Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.O>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. 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→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][N:30]=1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Reactant: COCCN(C)c1ncc(N)cn1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H17BrF3N5O3 (m/e) 500, obsd 501 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17].O>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added, with stirring, to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature. The mixture is heated to reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours, then cooled and added to water. The mixture is extracted with methylenechloride, and the organic phase is dried over sodium sulphate and evaporated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-ylmethyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27](O)=[O:28].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]1=2)=[O:28]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1nc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1nc2ccccc2o1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), benzooxazol-2-yl-acetic acid (0.023 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.022 g, 53%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.71 (m, 1H), 7.53 (m, 1H), 7.45 (dd, J=8.8, 4.8 Hz, 2H), 7.34 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 4.25 (s, 2H), 3.88 (m, 2H), 2.83 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H17FN4O2 [M+H]+ 377.1, found 377.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:43])[C:34]2[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCCC1>[CH2:20]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([C:7]2[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=2[O:18][CH3:19])([C:34]2[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=2)[OH:43])[CH2:31][CH2:32]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(C(C)C)cc2)C2CCN(Cc3ccccc3)CC2)c1C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
n-Butyllithium (1.6 M, 12.0 mL, 19.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (4.89 g, 18.87 mmol) in tetrahydrofuran (100 mL) at −78° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 1-benzyl-4-(4-isopropylbenzoyl)piperidine (5.02 g, 15.6 mmol). The mixture was stirred for 30 minutes at the same temperature, then poured into the water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (6.54 g, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: Cc1cnc(Cl)nc1Nc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To a vial with 6-aminobenzo[d]oxazol-2(3H)-one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol), solvents MeOH (20 mL) and H2O (5 mL) were added. The turbid mixture was stirred at room temperature for 2 days. Precipitate from the reaction mixture was collected by filtration, washing with H2O (3 mL×2) and EtOAc (3 mL×2), and was further drying in vacuo. 6-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as a light tan color solid: 1.59 g (86% yield); 1H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.3, 1H), 7.06 (d, J=8.3, 1H), 2.14 (s, 3H).
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@@H:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]([CH3:15])[CH3:14])=[O:5])=[N-].[BrH:22]>CC(O)=O>[Br:22][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@@H:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]([CH3:15])[CH3:14])=[O:5]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-])C(C)C
Reactant: Br
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A mixture of Example 173D (70 mg, 0.236 mmol) in HOAc (0.6 mL) at ambient temperature was added 48% HBr (80 μL, 0.709 mmol). Mixture was stirred at ambient temperature for 1 hour. Mixture was poured into ice/H2O and extracted with CH2Cl2 (3×75 mL). Organic was dried (Na2SO4), filtered and concentrated afford 63 mg (76%) of the title compound. MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[CH:33]=[C:32]1[CH:40]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]([CH3:22])[C:40]([C:32]4[N:31]([CH2:30][C:29]([F:43])([F:42])[F:28])[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:34]5[CH:33]=4)=[N:23][C:17]=3[CH:16]=2)=[O:26])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Temperature: 90 °C
Yield: 62.6 %

Procedure:
To a mixture of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (2.1 g, 5.55 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.3 g, 5.70 mmol) in ethanol (55 ml) was added portionwise a solution of sodium hydrosulfite (3.41 g, 16.65 mmol) in water (25 ml). The mixture was flushed with nitrogen and heated at 90° C. overnight for 17 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. DCM was added to the residue and the heterogeneous solution was dried over sodium sulfate. The solid was filtered off and the filtrate was concentrated under vacuo. The residue was loaded in dichloromethane and purified by SP4 SNAP on 2 silica (Si) 100 g columns using an initial gradient of 25-80% (15 CVs), followed by 80-100% (10 CVs) ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (1.934 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CCl

Procedure:
2-(3,4-Dichlorophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(3,4-dichloropheny)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5ccccc5)nc43)cc2)CCC1
Temperature: 100 °C

Procedure:
To a suspension of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (20 g) in toluene (200 mL) and ethanol (200 mL) was added saturated aqueous sodium bicarbonate (150 mL) and phenyl boronic acid (9.9 g). The reaction was degassed for 5 minutes and the Pd (PPh3)4 (1.0 g) was added. The reaction was again degassed for 5 minutes and then heated to 100° C. for 2 days or until reaction is complete by LCMS. The reaction mixture was cooled to room temperature, and dichloromethane (250 ml×3) and water (100 mL) were added to the reaction. The organics were washed with saturated sodium bicarbonate (1×250 mL) and water (1×250 mL), dried over sodium sulfate and concentrated. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product with some impurities. The solid was re-crystallized with ethyl acetate affording an off-white solid (7.2 g). 400 M Hz 1H NMR (DMSO-d6) δ: 8.23 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 3H), 7.94 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.46-7.35 (m, 6H), 7.18-7.14 (m, 1H), 6.90 (bs, 1H), 6.33 (dd, J=7.6 Hz and 4.4 Hz, 1H), 2.48-2.40 (m, 4H), 2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.30 (m, 9H); LCMS: 533 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1>>[OH:1][C:2]1([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cccc([Mg]Br)c1
Product: COc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 55 %

Procedure:
This compound was prepared from tert-Butyl 4-oxopiperidine-1-carboxylate and 3-methoxyphenylmagnesium bromide as described in Step 1 of Example 6 in 55% yield.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:40]=[N:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:48]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cnc3ccccc3c2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 3-aminoquinoline (260 mg, 1.80 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (24 mg, 12% yield).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)([OH:3])=[O:2].[CH2:29](I)[CH3:30].O>C1COCC1>[CH2:29]([O:2][C:1]([C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=1)=[O:3])[CH3:30]
Reactant: CCI
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-carboxy-2-fluoro-1-triphenylmethylimidazole (280 mg.) in THF (0.75 ml.) was treated, under argon with 1,5-diazabicyclo-5,4,0-undec-5-ene (0.112 ml.) followed by ethyl iodide (0.069 ml.). The mixture was stirred for two hours at room temperature, water was added and the mixture extracted, with ether. The ether extract was dried (MgSO4) and evaporated to give 4-ethoxycarbonyl-2-fluoro-1-triphenylmethylimidazole (185 mg.) as a yellow foam having the following n.m.r. in CDCl3 : 1.38 (t, 3H); 4.36 (q, 2H); 7.0-7.5 (m, 16H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8]O.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(CO)C(=O)NCc1ccccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CN1C(=O)c2ccccc2C1=O)C(=O)NCc1ccccc1Cl
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (0.50 g, 2.07 mmol) in THF (5 mL) were added phthalimide (0.457 g, 3.10 mmol, 1.5 equiv.) and PPh3 (0.813 g, 3.10 mmol, 1.5 equiv.). DIAD (600 μL, 3.10 mmol, 1.5 equiv.) was added dropwise into the reaction mixture. The resulting mixture was stirred overnight. LC/MS indicated that starting material was consumed. The reaction mixture was concentrated. The resulting residue was purified on silica gel column a mixture of hexanes and ethyl acetate to give N-(2-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-2,2-dimethylpropanamide (0.50 g, 65%). LRMS (M+H+) m/z 371.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:30]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:11]([N+:20]#[C-:21])[C:10]([N+:22]#[C-:23])=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCBr
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=Cc1ccc(OC)cc1)C(=Cc1ccc(OCCCCCC)cc1)[N+]#[C-]
Yield: 94 %

Procedure:
13 mg of xanthocillin X monomethyl ether was dissolved in 2 ml of DMF and 40 mg of potassium carbonate was added thereto. Further, 50 μl of n-hexyl bromide was added thereto and the mixture thus formed was extracted with 30 ml portions of ethyl acetate thrice. The extracts were combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled from the filtrate. Thus 15 mg of 1-(4'-n-hexyloxyphenyl)-4-(4'-methoxyphenyl)-2,3-diisocyano-1,3-butadiene was obtained in the form of a brown solid. Yield: 94%.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCN(C)C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)CC2
Temperature: -20 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (5 g, 26.17 mmol) in H2SO4(2.17 mL) was added HNO3 (1.95 g, 31.4 mmol) dropwise at −20° C. The mixture was stirred for 2 h at −20° C. The reaction was diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated under reduced pressure to afford 2-methyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (4.7 g, 75.8%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:25]([O-])=O)=[C:15]([CH:17]=[C:18]3[NH:22][C:21](=[O:23])[NH:20][C:19]3=O)[CH:16]=2)[O:6][C:5]1=[O:28])[CH3:3].CO.II>CN(C)C=O.[Pd]>[CH3:1][CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:25]=[C:19]4[NH:20][C:21](=[O:23])[NH:22][C:18]4=[CH:17][C:15]=3[CH:16]=2)[O:6][C:5]1=[O:28])[CH3:3]
Reactant: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)OC1=O
Agent: [Pd]
Agent: II
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)N1CC(COc2ccc3nc4[nH]c(=O)[nH]c4cc3c2)OC1=O
Reaction time: 21 h
Yield: 55.5 %

Procedure:
A solution of 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (8.80 g, 22 mmol) in dimethylformamide (150 mL) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.88 g) in a low pressure hydrogenation apparatus. After 21 hours, the mixture was filtered through kieselguhr and the solvent evaporated in vacuo at about 40° C. to leave a foamy solid. Methanol (180 mL) was added, the mixture heated to reflux and iodine (5.72 g 22 mmol) added portionwise over 15 minutes. After refluxing for a further 15 minutes, the mixture was concentrated to about 50 mL and diluted with 10% sodium sulfate solution and 10% sodium carbonate solution. A grey solid was filtered off, washed with water and air dried to give (4.18 g, 54%) of product. Three further crops amounting to (3.41 g, 46%) were subsequently collected. An analytical sample was purified by dissolving 2 g in 10% hydrochloric acid in methanol. Addition of diethyl ether afforded 1,3-dihydro-7-[[3-(1-methylethyl)-2-oxo-5-oxazolidinyl]methoxy]-2H-imidazo[4,5-b]quinolin-2-one hydrochloride (1.1 g, 50%) m.p. 264°-266° C.