Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][CH:24]=[CH2:25]>C(#N)C>[CH3:11][O:10][C:8]([C@@H:5]1[CH2:4][C@H:3]([F:2])[CH2:7][N:6]1[CH2:25][CH2:24][CH:23]=[CH2:22])=[O:9]
Reactant: C=CCCBr
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCN1C[C@@H](F)C[C@H]1C(=O)OC
Temperature: 70 °C
Reaction time: 48 h

Procedure:
In a 25 mL round-bottomed flask, (2S,4S)-methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride (160 mg, 871 μmol, Eq: 1.00) was combined with acetonitrile (3 mL) to give a white suspension. Hunig's base (282 mg, 380 μL, 2.18 mmol, Eq: 2.50) and 4-bromobut-1-ene (144 mg, 108 μL, 1.05 mmol, Eq: 1.20) were added sequentially. The reaction mixture was stirred at 70° C. for 2 days. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into an aqueous 5% Na2CO3 solution and extracted with DCM (2×). The organic layers were combined, washed with brine (1×), the organic layers were dried over Na2SO4 and concentrated in vacuo to yield a yellow liquid (160 mg; 91%). m/z=202.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:38]([NH:37][C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C(=O)NC(C)(C)C)cc4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(-c3ccc(C(=O)NC(C)(C)C)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-(4-{2-[2-(4′-tert-butylcarbamoylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product as a solid. 1H NMR (400 MHz, d6-DMSO) δ8.12 (t, J=1.2 Hz, 1H), 7.90-7.73 (m, 6H), 7.56 (t, J=7.2 Hz, 1H), 6.82-6.74 (m, 4H), 4.17 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.34 (s, 3H), 1.36 (s, 6H); MS (EI) 557.2 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([O:15][CH3:16])=[CH:8][C:9]([F:14])=[C:10]([CH2:12]O)[CH:11]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([CH2:12][Br:2])[C:9]([F:14])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(F)c(CO)cc1Br
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(F)c(CBr)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
PBr3 (4.7 g, 17.4 mmol) was added drop-wise to a solution of (5-bromo-2-fluoro-4-methoxyphenyl)methanol (4.1 g, 17.4 mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. The mixture was stirred at room temperature for 3 h and poured into ice water. The pH was adjusted to 8 with saturated aqueous NaHCO3. Extractive work up with CH2Cl2 gave the title compound (4.9 g, 94.8%) as a white solid which was carried on without purification. 1H NMR (DMSO-d6, 400 MHz) δ 7.56 (d, J=8.0 Hz, 1H), 6.65 (d, J=11.6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@@:19]1([CH:34]=[O:35])[CH2:31][CH2:32][CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@:19]1([CH2:31][CH2:32][CH3:33])[CH:34]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:35])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CCC[C@]1(C=O)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Product: CCC[C@]1(C(O)c2ccc(Cl)c(Cl)c2)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C

Procedure:
(R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-propyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by reaction of 3,4-dichlorophenyl magnesium bromide with (R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester following the procedure of step 1 of Example 11.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.I[CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C)C=O>[CH:20]([C:18]1[N:19]=[C:15](/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([O:1][CH2:33][CH:34]4[CH2:38][CH2:37][O:36][CH2:35]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Reactant: ICC1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(OCC4CCOC4)nc3c2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (210 mg, 0.670 mmol) was suspended in dimethylformamide (6.0 ml), added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl), and stirred overnight at 80° C. The reaction solution was further added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl) and stirred overnight at 80° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5, v/v) to obtain the title compound (277 mg, quantitative).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH:29][C:30]([C:32]3[CH:41]=[CH:40][C:35]4[N:36]=[N:37][N:38]([OH:39])[C:34]=4[CH:33]=3)=[O:31])[CH2:23][C@@H:24]([OH:28])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)C1C=CC=CC=1.[C:50]([O:53][CH2:54]Br)(=[O:52])[CH3:51].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.CO>[Pd]>[C:50]([O:53][CH2:54][O:39][N:38]1[C:34]2[CH:33]=[C:32]([C:30]([NH:29][C@H:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=4)=[CH:20][CH:19]=3)[CH2:23][C@@H:24]([OH:28])[C:25]([OH:27])=[O:26])=[O:31])[CH:41]=[CH:40][C:35]=2[N:36]=[N:37]1)(=[O:52])[CH3:51]
Reactant: CC(=O)OCBr
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1ccc2nnn(O)c2c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: OCc1ccccc1
Product: CC(=O)OCOn1nnc2ccc(C(=O)N[C@H](Cc3ccc(-c4cccc(Cl)c4)cc3)C[C@@H](O)C(=O)O)cc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 9.4 %

Procedure:
4.0 M HCl in 1,4-dioxane (270 mL, 1.1 mmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid (130 mg, 270 μmol) in benzyl alcohol (559 μL, 5.4 mmol), and stirred at 60° C. for 1.5 hours. The mixture was then purified (C18 column chromatography, 55 g column, using 30-90% MeCN in water with 0.05% TFA) to yield an off-white solid. Bromomethyl acetate (45.5 mg, 297 μmol) was added to a solution of this off-white solid and K2CO3 (82.2 mg, 595 μmol) in DMF (3.1 mL, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then purified (column chromatography, small column, using 40-90% MeCN in water with 0.05% TFA) to yield a clear colorless viscous liquid. 10% Pd/C, 50% wet (0.45 mmol/g loading; 30.0 mg, 13.5 μmol) was added to a solution of this clear colorless viscous liquid in MeOH (4.1 mL, 102 mmol) and the resulting mixture was stirred under hydrogen for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to yield a clear colorless liquid. The crude liquid was purified (C18 column chromatography, 55 g column, using 30-85% MeCN in water with 0.05% TFA) to yield the title compound (14.0 mg) as a white solid. MS m/z [M+H]+ calc'd for C27H25ClN4O7, 553.14. found 553.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:9][CH2:10]C)([O:6][CH2:7]C)[CH3:5])C.[Cl:12]Cl>C(O)C>[Cl:12][CH2:5][C:4]([O:9][CH3:10])([O:6][CH3:7])[O:3][CH3:1]
Reactant: ClCl
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: COC(CCl)(OC)OC
Reaction time: 4 h
Yield: 90.9 %

Procedure:
A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with a mixture of 648 g (4 mol) of 1,1,1-triethoxyethane and 70 g (approx. 11% by weight) of ethanol. Within 4 hours, 260 g (3.70 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 520 g of 2-chloro-1,1,1 trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CO.C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([C:20]2[C:15]([O:14][CH3:13])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: COc1ncccc1B(O)O
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: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc(Br)cc(C(C)(C)C)c1
Yield: 57.9 %

Procedure:
step 1—A sealed tube containing 3,5-dibromo-tert-butylbenzene (1.00 g, 3.425 mmol, CASRN 129316-09-2), 37 (522 mg, 3.413 mmol), Pd(PPh3)4 (194 mg, 0.168 mmol) and Na2CO3 (942 mg, 8.888 mmol) and a mixture of MeOH/DCM (8/2 10 mL) was irradiated in a microwave synthesizer at 100° C. for 10 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 2% EtOAc) to afford 0.633 g (58%) of 3-(3-bromo-5-tert-butyl-phenyl)-2-methoxy-pyridine (122) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[N:29]=[C:30]=[O:31]>ClCCCl>[F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH:4][C:30]([NH:29][C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[F:18])=[O:31]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: ClCCCl
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)OC1(C)C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.65 g, 32.3 mmol, 1 eq) in 1,2-dichloroethane (76.5 mL) was added 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (4.9 ml, 33.9 mmol, 1.05 eq). The reaction was allowed to stir overnight. White solids precipitated from the reaction mixture and were filtered and washed with hexanes (3×). The solids were dried under vacuum to obtain 8.75 g (61.3% yield) of the desired product. 1H-NMR (DMSO-d6) δ 9.45 (d, J=2.7 Hz, 1H), 9.32 (d, J=2.76 Hz, 1H), 8.63 (dd, J=7.2, 2.2 Hz, 1H), 8.28 (t, J=8.0 Hz, 1H), 7.50-7.34 (m, 4H), 1.27 (s, 12H); MS [M+H]+=443, LCMS RT=4.50 min
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[C:30](O)([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]2[C:29]=1[CH:30]([C:44]1[C:52]([OH:53])=[CH:51][C:47]3[O:48][CH2:49][O:50][C:46]=3[CH:45]=1)[C:31](=[O:43])[N:32]2[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4,7-dichloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (72%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.27-7.23 (m, 1H), 7.03 (d, 1H), 6.55 (s, 1H), 6.04 (s, 1H), 5.84 (dd, 2H), 5.03 (s, 1H), 4.09-3.99 (m, 2H), 1.72-1.62 (m, 2H), 1.33-1.24 (m, 4H), 0.86 (t, 3H); MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: NC(Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 104b, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-[4-(7-chloro-quinolin-4-ylamino)-phenyl]-propionic acid (prepared by reaction of 2-amino-3-(4-aminophenyl)-propionic acid with 4,7-dichloro-quinoline as in Example 104a) to provide the title compound in good yield.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]1[NH:18][C:17](=[O:19])[CH2:16][NH:15][C:14]1=[O:20])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]1[C:14](=[O:20])[NH:15][CH2:16][C:17](=[O:19])[NH:18]1)[C:9]1[CH:10]=[CH:11][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2NC(=O)CNC2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(=O)C(Cc2cccc(NCc3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[3-(tert-butoxycarbonylamino)benzyl]-2,5-piperazinedione. (0.75 g) in trifluoroacetic acid (10 ml) was stirred for 4 hours at room temperature. After removal of the solvent by evaporation, the residue was dissolved in a mixture of dichloromethane (10 ml) and methanol (3 ml) and thereto benzaldehyde (0.742 g) and sodium triacetoxyborohydride (2.11 g) were added. The whole was stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (25:1). The fractions containing the objective compound were collected and triturated with isopropyl alcohol to give 2-[3-(benzylamino)benzyl]-3,6-piperazinedione (0.43 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[N+:31]([O-:33])=[O:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[N:15][C:16]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:41][CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:24][C:23]=2[N+:31]([O-:33])=[O:32])=[N:17][CH:18]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cnc(Nc2ccc(C(=O)O)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methylpyrimidin-2-yl)amino)-3-nitrobenzoic acid (0.075 g, 0.164 mmol), 1-methylpiperidin-4-amine (37 mg, 0.33 mmol), HATU (140 mg, 0.37 mmol), and DIEA (0.1 mL, 0.6 mmol) in DMF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with aqueous saturated sodium bicarbonate solution and saturated brine solution. The crude mixture was loaded onto silica gel and purified using 0-10% MeOH/DCM gradient containing 10% NH4OH to give the title compound (73 mg, 80%). MS (ES+) C27H38N8O5 requires: 554. found: 555 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.O>[CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][N:5]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccnc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (231 mg) was added and the reaction mixture was stirred at room temperature for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as a colorless solid (yield 172 mg, 53%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
The photoinitiator dibenzoyl biphenyl was prepared by placing 200 mL nitrobenzene, 38.5 g (0.25 mole) biphenyl, and 140.6 g (1.00 mole) benzoyl chloride into a 1 liter 3-necked flask equipped with a water condenser. While stirring, 160 g (1.2 mole) aluminum trichloride was added slowly over a period of about 30 minutes. During the reaction, the temperature increased from 30° C. to 55° C. The color changed from yellowish to light brown, then reddish. The flask was kept in a water bath at a temperature of 55° C. to 60° C. for 3 hours while stirring. The reaction mixture was then cooled to 35° C. The reaction mixture was poured into 1.2 L of 8% HCl solution with vigorous stirring. The organic layer was separated and poured into a blender and 500 mL n-hexane was added. The mixture was vigorously stirred for 5 minutes and then filtered. The solid was washed with n-hexane. The thus-produced dibenzoyl biphenyl was dried and recrystalized twice in chloroform.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].COC(C)(C)C.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([O:20][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (344 mg) was dissolved in dry DMF (3 mL). 4-Nitrophenol (226 mg) Ethyl-dimethylaminopropylcarbodiimide hydrochloride (312 mg) and N,N-Dimethyl-4-aminopyridine (198 mg) was added. After stirring at room temperature for 20 hours, aqueous work up with tert-Butyl methyl ether and chromatography of the organics in a gradient from 0 to 40% EtOAc in pentanes afforded the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:7]([NH2:10])=[N:8][N:9]=1.C(N(CC)CC)C.S(OCCOS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.[C:51]([O:54][CH2:55][CH3:56])(=O)[CH3:52]>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][N:11]=[C:6]2[C:5]([CH2:4][CH2:3][CH2:2][N:1]3[CH2:56][CH2:55][O:54][CH2:51][CH2:52]3)=[N:9][N:8]=[C:7]2[NH2:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: NCCCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1=NN=C(CCCN2CCOCC2)C1=NNc1cccc(F)c1
Temperature: 96 °C

Procedure:
A suspension of 5-(3-aminopropyl)-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine, obtained in Example 32, (400 mg, 1.53 mmole) and triethylamine (6 mmole) in 10 mL of DMF was heated to 96° C. To this solution was slowly added a solution of ethylene glycol ditosylate (3 mmole) in 10 mL DMF. The reaction was worked up by the addition of saline and ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography and further by preparative TLC. The resulting 34 mg of oil was dissolved in a minimum amount of diethyl ether and then mixed with hexanes to yield 22 mg of the title compound as a yellow powder. MS (m/z, ES+): 333 (M+1, 100%).