium hydride (60%, oil-based), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 3-(2,2-difluoroethoxy)-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 10”).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13]CC(C)=C)[CH:9]=[CH:8][C:7]=2[CH3:18])[CH3:2]>C(Cl)(Cl)Cl.CO.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[C:9]([CH2:12][C:3]([CH3:4])=[CH2:1])=[CH:8][C:7]=2[CH3:18])[CH3:2]
Reactant: C=C(C)COc1ccc(C)c2[nH]c(=O)c(CC)cc12
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C(C)Cc1cc(C)c2[nH]c(=O)c(CC)cc2c1O
Yield: 150.8 %

Procedure:
Using 3-ethyl-5-(2-methyl-2-propenyl)oxy-8-methylcarbostyril (0.94 g, 3.66 mmol), the procedure of Reference Example 32 was followed (reaction, post-treatment, and recrystallization from chloroform-methanol-n-hexane) to obtain 710 mg of the title compound as pale yellow crystals (75.5%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([OH:19])[CH2:17][C@:16]54[O:37][C@H:15]5[CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C

Procedure:
Pure cholesterol epoxides are not generally available from commercial sources, so they were synthesized from cholesterol. Analytical grade cholesterol, purified through the dibromide, was employed in these syntheses. Cholesterol 5α,6α-epoxide was synthesized by the procedure of Fieser, L. F. and Fieser, M., in "Reagents for Organic Synthesis," Vol. 1, 1967 John Wiley, New York, p. 136. Cholesterol (50 mmol) in methylene chloride (75 ml) solution was treated at 25° C. over a 30 minute interval with m-chloroperbenzoic acid (54 mmol) in methylene chloride (120 ml) solution. Excess peracid was destroyed by the addition of 10% sodium sulfite. Extraction of the organic layer with 5% aqueous sodium bicarbonate, water, and finally with saturated aqueous sodium chloride, followed by drying and evaporation produced a crude product readily purified by recrystallization from 88% aqueous acetone or by silica gel chromatography. Cholesterol 5α,6α-epoxide (>95% purity, m.p. 142°-143°) was obtained in >90% yield.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([OH:22])=O)[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:38][CH2:39][CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1.[OH-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[NH:43]1[CH:42]=[C:41]([CH2:40][CH2:39][NH:38][C:20]([C@@H:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][C:6]4[C:19]5[C:18](=[CH:17][CH:16]=[CH:15][C:14]3=5)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)[N:9]([CH3:23])[CH2:10]2)=[O:22])[N:45]=[CH:44]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN(C)[C@@H]1C2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)NCCc3c[nH]cn3)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 3.5 g of (8β)-1-isopropyl-6-methylergoline-8-carboxylic acid in 80 ml of dimethylformamide were added 2.27 g of 1,1'-carbonyldiimidazole. After stirring for 3 hours at room temperature, the mixture was added dropwise to a solution of 2.27 g of histamine dihydrochloride in 100 ml of dimethylformamide to which 3.6 ml of triethylamine had been added. The reaction mixture was stirred at room temperature overnight and then poured into 2 liters of ice water to which 5 ml of ammonium hydroxide had been added. The resulting precipitate was recovered by filtration. The solid material was crystallized from methanol/water to provide 2.41 g of the desired title product hemihydrate as a light pink powder, m.p. 83°-86° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:24])(=[NH:23])[CH2:20][CH2:21][CH3:22]>>[CH2:20]([C:19]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:24]=1)[CH2:21][CH3:22]
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: CCCC(=N)N
Agent: Cl
Product: CCCc1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 84 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 84%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:8])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][NH:36][C:37]2=[O:40])=[CH:33][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][N:36]([C:2]3[O:6][C:5]([C:7]([NH:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:15]=4[N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[O:8])=[CH:4][CH:3]=3)[C:37]2=[O:40])=[CH:33][CH:32]=1
Reactant: COc1ccc2c(c1)C(=O)NC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccncc2NC(=O)c2ccc(Br)o2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1ccc(C(=O)Nc3cnccc3N3CCN(C(=O)OC(C)(C)C)CC3)o1)C2

Procedure:
A mixture of tert-butyl 4-(3-(5-bromofuran-2-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (1.3, 100 mg, 0.20 mmol), the 6-methoxy-2,3-dihydro-isoindol-1-one,(1.4, 1.2 equivalent), Tris(dibenzylideneacetone) dipalladium(0) (20 mg, 0.02 mmol), Xantphos (26 mg, 0.04 mmol), Potassium acetate (139 mg, 0.66 mmol) in 5 ml of Dioxane was heated to 85° C. for 16 hours. Resulting suspension was diluted with ethyl acetate and passed through a celite filter to remove insoluble solid. Organic layer was concentrated in vacuo. The crude compound was purified by Prep-LC to yield compound, tert-butyl 4-(3-(5-(6-methoxy-1-oxoisoindolin-2-yl)furan-2-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (1.5). HPLC-MS tR=3.84 min (UV254 nm); Mass calculated for formula C28H31N5O6, 533.23; observed LCMS m/z 534.20(M+H).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=C[C:41]([C:42]([N:44]3[C:50]4C=CC=C[C:49]=4[CH2:48][N:47]4[C:55](C(O)=O)=[CH:56][CH:57]=[C:46]4C3)=O)=CC=2)CCCCC1.N1(C2CCNCC2)CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:44]5[CH2:42][CH2:41][CH:48]([N:47]6[CH2:46][CH2:57][CH2:56][CH2:55]6)[CH2:49][CH2:50]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: C1CCN(C2CCNCC2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of the crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride (prepared in the manner of Example 23, from 1 g of the corresponding carboxylic acid of Example 22) in dichloromethane (25 mL) was treated with 4-(1-pyrrolidinyl) piperidine (0.74 g), N,N-diisopropylethyl amine (0.31 g) and 4-(dimethylamino)pyridine (0.05 g). The reaction mixture was stirred at room temperature overnight, washed with water and saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration of this solution through a short column of Magnesol® gave a pale yellow eluate which was evaporated to dryness to provide the title compound as a pale yellow amorphous material (0.42 g).
Reaction SMILES: Cl.[C:2]1([P:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[CH2:11][NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH2:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2CN[C@@H]2CCCC[C@H]2N)C=CC=CC=1.[C:63]1([P:69]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:70]2[CH:77]=[CH:76][C:75]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][C:83]([CH:86]=[CH2:87])=[CH:82][CH:81]=3)=[CH:74][C:71]=2[CH:72]=O)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>C(O)C.C(Cl)Cl>[C:2]1([P:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[CH2:11][N:12]([CH2:72][C:71]2[CH:74]=[C:75]([O:78][CH2:79][C:80]3[CH:85]=[CH:84][C:83]([CH:86]=[CH2:87])=[CH:82][CH:81]=3)[CH:76]=[CH:77][C:70]=2[P:69]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH2:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(COc2ccc(P(c3ccccc3)c3ccccc3)c(C=O)c2)cc1
Reactant: N[C@@H]1CCCC[C@H]1NCc1ccccc1P(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1ccc(COc2ccc(P(c3ccccc3)c3ccccc3)c(CN(Cc3ccccc3P(c3ccccc3)c3ccccc3)[C@@H]3CCCC[C@H]3N)c2)cc1
Reaction time: 3 h
Yield: 79 %

Procedure:
2.54 g of (1R,2R)-N-(2-diphenylphosphanylbenzyl)cyclohexane-1,2-diamine hydrochloride (6 mmol) are combined with 100 ml of methylene chloride and 100 ml of saturated sodium hydrogen carbonate solution. Once the phases have separated, the aqueous phase is extracted twice more with methylene chloride and the combined organic phases are washed with saturated sodium chloride solution. Drying is then performed with magnesium sulfate and the solvent removed in a rotary evaporator. After drying under a high vacuum, 1.71 g of (1R,2R)-N-(2-diphenylphosphanylbenzyl)cyclohexane-1,2-diamine (4.4 mmol) are obtained as an air-sensitive clear oil. This is dissolved in 250 ml of absolute ethanol under a protective gas atmosphere in a three-necked flask equipped with a reflux condenser. Once combined with 1.85 g of 2-diphenylphosphanyl-5-(4-vinylbenzyloxy)benzaldehyde (4.4 mmol) and 96 mg of 2,6-di-tert.-butyl-p-cresol (0.4 mmol), the reaction solution is refluxed for 1 hour under protective gas. The reaction mixture is then left to cool and combined with 1.66 g (44 mmol) of sodium hydridoborate. After 3 hours, the reaction is quenched by adding 50 ml of acetone and the solvent is completely removed in a rotary evaporator. The resultant residue is stirred with 100 ml of saturated ammonium hydrochloride solution and 100 ml of methylene chloride until completely dissolved. The aqueous phase is extracted twice more with methylene chloride and the combined organic phases are washed with water and saturated sodium chloride solution. Drying is then performed with magnesium sulfate and the solvent removed. After drying under a high vacuum, 2.83 g of the product, corresponding to a yield of 79%, are obtained as a white mass (stabiliser content according to NMR 9.4%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1coc2cc(O)ccc12
Temperature: 120 °C
Yield: 23.3 %

Procedure:
To a suspension of 6-hydroxy-benzofuran-3-one (5.0 g, 33.3 mmol) in xylene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (11.1 g, 33.3 mmol) and the resulting reaction mixture was heated (120° C., 24 h). The reaction mixture was concentrated in vacuo and the residue was treated with 1 M HCl adjusting the pH to 3. The organic layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-70%) to provide the title compound as a clear oil (1.6 g, 23%). MS (ESI): mass calcd. for C10H10NO4, 206.2; m/z found, 207.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.03-7.07 (m, 1H), 7.37 (d, J=8.4, 1H), 6.93 (d, J=2.2, 1H), 6.77 (dd, J=8.4, 2.2, 1H), 5.20 (br s, 1H), 3.74 (s, 3H), 3.67 (s, 2H).