Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.C(=O)([O-])O.[Na+]>COC(C)(C)C>[C:2]([O:5][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
219.1 g (1913 mmol, 1 equiv.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 equiv.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5% aqueous sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91% yield corrected for 8% residual tert-butyl methyl ether).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)c2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.1 equivalents of 4-methoxybenzoyl chloride and 3.0 equivalents of triethylamine in dichloromethane. The reaction was stirred for 1.5 hours at room temperature and the solvent was removed under a stream of nitrogen to give the titled compound. ESI+ MS: 664 [M+H]+.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CO>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(b) above from (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide (3.8 g; 7.82 mmol; from step (a) above), 50 mL of MeOH and 100 mL of HCl/EtOAc, isolating 2.68 g of the sub-title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].[N+]([O-])(O)=O>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[O:14]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1C=O
Reaction time: 16 h

Procedure:
A 102.1 gm. portion of 5-methyl-2-phenyl-4-imidazolemethanol is dissolved in 765 ml. of concentrated HNO3. The solution is cooled in an ice bath and allowed to stand for 16 hours. The solution is heated on a steam bath for 30 minutes, diluted with 2.3 liters of water and neutralized with 50% NaOH while cooling in an ice bath. The solid is collected, dried, recrystallized from 200 ml. of ethanol and then from one liter of 1:2 ethanol:water giving the desired product, m.p. 102°-115° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Zn+]>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2ccccn2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-pyridylzinc bromide.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.CN([CH:18]=[O:19])C1C=CC=CC=1.C(Cl)(Cl)=O>>[CH:6]1[C:7]([CH:18]=[O:19])=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: c1ccc2c(c1)OCO2
Reactant: CN(C=O)c1ccccc1
Agent: O=C(Cl)Cl
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Into a mixture of 97.6 g (0.80 mole) of 1,2-methylenedioxybenzene and 108 g (0.80 mole) of N-methylformanilide was introduced 87.1 g (0.88 mole) of phosgene at 50° C. over a 1-hour period. Then, the mixture was cooled to 15° C. On the other hand, 29.3 g (0.24 mole) of 1,2-methylenedioxybenzene was charged into another reactor and kept at 90° C. The above mixture was added to this reactor over a 5-hour period. After completion of the addition, the reaction mixture was kept at 90° C. for 30 minutes, poured into ice water, and allowed to stand for 1 hour. Then, the resulting mixture was extracted with toluene. By vacuum distillation, the toluene was removed and the distillate at 84°-85° C./30 mmHg was then collected to recover 63.4 g (0.52 mole) of unreacted 1,2-methylenedioxybenzene. Subsequently, the distillate at 131°-134° C./10 mmHg was collected to obtain 76.8 g (0.512 mole) of piperonal having a purity of 99.5%. The yield (expressed in terms of mole percentage based on the amount of N-methylformanilide used) and selectivity (expressed in terms of mole percentage based on the amount of 1,2-methylenedioxybenzene having reacted) of piperonal were 64.0% and 98.5%, respectively. This product had a melting point of 37° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]P(=O)(OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH3:46])=[C:29]([C:32]3[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=3[O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[CH:35]=O)[CH:30]=2)[C:25]([CH3:48])([CH3:47])[CH2:24][C:23]1=[O:49])[CH3:21]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[C:1]([O:5][C:6](=[O:7])[CH:8]=[CH:35][C:34]1[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]([F:43])([F:44])[F:45])=[C:32]([C:29]2[CH:30]=[C:31]3[C:26]([C:25]([CH3:48])([CH3:47])[CH2:24][C:23](=[O:49])[N:22]3[CH2:20][CH3:21])=[CH:27][C:28]=2[CH3:46])[CH:33]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OCC(F)(F)F)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
A flask charged with 6.43 mL of dimethyl t-butoxycarbonyl-methylphosphonate (32 mmol) in 50 mL of dry THF/DMPU (10:1) was cooled to −78° C. where 12.8 mL of n-butyl lithium (2.5M hexane solution, 32 mmol) was added slowly via syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then a solution of 4.4 g of Compound 1D (10.6 mmol) in 30 mL of dry THF was added. After warming to room temperature and an additional 20 minutes of stirring, the reaction was quenched with 30 mL of water and then partitioned with 30 mL of saturated ammonium chloride and 150 mL of ethyl acetate. The water layer was further extracted with ethyl acetate (2×75 mL) and the combined organic layers were then washed with brine (50 mL), dried over magnesium sulfate, filtered and excess solvent was removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%) to give 3.6 g (96%) of product Compound 1E as a white solid. MS (electrospray): mass calculated for C29H34F3NO4, 517.24; m/z found 518.4, [M+H]+. 1HNMR (300 MHz, CDCl3): 7.56 (d, J=16.5 Hz, 1H), 7.52 (dd, J=2.0, 8.5 Hz, 1H), 7.38 (d, J=2.01 Hz, 1H), 7.16 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 6.30 (d, J=16.5 Hz, 1H), 4.31 (q, J=8.0 Hz, 2H), 3.99 (q, J=5.1 Hz, 2H), 2.51 (s, 2H), 2.13 (s, 3H), 1.52 (s, 9H), 1.32 (s, 6H), 1.21 (t, J=7.07 Hz, 3H).
Reaction SMILES: [CH:1]1([C:10](O)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1([CH2:10][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 2,3-dihydro-1H-inden-1-carboxylic acid (0.50 g) in tetrahydrofuran (5.0 mL), lithium aluminum hydride (0.18 g) was added under ice-cooling and the resultant reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, water was added under ice-cooling and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=85:15 to 75:25) to obtain the subject compound (445 mg) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O.[Cl-].[Na+]>C(O)C>[CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCc2ccccc21
Yield: 88.5 %

Procedure:
1.28 g of 1-indanone in 13 ml of anhydrous ethanol is cooled to +5° C. 0.23 g of sodium borohydride at 95% is added in small fractions, with agitation at +10° C. for one hour. 0.23 g of sodium borohydride at 95% is again added at +5° C., with agitation at 20° C. for one hour 30 minutes. The reaction mixture is poured into 60 ml of water containing sodium chloride and is extracted with isopropyl ether; the extracts are dried and brought to dryness under reduced pressure and the residue is chromatographed on silica in a hexane-ethyl acetate mixture (6-4). 1.15 g of expected product is isolated.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH3:39][C:40]([CH3:44])([CH3:43])[CH:41]=O>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][C:40]([CH3:44])([CH3:43])[CH3:41])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C=O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NCC(C)(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using trimethylacetaldehyde. The final product was obtained in 47% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH:12]=[C:11]([C:10]([F:17])([F:16])[F:9])[CH:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cnn(-c2ncc(Br)cn2)c1
Temperature: 85 °C
Yield: 98.4 %

Procedure:
To a mixture of 5-bromo-2-chloropyrimidine (4.32 g, 21.5 mmol), 4-(trifluoromethyl)-1H-pyrazole (2.92 g, 21.5 mmol), and dried potassium carbonate (8.90 g, 64.4 mmol) was added anhydrous dimethylformamide (31.5 mL). The resulting suspension was heated at 85° C. for 4 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 12.4 g of crude yellow solid. The crude material was put through a plug of silica eluting with 15% ethyl acetate in heptanes to give 5-bromo-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (6.2 g, 99%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.83 (s, 2H), 8.02 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][S:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH:30]=2)(=[O:25])=[O:24])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][S:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH:30]=2)(=[O:25])=[O:24])[N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
Yield: 88 %

Procedure:
A solution of tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate Compound 11 (62 mg, 0.11 mmol), TFA (0.2 ml) in CH2Cl2 (1 ml) was stirred overnight. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford the title compound (45 mg, 88%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])=[O:21])[CH2:15][CH2:14]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([O:31][C:32](=[O:34])[CH3:33])[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=2[CH3:29])=[O:21])[CH2:17][CH2:18]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1)C1COc2ccccc2O1
Reaction time: 2 h

Procedure:
One g of 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is dissolved in 15 ml of pyridine and cooled in an ice bath to 0°-5° C. Acetic anhydride (0.6 g) is slowly added and the reaction mixture is stirred for 2 hr. After the addition of 100 ml of water, the reaction mixture is extracted twice with 100-ml portions of diethylether. After combining, the ether portion is washed twice with 100 ml of water and evaporated to dryness to produce 1-[2-(1,4-benzodioxan-2-yl)-2-acetoxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as an oil.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:16]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1C1=CCCCC1
Yield: 78.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 33a by using 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (WO 2010/079443; 1.20 g, 4.35 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.20 g, 5.77 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (250 mg, 0.342 mmol), potassium carbonate (2.00 g, 14.5 mmol) and DMF (13 mL), to yield the title compound (950 mg, 79%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N:26]1[C:27]2[C:22](=[CH:21][CH:20]=[C:19]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=3)[CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCc1ccc(-c2ccc3cccnc3c2)cc1
Yield: 68.1 %

Procedure:
A solution of 2-(4-bromophenyl)acetonitrile (2.55 mmol) in 1,4-dioxane (5 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.64 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.083 mmol), and 2M aq potassium carbonate (5.10 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 20 min. The resulting black mixture was diluted with water (100 mL) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-100% ethyl acetate/hexanes) afforded the title compound as a yellow solid (424 mg, 64%). MS(ES)+ m/e 245.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CCC1(CC)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)OC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,4-diethyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.00 g, 19.98 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (1.20 g-60%, 29.97 mmol). After 20 minutes, methyl iodide (3.8 mL, 61.00 mmol) was added and the reaction was warmed to room temperature. After stirring for one hour, the reaction was quenched with ammonium chloride (sat.) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine repeatedly and dried over magnesium sulfate. Solvent was removed and the residue was triturated with ether to give 4,4-diethyl-1-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one a yellowish-white solid (3.74 g, 71%). 1H NMR (DMSO-d6): δ 8.27 (dd, J=9.0, 2.6 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 3.37 (s, 3H), 2.15 (m, 4H), 0.80 (t, J=7.3 Hz, 6H); MS (ESI) m/z 265 ([M+H]+); Anal. calcd for C13H16N2O4: C, 59.08; H, 6.10; N 10.60. Found: C, 59.62; H, 6.20; N, 10.48.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:9]1[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:33][CH:34]=1)#[N:8]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 80 °C

Procedure:
Methyl bromoacetate (0.023 ml) was added to a suspension of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-hydroxybenzamide (0.06 g) and potassium carbonate (0.045 g) in DMF (3 ml) and the mixture was stirred and heated to 80° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether. The resultant solid was dried under vacuum at 55° C. to give the title compound as a solid (0.024 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.71 (s, 3H), 4.9 (s, 2H), 7.05 (d, 2H), 7.23 (d, 1H), 7.56 (d, 1H), 7.81 (s, 1H), 7.97 (m, 4H), 8.1 (d, 2H), 9.75 (s, 1H), 10.44 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].Cl.N1CCCC1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:24]2[CH2:25][CH2:26][CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 4-bromophenethyl alcohol (2.54 mmol) and p-toluenesulfonyl chloride (2.74 mmol) in anhydrous dichloromethane (5 mL) under nitrogen was added triethylamine (2.74 mmol) dropwise by syringe at room temperature. The reaction was stirred for 16 hours at room temperature. A white precipitate formed. 1N HCl solution (5 mL) was added to the suspension and the reaction became clear. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (5 mL), dried over magnesium sulfate and concentrated in vacuo to give a white solid. To this crude product was added pyrrolidine (1 mL) under nitrogen and the reaction was stirred at 50° C. for 90 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (20 mL) and washed successively with water (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (20-100% ethyl acetate/hexanes) afforded the title compound as a white solid (80%). ESMS [M+H]+: 254.2.