Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Yield: 97.9 %

Procedure:
5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N2. The flask was placed in an oil bath at 100° C. and heated until the 5-chloro-2-nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2×) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50° C. to a constant weight to yield 670 g (97.8%) of the title compound as a yellow powder.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:22]2[S:23][CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][O:17][C@@H:16]([CH3:19])[CH2:15][C@H:14]1[CH2:20][OH:21]>ClCCl>[Br:27][C:25]1[N:26]=[C:22]([C@@:13]2([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[C@H:14]([CH2:20][OH:21])[CH2:15][C@H:16]([CH3:19])[O:17][CH2:18]2)[S:23][CH:24]=1
Reactant: C[C@H]1C[C@@H](CO)[C@](N)(c2nc(Br)cs2)CO1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2nc(Br)cs2)CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzoyl isothiocyanate (6.92 g, 42.4 mmol) was added in a drop-wise manner to a solution of C4 (14.48 g, 47.13 mmol) in dichloromethane (420 mL), and the reaction mixture was stirred at room temperature for 24 hours. Volatiles were removed in vacuo, and the residue was purified via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane), providing the product as a yellow solid. Yield: 14.7 g, 31.2 mmol, 66%. 1H NMR (400 MHz, CDCl3) δ 11.70 (br s, 1H), 8.93 (br s, 1H), 7.86-7.90 (m, 2H), 7.62-7.67 (m, 1H), 7.51-7.56 (m, 2H), 7.25 (s, 1H), 5.47 (d, J=11.9 Hz, 1H), 3.91 (d, J=12.0 Hz, 1H), 3.83 (d, J=4.4 Hz, 2H), 3.74-3.81 (m, 1H), 2.44-2.52 (m, 1H), 1.80-1.87 (m, 2H), 1.33 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[O:12][CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].C(N(CC)CC)C>C(#N)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14][O:15][S:19](=[O:22])(=[O:21])[NH2:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOc1cccc(OCc2ccccc2)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCOc1cccc(OCc2ccccc2)c1
Yield: 44.3 %

Procedure:
This compound was prepared according to the procedure used in Example 101. Thus, a mixture of 14.7 g (0.06 mole) of 2-(3-benzyloxyphenoxy)ethanol, 17 ml (0.066 mole) of sulfamoyl chloride (3.9M solution in acetonitrile) and 7.0 g (0.069 mole) of triethylamine in 150 ml of acetonitrile gave a viscous, oily residue. The oil was triturated with benzenepetroleum ether (30°-60° C.) and the solid was collected by filtration. The solid was recrystallized from chloroform to yield 8.6 g (44%) of a white solid, mp 107°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[OH:18]O>ClCCl.O.C[Re](=O)(=O)=O.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N+:11]([O-:18])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: OO
Reactant: Fc1ccc(-c2ccncc2)cc1C(F)(F)F
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: [O-][n+]1ccc(-c2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Then, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine-1-oxide 74 was prepared as follows. To a solution of compound 73 (2.49 g, 10.3 mmol) in dichloromethane (10 mL) was added methyltrioxorhenium(VII) (0.128 g, 0.515 mmol), followed by hydrogen peroxide in water (30%, 5.15 mL). The reaction mixture was stirred at room temperature for 16 hours. Manganese (IV) oxide (0.050 g) was added. The mixture was stirred for another 30 minutes. The organic layer was separated. The aqueous layer was extracted with more dichloromethane (2×10 mL). The combined organic phase was washed with brine (3×30 mL), dried over MgSO4 and filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 10% methanol in ethyl acetate to give a white solid 74 (2.51 g, 94%). 1H-NMR (CDCl3, 400 MHz) δ 7.35 (t, J=9.3 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.74–7.82 (m, 2H), 8.30 (d, J=7.1 Hz, 2H); MS (DCI) m/z 258, 259 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[O:11][N:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc(OC)c1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)on2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20b) (387.38 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (25d) (546 mg, 80% yield).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>O1CCCC1.C1C=CC=CC=1>[CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14]
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a stirred solution of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (14.3 g., 0.047 mole) in tetrahydrofuran (150 ml.) under nitrogen is added dropwise over a 10 minute period 70% sodium bis(2-methoxyethoxy) aluminum hydride in benzene (17 ml.) in tetrahydrofuran (50 ml.) while maintaining the reaction temperature at 10°-15° C. The reaction mixture is stirred at 25° C. for 26 hours, cooled to 10° C, slowly treated with 10% hydrochloric acid until frothing ceases, then with 20% hydrochloric acid until acidic. The tetrahydrofuran is decanted from a pasty residue, evaporated to dryness and the residue taken up in benzene (300 ml.). The insoluble, homogeneous product which separates at this stage is primarily 2-methyl-2-phenyl-6,7-dichloroindane-1,5-diol (α-isomer), 800 mg., m.p. 177°-181° C. and is used without further purification. The benzene solution is dried over magnesium sulfate and evaporated to dryness to give 8.57 g. of a mixture of isomers. Three crystallizations from benzene gives 3.0 g. of 2-methyl-2-phenyl-6,7-dichloroindan-1,5-diol (β-isomer), m.p. 163°-165° C. and is used in Example 18 below without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2>CS(C)=O>[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([NH:1][CH2:2][CH2:3][OH:4])[N:7]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)=[CH:26][N:25]=1
Reactant: NCCO
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(NCCO)n(CC4CC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
2-Aminoethanol (79 mg, 1.3 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (70 mg, 66%) as a white solid.
Reaction SMILES: ClCC(O)CO.C(N)CC.Cl.[CH2:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:13][CH3:14].[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>CO.C(N(CC)CC)C>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:26]
Reactant: O=C=NCCCl
Reactant: CCCNCC(O)CO
Agent: Cl
Agent: OCC(O)CCl
Solvent: CO
Solvent: CCCN
Solvent: CCN(CC)CC
Product: CCCN(CC(O)CO)C(=O)NCCCl
Reaction time: 120 h
Yield: 42.6 %

Procedure:
A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 8 g of n-propylamine is allowed to stand at room temperature for 5 days. The reaction mixture is condensed to dryness under reduced pressure, whereby 5.0 g of N-n-propyl-2,3-dihydroxy-n-propylamine hydrochloride are obtained as a crude product. 5.0 g of said crude product and 3 g of triethylamine are dissolved in 40 ml of methanol. 3.2 g of 2-chloroethyl isocyanate are added to the solution at 0° to 5° C. Then, the reaction mixture is treated in the same manner as described in Example 62-(1). 3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22]
Reactant: CSc1ccc(Cl)cc1N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C)c1
Yield: 59.6 %

Procedure:
Following General Procedure B, the title compound (205 mg, 59%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (165 mg, 0.95 mmol) and 4-chloro-3-methyl-benzenesulfonyl chloride (215 mg, 0.95 mmol).
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([OH:18])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH3:28]>CC(C)=O>[Cl:1][C:2]([F:19])([F:20])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:27][CH3:28])[CH:4]=1
Reactant: CCI
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 82.2 %

Procedure:
This product was prepared as described in Example 8, 25. g (0.080 mol) of product of Example 5, 14.3 g (0.103 mol) of K2CO3, 37.5 ml (0.470 mol) of ethyl iodide in 100 ml of acetone were reacted affording 22.86 g of oil which was purified by HPLC using 3% ethyl acetate/cyclohexane as eluting solvent to give 14.73 g of solid. Crystallization in hot hexane gave 11.11 g (41.6%) of solid. A portion (0.98 g) of this solid was kugelrohr distilled at 29 Pa, pot temperature 70° C., to give 0.81 g of product as a white solid; mp 54.5°-56.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCCCCCBr)NC1CC1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 96.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (642.7 mg, 2.24 mmol) and N-cyclopropyl-11-bromoundecanesulfonamide (873.0 mg, 2.46 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-11-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]undecanesulfonamide (1210.0 mg) as a pale yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.4%).
Reaction SMILES: [C:1]12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:2]2=O.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([OH:28])=[O:27])[NH:17]1>C(O)C.Cl>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]([C:26]([O:28][CH2:1][CH3:2])=[O:27])[NH:17]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1Cc2ccccc2CN1
Yield: 103.1 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid camphor sulphonic acid salt (Preparation 120, 6 g, 17.2 mmol) was dissolved in ethanol (140 ml) and saturated with hydrogen chloride (gas). The reaction mixture was heated under reflux for 18 h before concentrating in vacuo. The crude residue was dissolved in dichloromethane (150 ml) and washed with sodium hydrogen carbonate (150 ml). The organic layer was collected and washed again with sodium hydrogen carbonate (2×100 ml) before drying (Na2SO4) and concentrating in vacuo to give the title compound as a yellow oil (3.64 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Cc1cccc(C=O)n1
Product: Cc1cccc(CNC2CC2)n1

Procedure:
prepared by reaction of 6-methylpyridine-2-carbaldehyde with cyclopropylamine
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][NH:30][CH:31]([CH3:36])[C:32]([CH3:35])([OH:34])[CH3:33])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][NH:30][CH:31]([CH3:36])[C:32]([OH:34])([CH3:33])[CH3:35])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(NCc1cccc(Br)n1)C(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(NCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(C)(C)O

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.080 g, 0.26 mmol) and 3-{[(6-bromopyridin-2-yl)methyl]amino}-2-methylbutan-2-ol (0.070 g, 0.26 mmol) as the starting materials.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8]2[O:13][C:11](=[O:12])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[C:4]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=Nc2ccccc2)O1
Solvent: ClCCl
Solvent: Oc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
10 g (0.058mole) of N-phenyl isomaleimide is dissolved in 100 ml of methylene chloride. To the solution are added 0.400 g (0.004 mole) of phenol and 0.4 ml (0.290 g; 0.0029 mole) of triethylamine. The reaction mixture is stirred at 20-25° C. for 3 hours, and is then extracted by shaking twice with 10% aqueous NaOH solution; it is washed twice with water, dried over sodium sulphate and the solvent is removed in a rotary evaporator. The residue is dried at 40° C. in vacuo to obtain 9.7 g (97% of theory) of yellow crystalline N-phenyl maleimide, m.p. 85-86° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([CH3:24])[C:18](=[O:25])[C:17]=1[CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:3])=[O:2].[N+](=[CH2:29])=[N-].CCOCC>CCOCC>[CH3:29][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([CH3:24])[C:18](=[O:25])[C:17]=1[CH3:26])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1

Procedure:
6-(6-Carboxy-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (29 g) was suspended in ether (500 ml). Diazomethane/ether solution was added until the raw material was disappeared on thin-layer chromatography. Then the ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrate was subjected to short column chromatography using silica gel (500 ml) and eluted with hexane/dichloromethane (1:1) to obtain 6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (25.5 g) as an orange oil. This oil was dissolved in ether (200 ml) and stirred at room temperature for 1.5 hours with a solution containing sodium hydrosulfite (52 g) in water (200 ml). The ether layer was separated and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylhydroquinone (25.5 g). Then this compound was dissolved in dichloromethane (35 ml), imidazole (9.37 g, 2 eq.) was added, tert-butyldiphenylsilyl chloride (28.36 g, 1.5 eq.) was added dropwise with stirring at room temperature and the mixture was allowed to react overnight. The deposited imidazole hydrochloride was filtered off, and the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel (800 ml) and eluted with dichloromethane/hexane (2:1) to obtain the desired compound as a pale yellow viscous oil (46 g).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:5])C.Br[C:22]1C=CC(C(O)=O)=CC=1.[H-].[Na+].C(OC(=O)C(Cl)C(=O)C(C)C)C.C([O-])(=O)C.[NH4+]>CN(C=O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]([CH:4]([OH:5])[CH3:22])=[C:7]([CH:18]([CH3:19])[CH3:20])[N:8]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1oc(-c2ccc(Br)cc2)nc1C(C)C
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(Cl)C(=O)C(C)C
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
2-(4-Bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acid ethyl ester A solution of 4-bromo-benzoic acid (34.0 g, 0.169 mol) in DMF (450 mL) is treated at ambient temperature portionwise with NaH (6.4 g, 0.16 mol, 60% oil dispersion). The suspension is heated to 90° C. and 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (27.7 g, 0.144 mol) is added neat. The remaining chloride is washed into the reaction flask using DMF (25 mL). The reaction mixture is stirred for 18 h, cooled, and treated with water (600 mL). The mixture is extracted with EtOAc (750 mL). The organic layer is washed with brine (2×250 mL), dried (Na2SO4), and concentrated to a foam (56 g). This diester is dissolved in acetic acid (500 mL), treated at ambient temperature with ammonium acetate (80 g, 1.0 mol), and heated at 120° C. for 20 h. The reaction mixture is cooled, concentrated, and partitioned between EtOAc (500 mL) and saturated NaHCO3 solution (3×125 mL). The organic layer is dried (Na2SO4), and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (6:1) to give the title compound (26.6 g, 55%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)cc(F)c1
Product: CC(C)N1c2cc(OCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluorophenyl)methanol.