Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@:3]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5].[F:10][C:11]([F:33])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:33][C:11]([F:10])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)=[O:19])[C:14](=[O:15])[NH:2][C@@:3]([CH2:4][OH:5])([CH3:9])[CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CCC[C@](C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@](C)(CO)NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A mixture of (S)-2-amino-2-methyl-pentan-1-ol hydrochloride (104.4 mg, 0.67 mmol), (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (231 mg, 0.67 mmol), EDCI (154 mg, 0.8 mmol), HOBT (108 mg, 0.8 mmol) and Diisopropyl ethylamine (0.23 mL) in DMF (2 mL) is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with cold 1N HCl, saturated NaHCO3 and then saturated NaCl solution. The organic phase is dried over MgSO4 and solvent evaporated under reduced pressure to give the crude product. Purification by Silica gel column chromatography, eluting with ethyl acetate and heptane mixture gives morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide (223 mg, 75%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[C:13]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]2=[CH:7][N:6]=1.Cl>CO.CCOCC>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]2=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2cnc(Oc3ccc(F)cc3F)nc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc(Oc2ncc3c(C=Cc4ccccc4)n[nH]c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-styryl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (42 mg, 0.08 mmol) was dissolved in 1 mL MeOH and treated with 1.1 mL of 10% HCl in Et2O. The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure. The residue was purified by preparative TLC (4:1 hexanes/EtOAc) to yield 0.037 g of 6-(2,4-difluoro-phenoxy)-3-styryl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=351.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (0.102 mol) is added to a solution of 4-(4-hydroxyphenyl)benzoic acid (0.102 mol) and 2.5 N sodium hydroxide (0.102 mol) and the mixture stirred at 70° C. for a period of 18 hours. The reaction mixture is allowed to cool and then acidified to pH 3 and partitioned between ethyl acetate and water. The organic phase is washed with water and brine and the solvent then removed to obtain the 4'-n-octyloxy-[1,1'-biphenyl]-4-ylcarboxylic acid, C21H23O3, M.W. 326.4
Reaction SMILES: [N:1]1([C:65](OC(C)(C)C)=O)[CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([N:44]([CH3:61])[C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])CCSC)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].F[C:73](F)(F)C(O)=O.[CH:79]([SH:82])(S)[CH3:80]>CSC>[NH:1]1[CH2:65][CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([N:44]([CH3:61])[C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:80][CH2:79][S:82][CH3:73])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Reactant: CC(S)S
Solvent: CSC
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.65 g.) and HDTrp-MeLeu-MetNH2 (1.34 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 (1.70 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-MeLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 67% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.C(N(CC)CC)C.[CH:34](OCC)=[O:35]>C(OCC)(=O)C>[CH:34]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)=[O:35]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CCOC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=CN1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (450 mg, 1.19 mM) and triethylamine (156 mg, 1.56 mM) were heated under reflux for 48 hours in ethyl formate (20 ml). The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water and brine. Drying (sodium sulfate) and evaporation gave a gum which crystallised on trituration with diethyl ether to give the desired product (358 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:13][C:14]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:14]=1[CH3:13])=[O:9])([O-:3])=[O:2]
Reactant: Cc1cccc(N)c1C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 16 h

Procedure:
To a solution of 3-nitrobenzoic acid (3.0 g ) and 2,3-dimethylaniline (2.17 g) in 20 mL of DMF was added 1-hydroxybenzotriazole (2.75 g), EDC (3.44 g) and triethylamine (7.39 mL). The resulting solution was stirred for 16 h. The DMF was evaporated in vacuo and the residue was partitioned with ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid. NMR (300 MHz, CDCl3) δ 8.72 (1H, s), 8.40 (1 H, d, J=6 Hz), 8.26 (1H, d, J=9 Hz), 7.93 (IH, s), 7.69 (1H, t, J=9 Hz), 7.45 (1 H,d, J=9 Hz), 7.14 (1H, t, J=8 Hz), 7.08 (1H, d, J=9 Hz), 2.32 (3H, s), 2.21 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:28][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Yield: 34.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (3.48 g, 10.0 mmol) in toluene (40 mL) was added with methanol (0.486 mL, 12.0 mmol), triphenylphosphine (3.93 g, 15.0 mmol) and a 40% solution of diethyl azodicarboxylate in toluene (6.53 g, 15.0 mmol), and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (1.25 g, 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[N:12]1[C:18](Cl)=[O:19].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:18]([N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])=[O:19])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1C(=O)NNc1ccc(F)cn1
Yield: 69.6 %

Procedure:
A solution of (5-fluoro-pyridine-2-yl)-hydrazine (21.7 g, 171 mmol), Intermediate 3a (31.5 g, 180 mmol) and DIPEA (44.7 mmol, 256 mmol) in DCM (350 mL) was stirred at RT for 4 days. Water (350 mL) was added, then the aqueous layer extracted with DCM (100 mL). The combined organic extracts were passed through a hydrophobic fit and concentrated under vacuum to leave a solid. Trituration with diethyl ether/pentane (1:4, 150 mL), and drying under vacuum at 50° C., gave Intermediate 3b (31.7 g, 70%, ˜90% purity). LCMS: Rt 2.58 min, m/z 289 [MH+]. 1H NMR (300 MHz, CDCl3): 1.29 (6H, d, J=7.0 Hz), 1.45-1.89 (6H, m), 4.26 (2H, apparent quin, J=6.5 Hz), 6.53 (1H, s), 6.65 (1H, br s), 6.77 (1H, dd, J=9.0, 3.6 Hz), 7.29-7.28 (1H, ddd, J=9.0, 8.0, 3.0), 8.02 (1H, d, J=2.9 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1.[H-].[Na+]>>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)[CH:13]=[N:12][CH:11]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=S1(=O)CCNCC1
Agent: [H-]
Agent: [Na+]
Product: O=S1(=O)CCN(Cc2cncc(Br)c2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], thiomorpholine 1,1-dioxide was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a white solid. MS: 304.9, 307.0 (M+H+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][OH:10]>O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][C:9]([OH:2])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CCCC(C)CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCCC(C)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (55.5 g, 0.555 mol) in water (68 ml) and 2M-sulphuric acid (12 ml) was added dropwise to a solution of 3,7-dimethyloctanol (43.7 g, 0.308 mol) in acetone (100 ml), the temperature was maintained at 40-60° C. and the reaction mixture was left stirring overnight. Acetone was carefully removed in vacuo, the reaction mixture was diluted in water and washed with diethyl ether (2×200 ml). The ethereal solution was washed with 10% sodium hydroxyde solution (200 ml); and the aqueous phase was acidified with 36% HCl (200 ml) and washed once more with diethyl ether (2×200 ml). The organic layer was dried (MgSO4) and the diethyl ether was removed in vacuo. The crude product was distilled to give a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]([F:12])([F:11])[F:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[C:4]([C:9]([F:12])([F:11])[F:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: FC(F)(F)c1ncccc1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccnc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 3-(bromomethyl)-2-(trifluoromethyl)pyridine (0.684 g, 2.84 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (0.242 g, 1.70 mmol) in anhydrous ethanol (100 mL) at 0° C. was added triethylamine (1.14 g, 1.57 mL, 11.36 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated, and ether was added to the precipitated triethylamine hydrobromide salt. The solid was filtered and washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by Combiflash using 0-10% MeOH:dichloromethane. 6-methyl-2-({[2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol was obtained as a white solid (0.438 g, 51% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.14 (t, 3H), 2.21 (s, 3H), 2.61 (q, 2H), 4.35 (s, 2H), 6.00 (bs, 1H), 7.69 (s, 1H), 8.31 (s, 1H) 8.45 (s, 1H); M+ 301.5.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22](O)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:34])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22]([Cl:34])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C2CCC2)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C(=O)Cl)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in dichloromethane (5 mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00 equiv) and N,N-dimethylformamide (˜5 mg) were added dropwise to the mixture. The resulting solution was stirred for 1 h at 40° C., then concentrated and dried under reduced pressure to yield 480 mg (92%) of the title compound as a light yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:21][CH:22]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)(=[O:36])[CH3:35]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)C2

Procedure:
A stirred solution of 0.954 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride is heated at reflux for 24 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetate-hexane (7:3) to give 0.800 g of a white solid; mass spectrum (M+H)519.
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1.O(Cl)[Li]>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: OCc1ccccc1
Agent: [Li]OCl
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 32.0 mmol), benzyl alcohol (8.2 mL, 80.0 mmol) and LiOCl (680 mg, 6.4 mmol) in toluene (50 mL) was refluxed for 48 h in flask equipped with a Dean-stark apparatus. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure to provide compound D20-1 (5.2 g, crude) as a brown oil.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)N=1)(=[O:5])[CH3:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1.[CH3:23]O>>[C:14]1([CH:13]=[CH:4][C:3]([C:6]2[CH:23]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: COc1ccc(C=O)cc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 76 %

Procedure:
Potassium hydroxide (18.2 g, 325 mmol) was dissolved in 100 mL of H2 O, and 100 mL of methanol was added. 2-Acetyl-6-bromopyridine (65 g, 325 mmol) and (68 g, 650 mmol) of p-anisaldehyde were dissolved together in 400 mL of methanol, and the solution was poured into the KOH solution. Precipitation of product began within a few minutes, and the reaction was allowed to stand at room temperature overnight. The precipitate was collected, washed with isopropanol, and dried to yield 79 g (76%) of the product as a yellow solid, mp 100°-102° C. FDMS (m/e) 317M. An aliquot was purified by column chromatography on Woelm Silica gel, elution with 100% dichloromethane. Anal. Calcd for C15H12 BrNO2 : C, 56.63; H, 3.80; N, 4.40. Found: C, 56.66; H, 3.87; N, 4.41. The NMR and IR spectra were consistent with the assigned structure and the product was homogeneous by TLC.
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1c[nH]c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cc(C=O)c[nH]1
Temperature: 105 °C
Yield: 67.6 %

Procedure:
5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2-methylphenylboronic acid (94 mg) and sodium carbonate (146 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixture was further degassed and refluxed at 105° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was extracted with water and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as colorless crystals (yield 72 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1.O1CCOCC1.[Na+].[I-:22].CN(C)CCN>CCOC(C)=O.[Cu]I>[I:22][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Brc1ccc(Oc2cncnc2)nc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Ic1ccc(Oc2cncnc2)nc1
Temperature: 110 °C

Procedure:
A mixture of 550 mg (2.18 mmol) 5-(5-bromopyridin-2-yloxy)pyrimidine and 2.5 mL 1,4-dioxane is charged with 42 mg (0.22 mmol) CuI, 650 mg (4.36 mmol) NaI and 50 μl (0.44 mmo) N,N-dimethylethylendiamine. The reaction mixture is stirred at 110° C. over night. The mixture is allowed to cool down to r.t. and diluted with EtOAc. The mixture is washed with 5% aq. ammonia solution and water. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo to yield the desired product without further purification.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])=[O:12])=[O:8].[CH3:18]O>CC(C)=O>[CH3:18][C:1]1([CH3:2])[NH:5][CH2:6][C:7](=[O:8])[N:9]1[CH2:10][C:11]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])=[O:12]
Reactant: CC(=O)O
Reactant: CO
Reactant: NCC(=O)NCC(=O)NCC(N)=O
Solvent: CC(C)=O
Product: CC1(C)NCC(=O)N1CC(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of glycylglycylglycinamide acetate (800 mg) in methanol (8 ml) and acetone (15 ml), Amberlite IRA-68 resin (2 ml) was added. The suspension was stirred at room temperature for 1 hour, then the resin was filtered off and the solution was evaporated under reduced pressure. The residue was suspended in acetone and stirred at room temperature overnight. The precipitate was collected and crystallized from ethyl acetate, to give the title compound, as a white powder, m.p. 102°-105° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 109.2 mg (0.59 mmol) (4-fluoro-3-nitro-phenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 9 hours and at 60° C. for 20 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 147 mg (40%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-fluoro-3-nitrophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.