Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:8]([NH2:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CCOC(C)=O.[OH-].[Na+].C1CCCCC1>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:6][C:7]=1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 51c (45.3 mg, 0.197 mmol) in EtOAc (1 mL) and aqueous NaOH (1M, 0.49 mL) was added 2,2,2-trichloroethyl chloroformate (0.0326 mL, 0.237 mmol) and the resulting mixture stirred at RT for 45 min. The layers were separated and the aqueous extracted with EtOAc (2 mL). The combined organics were washed with brine (2 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave an orange-red gum. FCC, using 0-50% EtOAc in cyclohexane, gave the title compound as a pale orange film (44.1 mg, 55%). LCMS (Method 3): Rt 2.87 min, m/z 404, 406 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([OH:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:53]1C=CC=CC=1.C(=O)([O-])O.[NH4+]>C(#N)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:53])=[O:34])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:36])[CH3:37])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid (97 mg, 0.180 mmol), di-tert-butyl dicarbonate (60 mg, 0.273 mmol), and pyridine (0.021 mL, 0.273 mmol) were combined into anhydrous acetonitrile (5 mL). The mixture was stirred at ambient temperature for half an hour. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness. The residue was washed with hexanes several times to remove the residual di-tert-butyl dicarbonate, and the solids were removed via filtration to give the title compound as a white solid (94 mg, 98%) 1H NMR (CDCl3): 8.48 (d, J=9 Hz, 1H), 7.88-8.00 (m, 2H), 7.75 (d, J=9 Hz, 1H), 7.68 (d, J=9 Hz, 1H), 7.58 (d, J=9 Hz, 2H), 7.36-7.51 (m, 3H) 7.25 (d, J=9 Hz, 1 H), 6.88 (d, J=9 Hz, 2H), 6.42 (broad s, 1H), 6.13 (broad s, 1H), 4.81 (s, 2H), 3.26-3.44 (m, 1H), 1.37-1.47 (m, 6H). ESI-LCMS m/z 531 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:1]([C:4]([C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:27]#[N:28])=[CH:30][CH:31]=1)([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesium chloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15 ml) at 0° C. The mixture was stirred at 20° C. for 1 hour, then a solution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml) was added. After stirring for 3 hours at 20° C., the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.52 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1.CCN(CC)CC.C(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([NH:25][C:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
Cis-3-amino-4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (450 mg, 1.288 mmol), from Part F of Example 112, was added to a cooled mixture (0° C.) of 5-chloro-thiophen-carboxylic chloride (233 mg, 1.288 mmol), Et3N (0.54 mL, 3.864 mmol), and CH2Cl2 (10 mL). The mixture stirred overnight at rt. EtOAc (70 mL) was added. The mixture was washed with brine, and the organic phase dried over MgSO4 and concentrated. The crude product was purified by silica gel flash column chromatography (30% MeOH/EtOAc) to yield cis-4-benzyloxycarbonylamino-3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (236 mg). LC-MS: (M-100): 394.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH+:7]([O-])[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][C:8]1[C:9]2[C:4](=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([CH3:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc2c(c1[N+](=O)[O-])C=C[NH+]([O-])C2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h

Procedure:
6-Methyl-5-nitroisoquinolin-1(2H)-one-N-oxide (3.1 g, 15.2 mmol) was taken up in chloroform (100 mL) and phosphorus oxychloride (7 mL, 80 mmol) was added dropwise to the reaction. The mixture was then heated to 70° C. After 3 h, the reaction was cooled and the volatiles removed in vacuo. Residual phosphorus oxychloride was azeotroped with toluene. The residue was then dissolved in chloroform and washed with cold water, saturated NaHCO3 and brine. The organic layer was then dried with sodium sulfate and purified by column chromatography using 10 to 40% ethyl acetate in hexanes as an eluent. The title compound was obtained an off-white solid (3.4 g, 96%). MS (M+H)+ 223.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ba+2].[F:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>[Pd].C1C2C(CCCC2)CCC1>[F:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:9]=1[CH:10]=[O:11]
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCC2CCCCC2C1
Product: O=Cc1ccc(F)cc1F
Temperature: 130 °C

Procedure:
30 ml (27 g) of decahydronaphthalene and 0.5 g (2.3×10-4 ml) of a catalyst of 5% palladium on a barium sulfate support were added to the flask containing the 2,4-difluorobenzoylchloride. The reaction was purged with H2 for 0.25 hour, then the temperature was raised to 130° C. Hydrogen was dispersed through the system for 6 hours. The product 2,4-difluorobenzaldehyde was isolated as a colorless liquid. Yield 9.8 g (82%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[NH:8]1[CH:7]=[C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]1=[O:2]
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2cccc(C(F)(F)F)c2)cn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NCc1ccc(=O)[nH]c1
Temperature: 60 °C
Reaction time: 28 h

Procedure:
A mixture of 2-[(6-Methoxypyrid-3-yl)methylamino]-N-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (Example 4; 1.4 g, 3.65 mmol) and trimethylsilyl iodide (Fluka, Buchs, Switzerland; 1.4 mL, 10.3 mmol) in chloroform (30 mL) is stirred at 60° C. for 28 hours. The cooled mixture is then treated with methanol (2 mL) and stirred at room temperature for 10 minutes. The solvent is evaporated off under reduced pressure and the residue is treated with an aqueous solution of ammonia (100 mL of 10%) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from hot ethyl acetate to give the title compound as a colourless crystalline solid, ma.p. 200-202° C.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([N:30]([CH3:32])[CH3:31])[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(N(C)C)C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N>>[CH3:32][N:30]([CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[NH:7][C:6]2[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)[CH3:31]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)N(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)N(C)C
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2[nH]1)N(C)C

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as described in Example 36-E. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.60 (s, 1H) 10.88 (s, 1H) 7.90 (s) 7.54-7.60 (m) 7.46 (m) 7.22 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.69 (dd, J=2.97, 1.96 Hz, 1H) 5.38 (s, 1H) 3.79 (s, 3H) 2.41 (d, J=0.63 Hz, 3H) 2.22 (s, 6H). MS (ESI−) m/z 358.2 (M−H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.CN1CCOCC1.[F:23][C:24]([F:31])([F:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>C(#N)C>[F:23][C:24]([F:31])([F:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1
Reactant: FC(F)(F)[C@@H]1CCCN1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: N#Cc1ccc(-n2nnnc2CN2CCC[C@H]2C(F)(F)F)cc1
Temperature: 160 °C

Procedure:
To a mixture of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (100 mg, 0.455 mmol, Intermediate 10) and polymer supported N-methylmorpholine (4 mmol/g, 171 mg, 0.683 mmol) in acetonitrile (3 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.683 mmol). The reaction mixture was heated at 120° C. for 20 min in a microwave reactor and at 140° C. for 20 min and at 150° C. for 30 min and finally at 160° C. for 30 min in the microwave reactor.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[C:19]1([NH:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in DME. ES-MS m/e (%): 332 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].N1SN=C2C(S(NC3C=C(I)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.COC(=O)[C@@H](N)C(C1C=CC(Cl)=CC=1)(C)C>>[N:36]1[S:35][N:34]=[C:33]2[C:28]([S:25]([NH:24][C:18]3[CH:19]=[C:20]([I:23])[CH:21]=[CH:22][C:17]=3[C:16]([NH:15][C@@H:4]([C:5]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)([CH3:7])[CH3:6])[C:3]([OH:38])=[O:2])=[O:37])(=[O:27])=[O:26])=[CH:29][CH:30]=[CH:31][C:32]=12
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(C)(C)c1ccc(Cl)cc1
Agent: COC(=O)[C@@H](N)C(C)(C)c1ccc(Cl)cc1
Agent: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Product: CC(C)(c1ccc(Cl)cc1)[C@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(=O)O
Yield: 90 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester. The title compound (61 mg, 90%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (S)-2-amino-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester (EXAMPLE 107, Part F) as in Example 94, Part A. 1H NMR (500 MHz, CDCl3): 11.26 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.21 (dd, J=8.8, 1.0, 1H), 8.07 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.35-7.25 (m, 5H), 6.89 (d, J=8.3, 1H), 6.32 (br d, J=9.2, 1H), 4.97 (d, J=9.0, 1H), 3.64 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)=O.N[C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=C[NH:19][N:18]=1>C(O)(=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:19]3[N:18]=[CH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCc1ccc(C(=O)C=CN(C)C)cc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(CC)cc3)ccnc12

Procedure:
A mixture of 4.07 g. of 3-dimethylamino-4'-ethylacrylophenone and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours. The compound is recovered from the reaction in the previously described fashion to yield crystals, m.p. 101°-103° C.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].[Li+].[Cl-].Br[CH2:13][C@H:14]([CH3:17])[CH2:15][OH:16]>C1COCC1.[Cu](Cl)Cl>[CH3:17][C@H:14]([CH2:13][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:15][OH:16]
Reactant: CC(C)CCBr
Reactant: C[C@H](CO)CBr
Agent: Cl[Cu]Cl
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (2.04 g, 84 mmol) and a crystal of iodine were suspended in 5 mL THF for the addition of 1-bromo-3-methyl butane (0.3 mL, neat). The mixture was heated to start the Grignard formation. The remaining 1-bromo-3-methyl butane (8.63 mL, 72 mmol) was diluted in THF (60 mL) and added dropwise. The mixture was stirred at ambient temperature for 2 hours and cooled to −5° C. A solution of copper chloride (1.21 g, 9 mmol) and LiCl (0.76 g, 18 mmol) in THF (50 mL) was added dropwise keeping the temperature below 0° C. The resulting mixture was stirred for 20 min, and (R)-3-bromo-2-methylpropanol in THF (20 mL) was added dropwise while keeping the temperature below 0° C. The mixture was allowed to slowly reach ambient temperature overnight. The reaction mixture was quenched with ammonium hydroxide and water. The mixture was diluted with EtOAc and extracted with 3×20 mL EtOAc. The organics were washed with brine, dried (MgSO4), filtered and concentrated. The residual oil was purified via silica gel chromatography (90/10 Hexane/EtOAc) to give 2.67 g (R)-2,6-dimethyl heptan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].C(O)(C(F)(F)F)=[O:13].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:13])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: Cc1c(Br)ccc(C#N)c1F
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Br)ccc(C(N)=O)c1F
Yield: 94 %

Procedure:
4-Bromo-2-fluoro-3-methylbenzonitrile (11 g, 51.4 mmol) in a 100 mL mixture of TFA-sulfuric acid (4:1, V/V) was stirred at 40° C. for 16 h. After complete conversion of starting material, the reaction mixture was poured into iced-cold water. The resulting solid was filtered off and washed with water and dried to give the desired product (11.24 g, 48.4 mmol, 94% yield) as a white solid. MS (ESI) m/z 234.1 [M+2]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C.O>[CH3:25][O:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 60 °C
Yield: 76.4 %

Procedure:
To methyl 5-hydroxy-2-nitrobenzoate (1.08 g, 5.5 mmol) in DMF (50 mL) was added potassium carbonate (1.52 g, 11 mmol) followed by 1-bromo-2-methoxyethane (1.55 mL, 16.4 mmol) and the mixture heated at 60° C. overnight. After cooling to room temperature, the reaction was diluted with H2O, extracted with EtOAc, and the organic layer washed with H2O and brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (12-100% EtOAc/hexanes) to give methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08 g, 4.2 mmol, 77%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, 1H), 7.31 (s, 1H), 7.29 (d, 1H), 4.29 (dd, 2H), 3.86 (s, 3H), 3.68 (dd, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>C(O)(=O)CS>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][NH:38][C:39]([CH2:41][CH3:42])=[O:40])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17][CH3:19])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: O=C(O)CS
Product: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
100 mg of H-Tyr-D-Met(O)-Gly-Phe-NHNH-CO-CH2CH3 is dissolved in 4% aqueous thioglycolic acid (6 ml) and kept to stand at 50° C. for10 hr. The solution is applied to a column of Sephadex G-25, which is eluted with 30% aqueous acetic acid. The fractions (270-310 ml) are combined and lyophilized to give the desired compound; yield 80 mg. Rf2 =0.61 [α]D21 +20.0° (c=0.2 MeOH).
Reaction SMILES: [C:1]([C:4](=[C:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[C:15](OC(=O)C)(=O)C.C(OC)(OC)OC.[H-].[Na+]>COCCOC>[OH:3][C:1]1[CH:2]=[CH:15][N:14]=[C:9]([C:10]([F:12])([F:13])[F:11])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: COC(OC)OC
Product: COC(=O)c1c(O)ccnc1C(F)(F)F
Temperature: 27.5 °C
Reaction time: 18 h

Procedure:
A mixture of 105 g (0.5 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate (example 2 of U. S. Pat. No. 4,655,816), acetic anhydride (152 9), and trimethyl orthoformate (106 g) was held at reflux for 16 h then distilled to remove low boiling material (bp 65-90° C.) The remaining material was concentrated in vacuo and the residue was kugelrohr distilled at 2 torr (80-120° C.) to give 114 g of distillate. This distillate (44 g) was added dropwise to a mixture of 14.5 g of 60% sodium hydride oil dispersion in 100 ml of 1,2-dimethoxyethane (DME). The reaction mixture was maintained at 25-30° C. with an ice-water bath. The reaction mixture was stirred at room temperature for 18 h and poured into 300 ml of ice-water. The aqueous layer was extracted with ether and filtered. The aqueous layer was acidified with concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with 10% potassium carbonate. The potassium carbonate layer was acidified with concentrated HCl. The precipitate was filtered and air dried to give 20.4 g of the product, mp 78-82° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[Br:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30](O)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[Br:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30]([NH:1][N:2]4[C:7](=[O:8])[C:6]5[S:9][CH:10]=[CH:11][C:5]=5[C:4]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:3]4)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(Br)(C3)C1)C2
Product: O=C(CC12CC3CC(CC(Br)(C3)C1)C2)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(3-bromoadamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.71-7.73 (m, 2H), 7.56-7.59 (m, 4H), 2.32-2.34 (m, 2H), 2.27-2.32 (m, 2H), 2.19-2.25 (m, 2H), 2.17 (s, 2H), 2.12-2.16 (m, 2H), 1.62-1.75 (m, 5H), 1.56-1.60 (m, 1H); MS (APCI+) M/Z 498 (M+H)+.
Reaction SMILES: [OH-].[Na+].Br[CH:4]([Br:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[OH:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:10][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:26][C:25]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][C:12]=1[Cl:11]
Reactant: CCCCCC(Br)Br
Reactant: O=C(c1ccccc1)c1ccc(O)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(OCCCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 ml of a 10 percent aqueous sodium hydroxide solution are added to a solution of 34.5 g of dibromohexane, 9.9 g of 3-chloro-4-hydroxy-benzophenone and 1.6 g of tetrabutylammonium bromide in 100 ml of methylene chloride. The heterogeneous mixture is stirred at room temperature overnight. The organic phase is separated, dried over sodium sulfate and evaporated. By chromatography of the residue on silica gel with hexane/ethyl acetate 7:3, there is obtained 4-[(6-bromo-hexyl)oxy]-3-chlorobenzophenone, m.p. 58° C.