Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]=[C:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][C:64](=[CH2:63])[CH2:65][CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C=C1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-methylene-piperidine in DMSO at ambient temperature.
Reaction SMILES: C[N:2](C)CCN(C)C.C([Li])(CC)C.[CH3:14][O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19].C([O-])(=O)C.[Na+].N[O:35][S:36]([OH:39])(=O)=O>C1COCC1.CCCCCC>[NH2:2][S:36]([C:25]1[CH:26]=[CH:27][CH:28]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])(=[O:39])=[O:35]
Reactant: CCN(CC)C(=O)c1ccccc1OC
Reactant: NOS(=O)(=O)O
Reactant: CN(C)CCN(C)C
Agent: CC(=O)[O-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)C(=O)c1c(OC)cccc1S(N)(=O)=O
Yield: 49.2 %

Procedure:
To a solution of 8.0 ml (0.053 mol) of tetramethyl-ethylenediamine (TMEDA) in 350 ml of THF at -70° C. was added 42 ml (0.055 mol) of a 1.3M solution of s-butyl lithium in hexane and the mixture was stirred for fifteen minutes. To the solution was added dropwise with stirring a solution of 10.36 g (0.050 mol) of 2-methoxy-N,N-diethylbenzamide in 150 ml of THF while maintaining the temperature at -60° C. or below and sulfur dioxide then bubbled into the reaction mixture, keeping the reaction temperature below -50° C. until the reaction mixture was acid to wet litmus paper. The mixture was then stirred at ambient temperature for two hours, diluted with 450 ml of hexane, and the solid material which had separated was collected, dissolved in 200 ml of water and the mixture treated with 65 g of sodium acetate, and 21.5 g (0.19 mol) of hydroxylamine-O-sulfonic acid was added in portions with stirring. The white solid which separated was collected and dried to give 7.04 g (49%) of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide, mp 190°-194.5° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:11][CH:10]=1.[I-].[Na+]>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(C(O[C@H]2CCC[C@H](Cn3ccnc3)O2)c2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
114 mg of 55% sodium hydride were added to a solution of 323 mg of imidazole in 10 ml of dimethylformamide, and, after the mixture had been stirred at 80° C. for 30 minutes, it was cooled to room temperature. There were then added 2.20 g of trans-6-[α-(4-chlorophenyl)-2,4-dichlorobenzyloxy]-2-tosyloxymethyltetrahydropyran, dissolved in 15 ml of dimethylformamide, and then 594 mg of sodium iodide were added to the mixture. The resulting mixture stirred under a stream of nitrogen at 90°-95° C. for 4 hours, after which it was cooled, diluted with water and extracted with diethyl ether. The ethereal extract was washed with water and dried over sodium sulphate, after which it was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 8:1:0.1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 1.346 g of the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[S:52](Cl)(=[O:54])=[O:53]>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12)[S:52]([C:48]1[S:47][CH:51]=[CH:50][CH:49]=1)(=[O:54])=[O:53]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2cccs2)c(OC)c1
Yield: 30.5 %

Procedure:
Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 211b starting with 0.80 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine and 0.114 g of 2-thiophenesulfonyl chloride instead of the 4-(trifluoromethoxy)benzenesulfonyl chloride used in Example 211b. 0.150 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH2:15]([NH2:18])[CH:16]=[CH2:17].[Cl-].[NH4+]>>[CH2:15]([NH:18][CH2:9][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])[CH:16]=[CH2:17].[CH2:15]([NH:18][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:8])[CH:16]=[CH2:17]
Reactant: c1ccc(C2CO2)cc1
Reactant: C=CCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCNC(CO)c1ccccc1
Product: C=CCNCC(O)c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 0.57 ml (5 mmol) 2-phenyl-oxirane in 5 ml tetrahydrofuran 0.26 g (1 mmol) magnesium bromide diethyl etherate was added at room temperature. The mixture was treated under argon with stirring with 0.56 ml (7.5 mmol) allylamine whereby a white suspension formed which dissolved after heating to 100° C. in a closed container. The yellow solution was heated at 100° C. for 2 hours, cooled to room temperature and stirred vigorously with 5 ml of 5N aqueous ammonium chloride solution for 10 minutes. The organic phase was separated, dried over 3 g of sodium sulfate, filtered and evaporated in a rotary evaporator. The oily residue containing the products was separated by chromatography on a silica gel column using tert.-butyl methyl ether containing 1% of conc. aqueous ammonia as the eluent to obtain 0.3 g of 2-allylamino-1-phenyl-ethanol (compound A) and 0.2 g 2-allylamino-2-phenyl-ethanol (compound B) as yellowish oils.
Reaction SMILES: N(C(C)=O)[C@H:2]([C:7]([NH:9][C@H](C(O)=O)CC(C)C)=[O:8])[CH2:3][CH:4]([CH3:6])C.C[CH2:22][N:23](C(C)C)C(C)C.CN(C(ON1N=N[C:40]2C=CC=C[C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]1([C:7]2[O:8][CH:22]=[N:23][N:9]=2)[CH:3]=[CH:4][CH:6]=[CH:40][CH:39]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetyl-L-leucyl-L-leucyl-arginine(Mtr) (N-methyl)-(N-Methoxy)-amide: Acetyl-Leu-Leu-OH (133 mg) and arginine (Mtr)-N-methyl-N-methoxy amide (200 mg) were dissolved in 10 mL of DMF and were treated with 243 uL of DIEA and 212 mg of HBTU. The reaction stirred at room temperature for 15 hours and was worked up according to method A. Drying over Na2SO4, rotary evaporation of the solvent and flash chromatography on silica gel (50% acetone in hexane) provided 270 mg of the title compound as a foam.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:5]=1.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10]([OH:14])=[C:11]2[C:15]([O:16][CH3:17])=[O:18])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc(Br)cc2C1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(O)CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a refluxing stirred suspension of sodium hydride (5.6 g of 80% in oil, 187 mmoles) in dry dimethyl carbonate (120 ml) under a nitrogen atmosphere was added a solution of 7-bromo-2-tetralone (14 g, 61 mmoles) in dry dimethyl carbonate (60 ml) dropwise over 40 minutes. Refluxing was continued for an additional 45 minutes and then cooled to room temperature. The reaction was carefully quenched with glacial acetic acid, diluted with one volume of water and extracted with ethyl acetate (150 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to leave a residue which was purified using silica gel column chromatography eluting with ethyl acetate:hexane (39:7) to give methyl 7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate as a white solid. (15.2 g, 86%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C([N:12](CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:12][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([C:8]#[N:9])[CH:6]=1)=[O:20]
Reactant: N#Cc1ccc(N)nc1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: N#Cc1cncc(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (2.0 g, 16.8 mmol) in dry chloroform (40 mL) was added triethylamine (2.54 g, 25.21 mmol) with stirring at 0° C. To the reaction mixture chloroacetyl chloride (2.08 g, 18.48 mmol) was added dropwise, and stirred at 0° C. for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with chloroform (100 mL) and washed with water (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was recrystallized from chloroform and petroleum ether to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:43])([CH3:42])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:40][CH3:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]([F:59])([F:58])[C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1)[CH2:49]Br.Cl.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[C:1]([O:5][C:6]([C:8]([CH3:42])([CH3:43])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:49][C:48]2[CH:51]=[C:52]([C:54]([F:56])([F:57])[F:55])[CH:53]=[C:46]([C:45]([F:44])([F:58])[F:59])[CH:47]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:40][CH3:41])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Reaction time: 4.5 h

Procedure:
Tetrabutylammonium iodide (53 mg) was added to a solution of the compound obtained in Example 9 (2) above (217 mg) in tert-butyl methyl ether (4 ml) under nitrogen atmosphere at 0° C. 3,5-Bis(trifluoromethyl)benzyl bromide (164 mg) was added dropwise and the solution was stirred for 4.5 hours while the temperature was gradually raised from 0° C. to room temperature. To the reaction mixture, were added with 1N hydrochloric acid and ethyl acetate, and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=19:1→4:1) to give the titled compound (182 mg). MS (m/z): 833 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[S:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1)(=[O:20])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC1(c2ccc(O)cc2)COC1
Solvent: ClCCl
Product: CCOC(=O)CC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)COC1

Procedure:
To a solution of ethyl 2-[3-(4-hydroxyphenyl)oxetan-3-yl]acetate (500 mg, 2.12 mmol), TEA (321 mg, 3.17 mmol), and DCM (40 mL) was added dropwise a solution of Tf2O (658 mg, 2.33 mmol) in DCM (20 mL) in 15 min at −5° C. (ice/salt bath). After stirring for an hour, the reaction was quenched by the addition of water (50 mL). The crude mixture was extracted with DCM (2×40 mL). The organic layers were combined and concentrated to a residue which purified by flash column chromatography on silica gel (1-5% EtOAc/petroleum ether) to afford compound 67a as white oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H15F3O6S: 369.3 (M+H). found: 369.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)[OH:13].[OH2:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([OH:13])=[O:17]
Reactant: O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 3-fluoro-4-nitrotoluene (2 g, 12.82 mmole) in 13 mL water, containing 5.72 g of Na2Cr2O7, was treated dropwise with 14.2 mL of concentrated sulfuric acid, stirred at room temperature for one hour and then diluted with 20 mL of water. The mixture was filtered and the recovered solid was gently heated in 50 mL 2% sodium hydroxide solution. The resulting solution was cooled and filtered and the filtrate was acidified with concentrated HCl. The aqueous phase was extracted with two 100 mL portions of ethyl acetate, the combined extracts were washed with 100 mL of aqueous saturated sodium chloride solution, dried over MgSO4, filtered and concentrated in vacuo to give 1.6 g (68%) of 3-fluoro-4-nitrobenzoic acid as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:47]=[CH:46][C:32]([O:33][CH2:34][C:35]([NH:38]C(=O)OC(C)(C)C)([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O>>[NH2:38][C:35]([CH3:36])([CH3:37])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:47][CH:46]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1ccccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@H]2CCc3cc(O)ccc3C2)cc1
Yield: 52.7 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH:30]([NH:29][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:34])([CH3:35])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)=[O:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (940 mg, 2 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (795 mg, 90%) as a white solid: LC/MS m/e calcd for C28H30N2O3 (M+H)+: 443.56, observed: 443.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:39]=[O:40])[C:5]([F:16])=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NN)c1F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CN1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
(1S,4S)-2-(2-Chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (170 mg, 0.62 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (190 mg, 0.62 mmol), and HOAt (93 mg, 0.68 mmol) were dissolved in 4 mL of DMF. NMM (0.27 mL, 2.5 mmol) was added, followed by EDC (131 mg, 0.36 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (90 mg, 55%).
Reaction SMILES: C(O)C.C([O:6][C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:20]([CH3:21])[CH2:19][C:18]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:17]=3[C:16]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[N:15]2)[S:12][CH:13]=1)=[O:8])C.[OH-].[Na+].C(O)(=O)C>O>[C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:20]([CH3:21])[CH2:19][C:18]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:17]=3[C:16]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[N:15]2)[S:12][CH:13]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nc(C(=O)O)cs1)OCO3
Temperature: 90 °C
Yield: 91.2 %

Procedure:
A mixture of 9 ml of ethanol, 0.85 g (1.89 mmol) of (±)-7-(4-ethoxycarbonyl-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (Example 8) and 7 ml of 1N sodium hydroxide solution was stirred at 90° C. After cooling, it was acidified with acetic acid, diluted with water and the precipitated crystals were filtered off, washed with water and dried to yield 0.78 g (98%) of the title compound; Mp.: >260° C.
Reaction SMILES: O=O.[C:3]([O:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH:10](=[O:17])C1C=CC=CC=1>CC1C=CC=CC=1>[C:3]([O-:6])(=[O:5])[CH3:4].[CH2:10]=[O:17].[C:3]([O:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4]
Reactant: O=Cc1ccccc1
Agent: O=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=O
Product: CC(=O)[O-]

Procedure:
The oxidation of methyl benzenes with air or oxygen in the presence of acetic anhydride, benzaldehyde and an acid catalyst under mild reaction conditions yields a phenolic acetate and formaldehyde or paraformaldehyde when the ratio of acetic anhydride to methyl benzene is adjusted to provide the selective formation of the phenolic acetate and formaldehyde or paraformaldehyde. In this process, it is essential that the flow of air or oxygen through the reaction medium be maintained at a sufficient rate to provide for the continuous removal of formaldehyde as it is formed. The formaldehyde may then be recovered in the form of paraformaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=S)[NH:13][NH2:14])[CH3:2].[Cl:16][CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(O)C>[ClH:16].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[NH:14][N:13]=1)[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCc1cccc(CC)c1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(CC)cccc2CC)n[nH]c1C
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A stirred slurry of 9.4 g (0.05 mole) of 4-(2,6-diethylphenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 8.25 g (0.05 mole) of ethyl 2-chloroacetoacetate. The reaction mixture was stirred at ambient temperature as the color changed from white to yellow then to a greenish-white. The reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr then filtered hot. The filtrate upon cooling yielded a pale yellow solid, 16 g. Recrystallization from benzene/ligroin gave 15.5 g of white granular solid which was dried at 82+ C. under high vacuum for 3 hr, mp 167°-170° C. Elemental analysis and its 1H NMR spectrum indicated the product was a hydrochloride salt.