Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:15]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (12 g, 0.3 mol, 60% in mineral oil) in 600 ml toluene and 400 ml dimethyl formamide was added 2,6-dihydroxynaphthalene (80 g, 0.5 mol) and the mixture was heated to reflux over a thirty minute period. Benzyl chloride (65 ml, 71.5 g, 0.56 mol) was added dropwise and the mixture was refluxed for 10 hours. After cooling to room temperature, the mixture was washed 6 times with water to remove the dimethyl formamide. The resulting toluene solution was washed twice with 150 ml 0.5N Sodium hydroxide to remove unreacted starting material and then with water and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated to 150 ml. The solid which had crystallized was collected by vacuum filtration and washed with a small amount of toluene to yield 2-benzyloxy-6-hydroxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)[CH:10]=[CH:9][C:8]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of N-(3,5-dichlorobenzyl)-5-fluoro-2-(methylsulfonyl)benzenamine (2.1 mmol), t-butyl piperazine-1-carboxylate (2.2 mmol), N,N-diisopropylethylamine (4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (23%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1 H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z: Calculated: 514.47; Observed: 515.6 (M+1).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].[OH2:12]>>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][C:7](=[O:12])[NH:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: O
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: O=c1[nH]c(=O)c2[nH]c(=O)[nH]c2[nH]1
Temperature: 37 °C

Procedure:
50 mM tris-hydrochloric acid buffer (2.9 ml) and 0.1 ml of a 10 mM aqueous solution of xanthine are mixed, and this mixture is pre-heated at 37° C. After 0.01 ml of enzyme solution is added and gently mixed, the increase of absorbance at 293 nm per minute is determined using a spectrophotometer thermostated at 37° C. with distilled water as the control. The xanthine oxidase activity is expressed on the assumption that the amount of enzyme which produces 1 μmol of uric acid per minute under the conditions described above is taken as 1 unit (U).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(C)(C)C>[CH2:10]([NH:17][CH2:6][CH2:5][N:4]([CH2:2][CH3:3])[CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CCN(CC)CCNCc1ccccc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
2-(diethylamino)-ethyl chloride hydrochloride (1 g, 5.81 mmol) and benzylamine (1.3 ml, 11.62 mmol) were dissolved in t-butanol (40 ml), triethylamine (3.2 ml, 23.24 mmol) was added thereto, and the resulting solution was refluxed for 12 hours. The solution was cooled to room temperature, and distilled under a reduced pressure to remove the solvent. The resulting solid was removed by filtration under a reduced pressure, and the residual solution was extracted with ethylacetate The separated organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain the title compound 560 mg (yield: 47%).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([N+:26]([O-:28])=[O:27])=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:19]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2Cl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 1.7 ml of concentrated sulfuric acid was added 0.26 g of 3-(2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-332) at 5° C. Furthermore, 85 til of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with chloroform. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.29 g (yield, 95%) of 3-(2,4dichloro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-333; m.p., 114.3° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:14][C@H:15]([O:17][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
To a solution of 2.8 g (7.8 mmol) (3R,5R)-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylic acid benzyl ester in 70 ml dry THF were consecutively added 1.0 g (8.5 mmol) benzoic acid, 1.7 g (8.5 mmol) diethyl azodicarboxylate and 2.2 g (8.5 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 2.8 g (78%) of the title compound as a yellow oil. MS m/e (%): 470 (M+H+, 100)
Reaction SMILES: [CH3:1]OC(=O)CCC(C1C=CC(O)=CC=1)=O.[C:16]([C:19]1[CH:43]=[CH:42][C:22]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][C:32]=3Br)[CH2:25]2)=[C:21]([CH2:44][CH2:45][CH3:46])[C:20]=1[OH:47])(=[O:18])[CH3:17].C(C1C=CC(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)=C(CCC)C=1O)(=O)C>>[C:16]([C:19]1[CH:43]=[CH:42][C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH3:1])=[O:39])=[CH:33][CH:32]=3)[CH2:25]2)=[C:21]([CH2:44][CH2:45][CH3:46])[C:20]=1[OH:47])(=[O:18])[CH3:17]
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1
Reactant: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)O)cc3Br)C2)ccc(C(C)=O)c1O
Agent: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Product: CCCc1c(O[C@@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3)C2)ccc(C(C)=O)c1O

Procedure:
By following Step A of Example 10, but substituting para-hydroxybenzeneacetic acid methyl ester for 4-(4-hydroxyphenyl)-4-oxobutyric acid methyl ester and substituting the title compound of Step D of Example 8 for the title compound of Step C of Example 8, the title compound of this step was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:52]=[CH:53][CH:54]=2)[O:46][CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:24]([NH:51][CH2:50][CH2:49][CH2:48][CH2:47][O:46][C:45]2[CH:52]=[CH:53][CH:54]=[C:43]([CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:44]=2)=[O:25])[CH3:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=O)NCCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.42 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 4-[3-(piperidinomethyl)phenoxy]butylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=605 ([M+H]+, 14), 229 (100); IR (KBr): 1631 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 115° C. (isopropanol/ether).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7]2.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:24].[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[C:3]3[C:4](=[O:18])[CH:5]=[C:6]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: O=c1cc(-c2ccccc2)oc2cccc(O)c12
Reactant: ClCCCCBr
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2cccc(OCCCCN3CCC(O)CC3)c12

Procedure:
The compound was prepared by the method of Example 21 from 5-hydroxyflavone, 1-bromo-4-chlorobutane, and 4-hydroxypiperidine: mp 161°-163° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a stirred suspension of 50 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.17 mmol) in N,N-dimethylformamide (3 mL), 0.09 mL of (3-amino-propyl)-carbamic acid tert-butyl ester (0.51 mmol) and 0.036 mL of triethylamine (0.26 mmol) were added. The reaction mixture was stirred at room temperature overnight, evaporated to dryness and then purified through preparative HPLC on a Waters X Terra RP 18 (19×250 mm, 5 m) column. Mobile phase A was 0.05% ammonia/acetonitrile:95/5 and mobile phase B was acetonitrile/water:95/5. Gradient from 10 to 75% B in 15 min. Fractions containing the desired compound were dried, affording 32 mg (44% yield) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=23)[S:7]1(=[O:19])=[O:18])[CH3:5].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH:4]([N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:15]=[CH:16][CH:17]=[C:8]([C:9]=45)[S:7]3(=[O:19])=[O:18])[CH3:5])[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(CCBr)N1c2cccc3cccc(c23)S1(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCN1CCN(c2ccc(F)cc2)CC1)N1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 17.9 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(4-bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.2 g), triethylamine (2.1 cc) and 4-(4-fluorophenyl)piperazine (2.8 g) in toluene (200 cc). The mixture is heated at boiling point for 8 hours and then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (90-10 as eluant, crystallization from isopropyl oxide (30 cc) and recrystallization from boiling acetonitrile (10 cc), 2-{4-[4-(4-fluorophenyl)-1-piperazinyl]-2butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g) is obtained, m.p. 116° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](=[C:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](=[C:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(C(=C2CCNCC2)c2cccs2)cc1
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccccc2)c2cccs2)CC1
Yield: 84 %

Procedure:
The title compound was prepared in a yield of 84% in a similar manner to that described in Preparation 1' by reacting N-(3-bromopropyl)phthalimide and 4-[α-(2-thienyl)benzylidene]piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=S)=[C:25]([CH3:32])[CH:24]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][C:25]=3[CH3:32])[N:17]([CH3:18])[C:12]=2[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: Cc1cc(F)ccc1N=C=S
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
To a glass scintillation vial was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (0.247 g, 0.854 mmol), followed by THF (5 mL) and a magnetic stir bar. To the resulting solution was added 4-fluoro-1-isothiocyanato-2-methyl-benzene (0.191 g, 1.14 mmol) and the solution was stirred at room temperature for 48 h. To the solution was then added mercuric oxide (0.222 g, 1.02 mmol), and stirring was continued at room temperature for 24 h. The brown suspension was then filtered through a ½ inch thick pad of silica, washed with THF, and concentrated to dryness. The resulting deep red solid was further purified by silica gel chromatography, eluting with ethyl acetate:hexane (0%-100%) to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.204 g, 56%) as a deep red solid. ESMS (m/z): (M+1)+ found, 423.
Reaction SMILES: [NH2:1][C@:2]([CH3:53])([C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].C(N(CC)CC)C.ClC(Cl)(Cl)[C:63]([N:65]=C=O)=[O:64]>ClC(Cl)C>[NH2:65][C:63]([NH:1][C@:2]([CH3:53])([C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28])=[O:64]
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(NC(N)=O)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 173, 20 mg, 0.027 mmol) and triethylamine (0.015 mL, 0.11 mmol) in dichloroethane (0.27 mL) was added trichloroacetyl isocyanate (0.004 mL, 0.032 mmoL). The solution was stirred at room temperature for 70 min and then evaporated to dryness. Methanol (0.5 mL) was added to the residue followed by solid potassium carbonate (14.6 mg, 0.11 mmol and the mixture was stirred at room temperature. After 55 min, water (0.1 mL) was added giving a clear solution. The solution was stirred at room temperature for 1 hour and then stored at 5° C. for 64 hours. The solution was evaporated and the residue purified by reverse phase HPLC using a 19×150 mm Sunfire Preparative C18 OBD column (elution with MeCN/water+0.05% TFA). Fractions containing the product were evaporated and freeze-dried from a mixture of ethanol and benzene to give the title compound (not a salt form) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Cl.Cl[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[S:28][C:29]4[C:30]([N:35]=3)=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][C:20]=2[O:19][CH:18]=1>CN(C=O)C>[S:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:35]=[C:27]1[O:26][C:24]1[CH:23]=[CH:22][C:21]2[C:17]([CH2:16][N:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][CH2:5][C:4]3=[O:13])=[CH:18][O:19][C:20]=2[CH:25]=1
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: O=C1CCc2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of 60% NaH (68 mg, 1.7 mmol) in DMF (2.5 mL) at 0° C. was added a solution of 3,4-dihydro-1H-quinolin-2-one (208 mg, 1.4 mmol) in DMF (2.0 mL). The reaction mixture was stirred (0° C., 30 min) before the addition of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (50 mg, 0.14 mmol). The reaction mixture was stirred (rt, 30 min), washed with water, extracted with ethyl acetate, dried, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the title compound (22 mg, 36%). MS (ESI): mass calcd. for C24H17N3O3S, 427.10; m/z found, 428.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.54-8.48 (m, 1H), 8.43-8.36 (m, 1H), 7.88-7.81 (m, 1H), 7.78 (d, J=8.5, 1H), 7.64 (d, J=2.1, 1H), 7.44-7.38 (m, 2H), 7.36-7.30 (m, 1H), 7.30-7.16 (m, 2H), 7.05-6.98 (m, 1H), 5.38 (s, 2H), 2.98-2.85 (m, 2H), 2.79-2.70 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>CO.C(Cl)Cl>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1F
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CNc3ccccc3F)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-fluoroaniline (55 mg, 0.50 mmol) as described in General Procedure X to afford Iai (12 mg, 18.2%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=392 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([NH:17]C(OC(C)(C)C)=O)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])([O-:3])=[O:2].Cl.[CH3:26][CH2:27]OC(C)=O>>[CH2:26]([CH:7]([O:6][C:5]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:10])=[O:9])[CH3:27]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: Cl
Product: CCC(Oc1ccc(N)cc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-2 (0.3 g, 0.88 mmol) was dissolved in EtOAc (10 mL), cooled to -78° C. and saturated with HCl gas, warmed to 0° C. for 1 hour and concentrated to give ethyl 2-(2-nitro-4-aminophenoxy)acetic acid as a white solid that was coupled immediately (0.26 g, 0.88 mmol) to 1-5 (0.29 g, 0.95 mmol) as described for 5--5 to give 5-9 as a yellow solid after chromatography in a gradient of 40 to 100% EtOAc/hexanes.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:6]=1)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:4](=[O:3])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:6]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: COc1ccc(-c2cc(C(=O)NCCCCCCc3ccccc3)cc(-c3cccc(C(F)(F)F)c3)c2OCCO)cc1

Procedure:
The product was prepared as a yellow gum (0.191 g, 74%) from 3-(4-methoxyphenyl)-5-(3-trifluoromethylphenyl)4-(2-hydroxyethoxy)benzoic acid ethyl ester and 6-phenylhexylamine using a procedure similar to step 2 of example 1; 1H NMR (300 MHz, DMSO-d6) δ 1.27-1.38 (m, 4H), 1.47-1.60 (m, 4H), 2.55 (t, J=7.5 Hz, 2H), 3.10 (q, J=7 Hz, 2H), 3.20-3.30 (m, 4H), 3.80 (s, 3H), 4.38 (t, J=6 Hz, 1H), 7.02-7.08 (m, 2H), 7.10-7.18 (m, 3H), 7.23-7.26 (m, 2H), 7.55-7.60 (m, 2H), 7.68-7.78 (m, 2H), 7.83-7.88 (m, 2H), 7.91-7.96 (m, 2H), 8.55 (t, J=4 Hz, 1H); mass spectrum [(+)ESI], m/z 592 (M+H)+.