Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[F:2][C:3]([F:25])([F:24])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([O-:19])=[O:18].Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>CN(C)C=O>[O:34]=[C:30]1[N:29]([CH2:28][CH2:27][O:18][C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:3]([F:24])([F:2])[F:25])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32][O:31]1
Reactant: O=C([O-])c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: O=C1OCCN1CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture comprising 10.62 g of N-(8-trifluoromethyl-4-quinolyl)-anthranilic acid sodium salt, 4.98 g of 90% 3-(β-chloroethyl)-oxazolidin-2-one and 60 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, filtered, and poured into 300 ml of water. The crude product was extracted with ethyl acetate, the solvent evaporated off and the residue crystallized from ethanol to give 6 g of N-(8-trifluoromethyl-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 158°-160° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: Nc1ccccn1
Product: CC(=O)N1c2ccc(C(=O)Nc3ccccn3)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 20.6 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 28 mg of 2-aminopyridine. Thus, 20 mg (21%) of the title compound was obtained as a yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:32][CH3:33]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:32][CH3:33])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CCI
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
32.94 g (100 mmol) of N-benzyloxycarbonyltyrosine methyl ester is mixed in 200 ml of DMF with 27.64 g (200 mmol) of ground potassium carbonate. 8.96 ml (110 mmol) of iodoethane is instilled in this suspension and stirred overnight at room temperature. The solution is concentrated by evaporation, distributed between ethyl acetate and water and, after drying (Na2SO4), the organic phase is mixed with hexane. The title compound crystallizes out.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH:36]O.[OH-].[Na+]>C1COCC1>[OH:36][CH:22]1[CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:35])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23]1
Reactant: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCN1CC(O)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1M BH3. THF in THF (3.66 ml, 3.66 mmol) was added dropwise to Ethyl 7-(2,3-dip-tolylpyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (1.145 g, 2.438 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0-5° C. using an ice bath. The mixture was treated with 35% H2O2 (1.067 ml, 12.19 mmol) followed by 2M NaOH (6.10 ml, 12.19 mmol). The mixture was allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The reaction mixture was washed with water (25 ml) and extracted with ethyl acetate (2×25 ml). The organic extracts were combined, dried over MgSO4, filtered and the filtrate concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification by chromatography on silica eluting with DCM/MeOH to afford the title compound;
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([NH:15][NH2:16])([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([BH3-])#N.[Na+]>C(O)C>[C:5]([NH:15][NH:16][CH:2]([CH3:4])[CH3:1])([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)NNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Acetone (0.377 g; 0.477 ml; 6.50 mmol) was added to a solution of carbobenzyloxyhydrazine (1.00 g; 6.02 mmol) in absolute ethanol (6 ml). After one hour, the solution was concentrated to dryness and then ethanol (5 ml) and sodium cyanoborohydride (0.19 g; 3.0 mmol) were added. The mixture was stirred for 18 hours and then evaporated to a thick syrup. Hydrochloric acid (0.50 N; 5 ml) and ether (50 ml) were added and the two-phase mixture was stirred for one hour. The aqueous layer was neutralized by addition of solid NaHCO3 and extracted with ether (2×25 ml). The combined ether portions were washed with water and brine and dried (MgSO4) Removal of solvent gave a solid which was recrystallized from hexanes - ether, giving pure hydrazide 4 (1.09 g; 5.25 mmol; 87%), mp 61°-62°. TLC (silica gel; CH2Cl2 --CH3OH; 20:1) Rf=0.5. MS m/e 208 (M+). Analysis: Calculated for C11H16N2O2 : (C, 63.44; H, 7.44; N, 13.45). Found: C, 63.22; H, 7.67; N, 13.71; NMR (CDCl3);δ0.97 (6H,d,J=6); 3.15 (1H, septet, J=6); 3.8-4.6(1H, broad); 5.13(2H,S); 6.2-7.0(1H, broad); 7.33 (5H,S); IR(CHCl3) 3500, 1720 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O1CCOCC1>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:35][C:32]3[CH:33]=[CH:34][NH:30][N:31]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: O=Cc1cc[nH]n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(C2CCN(Cc3cc[nH]n3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) and 1H-pyrazole-3-carbaldehyde (50.7 mg, 0.53 mmol) were stirred at ambient temperature in dichloromethane (5 ml) for 1 hour. Sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added and the mixture stirred at ambient temperature for 48 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give a foam. This was dissolved in 1,4-dioxane (2 ml), a 4M solution of hydrogen chloride in 1,4-dioxane (2 ml) was added and the solution stirred at ambient temperature for 48 hours. The product was filtered and washed with diethyl ether and air-dried. The resulting solid was dissolved in water, basified with 2N sodium hydroxide and the resulting solid filtered, washed with water and dried under vacuum to give the title compound (61 mg, 44%). NMR Spectrum: 1H NMR (DMSO d6) δ 1.71 (m, 4H), 2.07 (m, 2H), 2.56 (m, 1H), 2.95 (m, 2H), 3.53 (s, 2H), 4.86 (s, 2H), 6.16 (s, 1H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.18 (d, 1H), 7.37 (d, 2H), 7.64 (m, 1H), 7.91 (d, 2H), 9.55 (s, 1H), 12.59 (m, 1H); Mass Spectrum: M+H+ 376.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[OH-].[NH4+:24]>C1COCC1>[C:14]([C@@H:9]1[CH2:10][C@H:11]([F:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])[NH2:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a well stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (50 g, 0.2145 mmol) in dry THF (1000 ml) was added TEA (32.49 g, 0.3217 mmol) at room temperature. The mixture was cooled to −10° C. and ethyl chloroformate (34.93 g, 0.3217 mmol) was added over period of 20 min. The mixture was stirred for 30 min at the same temperature under nitrogen atmosphere and aqueous ammonium hydroxide (500 ml) was added. The aqueous mixture was stirred at room temperature for 18 h and THF in the mixture was evaporated under reduced pressure. The aqueous mixture was further diluted with water (100 ml) and extracted with chloroform (3×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was stirred in petroleum ether (250 ml) for 20 min to give a white filterable solid. The product was collected by filtration and dried to give 44.7 g of the product as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.48 (s, 9H), 2.20-2.80 (m, 2H), 3.51-3.85 (m, 2H), 4.38 (br s, 1H), 5.21 (d, J=52.2 Hz, 1H), 5.50 (br s, 1H), 6.16 (br s, 0.5H, rotomer), 6.59 (br s, 0.5H, rotomer)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[CH:24]([CH:26]=[CH2:27])=[O:25]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:27][CH:26]2[CH:24]=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: C=CC=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=CC1CC1(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
a solution of bis[3-(trifluoromethyl)phenyl]diazomethane, prepared as in Example 84 from 3,3'-(trifluoromethyl)benzophenone hydrazone (29.9 g) and activated manganese dioxide (30 g) in dichloromethane (150 mL) was added to a solution of acrolein (9.9 mL) in heptane (90 mL) over 15 minutes at 40° C. The solution was heated at 55° C. for 5.5 hours, then the dichloromethane was distilled off and replaced with heptane (100 mL). After the mixture was heated at 90° C. overnight, the solvent was removed in vacuo and the residue was purified by HPLC (dichloromethanehexane; 1:1). Evaporation of the appropriate fractions yielded 30.5 g of 2,2-bis[3-(trifluoromethyl)phenyl]cyclopropanecarboxaldehyde. Crystallization of a portion from hexane gave the analytical sample, 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:21]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)ccc1Sc1cccc(Cl)c1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
To a mixture of 3-chlorothiophenol (20 g, 0.138 mol), cupric acetate (1.75 g) and DMF (199 mL) under N2 was added in portions K2CO3 (23 g). The mixture was heated to 150° C. and then 2,5-dibromobenzoic acid (43.5 g) was added. The mixture was heated overnight, poured into water (600 mL), filtered, the filtrate was treated with charcoal and filtered again. The filtrate was acidified with conc. HCl, extracted with CHCl3, the organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford 28.9 g of 2-[(3-chlorophenyl)thio]-5-bromobenzoic acid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:15][CH2:16][CH3:17]>C(O)C>[C:2]([NH:5][C:6]([C:12]#[N:13])([CH2:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(C#N)NC(C)=O
Reactant: CCCBr
Agent: [Na]
Solvent: CCO
Product: CCCC(C#N)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.35 g of sodium (58.8 mmol) are dissolved in 200 ml of ethanol and the resulting solution is cooled down to 0° C. 10 g (58.8 mmol) of ethyl acetamidocyanoacetate are added. After a clear solution has formed, a solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is added dropwise and the reaction mixture is stirred at room temperature for 2 hours. A solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is added once again and the reaction mixture is heated under reflux for 16 hours. The solvent is removed in vacuo and the residue is taken up in dichloromethane; the solution is washed with water and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is stirred up with petroleum ether. After filtering off with suction, 7.5 g (60%) of ethyl 2-acetylamino-2-cyanopentanoate are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:40])[CH2:10][C:11]1([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42].O>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:40])[CH2:10][C:11]1([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:44]([NH:43][CH2:41][CH3:42])=[O:45])[CH:34]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]1
Reactant: CCN=C=O
Reactant: Nc1cccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(C(=O)c4ccccc4)CCS3(=O)=O)s2)c1
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)Nc1cccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(C(=O)c4ccccc4)CCS3(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(3-aminophenyl)-2-thienyl)-4-benzoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (150 mg) in dichloromethane (3 ml) was added ethyl isocyanate (22 mg) at 0° C. and the reaction mixture was stirred at ambient temperature for 5 hours. The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel 60 (3% methanol-chloroform) to give N-(2-tetrahydropyranyloxy)-2-[4-benzoyl-7-(5-(3-(ethylaminocarbonylamino)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (75 mg) as a white powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=O)(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:39])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCN2CC[C@@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(4-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-methyl-1 H-indole-3-carboxamide (1.94 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.67 g) to give N-(4-((3S)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22](O)[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]1(=[O:39])[N:33]([CH:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([CH2:19][CH2:18][C@@H:17]4[C@@H:16]3[CH2:15][CH2:14][C@@:13]3([CH3:28])[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:21]2)[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of dihydrocholesterol (5.0 g, 12.9 mmol, Aldrich), phthalimide (2.0 g, 13.6 mmol, Aldrich), and triphenylphosphine (3.8 g, 13.6 mmol, Aldrich) in THF (20 ml, Aldrich) stirred at 0° C. under a nitrogen atmosphere was added dropwise diethylazodicarboxylate (2.3 ml, 14.5 mmol, Aldrich). Upon the completion of addition the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated in vacuo to a residue. This residue was dissolved in 50 ml hexane/ethyl acetate 95/5 and a precipitate formed. The mixture was filtered. The filtrate was concentrated to dryness in vacuo, dissolved in 25 ml of hexane/ethyl acetate 95/5 and chromatographed on 200 g silica gel (eluent 2 L hexane/ethyl acetate 95/5 then 1 L hexane/ethyl acetate 90/10). A 7.6% yield of the desired 3-phthalimidocholestane (5.43 g) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.O[CH2:26][C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)C>C1COCC1>[Br:24][CH2:21][C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CBr)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (12.54 g, 47.8 mmol) was dissolved in 100 ml of anhydrous THF and at 0° C. tetrabromomethane (15.85 g, 47.8 mmol) in 100 mL of anhydrous THF was added dropwise. This was followed by the dropwise addition, after 15 min, of benzyl ((S)-2-hydroxy-1-methylethyl)carbamate (5.0 g, 23.9 mmol), dissolved in 150 ml of THF. After 10 min at 0° C. the cooling bath was removed and the mixture was stirred at room temperature overnight. The precipitate which had formed was separated off and washed with ethyl acetate and the combined organic phases were concentrated. The residue obtained was purified over silica gel (ethyl acetate-n-heptane=20:80). Yield: 3.41 g (52%).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[ClH:5].[CH3:1][S:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]3[N:19]4[CH2:29][CH2:28][N:27]=[C:20]4[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[N:17]3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(C2CCN3c4ccccc4C4=NCCN4C23)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
6 ml of methylsulfonyl chloride were added dropwise at 0°-5° C. to a vigorously stirred suspension of 8.55 g of 2,3,5,6,7,8-hexahydro-5-(4-hydroxyphenyl)imidazo[1,2-c]pyrrolo[1,2-a]quinazoline hydrochloride in 100 ml of methylene chloride and 25 ml of pyridine, and the reaction mixture was stirred at room temperature for 70 h. The solvent was removed by distillation and then 1N HCl was added, and the resulting precipitate was recrystallized from ethanol/methyl t-butyl ether. Yield: 8.0 g (76%); melting point 241°-242° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)[N:19]=1
Reactant: Cc1cc[nH]n1
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1-n1ccc(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-1H-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) was added sodium hydride (1.0 g, 60% in oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then. A solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0° C. After addition, the mixture was heated to 80° C. and stirred for 12 h. After this time, the mixture was poured into ice-water and extracted and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and then purified by normal phase silica gel column (EtOAc/hepate) to provide methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate as a brown semi-solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].[CH:9](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:10]1([CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of methyl thioglycolate (5.95 g, 56 mmol) in 225 mL of tetrahydrofuran is added sodium hydride (2.5 g of 60% NaH in oil, 62.5 mmol). The mixture is stirred at room temperature for 10 minutes. Benzhydryl bromide (Aldrich of Milwaukee, Wis.; hereinafter "Aldrich") (15.3 g, 62 mmol) is added and the reaction mixture is stirred at room temperature for 3 days and then concentrated in vacuo. The residue is taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, 10% aqueous citric acid, and brine and then dried over magnesium sulfate. Chromatography on silica gel, eluting with 4% ethyl acetate in hexane provides methyl [[(diphenyl)methyl]thio]acetate as a colorless oil in 15% yield.