Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[O-:16][C:17]#N.[K+]>O>[Cl:9][C:7]1[C:6]([Cl:10])=[CH:5][C:4]2[N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:17](=[O:16])[NH:2][C:3]=2[CH:8]=1
Reactant: N#C[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred mixture of 31.2 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minutes-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15° and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48%) of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethyl-ethanamine and 260 parts off dichloromethane are added dropwise 7,4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is washed with water, dried, filtered, and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: Cc1onc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br

Procedure:
N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide was prepared, using the method in Example 193b, from 3-amino-4-bromo-5-methylisoxazole and 4-biphenylsulfonyl chloride in 5% yield. The crude product was purified by column chromatography. After recrystallization from ethyl acetate/hexanes, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide (m.p. 154-156° C.) was obtained in 51% yield.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15]>>[CH3:11][O:12][CH2:13][CH:14]([O:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:15]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: COCC(C)O
Product: COCC(C)Oc1ncccc1[N+](=O)[O-]

Procedure:
Prepared analogously to example XI.1 using 2-fluoro-3-nitropyridine (142 mg) and 1-methoxypropan-2-ol (108 mg).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:24]4[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH3:18])=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 120 °C
Yield: 22.2 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.15 g), 4-fluoroacetophenone (0.133 g) and potassium carbonate (0.177 g) were dissolved in DMSO (2 ml) and heated at 120° C. for 7 min in the microwave reactor. The crude reaction mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). Chromatography of the crude ketone (silica gel, eluting with methanol/dichloromethane, 0-25%) afforded the title compound (E25) (0.05 g). MS electrospray (+ion) 355 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[S:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[S:34]>C(O)(=O)C>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:38]3[S:32][C:33](=[S:34])[NH:35][C:36]3=[O:37])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CCCc1c(OCc2ccc(C=O)cc2)ccc(C(C)=O)c1OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(OCc2ccc(C=C3SC(=S)NC3=O)cc2)ccc(C(C)=O)c1OC(C)=O

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(4-acetyl-3-acetoxy-2-propylphenoxy)methyl]benzaldehyde (70 mg, 0.20 mmol) was dissolved in acetic acid (1 ml). To this solution was added sodium acetate (59 mg, 0.72 mmol) and then rhodanine (27.5 mg, 0.21 mmol). The reaction mixture was then heated to reflux and the progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:30][C@H:22]([C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: COCCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: COCCOC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-propionic acid 2-methoxy-ethyl ester to provide after chromatographical separation the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCNCC3)cc12
Reaction time: 3 h

Procedure:
A solution of Example 135A (0.955 g, 2.24 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1.73 mL, 22.4 mmol) and the mixture was stirred for 3 hours. After concentration, the residue was dissolved in 10 mL methanol and treated with 30 mL 1M hydrogen chloride in ether. After stirring for 15 minutes, the mixture was treated with ether and the solids were filtered, washed with ether and oven-dried to afford the title compound as a hydrochloride salt. MS (ESI+) m/z 326.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]1[N:14]=[C:13]([NH:15][O:16]C2CCCCO2)[C:12]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[CH:11][N:10]=1.[OH-].[Na+]>Cl.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]1[N:14]=[C:13]([NH:15][OH:16])[C:12]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[CH:11][N:10]=1
Reactant: COc1cc(Cc2cnc(NOC3CCCCO3)nc2NOC2CCCCO2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(Cc2cnc(NOC3CCCCO3)nc2NO)cc(OC)c1OC

Procedure:
3.8 g of 2,4-bis-[(tetrahydropyran-2-yloxy)-amino]-5-(3,4,5-trimethoxybenzyl)-pyrimidine is stirred in 30 ml of 1N hydrochloric acid for 10 minutes at room temperature. The reaction mixture is then neutralised with 1N sodium hydroxide solution and the precipitating oil is taken up in methylene chloride. Chromatography on silica gel with the use of methylene chloride as eluant yields 2-[(tetrahydropyran-2-yloxy)-amino]-4-(hydroxyamino)-5-(3,4,5-trimethoxybenzyl)-pyrimidine, M.P. 190°-192°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:11])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:25]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:11])=[N:4][C:5]1=[O:8])=[O:26])[CH3:23]
Reactant: CCN=C=O
Reactant: COc1ccccc1CNC(=O)Nc1nc(=O)[nH]cc1F
Solvent: C1CCOC1
Product: CCNC(=O)n1cc(F)c(NC(=O)NCc2ccccc2OC)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a suspension of 1-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-(2-methoxybenzyl)urea (as prepared in U.S. Patent Appl. Publ. 2010022538; 0.25 g, 0.855 mmol) in dry THF (5 mL) was added ethyl isocyanate (0.074 mL, 0.941 mmol), and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid residue was suspended in Et2O (10 mL). The suspension was suction filtered and washed with Et2O (2×10 mL). The resulting solid was dried in vacuo to yield N-ethyl-5-fluoro-4-(3-(2-methoxybenzyl)ureido)-2-oxopyrimidine-1(2H)-carboxamide (0.150 g, 48%) as a white solid: mp 248-250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.92 (s, 1H), 9.68 (s, 1H), 8.55 (d, J=6.6 Hz, 1H), 7.33-7.20 (m, 2H), 7.02 (d, J=7.9 Hz, 1H), 6.91 (dd, J=7.9, 6.9 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 3.38-3.24 (m, 2H), 1.14 (t, J=7.2 Hz, 3H). ESIMS m/z 362 ([M−H]−).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][NH2:14]>ClCCl>[Br:1][C:6]1[C:5]([CH2:12][CH2:13][NH2:14])=[C:4]([CH3:3])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=1
Reactant: COc1cccc(CCN)c1C
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(Br)c(CCN)c1C
Yield: 114.6 %

Procedure:
Bromine (2.38 g; 14.9 mmol) in dichloromethane (10 ml) was added to a solution of {2-[2-methyl-3-(methyloxy)phenyl]ethyl}amine (Preparation 10; 2.73 g; 16.52 mmol) in dichloromethane (150 ml) over 3 min at 0° C. Removal of the solvent, trituration with diethyl ether, filtration and drying under vacuum gave the title compound (4.17 g) as a pale orange solid.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:27][N:11]1[CH2:12][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCNCC(NC(=O)c2n[nH]c3ccccc23)C1

Procedure:
N-(1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (850 mg) is dissolved in ethanol (40 ml) and hydrogenated over 10% palladium on carbon (100 mg) at about 50° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound as an oil. The free base thus obtained is converted to the oxalate 3/2 hydrate of the title compound in a usual manner, m.p. 163°-166° C. (recrystallzed from ethanol-diethyl ether).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@@H:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@@H:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C[C@H]1CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C

Procedure:
A mixture of lithium hydroxide (11.2 mg, 0.468 mmol) and ethyl 2-((5S,6S,9R)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetate (118.1 mg, 0.256 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred at room temperature over night. LCMS showed complete conversion. The reaction was dried under high vacuum and the crude product (MS(ESI)[M+H+]=433.17) was used as is in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[C:5]2[NH:4][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[NH:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=[C:9]([O:16][CH3:17])[C:10]=1[O:14][CH3:15]
Reactant: C1CNCCN1
Reactant: COc1cc2nc(CCl)[nH]c2c(OC)c1OC
Product: COc1cc2nc(CN3CCN(Cc4nc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC

Procedure:
2-Chloromethyl-4,5,6-trimethoxybenzimidazole (250 mg) and piperazine (34 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[ClH:29].[Cl:30][CH2:31][C:32]([NH:34][C:35]1[C:36]([CH3:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:30].[ClH:29].[ClH:30].[NH2:21][C:19]([CH:14]1[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][N:16]([CH2:31][C:32]([NH:34][C:35]2[C:36]([CH3:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])=[O:33])[CH2:15]1)=[O:20]
Reactant: NC(=O)C1CNCCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(C)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
A mixture of 6.1 parts of 1-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 4.3 parts of 2-chloro-N-(2,4,6-trimethyl-3-pyridinyl)acetamide monohydrochloride, 3.7 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred for 15 hours at 70° C. The reaction mixture was filtered, washed with N,N-dimethylformamide and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off, washed twice with 2-propanone and once with 2,2'-oxybispropane and dried overnight at 100°-110° C., yielding 6.58 parts (61.2%) of 3 -(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(2,4,6-trimethyl-3-pyridinyl)-1-piperazineacetamide trihydrochloride, hemihydrate; mp. 224.7° C. (compound 115).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([NH:31][C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C@@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:45][CH:44]=3)=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])=[O:43])=[CH:34][CH:35]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)O)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A crude solution of (S)-4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.15 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 12.3 mg (33%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-((4-(heptyloxy)benzoyl)oxy)phenyl)propanoic acid 57. LCMS-ESI (m/z) calculated for C34H41NO6: 559; found 560 [M+H]+, tR=12.14 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 8.65 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 4.63 (ddd, J=10.8, 8.2, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.22 (dd, J=13.9, 4.3 Hz, 1H), 3.10 (dd, J=13.8, 10.8 Hz, 1H), 1.81-1.66 (m, 2H), 1.50-1.20 (m, 8H), 1.29 (s, 9H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C(N(CC)CC)C>[O:25]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[C:1]1[C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Oc1cccnc1Br
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(c1cc3ncccc3o1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromo-3-hydroxypyridine under the conditions described in Example 26, but using twice as much triethylamine and lengthening the reaction time to 3 days. Chromatography of the crude product over the 40-fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride followed by crystallization from ether/hexane and recrystallization from ethyl acetate/hexane gave off-white crystals with m.p. 168°-169°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:14]([CH3:19])[C:15](S)=[N:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].ClCCl.OO.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[N:14]([CH3:19])[CH:15]=[N:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(-c2nnc(S)n2C)ccc1[N+](=O)[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(-c2nncn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 59.1 %

Procedure:
5-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol (Preparation 117, 1.16 g 4.14 mmole) was stirred with dichloromethane (11.8 mL) and the suspension cooled in ice. A solution of 35% hydrogen peroxide (0.91 mL, 12.2 mmole) in acetic acid (6 mL) was added dropwise and the reaction was stirred at room temperature for 70 minutes. Dichloromethane (50 mL) was added followed by 2M aqueous sodium hydroxide (48 mL) to pH=7. The layers were separated, the aqueous extracted with more dichloromethane, the organic layers combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-10% EtOH in DCM to afford the title compound (607 mg, 60%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1>>[Br:1][CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CSc1ccc(Cl)cc1
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Yield: 98.7 %

Procedure:
64 g (0.4 mol) of bromine were slowly added to 97 g (0.4 mol) of 1-(4-chlorophenylmercapto)-2,2-dimethyl-butan-3-one at room temperature. The reaction mixture was worked up in a manner corresponding to that in Example 1. 127 g (99% of theory) of 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a viscous oil. ##STR823##
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl)([O-:26])=[O:25].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1
Reactant: COc1ccc2c(c1)OC(CCO[Si](C)(C)C(C)(C)C)C(=O)N2
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc2c(c1)OC(CCO)C(=O)N2Cc1cccc([N+](=O)[O-])c1
Yield: 30 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and I, alkylating with 3-nitrobenzyl chloride, in 30% yield, mp 116°-118° C.; MS (Cl) MH+ 359; IR (KBr) 3306, 3086, 2926, 2872, 1628, 1595, 1476, 1309, 1290, 1255, 1087, 999, 713, 458 cm-1 ; 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 8.11 (s, 1H), 7.63 (m, 2H), 6.97 (d, 1H, J=8.93 Hz), 6.66 (d, 1H, J=2.42 Hz), 6.53 (d, 1H, J=8.87 Hz), 5.26 (s, 2H), 4.87 (dd, 1H, J=8.98, 3.78 Hz), 4.72 (t, 1H, J=5.23 Hz), 3.68 (s, 3H), 3.61 (m, 2H), 2.01 (m, 1H), 1.90 (m, 1H). Anal. Calc'd for C18H18N2O6 : C 60.33 H 5.06, N 7.82. Found: C 59.96, H 5.08, N 7.62.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl.N>O>[C:18]([CH2:17][CH2:16][C:15]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)([OH:20])=[O:19]
Reactant: O=C(O)CCC(=O)O
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Agent: N
Solvent: O
Product: CC1(C)C(=O)Nc2cc3[nH]c(CCC(=O)O)nc3cc21

Procedure:
Analogously to Example 1, a solution of 3.82 g. 5,6-diamino-3,3-dimethylindolin-2-one and 2.36 g. succinic acid in 10 ml. 4N hydrochloric acid is heated for 4 hours at 135° C. (bath temperature). The reaction mixture is then evaporated in a vacuum until a thick slurry has formed. 10 ml. water are added thereto and the pH is adjusted to 10 with concentrated aqueous ammonia solution. Insoluble material is filtered off with suction and washed with water and the filtrate is treated with charcoal, filtered and the filtrate evaporated in a vacuum. The evaporation residue is taken up in 10 ml. water and acidified with glacial acetic acid, the title compound thereby precipitating out. After drying for 4 hours in a vacuum at 60° C., there are obtained 2.2 g. of desired compound with a melting point of 130°-135° C. (foaming). This compound contains 1.6 mole of water per mole of compound.